FAQs

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Red blood cells

Kidney disease

Yes. In some centers, the DAT (direct antiglobulin test) has largely replaced the term Coombs test. Coombs test was named after Robin Coombs, a British immunologist who developed the principle behind the antiglobulin test while travelling back to Cambridge on a wartime train.

Yes, vitamin B12 is naturally present in foods of animal origin, including fish, meat, poultry, eggs, and dairy products. In addition, fortified breakfast cereals and fortified nutritional yeasts are readily available sources of vitamin B12 that have high bioavailability. The bioavailability of vitamin B12 appears to be about three times higher in dairy products than in meat, fish, and poultry, and the bioavailability of vitamin B12 from dietary supplements is about 50% higher than that from food sources Vegans are at increased risk for developing vitamin B12 deficiency. From NIH.

*DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin B12 is 2.4 mcg for adults and children aged 4 years and older [21]. FDA does not require food labels to list vitamin B12 content unless vitamin B12 has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. From NIH

Yes

Rarely it is increased owing to inhibition of the macrophage uptake of the haptoglobin-hemoglobin complex by CD163 receptor.

Rarely, owing to skewed X chromosome inactivation. Learn more here.

Yes, G6PD seems to be protective, as are many of the hemoglobinopathies and ethnic neutropenia. Learn more about hemoglobinopathies and malarial infection here.

About one-half of patients with sickle cell disease have chronic ophthalmologic complications.

Prevalence is 25-30%.

Prevalence is 10%-40% in adults with sickle cell disease (less common in children).

Thrombocytosis occurs in about 10-15% of patients with iron deficiency anemia. Learn more here.

If Hct > 54%, either reduce or stop testosterone therapy or initiate phlebotomy while continuing testosterone therapy.

Glucose indirectly represses ALA synthase. ALA synthase shown in heme biosynthesis pathway (from PMC8391404).

Hemin (available in the United States as Panhematin) suppresses aminolevulinic acid (ALA) synthase activity and thereby decreases overproduction of ALA and porphobilinogen (PBG).

Small clinically silent PNH clones are found in up to 70% of adults. Learn more here.

About 70% of patients with pernicious anemia have macrocytosis. Learn more here.

Reduction in hemoglobin ≥ 2 g/dL (20 g/L) below baseline (per NIH 2014 clinical practice guideline).

Two main classification schemes: 1) based on kinetics (hypoproliferative vs. hyperproliferative); 2) based on red cell morphology (microcytic [with or without hypochromia]) vs. normocytic vs. macrocytic). Image of morphological classification here.

Elevated urine porphobilinogen (PBG) confirms diagnosis in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), or variegate porphyria (VP). PBG level is normal in the very rare ALA dehydratase deficiency porphyria. Discriminating between AIP, HCP, and VP requires additional testing.

Heme biosynthesis pathway shown here.

Absolute erythrocytosis (elevated red blood cell mass) and apparent or relative erythrocytosis (reduced plasma volume relative to red blood cell mass). Absolute erythrocytosis is further divided into primary or secondary depending on whether the cause is intrinsic or extrinsic to the red blood cell. Learn more here.

Urine dipstick positive for blood, urine microscopy negative for red cells.

British Committee for Standards in Haematology (BCSH) clinical guideline:

Newly diagnosed patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular hemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests (grade 1 recommendation, grade A evidence).

If the diagnosis is equivocal, a screening test with high predictive value for HS is helpful. The recommended
screening tests are the cryohaemolysis test and EMA binding

Flow cytometry using ≥ 2 different monoclonal antibodies against 2 different glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) on ≥ 2 different blood cell lineages. Learn more here.

About 4,500

Ferritin Structure: Apoferritin forms a roughly spherical container within which ferric iron is stored as a ferrihydrite mineral. Apoferritin refers to the iron-free form of the protein; the iron-containing form is termed holoferritin or simply ferritin. The apoferritin shell is composed of 24 subunits of two types, termed H and L, the ratio of which varies widely depending on tissue type and inflammation. Iron is toxic in cellular systems because of its capacity to generate reactive species (shown as yellow spheres) which can directly damage DNA and proteins. From Knovich et al.
ferritin structure
Ferritin is a hollow protein shell composed of 24 subunits. Two subunits have been removed to allow visualization within the core where up to 4500 iron atoms can be stored. Source

About 2 x 1011 (200 billion) or 1% of all red cells

There are 8 enzymes in the heme biosynthesis pathway. Mutations in each enzyme can cause porphyria. Therefore there are 8 different kinds of porphyria.

Heme biosynthesis pathway (from PMC8391404) shown here.

1-2 mg

Regulation of systemic iron metabolism. Organs and cell types involved in systemic iron
balance are shown. Duodenal enterocytes absorb dietary iron via DMT1 located on the
apical surface upon reduction of Fe3+ to Fe2+ by DcytB. Spleenic reticuloendothelial
macrophages recycle iron from senescent red blood cells. Both cell types release iron via
ferroportin with the aid of hephaestin, which oxidizes Fe2+ to Fe3+. Iron is also oxidized by
ceruloplasmin in the circulation. Plasma Tf captures and circulates iron in the body. Hepatic
hormone, hepcidin regulates iron efflux from these cells by regulating the stability of
ferroportin. Synthesis and secretion of hepcidin by hepatocytes is influenced by iron levels
in the body as well as conditions that affect iron metabolism indirectly such as
inflammation, ER stress, erythropoiesis, and hypoxia. From Pantopoulos et al)

3-4 g

25-40% larger; mean cell volume about 120 fL, though quite variable. Learn more here.

No

IV carbohydrate loading has potential risk of hyponatremia, which can lead to cerebral edema and os

According to the British Society of Haematology: Hct > 52% in men and > 48% in women persisting for > 2 months

Yes, and this is the justification for periodic surveillance endoscopies in these patients. Learn more here.

Yes. Cyanocobalamin is a synthetic form of vitamin B12 found only in supplements.

Yes, typically for complement only. However, it is also weakly positive for IgG in about one quarter of cases. Learn more here.

X-linked. Learn more here.

Yes, on both venous and arterial sides of the circulation. Learn more here.

Serum erythropoietin is low in about 90% of patients with polycythemia vera. Learn more here.

Retinopathy has been reported in 70% of patients with HbSC compared with about 45% in sickle cell anemia. Learn more here.

No. Serum iron levels are highly dependent on recent food intake and they follow a diurnal rhythm (though there is no evidence that fasting samples perform better than random samples). Learn more here.

Hemoglobin (Hb) and hematocrit (Hct). Hct correlates a little better with red cell mass compared with Hb (learn more here).

Depends on the clinical context. In patients with anemia, we should refer to Hb because oxygen carrying capacity is limiting, while patients with the Hct should be considered in those with polycythemia since blood viscosity is limiting. For those with normal Hb/Hct, take your choice.

The RDW-CV is inversely proportional to the MCV. As a result patients with microcytosis have elevated RDW-CV regardless of variation in cell size, while those with macrocytosis have lower RDW-CD values. By contrast, the RDW-SD is not influenced by the MCV and therefore may be preferable. An RDW-SD > 45 fL represents anisocytosis.

Hydroxyurea (since 1998), L-glutamine, crizanlizumab, voxelotor

Blood loss, hemolysis, erythropoietin administration, high altitude

  • Changes in hemoglobin oxygen affinity, for example high-affinity hemoglobin mutations
  • Mutations in oxygen sensing/hypoxia-inducible factor (HIF) signaling pathway, for example Chuvash polycythemia (mutations in VHL gene, autosomal recessive)
  • Learn more here

    Primary

    • Congenital (EPO receptor mutations)
    • Polycythemia vera
    • Idiopathic erythrocytosis

    Secondary

    • Congenital
      • Defects in oxygen sensing pathway – Chuvash erythrocytosis (VHL mutation)
      • Left shift of Hb oxygen dissociation curve
        • high affinity Hb
        • 2,3-DPG deficiency
    • Acquired
      • Hypoxia-driven
        • Central process
          • Chronic lung disease
          • Right-to-left cardiopulmonary shunts
          • CO poisoning
          • Smoking
          • Sleep apnea
          • High altitude
        • Local process
          • Renal artery stenosis
          • Hydronephrosis
          • Renal cysts
      • Pathological EPO production
        • Tumors
          • Hepatocellular carcinoma
          • Renal cell cancer
          • Cerebellar hemangioblastoma
          • Uterine leiomyoma
          • Pheochromocytoma
          • Meningioma
      • Drug-associated
        • Epo
        • Androgens
        • Diuretics
    • Learn more here.
    First branchpoint in diagnostic algorithm is immune vs. non-immune. Virtually all cases of immune-mediated hemolysis (whether alloimmune or autoimmune) will be associated with a positive DAT (Coombs test).
    If DAT negative, the differential diagnosis includes extracorpuscular and intracorpuscular non-immune conditions. Extracorpuscular causes are those in which the red cells are innocent bystanders, reacting to changes within their extracellular environment. Intracorpuscular causes are those that are inherent in the red cell itself.
    Intracorpuscular causes of hemolysis involve three broad categories: defects in hemoglobin, membrane or enzymes. The hemoglobin ‘bucket’ includes thalassemia and sickle cell disease; the membrane causes include hereditary spherocytosis, hereditary elliptocytosis and hereditary stomatocytosis, and PNH (the only acquired condition in the intracorpuscular category); and defects in enzymes causing hemolysis include G6PD and PK deficiencies.
    On the extracorpuscular side are conditions associated with thrombotic microangiopathy, including primary and secondary TTP and HUS, and DIC; and a series of non-TMA causes (“other”) including burns/thermal injury, microangiopathic hemolytic anemia from prosthetic valves or foot strike anemia, clostridial sepsis, Wilson’s disease and spur cell anemia.

    Lactate dehydrogenase (LDH), indirect (unconjugated) bilirubin, haptoglobin, and AST. Learn more here.

    Hemolysis associated with elevated serum levels of leakage products, LDH and AST; reduced levels of haptoglobin (Hp) owing to binding to free Hb and internalization in macrophages (without recycling); and elevation of unconjugated (indirect) bilirubin from breakdown of heme inside macrophages.

    Large precipitates of denatured hemoglobin); often seen in patients with G6PD deficiency and hemolysis. Requires special stain of blood using methyl violet. See images.

    Less avascular necrosis, pulmonary hypertension, leg ulcers, and stroke; more retinopathy. 0.4% painful crises per patient year in those with HbSC, less than half the rate in sickle cell anemia. Learn more here.

    Conditions associated with appropriate release of erythropoietin from oxygen sensing cells in the kidney, including cardiopulmonary disease, high altitude or hereditary hemoglobin mutations associated with high oxygen affinity; conditions associated with inappropriate release of erythropoietin from 1) oxygen sensing cells in the kidney, including renal disorders and drugs and 2) tumor cells. See list of causes from PMC7829024. Learn more here.

    Renal artery stenosis, hydronephrosis, renal cysts, and renal tumors

  • Sleep study
  • Pulmonary function tests
  • Abdominal ultrasound
  • P50 measurement
  • Imaging to rule out erythropoietin-secreting tumor
  • Gene sequencing for congenital erythrocytosis
  • Bone marrow biopsy
  • Cerebellar hemangioblastoma, hepatocellular carcinoma uterine leiomyoma, and renal cell carcinoma

    Teardrop cells are red cells appearing in the shape of a teardrop or a pear with a single, short or long, often blunted or rounded end are called teardrop cells. True tear drops have blunted tips and point in different directions. Teardrop cells are commonly seen in chronic idiopathic myelofibrosis.

    Teardrop cell (arrow) from a 68-year-old woman with cirrhosis (100x, oil).

    Hemoglobinuria and myoglobinuria

    Type I cells – red cells express GPI-APs (for example, CD59) at normal density

    • Red cells express normal amounts of GPI-anchored proteins (GPI-AP), such as CD59
    • Full protection against complement-mediated lysis
    • Normal RBC lifespan of about 120 days

    Type II cells – red cells partly deficient in GPI-APs;

    • Red cells partly deficient in GPI-APs
    • Partial protection against complement-mediated lysis
    • Lifespan intermediate between type1 and type 3 cells

    Type III cells – red cells completely deficient in GPI-APs.

    • Red cells completely deficient in GPI-APs
    • No protection against complement-mediated lysis
    • RBC lifespan 10-15 days

  • Acute intermittent porphyria (the most common), caused by mutation in gene that encodes porphobilinogen deaminase
  • Hereditary coproporphyria, caused by mutation in CPOX which encodes coproporphyrinogen oxidase
  • Variegate porphyria, caused by mutation in PROX which encodes protoporphyrinogen oxidase
  • Aminolevulinic acid dehydratase deficiency porphyria (very rare), caused by mutation in gene that encodes aminolevulinic acid dehydratase
  • Heme biosynthesis pathway (from PMC8391404) shown here

    MM, multiple myeloma; MDS, myelodysplastic syndrome; mets, metastases; DIC, disseminated intravascular coagulation

    Another perspective:

    From Gnanaraj et al

    WHO criteria:

    PV diagnosis requires meeting either all three major criteria or the first two major criteria and one minor criterion.

    Learn more here.

    Helmet cells, keratocytes (horn cells), crescents, triangles, and microspherocytes. For more information see. Additional images shown here.

  • Eliminate precipitating factors
  • Treat patient’s symptoms
  • Reduce 5-aminolevulinic acid synthase 1 (ALAS-1) activity and production of 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) using carbohydrate loading and/or heme infusion
  • Heme biosynthesis pathway shown here

    Thrombosis and disease progression to myelofibrosis or acute leukemia. Learn more here.

    Homozygous sickle cell disease (HbSS), sickle beta0 thalassemia, sickle hemoglobin C disease, sickle beta+ thalassemia

    From NHLBI 2014 clinical guideline

    Thrombophlebitis, coagulopathy, hepatic iron overload (with chronic use). Learn more here.

    Acquired mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene in an hematopoietic stem cell. Leads to deficiency of  GPI-anchored proteins on hematopoietic cells, including CD55 and CD59, which in turn leads to  activation of the alternative complement pathway and complement-mediated hemolysis. For more information, see.

    (A) In healthy subjects, GPI-anchored protein biosynthesis proceeds unperturbed in the endoplasmic reticulum. The full-length GPI anchor with attached protein (e.g., CD55 and CD59) resides in the membrane rafts of blood cells; thus red cells are protected from complement-mediated hemolysis. (B) In PIGA-PNH, a somatic mutation in PIGA  (required for the initial step in GPI-anchored biosynthesis) leads to failure to generate the GPI anchor in hematopoietic cells. After expansion of the PNH clone (often through immunologic escape) the PNH red cells are susceptible to complement-mediated hemolysis due to an absence of the GPI-anchored CD55 and CD59 from the cell surface. From RA Brodsky.

    Aggregation of sickled cells, causing vaso-occlusion of small blood vessels, leading, in turn, to ischemia-reperfusion injury.

    From Shutterstock, with permission

    HLH, pernicious anemia, and resorbing hematoma, all involving macrophage-mediated ingestion or red cells. Cirrhosis may also mimic hemolysis because the liver is responsible for synthesizing haptolgobin and hepatocytes release LDH and (especially in alcoholic liver disease) AST>ALT.

    Autoimmune hemolytic anemia

    Acute intermittent porphyria

    Direct antiglobulin test

    Erythropoietin

    Glucose-6-phosphate dehydrogenase. Learn more here.

    Microangiopathic hemolytic anemia

    Paroxysmal nocturnal hemoglobinuria

    Packed red blood cells, used for transfusion.

    Polycythemia vera

    Red cell distribution width

    Sickle cell anemia

    Sickle cell disease

    Transferrin saturation. Represents the % of iron binding sites on serum transferrin that are bound by iron atoms.

    Vaso-occlusive crisis, occurs in patients with sickle cell disease. The most frequent cause of recurrent morbidity and SCD-related admission to hospital.

    Methyl vitamin B12 (methylCbl) and adenosyl vitamin B12 (adenosylCbl) 

    Vitamin B12 is a cofactor in conversion of methylmalonyl coenzyme A to succinyl coenzyme A and of homocysteine to methionine. Elevated levels of the substrates methylmalonic acid and homocysteine can be used to identify vitamin B12 inactivation despite normal serum B12 concentrations. MS = methionine synthase, MCCoAM = methylmalonyl coenzyme CoA mutase. From PMCID: PMC8171132

    British Society for Haematology recommends investigating patients with persistently elevated venous hematocrit (Hct) (> 52% in males and > 48% in females)

    Burr cells are red blood cells with 10-30 uniform, short, blunt projections distributed evenly around the circumference of the cell, giving the red cell surface a serrated appearance. The red blood cells retain central pallor. Seen in uremia, and to a lesser extent post splenectomy.

    Echinocyte - Wikipedia
    Scanning electron microscopy (SEM) of echinocytes (from Wikipedia)
    Wright stained peripheral blood smear from a patient with end-stage kidney disease showing multiple burr cells.

    A cold reactive antibody that causes agglutination without antiglobulin antisera at 4 degrees C (39.2 degrees F).

    Howell-Jolly bodies are nuclear remnants in red blood cells, typically about 1 μm in diameter. As such, they are composed of DNA. Their presence indicates asplenia. Learn more about the history of discovery of the Howell-Jolly body here.

    On average about 1/3 of iron binding sites are occupied with iron atoms. Normal values, however, can range between 20-45%.

    An abnormally shaped red cell

    Poikilocytes include

    • Sickle cells (drepanocytes)
    • Burr cells (echinocytes)
    • Spur cells (acanthocytes)
    • Target cells (codocytes)
    • Spherocytes
    • Elliptocytes (includes pencil cells)
    • Stomatocytes
    • Bite cells
    • Tear drop cells (dacrocytes)
    • Schistocytes (includes helmet cells, horn cells, triangular cells, microspherocytes)
    • Fish-shaped red cells

    Schistocytes, or schizocytes (from the Greek word schisto, broken or cleft) are circulating fragments of red blood cells or red blood cells from which cytoplasmic fragments have been lost. They lack central pallor and are often deeply staining. For more information see. Additional images shown here.

    A target cell is a red cell with centrally located disk of hemoglobin surrounded by an area of pallor with an outer rim of hemoglobin adjacent to the cell membrane giving the cell the appearance of a bull’s eye or shooting target. Seen in liver disease (macrocytic targets), iron deficiency anemia, thalassemia (microcytic target cells). Target cells may also be seen in hemoglobin C and E disease, and following splenectomy.

    Peripheral smear showing multiple target cells (100x, oil)

    Red cell mass > 25% above that predicted for sex and body mass

    Acanthocytes are densely stained, spheroidal red blood cells that lack central pallor and have 3-20 irregularly distributed, thorn-like projections of variable size/length/thickness, often with drumstick (knobby) ends. Spicules may occasionally have branches. Typically seen in cirrhosis, but also in hereditary abetalipoproteinemia and related neurological syndromes. Small numbers may be observed post-splenectomy.

    Peripheral smear showing acanthocyte in middle of field
    3D graphic of acanthocytes in blood (Shutterstock with permission)

    Abrupt reduction in hemoglobin in a patient with sickle cell disease, typically caused by parvovirus B19-mediated suppression of red blood cell production.

    Mild-moderate decrease in serum hemoglobin (Hb rarely < 8 g/dL [80 g/L]), associated with acute or chronic inflammation, in which inflammatory mediators lead to iron sequestration and reduced erythropoiesis. Learn more here.

    Echinocyte

    Drepanocyte

    Dacrocyte

    Spur cell

    Burr cell

    Chronic autoimmune atrophic gastritis

    Acanthocyte

    Anemia of inflammation

    A rare, life-threatening disorder characterized by hypocellular bone marrow resulting in progressive pancytopenia (low reticulocyte, granulocyte, and platelet count) without bone marrow infiltrate dysplasia or fibrosis. See more here.

    Itching of skin (often intense) that occurs within 30 minutes of contact with water. Characteristic symptom in polycythemia vera. Learn more here.

    Congenital secondary erythrocytosis caused by mutations in oxygen sensing/hypoxia-inducible factor (HIF) signaling pathway (autosomal recessive mutations in VHL gene)

    Acquired uncompensated agglutination and premature destruction of red blood cells (RBCs) by autoantibodies that target RBC antigens with optimal activity between 0 and 4 degrees C (32-39.2 degrees F), but also react at temperatures > 30 degrees C (86 degrees F). Learn more here.

    British Committee for Standards in Haematology (BCSH) guideline suggests using serum cobalamin (vitamin B12) cutoff < 148 pmol/L (200 pg/mL) or cutoff derived from local reference range in patient with strong clinical suspicion for vitamin B12 deficiency. Learn more here.

    Rare Diseases NIH: Autosomal dominant (rarely X-linked) inherited blood disorder that leads to anemia and is associated with physical abnormalities such as small head size (microcephaly) characteristic  facial features, cleft palate, cleft lip, short and webbed neck, small shoulder blades, and defects of the hands (mostly of the thumbs), as well as defects of the genitalia, urinary tract, eyes and heart. Caused by mutations in several genes. Learn more here.

    A sickle cell. Some authors used to refer to sickle cell disease as drepanocytosis (for example, see this 1944 paper).

    Relative erythrocytosis: an increase in RBC numbers without an increase in total RBC mass; absolute erythrocytosis: increased red cell mass above 125% of the predicted value for the body mass of the patient.

    Combined ITP and autoimmune hemolytic anemia. Learn more here.

    Acute hemolytic anemia resulting from ingestion of fava beans. Learn more here.

    Eculizumab or ravulizumab (C5 inhibitors). Learn more here.

    Fluorescent aerolysin, used in flow cytometry to diagnose PNH (selectively binds the GPI anchor with high affinity).

    Flow cytometric analysis of granulocytes using FLAER. (A) As a control setting, there was no evidence of decreased (type II PNH cells) or absent (type III PNH cells) expression of FLAER. (B) In this patient, decreased (42.4%) and absent (57.0%) FLAER fractions were detected, suggesting that 99.4% of PNH granulocyte clones had a FLAER deficiency, which is consistent with classic PNH. From PMCID: PMC5503897.

    A condition in which body iron stores are normal or increased, but iron incorporation into red cell precursors is impaired. One example is anemia of inflammation.

    An X-linked genetic disorder caused by mutations in G6PD gene resulting in reduced activity of the G6PD enzyme. Learn more here.

    Cureus | Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency Among  Children in Eastern Saudi Arabia

    A peptide hormone produced by liver hepatocytes in response to circulating iron levels which inhibits iron absorption from the intestinal mucosal cells and release by macrophages by degradation of ferroportin-1. Hepcidin plays a critical role in iron absorption and recycling. Learn more here.

    Hydroxyurea is a ribonucleotide reductase inhibitor

    Ribonucleotide reductase, one of the most essential enzymes of life, and how it buries the RNA world Fcimb_04_00052_pdf_Page_1
    From the following link.

    Lactate dehydrogenase (LDH) is a ubiquitous enzyme that catalyzes the conversion of lactate to pyruvate and back, resulting in conversion of NAD⁺ to NADH and back. LDH exists in four distinct enzyme classes.

    The red cell is a “fermenter”. It generates all of its energy (ATP) from glycolysis without use of the Krebs cycle. Instead of entering the Krebs cycle in the mitochondria (red cells do not have any mitochondria) to, pyruvate is metabolized to lactate via LDH.

    Meets the criteria for diagnosis polycythemia vera despite lower-than-threshold hemoglobin/Hct

    Hemolytic anemia + schistocytes caused by high shear environment caused by partially occluded vessels or paravalvular jet streams

    A disorder of heme biosynthesis

    Hematocrit > 51% lasting > 1 month post transplantation (usually develops within the first year post transplant). Occurs in 10%-15% of renal transplant recipients and is usually self-limiting. Most common after kidney transplant, but may also occur after other types of transplant, including hematopoietic stem cell transplantation.

    A type of absolute erythrocytosis (increased red cell mass) caused by autonomous proliferation of red cell progenitors within the bone marrow. There are two types of primary erythrocytosis: 1) congenital erythrocytosis (primary familial or congenital polycythemia) caused by gain of function mutations in the erythropoietin receptor, and 2) acquired erythrocytosis (polycythemia vera) caused by a somatic mutation in the Jak2 gene.

    A syndrome characterized by isolated normocytic normochromic anemia with severe reticulocytopenia and significant reduction or absence of erythroid precursors in bone marrow. Learn more here.

    A trace byproduct of the last step in heme synthesis. In iron deficiency, zinc, instead of iron, is incorporated into the protoporphyrin ring, resulting in increased zinc protoporphyrin levels (iron protoporphyrin is also called heme). ZPP may be used as an assay for iron deficiency.

    Heme synthesis from succinyl-CoA to PPIX and ultimately heme. Synthesis of ALA is the rate-limiting step and under negative feedback control of heme (green/ dashed). A deficiency of iron supply limits heme synthesis and leads to PPIX accumulation. Zinc can then substitute for iron and ferrochelatase catalyzes the formation of zinc PPIX (red/dotted). From the following link.

    An increase in RBC numbers without an increase in total RBC mass

    • Absence of presence of PNH clone
    • Clone size in the red cells
      • Total PNH clone size
      • Percentages of Type II and type III cells
    • PNH clone size in white blood cells
      • Neutrophils
      • Monocytes

    Learn more here.

    Rouleaux is the arrangement of >3 red cells in a linear of branched pattern resembling a stack of counts. Seen in conditions associated with an inflammatory response and acute phase reaction or multiple myeloma.

    Elevated red cell mass (absolute erythrocytosis) caused by a factor external from the bone marrow, typically erythropoietin (other factors include testosterone and cortisol). Learn more here.

    A group of chronic hemolytic anemias characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant leading to excessive production of hemoglobin S (HbS). Learn more here.

    7.5 microns

    Morphological Abnormalities of Red Blood Cells – The Art Of Medicine
    Source

    Partial deficiency of the third enzyme of heme synthesis, porphobilinogen deaminase (or hydroxymethylbilane synthase). It is an autosomal dominant condition.

    Heme biosynthesis pathway (from PMC8391404) shown here.

    Autoimmune-mediated atrophic gastritis, leading to deficient production of intrinsic factor (necessary for vitamin B12 absorption), and reduced vitamin B12 absorption. See more here.

    Congenital gain-of-function mutations in erythropoietin receptor (EPOR)

    Autoantibody, typically IgG, directed against red blood cell self-antigens with maximal reactivity at 37 degrees C (98.6 degrees F). Learn more here.

    About 10%

     Hemolytic anemia, bone marrow failure, and thrombosis

    Hb<13 g/dL in men, Hb < 12 g/dL in women (<11 g/dL if pregnant)

    Although the terms are often used interchangeably, they have slightly different meanings. Erythrocytosis is an increase in RBCs relative to the volume of blood (increased RBC count). Primary erythrocytosis is associated with an elevated red cell mass (a change in the numerator in RBC/volume), relative polycythemia is not (a change in the denominator in RBC/volume). Polycythemia refers to increased red cell mass, manifested by increased Hct and/or hemoglobin, and usually caused by increased RBC count (erythrocytosis). In theory, an elevated MCV could produce increased red cell mass independent of RBC number (Hct=MVC x RBC count). As the name ‘poly’ implies, polycythemia more accurately refers to pan-myeloproliferation, but this definition is not normally adhered to.

    Hb measures the total weight of hemoglobin contained within a given volume of blood. It is reported in g/dl or g/L. The Hct is the fractional volume of blood that is comprised of red cell cells. The Hct is expressed as a percentage.

    A polychromatophilic cell is a red cell that is slightly larger than a mature red cell whose cytoplasm has a bluish tinge when observed on a normally stained peripheral smear. Most if not all of these cells correspond to reticulocytes, which are RNA containing red cells that are detected either with intravital stains (where blood is not fixed, but rather incubated alive with stain) or FACS analysis using an RNA fluorochrome. Reticulocyte staining is more sensitive than Wright-Giemsa staining for detecting reticulocytes: all true polychromatic cells are reticulocytes, whereas not all reticulocytes would be detectable as polychromatic cells.

    Peripheral smear (Wright stained) showing polychromatophilic cell (arrow) (100X, oil)
    Intravital stain of peripheral blood showing several reticulocytes, notable for their slightly larger size than mature red cells and presence of reticulin network within the cytoplasm. From Shutterstock with permission

    Sickle cell anemia is a subset of sickle disease that includes the 2 most severe forms: homozygous sickle cell disease (HbSS), sickle beta0 thalassemia.

    MDS, myelodysplastic syndrome; AA, aplastic anemia; MGUS, monoclonal gammopathy of unknown significance

     1-4 mg/kg/day IV for 3-14 days based on clinical signs; do not exceed 6 mg/kg/day. Learn more here.

    Erythrocyte sedimentation rate, measured as the distance red cells have fallen by gravity in a vertical tube of anticoagulated whole blood. Learn more here.

    From Shutterstock, with permission

    Involved in the biosynthesis of GPI anchors, including CD55 and CD59.

    Typically to maintain HbS level at < 30% immediately prior to next transfusion.

  • CBC
  • Oxygen saturation
  • Renal function
  • Lliver function
  • Erythropoietin level
  • Jak2 mutation test
  • G to T somatic mutation at nucleotide 1,849 in exon 14 of JAK2, leading to constitutive activation of signaling pathways downstream of the erythropoietin receptor. Learn more here.

    Jak2 V617F mutation is a G to T somatic mutation at nucleotide 1,849 in exon 14 of JAK2, leading to constitutive activation of signaling pathways downstream of the erythropoietin receptor. It occurs in 95% of patients with polycythemia vera as well as a smaller percentage of patients with other myeloproliferative neoplasms, encodes a constitutively active Janus kinase that upregulates JAK/STAT signal transduction, resulting in unregulated myeloproliferation (erythrocytosis, often with leukocytosis and/or thrombocytosis). Learn more here.

    JAK-2 V617F Mutation | Decode Lab
    From Decode

    120 days

    Crizanlizumab inhibits white blood cell-endothelial and platelet-endothelial interactions on blood vessel wall.

    Overproduction of neurotoxic heme precursor from the liver caused by deficient enzyme in heme biosynthesis pathway, often in conjunction with precipitating factor that increases rate of heme synthesis

    Jak2 mutation (V617F)

    Vaso-occlusive crisis Learn more here.

    Babesia microti

    80-100 fL

    32-36 g/dL

    Anemia of inflammation (the anemia is not always chronic in nature)

    0.01%-0.1%

    About 20%. Learn more here.

    30-45% of patients

    Acute chest syndrome

    Anemia of inflammation

    CBC, renal and liver function, arterial oxygen saturation, carboxyhemoglobin, serum ferritin, serum erythropoietin, Jak2 mutational analysis (peripheral blood). Learn more here.

    Morning

    About 50%

    About 70-80%

    10%-20% of patients. Learn more here.

    >90% of such patients have evidence for a clonal expansion of kappa-positive B cells and a monoclonal IgM paraprotein. Learn more here.

    About 30%

    20-25%

    IgM, reacting optimally between 0 and 4 degrees C. Learn more here.

    Homozygous sickle cell disease (HbSS) and sickle beta0 thalassemia. Learn more here.

    Both markers are highly sensitive, but MMA is more specific (for example, homocysteine levels may also be increased in patients with folate deficiency). MMA values considered high vary from 0.28 to 0.75 mcmol/L Learn more here.

    Intrinsic factor antibodies are more specific (98-99% vs. 50%) but less sensitive (40-60% vs. 80-90%) than antiparietal antibodies. Learn more here.

    Anti-parietal cell antibodies, which target the gastric enzyme H+/K+ATPase proton pump. Learn more here.

    Louis Diamond and Kenneth Blackfan, who first described the disorder in 1938 (Diamond LK, Blackfan KD. Hypoplastic Anemia. American Journal of Diseases of Children. 1938;56:464–467)

    Robert S. Evans, first author on paper that first described the syndrome in 1951.

    Because megaloblastic red cell precursors are destroyed in the bone marrow (ineffective erythropoiesis) and these immature cells contain Hb, LDH and AST.

    White blood cells

    Lymphocyte count > 3.5-4.5 × 109/L

    1.6 billion leukocytes per kilogram body weight

    • Familial or congenital (rare)
    • Acquired
      • Primary (clonal)
        • MPN
        • MDS
        • MDS/MPN overlap syndromes
        • AML
        • Mastocytosis
        • Myeloid/lymphoid neoplasms with eosinophilia (rearrangement of PDGFRAPDGFRB, or FGFR1, or with PCM1-JAK2)Secondary (reactive)
      • Secondary (reactive)
        • Allergies
        • Helminth infections
        • Drug reactions
        • Autoimmune disorders
        • Cancer
        • Lymphocyte variant hypereosinophilia syndrome (HES)
    Learn more here.
    MM, multiple myeloma; MDS, myelodysplastic syndrome; mets, metastases; DIC, disseminated intravascular coagulation

    Another perspective:

    From Gnanaraj et al

    Chronic myelogenous leukemia; polycythemia vera; primary myelofibrosis; essential thrombocythemia; chronic neutrophilic leukemia; chronic eosinophilic leukemia, not otherwise specified (NOS); MPN, unclassifiable.

    2016 WHO classification of MPN

    Dohle bodies, toxic granulation and vacuolization

    Reactive (secondary): viral, bacterial, or parasitic infection, vaccinations, connective tissue disease, and smoking. Clonal (primary): chronic lymphocytic leukemia (CLL) and certain B-cell and T-cell leukemia/lymphomas.

    From Cerny et al.

    Reactive (secondary): viral or bacterial infection, corticosteroids, malignancy, postsplenectomy state, autoimmune disorders (such as inflammatory bowel disease or sarcoidosis), and vasculitides. Clonal (primary): monocytic leukemia, chronic myelomonocytic leukemia, and mastocytosis.

    From Cerny et al

    Myelodysplastic syndrome

    Myeloproliferative neoplasm

    A band neutrophil is a young neutrophil with deeply indented nucleus. The nucleus is indented to more that half the distance to the farthest nuclear margin. Chromatin is consistently present between edges of nuclear membrane, but in no area is it condensed to a single filament. Normally comprise < 10% of circulating white cells. Increased numbers in left shift (as occurs with inflammation and infection) and myeloproliferative neoplasms.

    From Shutterstock, with permission
    Peripheral smear showing band neutrophil in center. From Shutterstock, with permission

    Döhle bodies appear as single or multiple blue or gray-blue inclusions of variable size (0.1 to 5.0 μm) and shape (round or elongated or crescent shaped) in the cytoplasm of neutrophils, bands, or metamyelocytes. They are often found in the periphery of the cytoplasm, near the cell membrane. Seen in conditions associated with increase cytokine release such as infection, burns, trauma, and administration of G-CSF.

    Peripheral smear showing Dohle body (arrow) in a neutrophil

    A leukemoid reaction is defined by a leukocyte count greater than 50,000 cells/μL, caused by reactive causes outside the bone marrow. Learn more here.

    4-11 x 109/L

    Smudge cells are remnants of fragile lymphocytes that are generated during preparation of peripheral smear. They lack any identifiable cytoplasmic membrane or nuclear structure. They contain dense nuclear material and or chromatic strands. They are characteristic of chronic lymphocytic leukemia.

    Peripheral smear showing smudge cell

    Persistent blood eosinophil count >1.5 x 109/L (on 2 examinations over ≥ 1 month without evidence of organ damage). Learn more here.

    WBC > 100 x 109/L

    Immature neutrophil precursors – in absence of presence of elevated white count – and nucleated red blood cells in the peripheral blood, indicative of severe disruption of the marrow by overwhelming infection, myelofibrosis, or bone marrow invasion due to cancer. Learn more here.

    Intravascular accumulation of white cells causing obstruction of blood flow in patients with hyperleukocytosis (defined as WBC count >100 x 10^9/L), especially those with acute leukemia, in which the white cells are “stickier” compared to reactive causes or those with CLL. May lead to organ compromise. Learn more here.

    Pathophysiology of leukostasis from Ali et al
    Source

    A heterogeneous group of clonal disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenias and an increased risk of transformation to acute myeloid leukemia.1

    Reactive (polyclonal) eosinophilia secondary to malignancy

    Basophil count > 0.1 x 109/L

    White cell count > 11 x 109/L

    Monocyte count > > 0.8-1.0 × 109/L

    Neutrophil count > 7-7.7 × 109/L

    Reactive (secondary): drug reactions, allergy/hypersensitivity reaction, infections (especially tissue-invasive parasites, such as strongyloides), cancer, sarcoidosis, connective tissue diseases, adrenal insufficiency, pulmonary diseases such as eosinophilia pneumonia. Clonal (primary): chronic eosinophilic leukemia, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRAPDGFRB, or FGFR1, or with PCM1-JAK2, and other acute and chronic primary bone marrow processes such as myeloproliferative neoplasms.

    Infection, chronic inflammation, smoking, stress, obesity, drugs (for example corticosteroids, beta-agonists, lithium, or epinephrine), endocrine disorders (such as hypercortisolism, thyroid storm, pre-eclampsia), splenectomy, bone marrow stimulation, and nonhematologic malignancy, and rarely in inherited disorders.

    Hypereosinophilia (of any cause) associated with clear evidence of hypereosinophilia-related organ damage. Learn more here.

    • Defined as immature neutrophil count (myelocytes + metamyelocytes + bands +/- promyelocytes)/total neutrophil count
    • Used as an indicator of a granulocyte left shift

    Toxic granulation is the presence of large purple or dark blue cytoplasmic granules (primary granules) in neutrophils, bands, and metamyelocytes. The granules have increased staining density compared to normal neutrophils. Seen in conditions associated with increase cytokine release such as infection, burns, trauma, and G-CSF administration.

    Platelets

    Typically 5-10 days. Learn more here.

    Yes, especially in primary thrombocytosis, because platelet glycoprotein 1b binds to circulating von Willebrand factor, leading to acquired von Willebrand syndrome.

    No, the pathogenesis of iron deficiency-associated thrombocytosis is unclear, but may involve increased commitment of bipotential (erythroid/megakaryocytic) progenitor cells to the megakaryocytic lineage. Learn more here.

    Yes, they are 20-25% lower in individuals with type O blood group. 14% of individuals with type O blood have vWF levels ≤ 50 units/dL. Learn more here.

    <30 x 109/L according to 2019 ASH guideline:

    <20-30 09/L according to International Consensus Report:

    ADAMTS13 activity level

    No

    Yes, and in fact they are now recommended as an option in the latest ASH guideline, especially for those who are not at high risk of bleeding and who do not have extensive clot burden.

    ASH 2018

    At minimum, all critically ill non-bleeding patients with DIC should receive prophylactic anticoagulation for VTE. According to the 2013 ISTH harmonization of guideline recommendations: “Anticoagulant treatment may be a rational approach based on the notion that DIC is characterized by extensive activation of coagulation. Although experimental studies have shown that heparin can at least partly inhibit the activation of coagulation in DIC [36], there are no RCTs demonstrating that the use of heparin in patients with DIC results in an improvement in clinically relevant outcomes”. They conclude: “Therapeutic doses of heparin should be considered in cases of DIC where thrombosis predominates (low quality evidence). The use of low molecular weight heparin (LMWH) is preferred to the use of unfractionated heparin (UFH) in these cases (low quality evidence)”.

    Yes! Proposed mechanisms include formation of platelet-white cell complexes, direct effect of pathogens on platelet activation and aggregation, hemophagocytosis or altered platelet production. Learn more here.

    Yes

    Patients with type 2B vWD may have thrombocytopenia. Learn more here.

    No, they are not different between the two conditions.

    No

    Yes, it is much more common in later stages of cirrhosis (about 5% prevalence with I-IV fibrosis vs. 65% in patients with stage III-IV fibrosis). Learn more here.

    CCI = CI × body surface area (in m2)/number of platelets transfused

    Posttransfusion platelet count – pretransfusion platelet count

    By apheresis or from whole-blood by platelet-rich plasma or buffy coat methods

    They are pinched off from proplatelet tips and released into the circulation. Learn more here.

    From Thon and Italiano

    They are stored in gas-permeable storage bag with gentle agitation at 20-24 degrees C (68-75.2 degrees F); maximum total time for platelets to be stored without agitation is 30 hours.

    2-4 × 0.5 micrometers with mean volume of 7-11 fL

    15%-20% of patients presenting with acute lymphoblastic leukemia, > 90% of patients presenting with acute promyelocytic leukemia

    About 1%

    Over 95% of patients with DIC have thrombocytopenia.

    Occurs in about 50-60% of such patients.

    About 8%-68% of patients at time of admission, up to 50% of patients during stay in ICU. Learn more here.

    Thrombocytosis occurs in about 10-15% of patients with iron deficiency anemia. Learn more here.

    10-20% of patients

    They block platelet aggregation by inhibiting fibrinogen binding to surface glycoprotein GPIIb/III.

    DDAVP 0.3 mcg/kg IV in 30-50 mL normal saline over 30 minutes. May be repeated 12-24 hours after first dose, depending on how well the patient responds, but no more than 2-3 doses should be given in order to avoid tachyphylaxis.

    Decrease platelet clearance and increase platelet production. Also, steroids may reduce bleeding, independent of their effect on platelet counts, by a direct effect on blood vessels. Learn more here.

    1 unit vWF:RCo/kg infused will result in recovery of 1.5-2 units vWF:RCo/dL in adults; 50 units vWF:RCo/kg will give a recovery of 75-100 units vWF:RCo/dL.

    Direct toxic effect on the bone marrow. Learn more here.

    Aspirin inhibits cyclooxygenase 1 (COX1) thereby decreasing production of thromboxane A, a major mediator of platelet activation.

    DDAVP increases the release of vWF and factor VIII from endothelial cell stores by releasing vWF from cytoplasmic organelles called Weibel-Palade bodies.

    Removes autoantibodies and replenishes ADAMTS13 levels

    Rarely below 30-40 × 109/L

    70%-80% of cases

    Thrombosis occurs in one-third to one-half of patients with HIT. It may occur in veins, arteries or microvessels.

    aPTT; adjust to 1.5-3.0 times baseline 

    aPTT; adjust to 1.5-2.5 times baseline 

    DDAVP may be administered IV, subcutaneously, or by nasal spray.

    No one laboratory test is specific for DIC. Clinical practice guidelines recommend using a clinical scoring system, such as the ISTH scoring system, which includes consideration of the platelet count, D-dimers, fibrinogen and the prothrombin time.

    Based on clinical presentation (thrombocytopenia and/or thrombosis in temporal association with heparin therapy without other obvious causes) plus presence of platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies. Clinical prediction scores, especially the 4T score, are helpful in estimating the pretest probability of HIT and determining whether heparin should be discontinued and further testing for antibodies (functional assay) carried out.

    Based on clinical presentation (thrombocytopenia and/or thrombosis in temporal association with heparin therapy without other obvious causes) plus presence of platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies

    Low CCI < 1 hour after transfusion suggests immune-mediated platelet refractoriness

    Platelet count < 100 × 109/L in absence of other causes of thrombocytopenia.

    From the 2019 International Consensus Report

    Nonimmune mediated refractoriness is indicated if normal CCI at < 1 hour, followed by low CCI at 18-24 hours after transfusion.

    A typical strategy is to administer plasma exchange 3 times per week for first week, 2 times per week the second week, and 1 time per week the following weeks (CBC and LDH are monitored after stopping)

    Options include Increased frequency of plasma exchange, rituximab, and immunosuppressive therapies such as cyclophosphamide and vincristine.

    According to mechanism (decreased production, increased destruction and sequestration) or clinical context (outpatient, obstetrical patient, emergency department or acute care clinic, medical vs. surgical/ICU vs. non-ICU inpatient)

    A limitation of the mechanistic approach for isolated thrombocytopenia is that the vast majority of causes are in the increased destruction category, so the scheme is not always helpful in narrowing the differential diagnosis.
    Patients with isolated thrombocytopenia in the outpatient clinic may have stable ITP, cirrhosis, or they may be drinking. Patients with thrombotic microangiopathy, ITP complicated by bleeding, or alcohol toxicity may present to to the ED (or acute care clinic). Thrombocytopenia that develops in medical inpatients is almost always caused by infection (with or without DIC) or drugs (heparin or other medications). Rarely, it may develop as a complication of transfusion (post-transfusion purpura). Transient thrombocytopenia is a common occurrence following major surgery. In the ICU, patients who are on extracorporeal support may develop thrombocytopenia from consumption on the circuit membranes. Patients who receive massive transfusions without appropriate platelet support may develop dilutional thrombocytopenia. Pregnant women may develop thrombocytopenia from HELLP, eclampsia, preeclampsia or HUS/TTP.

    Primary (clonal) and secondary (reactive)

    Platelet count > 450 × 109/L

    ≤ 5 days in the United States; however, most blood collection centers culture apheresis platelets and release the unit 24-36 hours after collection.

    4-8 weeks, including taper

    The 2019 ASH clinical guideline recommends treating for <6 weeks:

    The 2019 International Consensus Report suggests a maximum of 8 weeks:

    About 12 million in the United States!

    1011

    1 apheresis platelet unit is equivalent to pool of 4-6 units of whole blood-derived platelets; typically contains ≥ 3 × 10^11 platelets.

    About 5000. Learn more here.

    As of 2021, there are 27 known forms arising from mutations in 31 genes.

    Three: Type 1, Type 2, and Type 3

    From Sadler et al
    From Leebeek and Eikenboom

    If the patient has primary thrombocytosis (for example, essential thrombocythemia), they are at higher risk of thrombosis (though the risk does not correlate well with the platelet count). In patients with secondary or reactive thrombocytosis, there is no compelling evidence supporting an increased risk of thrombosis.

    Once the platelet count is over 150 x 109/L. Switch to warfarin (with appropriate overlap) or preferably to a DOAC. In case of HIT without thrombosis, continue for up to 4-6 weeks. In the case of HITT, treat for 3 months.

    2018 ASH guideline

    May be repeated up to 3 times, according to the 2019 International Consensus Report

    Even with platelet count recovery, patients remain at risk for thrombosis for 4 to 6 weeks after diagnosis because of circulating anti-PF4/heparin antibodies

    Platelet count recovery occurs within 7 days in 90% of cases. Functional assays become negative at a median of 50 days after heparin is suspended, while Circulating anti-PF4/heparin antibodies are no longer detectable by immunoassay at a median of 85 days.1

    Median 50 days for platelet activation assays and 85 to 90 days by immunoassays

    No. Patients who are reexposed to the drug months to years after antibody disappearance often do not manifest anamnestic responses, and seroconversion risk appears similar to de novo heparin exposure.

    In one study, 21-33 days postoperatively at median platelet count of 700 × 109/L before stabilizing after 45 days.

    First heparin exposure

    Highest platelet count that immediately precedes the putative HIT-related fall in platelet count

    • < 72 hours post-surgery
    • Infection (confirmed bacteremia/fungemia)
    • Chemotherapy or radiation < 20 days
    • DIC
    • Posttransfusion purpura
    • Other drugs implicated in drug-induced thrombocytopenia

    No. There are 4 parameters that are used in clinical scoring systems for DIC: fibrinogen, prothrombin time (PT), platelet count and D-dimers/fibrin degradation products. Fibrinogen is the least sensitive of these markers (overall sensitivity of low fibrinogen level reported to be 28%) because it is an acute phase reactant and therefore often elevated in conditions associated with DIC.

    No, it is a complication of an underlying diseases such as sepsis or cancer.

    Yes, in about 50% of cases. Learn more here.

    No

    No, there is no evidence that it is. Learn more here.

    No. Platelet-associated IgG is elevated in both immune and nonimmune thrombocytopenia and assays for antibodies to specific platelet glycoproteins, while quite specific, have poor sensitivity. Clinical practice guidelines do not recommend ordering the test.  

    From 2019 International Consensus Report

    The aPTT may be increased in Type 2N vWD (the mutation specifically impairs the ability of vWF to carry FVIII) and Type 3 vWD (since vWF carries and stabilizes FVIII in the circulation, the very low levels of vWF associated with Type 3 vWD result in low FVIII activity).

    Yes, It’s called Vonvendi.

    Yes, treatment with plasma exchange should begin as soon as possible, preferably within 4-8 hours of initial clinical diagnosis.

    British Committee for Standards in Haematology guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies
    British Committee for Standards in Haematology guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies

    Not in patients with a typical presentation of ITP.

    2019 ASH clinical guideline

    Antiplatelet therapy is not recommended, even in patients with extreme thrombosis, due to lack of evidence for thrombotic risk and theoretical risk of paradoxical bleeding from acquired von Willebrand syndrome. In cases where thrombosis has been reported in patients with reactive thrombocytosis, it is not known whether elevated platelet counts are causal or simply a marker of underlying disease with high thrombotic risk. Learn more here.

    Yes, bilateral dopplers of the lower extremities are recommended.1

    2018 ASH guideline

    Only if the patient has an upper-extremity central venous catheter, or with signs or symptoms suggestive of upper extremity DVT. See ASH guideline.

    In a randomized trial, high-dose dexamethasone (40 mg daily x 4 days) was shown to lead to a faster response compared to steroids, and without additional toxicity. However there was no difference in platelet count response at 6 months. Consider dexamethasone if quick response is particularly important, for example in a patient who is bleeding or needs to have surgery.

    The following data are from the randomized trial mentioned above. The legends speak for themselves:

    2019 International Consensus Report (the 2019 ASH guideline does not make a recommendation on prednisone vs. dexamethasone; they simply state “high-dose dexamethasone led to faster responses without additional toxicity”, referring to the randomized trial published in 2016).

    No, not unless there is another indication for these drugs, for example a coronary stent, and provided the risk: benefits are acceptable. Learn more here.

    2018 ASH guideline

    No, platelet transfusions may exacerbate the thrombotic tendency in HIT. Platelet transfusion should be reserved for patients with active bleeding or at high risk of bleeding. Learn more here.

    2018 ASH guideline

    Consider admission to hospital of patients with platelet < 20 x 109/L, even if they are asymptomatic.

    2019 ASH guideline

     No, not unless there is life-threatening bleeding

    It may be considered once the platelet count increases to a safe level (e.g., > 50 x 109/L), but there is no evidence of clinical efficacy in this setting.

    • Reduce rates of alloimmunization
    • Reduce rates of febrile nonhemolytic transfusion
    • Prevent transmission of intracellular pathogens such as:
      • cytomegalovirus (CMV)
      • human T-lymphotropic virus
      • types I and II (HTLV- I/II)

    Immunoassays that detect presence of antibodies to platelet factor (anti-PF4/heparin antibodies) and functional assays detect anti-PF4/heparin antibodies capable of activating platelets (e.g., serotonin-release assay [SRA]). Learn more here.

    • Argatroban
    • Bivalirudin
    • Danaparoid
    • Fondaparinux especially in clinically stable patients at average risk of bleeding
    • DOAC
      • especially in clinically stable patients at average risk of bleeding
      • most of the published experience in HIT is with rivaroxaban
    See ASH guideline

    A) Immune-mediated: alloimmunization to human leukocyte, platelet-specific, or ABO antigens; autoimmune (immune thrombocytopenia); B) Non-immune-mediated: hemorrhage, fever, sepsis, disseminated intravascular coagulation (DIC), splenic sequestration, use of older stored platelets, thrombotic microangiopathy

    Essential thrombocythemia, polycythemia vera, primary myelofibrosis, CML, MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), CMML and myelodysplastic syndrome with del (5q)

    Aminocaproic acid and tranexamic acid

    Quinine, quinidine, trimethoprim/sulfamethoxazole, and vancomycin

    • Transfusion-associated graft-versus-host disease
    • Immunocompromised patients
    • Hematologic malignancies or certain solid tumors
    • Recipients of marrow or peripheral blood stem cell transplantation
    • Patients receiving blood components from blood relatives or human leukocyte antigen-compatible donors
    • Patients receiving fludarabine therapy
    • Prematurity, low birthweight, or erythroblastosis fetalis in newborn

    Patients with low circulating platelet counts, to prevent or control bleeding or functionally abnormal platelets

    Patients who are IgA deficient with documented presence of antibodies against IgA, for whom no IgA-deficient products are available, patients experiencing posttransfusion purpura (washing can help remove complement), patients with history of repeated severe allergic reactions to plasma-containing products

    von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor (vWF:RCo) activity and FVIII activity. Learn more here.

    Thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia

    Unfractionated heparin > low molecular weight heparin (these differences are especially true at prophylactic doses); IV heparin > SC heparin; therapeutic or prophylactic dose heparin associated with higher risk than heparin flush; bovine>porcine heparin

    Collected using automated instrumentation (also called apheresis platelets).

    • Cyclooxygenase 1 (COX1) inhibitors such as aspirin
    • P2Y12 inhibitors such as
      • clopidogrel
      • prasugrel
      • ticagrelor
      • cangrelor
    • Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors such as
      • tirofiban
      • eptifibatide
      • abciximab
    • Thrombin receptor protease activated receptor inhibitor, vorapaxar

    Systemic infection, solid and hematological malignancies, obstetric diseases (for example, abruptio placentae or amniotic embolism), trauma, aneurysms, and liver diseases

    From ISTH guideline on DIC

    abciximab, eptifibatide, and tirofiban

    Headache, facial flushing, tachycardia, and hyponatremia

    Thrombotic type DIC and fibrinolytic type DIC

    Hereditary mutations in thrombopoietin gene (TPO), TPO receptor, or Jak2

    MM, multiple myeloma; MDS, myelodysplastic syndrome; mets, metastases; DIC, disseminated intravascular coagulation

    Another perspective:

    From Gnanaraj et al

    WHO requires 4 major criteria or first three major criteria + 1 minor criterion. Major:  sustained platelet count > 450 × 109/L; bone marrow biopsy with characteristic changes; not meeting WHO criteria for BCR-ABL+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasm; presence of JAK2CALR, or MPL mutation. Minor: presence of clonal marker or absence of evidence for secondary thrombocytosis


    ET diagnosis requires meeting all four major criteria or first three major criteria and one minor criterion.

    Learn more here.

    ISTH/SSC Harmonization of the Recommendations: FFP recommended in patients with active bleeding or requiring an invasive procedure and either prolonged PT/aPTT (> 1.5 × normal) or decreased fibrinogen (< 1.5 g/L); cryoprecipitate recommended for patients with active bleeding plus severe hypofibrinogenemia (< 1.5 g/L) that persists despite FFP replacement; platelet transfusion recommended in patients with active bleeding plus platelet count < 50 × 109/L, or high risk of bleeding plus platelets < 20 × 109/L

    In patients with major bleeding (often in combination with corticosteroids) or in patients who require acute treatment and either cannot
    tolerate or do not respond to corticosteroids. Learn more here.

    2011 ASH guideline, not addressed in the 2019 update
    2019 International Consensus Report
    • Cyclooxygenase 1 (COX1) inhibitors such as aspirin
    • P2Y12 inhibitors, including
      • clopidogrel
      • prasugrel
      • ticagrelor
      • cangrelor
    • Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors
      • tirofiban
      • eptifibatide
      • abciximab

    Atypical HUS and infection-induced HUS, including shiga toxin-producing Escherichia coli-associated (STEC) HUS and S. pneumoniae-associated HUS

    Systemic lupus erythematosus (SLE), infections (especially HIV and hepatitis C virus [HCV]), and lymphoproliferative disorders

    Infection (with or without DIC) and medications (including heparin and non-heparin agents)

    3 pillars of treatment are 1) treat underlying disease that triggered DIC, 2) provide replacement therapy where appropriate, 3) inhibit thrombin and fibrin formation where appropriate

    Type 1, 75%; Type 2, 20%; Type 3, 5%

    Type 2A (decreased secretion or increased cleavage of high-molecular-weight multimers), Type 2B (increased vWF binding to platelet glycoprotein Ib (GPIb) alpha receptor with rapid clearance of platelet-vWF complex), Type 2M (defective binding to platelet GPIb alpha receptor or collagen; M for multimer) and Type 2N (defective vWF binding to factor VIII; N for Normandy, where it was discovered). See more here.

    From Leebeek and Eikenboom

    Increased platelet destruction, decreased platelet production and sequestration (hypersplenism).

    A group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and microthrombi leading to ischemic tissue injury. Laboratory tests reveal thrombocytopenia and hemolytic anemia with red blood cell fragmentation on the blood smear.

    Aging, pregnancy, inflammation (vWF is an acute phase reactant)

     Discontinue non-heparin anticoagulant and resume heparin.

    Continue heparin. No need for alternative anticoagulant HIT testing not recommended.

    • Discontinue heparin
    • Initiation a non-heparin anticoagulant at therapeutic intensity
    • Test for HIT antibodies

    Anti-PF4/heparin antibodies of all isotypes (IgG, IgA, IgM, or polyclonal or polyspecific assays) or IgG isotypes

    Thrombocytopenia with normal Hb and white cell count

    A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13

    Atypical hemolytic uremic syndrome

    1-desamino-8-D-arginine vasopressin, also called desmopressin

    Disseminated intravascular coagulation 

    Drug-induced thrombocytopenia

    Essential thrombocythemia

    Heparin-induced thrombocytopenia

    Heparin-induced thrombocytopenia with thrombosis

    Immune thrombocytopenia

    Thrombopoietin (TPO) receptor

    Platelet factor 4

     Shiga-like toxin producing Escherichia coli (E. coli) hemolytic-uremic syndrome (STEC-HUS)

    Thrombotic microagniopathy

    Thrombopoietin 

    Thrombotic thrombocytopenia purpura

    von Willebrand disease

    Von Willebrand Factor

    Reduces mortality rates from 90% to 10%

    von Willebrand disease and inherited platelet function disorders (IPFDs)

    Platelet count > 1,000-1,500 × 109/L

    Most platelets are 1.5-3 μm in diameter. Small platelets are less than 1.5 μm in diameter. Large platelets usually range from 4 to 7 μm. Giant platelets are larger than 7 μm and usually 10-20 μm in diameter. Platelets that are larger than the size of the average red cell in the field qualify as giant platelets. Seen in many different reactive, neoplastic, and inherited conditions including myeloproliferative and myelodysplastic disorders, autoimmune thrombocytopenia, in association with severe leukemoid reactions, May-Hegglin anomaly and Bernard-Soulier syndrome.

    150-450 x 109/L

    150-450 x 109/L

    A platelet transfusion to prevent bleeding

    Alphanate is a high-purity factor VIII/vWF lyophilized concentrate used in patients with vWD. it is FDA approved for adult and pediatric patients with vWD having surgery or invasive procedures in whom desmopressin (DDAVP) is ineffective or contraindicated.

    Upshaw-Schulman syndrome

    Immune TTP

    A type of thrombotic microangiopathy characterized by uncontrolled complement activation, microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction, especially renal failure. Learn more here.

    Autosomal recessive disorder characterized by moderate to severe mucocutaneous bleeding, caused by mutations in genes encoding proteins in the glycoprotein (GP) Ib/IX/V complex. Learn more here.

    Autosomal recessive disorder characterized by moderate to severe bleeding, primarily mucocutaneous, from childhood. Characterized by mild thrombocytopenia with giant platelets, normal aggregation to all agonists except ristocetin and a prevalently severe bleeding phenotype.

    A humanized anti-von Willebrand factor (vWF) single-variable-domain immunoglobulin (nanobody) that targets AI domain of vWF, preventing its interaction with platelet glycoprotein 1b-IX-V, FDA approved for treatment of adults with immune TTP in combination with plasma exchange and immunosuppressive therapy

    DDAVP is a synthetic derivative of antidiuretic hormone vasopressin that acts through type 2 vasopressin receptor.

    HIT that develops or worsens after heparin has been discontinued. Thrombotic manifestations are delayed for days to weeks after heparin discontinuation and discharge.

    Acquired clinicopathological syndrome characterized by systemic activation of coagulation that may cause organ-damaging thrombosis and/or hemorrhage due to consumption of coagulation factors and platelets. Defined by ISTH as “an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes; can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”.

    Autosomal dominant disorder characterized by cleft palate, congenital cardiac abnormalities, developmental disabilities, facial dysmorphisms, immunodeficiency with parathyroid and thymus abnormalities, and mild to significant bleeding caused by microdeletion of chromosome 22q11.2 including the GP1BB gene (encodes glycoprotein 1b-beta [GPIbβ]). Learn more here.

    Eculizumab is a monoclonal C5 antibody that inhibits terminal complement complex formation used as first line therapy in aHUS and PNH.

    The complement system is a major innate immune defense mechanism. Complement may be activated by the classical, lectin or alternative pathways, all leading to the cleavage of the inactive central component C3 to biologically active C3b. C3b binds covalently to any surface, either foreign or self. When C3b is bound to positively charged surfaces (called alternative pathway activator surfaces as present in microorganisms) C3b interacts with factor B (FB) to form the C3 convertase (C3bBb) of the alternative pathway amplification loop and may generate a C5 convertase leading to the release of C5a, which is also an anaphylatoxin, and C5b which initiates the formation of the membrane attack complex (MAC), by binding C6 and C7. The C5b67 inserts into the membrane where it binds C8 and many molecules of C9, forming a pore. It can be cytolytic, forming a transmembrane channel, which causes osmotic lysis of the target cell or sublytic, associated with cell activation. In order to avoid complement hyperactivation, the alternative pathway C3 convertase is tightly regulated. From PMC4400466

    Intermittent attacks with triad of increased temperature, erythema, and burning pain that primarily affects the feet and hands. A characteristic symptom of essential thrombocythemia. Learn more here.

    Combined ITP and autoimmune hemolytic anemia. Learn more here.

    A group of rare hereditary disorders associated with low platelet count and variable degree of bleeding complications. Learn more here.

    Inborn error of metabolism leading to accumulation of glucocerebroside within lysosomes of cells

    Autosomal recessive inherited platelet function disorder characterized by moderate to severe mucocutaneous bleeding. Caused by mutation in genes that encode for glycoproteins αIIbβ3 on platelet surface, leading to impaired platelet aggregation.

    Most common autosomal recessive inherited platelet function disorder characterized by moderate to severe bleeding from childhood such as gastrointestinal bleeding, epistaxis, and gingival bleeding (heterozygotes are typically asymptomatic). Caused by mutations in genes that encode for glycoproteins αIIbβ3 on platelet surface, leading to impaired platelet aggregation.

    Humate-P is pasteurized plasma-derived vWF/factor VIII lyophilized concentrate with high vWF activity and higher proportion of high-molecular-weight vWF multimers than other vWF/factor VIII concentrates. Humate-P is FDA approved for adults and children with vWD.

    The prothrombin time (PT)

    Thrombotic thrombocytopenic purpura (TTP), named after the physician Eli Moschcowitz who first described the condition.

    Subtle hemostatic dysfunction without obvious clinical symptoms. May progress to overt DIC.

    Decompensated hemostasis with bleeding and thrombotic manifestations

    A rapid and reproducible test that measures primary platelet-related hemostasis using small amount of anticoagulated whole blood under conditions of high shear, with platelet plug formation; assay is dependent on von Willebrand factor (vWF) and not fibrinogen

    Repeated failure to achieve adequate response to platelet transfusions

    Genetic or acquired conditions associated with absent or reduced numbers platelet granules or granules that are unable to empty their contents into the bloodstream. Learn more here.

    Autosomal dominant condition caused by a mutation in the gene encoding platelet GPIb alpha receptor, which leads to increased binding of platelets to vWF. Learn more here.

    Autosomal dominant condition associated with mild to moderate mucocutaneous bleeding caused by gain-of-function mutation in the gene encoding GPIbα , leading to increased affinity to von Willebrand factor, removal of high-molecular-weight von Willebrand factor from the circulation and thrombocytopenia. Often confused with type 2B-VWD, a disorder in which gain-of-function variants of VWF are responsible for increased GPIbα-vWF binding. learn more here.

    A rare, life-threatening syndrome caused by marked protein C deficiency and characterized by DIC and endovascular thrombosis resulting in characteristic pattern of cutaneous purpura. See image.

    HIT associated with abrupt platelet count fall (within 24 hours); occurs in patients who already have circulating anti-PF4/heparin antibodies because of recent heparin exposure.

    First-line therapy includes corticosteroids and/or IV immunoglobulin (IVIG [or anti-D immune globulin (anti-D)]. Patients who are not bleeding should be started on steroids (prednisone 1-2 mg/kg up to a maximum of 80 mg daily) or dexamethasone 40 mg PO or IV daily x 3 days. If there is a particularly high risk f bleeding, IVIG may be added to the regimen.

    2019 ASH clinical guideline

    Plasma exchange (mainstay of treatment; ideally started within 4-8 hours of initial clinical diagnosis) and methylprednisolone (1 g/day IV for 3 days for adults) or high-dose oral prednisolone (for example, 1 mg/kg/day) and (in some cases) rituximab; for secondary TTP, same treatment as with primary TTP in addition to treatment of the underlying disorder.

    Rituximab is a monoclonal antibody that targets CD20 antigen present on B lymphocytes

    autosomal dominant or recessive disorder characterized by moderate to severe bleeding including menorrhagia, hematoma, and epistaxis. Caused by mutations in TMEM16F (ANO6) gene encoding transmembrane protein 16F (calcium-activated chloride channel).

    A rare variant that develops without prior heparin exposure

    Thrombocytopenia that results from in vitro artifact. May result from EDTA-dependent antibodies, and poor specimen collection and/or handling.

    HIT in which platelets are recovered, but HIT antibody is still positive

    A clinical prediction rule used to predict the likelihood (pretest probability) of HIT. Includes a consideration of magnitude of platelet count drop, timing of platelet count drop, presence of thrombosis and presence of alternative causes of the reduced platelet count. See calculator.

    Parameter2 points1 point0 pointsComment
    ThrombocytopeniaPlatelet count fall > 50% AND platelet nadir ≥ 20 × 109 L−1Platelet count fall 30%–50% OR platelet nadir 10–19 × 109 L−1Platelet count fall < 30% OR platelet nadir < 10 × 109 L−1Fall from highest platelet count that immediately precedes the putative HIT-related platelet count fall. 95% of cases of HIT are reported to develop in temporal association with heparin therapy; typically > 50% platelet count fall, but not to levels < 20 × 10 9 /L; only a few patients show 30%-50% platelet count fall; typical nadir is 40-80 × 109/L, with median of 55 × 109/L
    Timing of platelet count fall

    Clear onset between days 5 and 10 OR platelet fall ≤ 1 day (prior heparin exposure within 30 days)Consistent with days 5–10 fall, but not clear (e.g. missing platelet counts) OR onset after day 10 OR fall ≤ 1 day (prior heparin exposure 30–100 days ago)Platelet count fall < 4 days without recent heparin exposureDay 5 to 10 for initial platelet count fall with day 0 representing first heparin exposure; earlier fall if patient exposed to heparin with previous 30 days. Days are rounded off. For example, day 4.3 would count as day 4.
    Thrombosis or other sequelae

    New thrombosis (confirmed) OR skin necrosis at heparin injection sites OR acute systemic reaction after intravenous heparin bolusProgressive or recurrent thrombosis or nonnecrotizing (erythematous) skin lesions or suspected thrombosis (not provenNone
    Other causes for thrombocytopeniaNone apparentPossibleDefinite

    Scoring 0, 1, or 2 points for each of 4 categories, maximum possible score = 8 Low score (0-3 points), intermediate score (4 or 5 points), high score (6-8 points).

    • Low score 0-3 points
    • Intermediate score 4-5 points
    • High score 6-8 points

    Low 4Ts score may rule out HIT but high 4Ts score may not be sufficient to diagnose HIT.

    >10%

    Autoantibodies to ADAMTS13

    Caused by mutations in genes encoding proteins in the glycoprotein (GP) Ib/IX/V complex.

    Caused by mutation in genes that encode for glycoproteins αIIbβ3 on platelet surface, leading to impaired platelet aggregation. Learn more here.

    Autoantibodies that recognize platelet factor 4 (PF4) bound to heparin; the resulting antibody-antigen complex activates platelets, resulting in mild to moderate thrombocytopenia. Learn more here.

    Congenital or acquired deficiency of the von Willebrand factor (vWF) cleaving protein, ADAMTS13

    Autosomal recessive disorder characterized by variable oculocutaneous albinism, progressive neurologic dysfunction, severe immunodeficiency, recurrent life-threatening infections , and mild bleeding. caused by mutations in the LYST gene encoding a protein involved in granule trafficking and fusion.

    thrombocytopenia, microangiopathic hemolytic anemia (MAHA), neurological changes (often fluctuating), renal impairment and fever – present in only 5% of patients.

    Defined by the Scientific and Standardization Committee (SSC) on DIC of the International Society on Thrombosis and Haemostasis (ISTH) as an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes; can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.

    Platelet count that is < the 2.5th percentile of normal platelet count range, with the traditional cutoff for the lower limit being 150 × 109/L.

    Primary thrombocytosis is caused by a clonal disorder of hematopoietic stem cells or by inherited mutations (familial or congenital thrombocytosis). Secondary or reactive thrombocytosis occurs when signals (often cytokines like IL-11) promote proliferation and differentiation of normal megakaryocytes. Learn more here.

    Mechanisms of thrombocytosis. Primary or clonal thrombocytosis involves autonomous growth of stem cells or megakaryocyte progenitor cells owing to mutations in genes involved in cell growth and differentiation/maturation. In these cases, the megakaryocyte progenitors are impervious to normal inhibitory signals and proliferate uncontrollably. In secondary (reactive) thrombocytosis, the megakaryocytes are perfectly normal. They are simply marching to the tune of the microenvironment, dividing and differentiating in response to extracellular signals such as thrombopoietin and interleukn-6. Finally, the spleen normally pools about one-third of the circulating mass of platelets. When it is removed, or it is hypofunctioning, the sponge effect of the spleen is lost and platelet counts may increase.

    In primary ITP, there is no underlying predisposing condition. By contrast, secondary TTP is associated with another clinical diagnosis or underlying cause. In both cases, ADAMTS13 activity levels are, by definition, <10%.

    • Normal organ function → 2 μg/kg/min 
    • Liver dysfunction (bilirubin >1.5 mg/dL) → 0.5-1.2 μg/kg/min 
    • Heart failure, anasarca, postcardiac surgery → 0.5-1.2 μg/kg/min 

    Learn more here.

    Normal organ function → 0.15 mg/kg/h; renal or liver dysfunction → dose reduction may be appropriate 

    375 mg/m2 IV weekly for 4 weeks

    • HITT: 15 mg twice per day × 3 weeks, then 20 mg once per day 
    • Isolated HIT: 15 mg twice per day until platelet count recovery 

    Learn more here.

    Usually platelets > 30K, though there are exceptions. For example, in patients taking anticoagulants or anti-platelet agents, or in those undergoing a procedure.

    Autosomal recessive disorder characterized by oculocutaneous albinism with nystagmus and visual acuity loss, immunodeficiency, mild bleeding pulmonary fibrosis, granulomatous colitis, and neutropenia, depending on the subtype. Caused by mutations in genes encoding proteins involved in vesicle formation and trafficking.

    ParameterScoreComment
    Fibrinogen (g/L)>1 (0)
    <1 (1)
    Overall sensitivity of low fibrinogen level reported to be about 30%
    Prothrombin time (PT) (seconds)<3 (0)
    3-6 (+1)
    >6 (+2)
    Elevated in 50%-60% of patients with DIC at some point during course of illness
    Platelet count (109/L)>100 (0)
    50-100 (+1)
    <50 (+2)
    Thrombocytopenia reported to occur in up to 98% of DIC cases
    D-dimers or FDPsNo increase (0)
    Moderate increase (+2)
    Severe increase (+3
    )
    Elevated FDPs and D-dimers are sensitive, but not specific for DIC
    Data are presented as values with number of points in parentheses. A total score of ≥5 is compatible with diagnosis of DIC

    See ISTH calculator

    Original publication on the ISTH score can be found here.

    7-10 days

    7-10 days

    IVIG reduces Fc receptor-mediated clearance of platelets by the reticuloendothelial system

    8-10 g/dL

    50-70 x 109/L

    10-30 × 109/L

    von Willebrand disease – prevalence 0.1-1% of general population

    Veins, including lower-limb deep vein thrombosis (DVT) and pulmonary embolism (PE)

    Plasma exchange

    Receptor for murine myeloproliferative leukemia virus, subsequently discovered to be the receptor for thrombopoietin, the primary driver of platelet production. Learn more here.

    Encompasses Sebastian, May-Hegglin, Fechtner, and Epstein syndromes. Autosomal dominant disorder characterized by variable bleeding tendency, and variable association to hearing loss, cataracts, and nephritis. caused by mutation in MYH9 encoding nonmuscle myosin IIA

    Autosomal dominant disorder characterized by mild bleeding tendency, developmental delay, cardiac, skeletal, urogenital, central nervous system, gastrointestinal, and craniofacial abnormalities. Moderate to severe thrombocytopenia with giant alpha-granules in platelets that fail to release their contents upon stimulation with thrombin.

    ADAMTS13 deficiency leads to reduced cleavage of ultra large vWF multimers, which leads to increased platelet aggregation and occlusion of small blood vessels.

    A clinical prediction score that predicts severe ADAMTS13 deficiency in hospitalized patients with suspected thrombotic microangiopathy.

    Plasmic score from MdCal

    About 1 in 5,000 hospitalized patients develop HIT

    About 15%

    Thrombocytopenia reported in 77%-85% of patients with cirrhosis.

    7%-10% of pregnancies are associated with thrombocytopenia. 70-80% of these patients have “gestational” thrombocytopenia.

    About 50%

    15-50%

    IVIG can be administered either high dose (1 g/kg daily for 1–2 days) in emergent settings or lower dose (e.g., 0.4 g/kg daily for up to 5 days). Learn more here.

    UFH is associated with an ∼10-fold greater risk of HIT than LMWH.

     5% to 10% daily risk of thromboembolism, amputation, and death

    Functional assay used to diagnose HIT. It identifies pathogenic IgG antibodies capable of binding and cross-linking platelet Fc gamma RIIA and triggering platelet activation. Test results are expressed as percentage of serotonin release compared to maximum release after detergent-induced platelet lysis (100%). Positive test is > 20% release at therapeutic heparin levels and < 20% release at supratherapeutic heparin levels. Specificity about 95%, but lower sensitivity reported compared with immunoassays.

    Serotonin release assay is a functional assay used to identify pathogenic IgG antibodies capable of binding and cross-linking platelet Fc gamma RIIA and triggering platelet activation. SRA assay is highly specific with positive predictive values of 90-100%. Used to confirm or rule out diagnosis of HIT. Learn more here.

    Eculizumab (plasma exchange within 24-48 hour of onset or admission if eculizumab is not immediately available). Eculizumab is a monoclonal C5 antibody that inhibits terminal complement complex formation.

    40-80 × 109/L, with median of 55 × 109/L

    5-10 days heparin exposure

    HIT is an iatrogenic disorder usually mediated by IgG antibodies that target multimolecular complexes of PF4 and heparin, leading to platelet activation, generation of procoagulant platelet-derived microparticles and activation of white blood cells and endothelial cells. The net result is a profoundly hypercoagulable state.

    Congenital TTP

    X-linked recessive inheritance disorder characterized by eczema, microthrombocytopenia, immune deficiency, likely to develop lymphoma and autoimmunity, and clinically significant bleeding present from infancy

    A group of disorders characterized pathologically by occlusion of small (and occasionally large) blood vessels and clinically by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and end organ dysfunction. Learn more here.

    A clinical syndrome that includes microangiopathic hemolytic anemia, thrombocytopenia, and organ damage caused by endothelial cell injury and thrombotic occlusion of small blood vessels. Learn more here.

    A thrombotic microangiopathy (TMA) caused by deficiency of ADAMTS13, a von Willebrand factor cleaving protease, that leads to platelet-mediated occlusion of microvessels, thrombocytopenia, microangiopathic hemolytic anemia, and widespread multiorgan thrombosis and injury.

    Type 1 vWD is the least severe form of the vWD. It is inherited in an autosomal manner and is associated with mild-to-moderate quantitative vWF deficiency (5-30 units/dL). See more here.

    From Leebeek and Eikenboom

    Type 2 vWD involves a qualitative abnormality of the von Willebrand factor. There are 4 subtypes, each associated with a specific functional defect. See more here.

    From Leebeek and Eikenboom

    Type 3 vWD (autosomal inheritance) is the most severe form of vWD. It is associated with complete deficiency in vWF. Represents only 5% of all vWD. See more here.

    From Leebeek and Eikenboom

    A  multimeric plasma glycoprotein that mediates the adhesion of platelets to the subendothelial surface of blood vessels. Synthesized and released by endothelial cells and platelets, and circulates as large multimers of varying size.

    From Sadler et al

    Vonvendi is a recombinant von Willebrand factor, FDA approved for use in adults with vWD for on-demand treatment and control of bleeding episodes. Contains large and ultra-large vWF multimers but lacks FVIII so that patients may have to be supplemented with FVIII product.

    Wilate is a high-purity factor VIII/vWF concentrate FDA approved for adult and pediatric patients with vWD in whom desmopressin is ineffective or contraindicated for on-demand treatment and control of bleeding and perioperative management of bleeding.

    Humate P, Alphanate, Wilfactin, Vonvendi

    Platelet count < 10-20 × 109

    Prophylaxis for meningococcal infection (Neisseria meningitides) with vaccination, and antibiotics if treatment with eculizumab cannot be delayed until vaccine response.

    80% primary, 20% secondary

    Genetic abnormalities found in about 50%-70% of patients with atypical HUS. Learn more here.

    Fresh froze plasma transfusion, platelet transfusion, and cryoprecipitate

    Stop the coumadin and reverse with vitamin K (while stopping heparin and starting an alternative anticoagulant).

    Stop the vitamin K antagonist, and reverse with vitamin K concomitant with initiation of a non-heparin anticoagulant. Learn more here.

    2018 ASH guideline

    Type 2B, as these patients are at risk for platelet aggregation and thrombocytopenia.

    Cardiac troponin, BUN and creatine, urinalysis, electrocardiogram and CT brain if neurological symptoms

    Mucocutaneous bleeding, including ecchymosis, petechiae, purpura, menorrhagia, and bleeding from lesions in the mouth and GI tract.

    Mucocutaneous bleeding is most common: petechiae, purpura, ecchymoses, oral cavity bleeding, gastrointestinal bleeding, epistaxis, menorrhagia, and hematuria. Intracerebral bleeding is rare. Hemarthrosis or extensive soft tissue hematoma suggest defects in coagulation.

    Gray platelet syndrome, FI1B-RT, MYH9-related disease, and GATA1-related disease

    WAS, XLT and CYCS-related thrombocytopenia

    Secondary (reactive) thrombocytosis accounts for ≥ 85% of cases.

    Endothelial cells and platelets

    Patients undergoing cardiac surgery.

    Robert S. Evans, first author on paper that first described the syndrome in 1951.

    Erik Adolf von Willebrand was a Finnish internist who described the first case of vWD in 1926.

    From Thrombosis Research (2007) 120, S1

    Hemodilution and platelet consumption cause reduction in platelet count in early days post op (typically within within 4 days of surgery), which leads to increased levels of thrombopoietin. The thrombopoietin response to acute thrombocytopenia takes 3 to 4 days to increase platelet production by the bone marrow megakaryocytes, and results in a physiological “overshoot” in the platelet count. Postoperative platelet counts peak at two- to threefold the patient’s preoperative platelet count at approximately POD14, before gradually returning to the patient’s baseline value over the following 14 days. This overshoot occurs because of a delay between an increase in thrombopoietin that stimulates megakaryocytes and the release of new platelets from the bone marrow. Learn more here.

    Coagulation

    Yes. Desmopressin/DDAVP (1-deamino-8-D-arginine vasopressin) synthetic analogue of hormone 8-arginine vasopressin, an antidiuretic hormone.

    Yes, they are 20-25% lower in individuals with type O blood group. 14% of individuals with type O blood have vWF levels ≤ 50 units/dL. Learn more here.

    No

    No, they should be avoided in pregnancy. Vitamin K antagonists are also contraindicated in pregnancy. Pregnant women requiring anticoagulation should receive low molecular weight heparin.

    From 2018 ASH guideline

    Yes, and in fact they are now recommended as an option in the latest ASH guideline, especially for those who are not at high risk of bleeding and who do not have extensive clot burden.

    ASH 2018

    Yes, DVT may rarely occur in arms of the upper extremity, splanchnic veins and cerebral veins.

    No, it is detected by ammonia release or amine incorporation assays.

    There is an increasing trend towards using DOACs in this clinical context based on recent clinical trials. For example, it was shown that edoxaban (a DOAC used in Europe) may be as effective as LMWH in reducing VTE recurrence/bleeding. The latest guidelines from ACCP and NCCN (see below) recommend administering oral factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban) rather than LMWH during initiation and treatment phase of DVT. Because edoxaban and rivaroxaban reported to be associated with higher risk of gastrointestinal major bleeding compared to LMWH in patients with luminal gastrointestinal malignancy, apixaban or LWMH may be preferred in these patients. Learn more here.

    2021 ACCP clinical guideline
    2021 ASH clinical guideline
    Therapeutic anticoagulation for venous thromboembolism in patients with cancer (NCCN Version 2.2021)

    At minimum, all critically ill non-bleeding patients with DIC should receive prophylactic anticoagulation for VTE. According to the 2013 ISTH harmonization of guideline recommendations: “Anticoagulant treatment may be a rational approach based on the notion that DIC is characterized by extensive activation of coagulation. Although experimental studies have shown that heparin can at least partly inhibit the activation of coagulation in DIC [36], there are no RCTs demonstrating that the use of heparin in patients with DIC results in an improvement in clinically relevant outcomes”. They conclude: “Therapeutic doses of heparin should be considered in cases of DIC where thrombosis predominates (low quality evidence). The use of low molecular weight heparin (LMWH) is preferred to the use of unfractionated heparin (UFH) in these cases (low quality evidence)”.

    Yes

    Yes

    Patients with type 2B vWD may have thrombocytopenia. Learn more here.

    No

    In patients with synthetic liver dysfunction, the vitamin K cycle is impaired, so even large doses of vitamin K are not effective. Partial response may be seen in those patients who are vitamin K deficient, for example those receiving broad-spectrum antibiotics. Example of a negative study here. AISF/SIMI recommends against the routine administration of vitamin K to increase the plasma levels of coagulation factors in patients with cirrhosis.

    All are equally efficacious in patients without cancer and with normal renal function.

    No, because neither test accurately reflects the in vivo hemostatic balance. 2016 AASLD practice guideline: “INR is not a reliable indicator of coagulation status in cirrhosis”.

    One daily dose is sufficient. Recommended s.c. adult dosing of enoxaparin (Lovenox): 1 mg/kg twice daily or 1.5 mg/kg/day. Learn more here.

    Generally no, unless the patient has underlying kidney disease or is pregnant

    Because these patients have reduced levels of both procoagulants and anticoagulants, and the INR/PT and aPTT do not detect changes in anticoagulants.

    About 6.5 adverse events per 10,000 units reported in Canada. Such reactions include allergic reactions, TRALI and TACO. Learn more here.

    15%-20% of patients presenting with acute lymphoblastic leukemia, > 90% of patients presenting with acute promyelocytic leukemia

    Distal DVT 20%, proximal DVT 80%

    10-20% of patients

    Comparable protection against VTE recurrence, less overall risk of bleeding (especially intracranial bleeding). Studies have shown that GI bleeding may be increased in patients taking DOAC but these studies involve cohorts with atrial fibrillation, not VTE.

    DDAVP 0.3 mcg/kg IV in 30-50 mL normal saline over 30 minutes. May be repeated 12-24 hours after first dose, depending on how well the patient responds, but no more than 2-3 doses should be given in order to avoid tachyphylaxis.

    Protamine sulfate 1 mg per 100 anti-Xa units if LMWH administered within last 9 hours. If ineffective, may give additional protamine sulfate 0.5 mg per 100 anti-Xa units.

    Protamine sulfate 1 mg per 90-100 units of heparin, if heparin was given in the previous 2-3 hours (maximum dose is 50 mg).

    1 unit vWF:RCo/kg infused will result in recovery of 1.5-2 units vWF:RCo/dL in adults; 50 units vWF:RCo/kg will give a recovery of 75-100 units vWF:RCo/dL.

    DDAVP increases the release of vWF and factor VIII from endothelial cell stores by releasing vWF from cytoplasmic organelles called Weibel-Palade bodies.

    Thrombosis occurs in one-third to one-half of patients with HIT. It may occur in veins, arteries or microvessels.

    About 25% of all VTE events reported to be due to recurrent VTE.

    Blood drawn from a patient in a tube containing anticoagulant (citrate)
    Blood is spun in a centrifuge to separate plasma from red cells and platelets
    Following centrifugation, plasma is on top, red cells on bottom
    Patient’s platelet poor plasma is incubated with a negatively charged substance such as silica, phospholipid (PL) and calcium (Ca2+) at 37 degrees Celsius. The activated partial thromboplastin time (measured in seconds) is the time it takes for clot to form (typically monitored by automated machine). The human eye and the automated machine cannot distinguish between uncrosslinked and crosslinked fibrin. That is why assays such as the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal in FXIII deficiency (FXIII is responsible for crosslinking fibrin).
    Blood drawn from a patient in a tube containing anticoagulant (citrate)
    Blood is spun in a centrifuge to separate plasma from red cells and platelets
    Following centrifugation, plasma is on top, red cells on bottom
    Patient’s platelet poor plasma is incubated with tissue factor (TF), phospholipid (PL) and calcium (Ca2+) at 37 degrees Celsius. The prothrombin time (measured in seconds) is the time it takes for clot to form (typically monitored by automated machine). The human eye and the automated machine cannot distinguish between uncrosslinked and crosslinked fibrin. That is why assays such as the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal in FXIII deficiency (FXIII is responsible for crosslinking fibrin).

    aPTT; adjust to 1.5-3.0 times baseline 

    aPTT; adjust to 1.5-2.5 times baseline 

    A condition in which the blood’s ability to clot is impaired. Learn more here.

    DDAVP may be administered IV, subcutaneously, or by nasal spray.

    No one laboratory test is specific for DIC. Clinical practice guidelines recommend using a clinical scoring system, such as the ISTH scoring system, which includes consideration of the platelet count, D-dimers, fibrinogen and the prothrombin time.

    Subcutaneously, once daily. Learn more here.

    ≥ 35,000 units/day of unfractionated heparin needed to achieve therapeutic aPTT. Learn more here.

    Based on clinical presentation (thrombocytopenia and/or thrombosis in temporal association with heparin therapy without other obvious causes) plus presence of platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies. Clinical prediction scores, especially the 4T score, are helpful in estimating the pretest probability of HIT and determining whether heparin should be discontinued and further testing for antibodies (functional assay) carried out.

    Based on clinical presentation (thrombocytopenia and/or thrombosis in temporal association with heparin therapy without other obvious causes) plus presence of platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies

    If necessary, it can be monitored by anti-Xa level.

    Mild, factor VIII activity > 5%-40%; moderate, factor VIII activity 1%-5%; severe, factor VIII activity < 1%

    Calculated from the PT ratio (patient PT/control PT) adjusted for the international sensitivity index (ISI); ISI derived from a cohort of patients on stable anticoagulation with vitamin K antagonists.

    Two options: 1) weight based – 80 units/kg bolus followed by 18 units/kg/hour infusion, 2) fixed dose – bolus of 5,000 units followed by 1,000 units/hour

    Protamine sulfate

    About 6 days because factor II (prothrombin) has a long half-life.

    About 12 million in the United States!

    About 30% of patients within 10 years

    About 30% of patients

    About 70%

    Three: Type 1, Type 2, and Type 3

    From Sadler et al
    From Leebeek and Eikenboom

    25%-40% of cases

    Start initial treatment with parenteral anticoagulation. Administer VKA early (for example, same day as start of parenteral therapy) and continue parenteral anticoagulation for ≥ 5 days and until INR is ≥ 2 for at least 24 hours. Learn more here.

    Lower rates of pulmonary embolism, DVT recurrence and postthrombotic syndrome

    Vitamin K antagonist is preferred over LMWH (see ACCP guideline) .

    Once the platelet count is over 150 x 109/L. Switch to warfarin (with appropriate overlap) or preferably to a DOAC. In case of HIT without thrombosis, continue for up to 4-6 weeks. In the case of HITT, treat for 3 months.

    2018 ASH guideline

    Even with platelet count recovery, patients remain at risk for thrombosis for 4 to 6 weeks after diagnosis because of circulating anti-PF4/heparin antibodies

    Platelet count recovery occurs within 7 days in 90% of cases. Functional assays become negative at a median of 50 days after heparin is suspended, while Circulating anti-PF4/heparin antibodies are no longer detectable by immunoassay at a median of 85 days.1

    Median 50 days for platelet activation assays and 85 to 90 days by immunoassays

    No. Patients who are reexposed to the drug months to years after antibody disappearance often do not manifest anamnestic responses, and seroconversion risk appears similar to de novo heparin exposure.

    If the clot extends proximally, especially into the proximal veins. The recommendation to anticoagulate if the clot is found to extend within the distal veins is weaker. (October, 2021)

    First heparin exposure

    Highest platelet count that immediately precedes the putative HIT-related fall in platelet count

    • < 72 hours post-surgery
    • Infection (confirmed bacteremia/fungemia)
    • Chemotherapy or radiation < 20 days
    • DIC
    • Posttransfusion purpura
    • Other drugs implicated in drug-induced thrombocytopenia

    No. There are 4 parameters that are used in clinical scoring systems for DIC: fibrinogen, prothrombin time (PT), platelet count and D-dimers/fibrin degradation products. Fibrinogen is the least sensitive of these markers (overall sensitivity of low fibrinogen level reported to be 28%) because it is an acute phase reactant and therefore often elevated in conditions associated with DIC.

    No, unless a decision has been made to stop anticoagulation in such patients

    No, it is a complication of an underlying diseases such as sepsis or cancer.

    Yes

    No

    X-linked

    X-linked

    Yes

    No, all are associated with similar reduction in VTE recurrence.

    The aPTT may be increased in Type 2N vWD (the mutation specifically impairs the ability of vWF to carry FVIII) and Type 3 vWD (since vWF carries and stabilizes FVIII in the circulation, the very low levels of vWF associated with Type 3 vWD result in low FVIII activity).

    No

    Yes, It’s called Vonvendi.

    Tranexamic acid is 6- to 10-fold more potent compared with aminocaproic acid.

    Dabigatran and edoxaban (parenteral anticoagulation administered for 5-10 days before)

    No, but ABO compatibility is preferred.

    Routine use of compression stockings to prevent PTS In patients with acute DVT of the leg is not recommended, though they may be considered in patients with symptomatic swelling.

    Yes, bilateral dopplers of the lower extremities are recommended.1

    2018 ASH guideline

    Only if the patient has an upper-extremity central venous catheter, or with signs or symptoms suggestive of upper extremity DVT. See ASH guideline.

    Not clear whether anticoagulation therapy is beneficial in this low risk case, but clinical practice guidelines recommend treating with anticoagulant if patients are highly symptomatic or if there is a high risk for extension. The alternative is to withhold anticoagulation and carry out serial imaging for 2 weeks to rule out extension.

    Routine administration of vitamin K is not recommended to increase the plasma levels of coagulation factors in patients with cirrhosis. 

    No, it is not routinely recommended.

    Not necessarily. In cases where the risk for clot extension is not high, they may be followed by serial doppler imaging of the legs.

    For example, 2020 ACCP clinical guideline recommendations:

    2021 ACCP clinical guideline

    Patients can be treated at home provided they are feeling well enough to be at home and have the necessary support.

    No, not unless there is another indication for these drugs, for example a coronary stent, and provided the risk: benefits are acceptable. Learn more here.

    2018 ASH guideline

    No, platelet transfusions may exacerbate the thrombotic tendency in HIT. Platelet transfusion should be reserved for patients with active bleeding or at high risk of bleeding. Learn more here.

    2018 ASH guideline

    No. Patients should be encouraged to ambulate early, if possible.

    Patients without cancer should receive a DOAC. DOACs are preferred over vitamin K antagonists such as warfarin/coumadin 1.

    Immunoassays that detect presence of antibodies to platelet factor (anti-PF4/heparin antibodies) and functional assays detect anti-PF4/heparin antibodies capable of activating platelets (e.g., serotonin-release assay [SRA]). Learn more here.

    • Argatroban
    • Bivalirudin
    • Danaparoid
    • Fondaparinux especially in clinically stable patients at average risk of bleeding
    • DOAC
      • especially in clinically stable patients at average risk of bleeding
      • most of the published experience in HIT is with rivaroxaban
    See ASH guideline

    Autoantibodies that deplete or inhibit activity of target coagulation factors (most commonly FVIII) leading to development of bleeding complications. Learn more here.

    • Bradycardia
    • Hypotension
    • Allergic reactions
    • Pulmonary edema

    Learn more here.

    Deficiency or inhibitor of contact pathway factor (especially FXII, but also HMWK and prekallikrein), FXI, FIX, FVII; lupus anticoagulant

    Factor VII deficiency, FVII inhibitor (rare), vitamin K deficiency, vitamin K antagonist, chronic liver disease, DIC

    Inflammation (FVIII is an acute phase reactant), increased levels of vWF (which binds and stabilizes FVIII) and, rarely, reduced clearance.

    Deficiency or inhibitor of common pathway factors (FX, FV and prothrombin) or combined deficiencies of intrinsic and extrinsic pathways (for example chronic liver disease, heparin treatment, DIC)

    Aminocaproic acid and tranexamic acid

    • Degradation product of cross-linked fibrin
    • The smallest circulating fibrin degradation product that is specific for fibrinolysis (as distinct from fibrinogenolysis)
    • Contains two cross-linked D fragments of the fibrin protein, hence its name
    • High in patients with DIC, but high levels can also be found in patients with venous thromboembolism, recent surgery, or inflammatory condition
    Fibrinogen is cleaved by thrombin to generate fibrin. Fibrin is then crosslinked by FXIII, resulting in an insoluble gel. Crosslinked fibrin is degraded by plasmin. This process, termed fibrinolysis yields soluble fibrin degradation products (FDPs). Fibrinogen may also be cleaved by plasmid to generate FDPs (fibrinogenolysis) . Fibrin and fibrinogen-derived FDPs are identical with the exception of D-dimer, which requires the action of plasmin on crosslinked fibrin.
    A more granular look at formation of FDPs and D-dimers from fibrinogen and fibrin. Fibrinogen is a dumbbell shaped molecule with 2 D domains flanking a single E domain. The sequential action of thrombin and FXIII results in the formation of crosslinked fibrin, with the crosslinks occurring between D domains on the longitudinal axis. Plasmin degrades fibrinogen and fibrin into fibrin degradation products (FDPs). Note that the D-dimer is unique to the breakdown of crosslinked fibrin. Other FDPs, namely D and E fragments are generated from plasmin-mediated degradation of both fibrinogen and fibrin. FDP assays pick up all FDP fragments (from fibrinogen and fibrin breakdown), whereas the D-dimer assay measures D-dimer alone (from fibrin breakdown).

    If cirrhosis is decompensated, consider anticoagulation in patients who are candidate for liver transplantation, those with symptoms, and those in whom the thrombus extends into the superior mesenteric vein leading to suspected intestinal ischemia. If cirrhosis is compensated, anticoagulation is recommended (though the decision should be individualized). Anticoagulation is for at least 6 months. Before starting anticoagulation, consider screening for varices. Acute development of portal vein thrombosis favors anticoagulation therapy.

    Conditions associated with fibrinogen consumption and/or loss or fibrinogen dysfunction. Examples include major bleeding, postpartum hemorrhage, disseminated intravascular coagulation, and cardiac surgery.

    von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor (vWF:RCo) activity and FVIII activity. Learn more here.

    Unfractionated heparin > low molecular weight heparin (these differences are especially true at prophylactic doses); IV heparin > SC heparin; therapeutic or prophylactic dose heparin associated with higher risk than heparin flush; bovine>porcine heparin

    Systemic infection, solid and hematological malignancies, obstetric diseases (for example, abruptio placentae or amniotic embolism), trauma, aneurysms, and liver diseases

    From ISTH guideline on DIC

    Headache, facial flushing, tachycardia, and hyponatremia

    Thrombotic type DIC and fibrinolytic type DIC

    Soleal muscle veins connected with posterior tibial or peroneal veins and gastrocnemius muscle veins that drain into the popliteal vein. Thrombosis of these veins is termed isolated calf muscle vein thrombosis [ICMVT], and is treated the same as other forms of distal DVT.

    Thromboelastography (TEG) and rotational thromboelastometry (ROTEM). The following is a helpful description of the similarities and differences between the two. “Whole blood (a minute amount of it, no more than 1 ml) at body temperature (37º) is added to a heated cuvette (a little cup). A pin is suspended into the cup, and then some sort of rotation takes place. In fact  the main difference between TEG and ROTEM is the bit which rotates (TEG rotates the cup, and ROTEM rotates the pin). Irrespective of which bit is rotating, some impediment to the rotation develops as the blood clots. The degree of this impediment is recorded as “amplitude”, and displayed on the time vs. amplitude graph.” An example of the type of graph generated by these instruments is shown here (the details are not important in the context of this short answer).

    Faster reconstitution, ease of use, and not requiring thawing or ABO compatibility

    AT deficiency, increased heparin clearance, increased levels of heparin-binding proteins, high levels of FVIII. Learn more here.

    Unexplained extremity swelling, pain, warmth, or erythema

    Prevent pulmonary embolism, recurrence of DVT and occurrence of post-thrombotic syndrome

    ISTH/SSC Harmonization of the Recommendations: FFP recommended in patients with active bleeding or requiring an invasive procedure and either prolonged PT/aPTT (> 1.5 × normal) or decreased fibrinogen (< 1.5 g/L); cryoprecipitate recommended for patients with active bleeding plus severe hypofibrinogenemia (< 1.5 g/L) that persists despite FFP replacement; platelet transfusion recommended in patients with active bleeding plus platelet count < 50 × 109/L, or high risk of bleeding plus platelets < 20 × 109/L

    UFH, LMWH, fondaparinux, argatroban and bivalirudin

    From Levy and Connors

    Atypical HUS and infection-induced HUS, including shiga toxin-producing Escherichia coli-associated (STEC) HUS and S. pneumoniae-associated HUS

    Peroneal veins (paired), posterior tibial vein and anterior tibial vein. Learn more here.

    3 pillars of treatment are 1) treat underlying disease that triggered DIC, 2) provide replacement therapy where appropriate, 3) inhibit thrombin and fibrin formation where appropriate

    Type 1, 75%; Type 2, 20%; Type 3, 5%

    Tachycardia, tachypnea, pleural rub, loud P2 (pulmonic valve closure sound), neck vein distention. In severe cases, arterial hypotension and shock may be seen.

    Type 2A (decreased secretion or increased cleavage of high-molecular-weight multimers), Type 2B (increased vWF binding to platelet glycoprotein Ib (GPIb) alpha receptor with rapid clearance of platelet-vWF complex), Type 2M (defective binding to platelet GPIb alpha receptor or collagen; M for multimer) and Type 2N (defective vWF binding to factor VIII; N for Normandy, where it was discovered). See more here.

    From Leebeek and Eikenboom

    Initiation phase: administration of anticoagulant after diagnosis of DVT, and consisting of parenteral or full dose oral anticoagulation for 5-12 days, depending on anticoagulant used. Treatment phase: administration of anticoagulation following initiation phase, consisting of anticoagulation administered at standard therapeutic doses and considered complete after 3 months of anticoagulation. Extended phase: administration of anticoagulants without pre-planned stop date, at full or reduced dose, as secondary prevention (to reduce recurrent DVT).

    Initial (at diagnosis), maintenance (3 months), extended (>3 months)

    Vitamin-dependent coagulation factors II, VII, IX, X; and anticoagulants protein C and protein S

    Factors II, VII, IX, X

    A group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and microthrombi leading to ischemic tissue injury. Laboratory tests reveal thrombocytopenia and hemolytic anemia with red blood cell fragmentation on the blood smear.

    Point-of-care assays used to assess all phases of coagulation, providing quantitative graphic measure of platelet function, clotting strength, and fibrinolysis.

    Aging, pregnancy, inflammation (vWF is an acute phase reactant)

    Fibrinogen, von Willebrand factor, factors VIII and XIII

    All except factor VIII, which is synthesized by endothelial cells in the liver and elsewhere in the body.

     Discontinue non-heparin anticoagulant and resume heparin.

    Continue heparin. No need for alternative anticoagulant HIT testing not recommended.

    • Discontinue heparin
    • Initiation a non-heparin anticoagulant at therapeutic intensity
    • Test for HIT antibodies

    Anti-PF4/heparin antibodies of all isotypes (IgG, IgA, IgM, or polyclonal or polyspecific assays) or IgG isotypes

    1-desamino-8-D-arginine vasopressin, also called desmopressin

    Disseminated intravascular coagulation 

    Direct oral anticoagulant

    Normal levels of coagulation factors, antithrombin, and ADAMTS13 

    Heparin-induced thrombocytopenia

    Heparin-induced thrombocytopenia with thrombosis

    International normalized ratio

    Low molecular weight heparin

    Prothrombin complex concentrate

    Integrity of the extrinsic pathway of the clotting cascade.

    Postthrombotic syndrome

     Rotational thromboelastometry. See image of ROTEM device from Werfen.

    Thromboelastography, a type of viscoelastic test of whole blood clotting function. TEG contrasts with ROTEM, another type of viscoelastic test.

    Thrombotic microagniopathy

    Unfractionated heparin

    Vitamin K antagonist

    Venous thromboembolism

    von Willebrand disease

    Von Willebrand Factor

    Refers to DVT isolated to the deep veins below the knee. Compared with proximal DVT, distal DVT is associated lower rates of pulmonary embolism. Distal veins include paired peroneal veins, posterior tibial vein, and anterior tibial vein.

    A DVT caused by a clear trigger, for example, surgery, and bed confinement.