Case of polycythemia • The Blood Project

Describe the complete blood count (CBC)

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Leukocytosis, polycythemia, microcytosis, anisocytosis and thrombocytosis

Describe the white blood cell differential

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Neutrophilia, monocytosis, basophilia

How do we know what qualifies for lower- or higher-than-normal white cell counts? Consult a cheat sheet like this one!

What does the presence of basophilia suggest?

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Myeloproliferative neoplasm, such as polycythemia vera

Before we get to the Twitter questions, let’s consider the definition and classification/differential diagnosis of polycythemia:

Definitions

Classification

At this point, what is the likeliest diagnosis?

a

Congenital heart disease

b

HIgh-altitude dwelling

c

Polycythemia vera

Correct, given the degree of Hct elevation, elevated white cell count, basophilia and thrombocytosis (“pan-myelosis”).

d

Hepatoma

e

Testosterone supplements

What is the most likely explanation for the low MCV?

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Iron deficiency. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease.

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

What skin symptom might the patient complain of?

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Aquagenic pruritis

Aquagenic pruritus (AP):

Debilitating dermal condition characterized by the development of intense itching, stinging, tingling or burning sensations, without observable skin lesions, precipitated by contact with water at any temperature.
Typically occurs after a shower with warm water.
One of the common symptoms in polycythemia vera (PV).
In cohort of 1,545 of patients diagnosed with PV according to WHO definition, pruritus in 36% at diagnosis and during median 6.9 years of follow-up.
Pathogenesis likely involves role of mast cells and basophils.
Can precede, be concomitant with, or follow diagnosis of PV.
Has significant influence on patients’ quality of life and personal hygiene.

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

Why does the patient have a ruddy complexion?

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Elevated Hb/Hct/red blood cell count
Vasodilation of dermal microvessels

The color of the skin in cases of polycythemia vera is due largely to:

The large increase in the circulating red blood cells and hemoglobin.
The number of capillaries for each unit area of skin.
The degree of vasodilation of skin microvessels.

The authors wrote: “The color of the skin in cases of polycythemia vera is predominately red but subject to marked variations. The redness affects largely the facial and acral regions; the hands to the glove line, and the face and neck to the decollete margin. The feet are usually less red than the hands. The mucous membranes appear cyanotic when the skin is definitely red. Clinical descriptions of the color of the skin in our cases by various co-workers were “markedly red,” “brick red,” “reddish cyanosis,” and “markedly cyanotic.” Observation of the color by different or by the same observers have shown variations during the same, and on different, days. Redness is common during the warmer months, and cyanosis during the colder months.” Source.

When the morphological structures of capillaries were examined, no giant capillary was observed in the control group, whereas it was identified in the PV group with a rate of 66.7% (p<0.001). There was no significant difference between the two groups in terms of other morphological parameters. In the PV group, the arterial, venous, and apical diameters of the capillaries were significantly higher than the control group. *Arch Rheumatol* 2022;37(3):404-410.

What is the hemodynamic advantage of vasodilation in a patient with polycythemia vera?

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Offsets the effect of increased viscosity on total peripheral resistance, hence cardiac output (see next slide)

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

Is this patient or one with anemia more likely to develop cyanosis at a given SaO2?

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This patient is more likely to develop cyanosis because > 3-5 g/dL desaturated Hb is needed to detect cyanosis; at an SaO2 of 75%, a patient with Hb 20 would have 5 g/dL deoxyHb, while a patient with Hb of 10 would have only 2.5 g/dL.

Cyanosis:

Clinical manifestation of bluish discoloration of skin or mucosa resulting from the presence of deoxygenated hemoglobin within the superficial dermal capillaries, subpapillary venous plexus and mucous membranes (not the deeper arteries and veins).
Sometimes difficult to detect clinically due to factors such as skin color, dermal thickness, exposure to light, presence of jaundice and state of the cutaneous capillaries.
Best appreciated in areas of the body where the overlying epidermis is thin and the blood vessel supply abundant, including the lips, cheeks, nose, ears, mucous membranes, and nailbeds.
Classified as:
- Central cyanosis:
  - Apparent at the:
    - Lips
    - Tongue
    - Sublingual tissues.
  - Results from:
    - Reduced arterial oxygen saturation (PaO2)
    - Abnormal hemoglobin derivatives (methemoglobin or sulfhemoglobin)
  - Causes include:
    - Decreased arterial oxygen saturation
      - Decreased atmospheric pressure (altitude)
      - Impaired pulmonary function
        
        Pneumonia
        
        Pulmonary embolism
        
        Obstructive lung disease
        
        Pulmonary edema
        
        Alveolar hypoventilation
      - Anatomic shunts
    - Hemoglobin abnormalities
      - Hemoglobin with low oxygen affinity
      - Methemoglobinemia (hereditary or acquired)
      - Sulfhemoglobinemia (acquired)
- Peripheral cyanosis:
  - Apparent on the hands and feet but not oral mucosa.
  - Results from vasoconstriction and diminished peripheral blood flow, as seen in:
    - Reduced cardiac output
    - Cold exposure
    - Redistribution of blood flow from extremities
    - Arterial or venous obstruction
Pathophysiology:
- Cyanosis is discernible to the human eye when the deoxygenated hemoglobin (Hb) in the blood > 3-5 g/dL.
- The increased amount of deoxygenated hemoglobin is due to either:
  - Increased amount of venous admixture (due to vasodilatory effects on the venous plexi).
  - Reduced arterial oxygen tension in the capillaries.
- Note that it is the absolute, not relative, quantity of deoxygenated hemoglobin that determines whether cyanosis is observed. Thus, the level of SaO2 at which cyanosis becomes apparent depends on their total hemoglobin concentration.
  - Severely anemic patients with marked arterial desaturation may not have cyanosis.
  - Patients with polycythemia develop obvious cyanosis at much higher SaO2.
For a nice review on cyanosis, click here.

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

What is the PT and aPTT likely to be?

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Elevated

The patient’s initial coagulation screen showed the following:

What is the likeliest explanation for the elevated PT and aPTT?

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Artifact from the low fractional plasma volume (see next slide for explanation)

**Elevated PT and aPTT in polycythemia.** The PT and aPTT are run on blood samples collected in sodium-citrate-containing blue top tubes. The sodium citrate is not a powder, but rather is in solution (there is a little “puddle” at the bottom of the tube). Sodium citrate serves as an anticoagulant by chelating calcium in blood. When the PT and aPTT assays are performed, a specified amount of calcium is added to the mixture to neutralize the effect of citrate and promote clotting. ***In patients with polycythemia, there is disproportionately less plasma in the blue top tube relative to the volume of citrate.*** As a result, the chelation effect is stronger, and the addition of calcium per the usual PT and aPTT protocol is not sufficient to completely inactivate it. This leads to an artifactually prolonged PT and aPTT. The artifact is corrected by reducing the amount of citrate in the collection tube.

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

Why is the LDH elevated?

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LDH may be elevated in polycythemia vera (see next slide)

Serum lactate dehydrogenase (LDH) is a surrogate quantitative measure of cell turnover and tumor burden. The following is an abstract that reported the LDH level in 216 patients with polycythemia vera:

***Increased serum LDH was recorded in 110 (51%) patients*** that included 26 (12%) patients with LDH ≥1.5 x UNL. A significant correlation was demonstrated between increased serum LDH and older age (p=0.007), female sex (p=0.04), leukocytosis (p=0.01), venous thrombosis history (p=0.005) and, interestingly, absence of active tobacco use (p=0.003).

Twitter questions:

What skin symptom might the patient complain of?
Why does the patient have a ruddy complexion?
Is this patient or one with anemia more likely to develop cyanosis at a given SaO₂?
What is the PT and aPTT likely to be?
Why is the LDH elevated?
What is the one highest-yield test to order?

What single lab test would you like to order to definitively rule in/out polycythemia vera?

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Jak2 V617F mutation

Here are the results of the Jak2 mutations status:

Does the patient meet criteria for diagnosis of polycythemia vera?

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Not quite (see next slide)

² Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute erythrocytosis; hemoglobin levels >18.5 g/dL in men (hematocrit, 55.5%) or 16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present. However, initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a BM biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV MF). ³ More than 25% above mean normal predicted value. From NCCN, based on 2017 WHO diagnostic criteria.

Our patient has 2 major criteria (Hb > 16.5) and presence of Jak2 V617F. For formal diagnosis, he would require a bone marrow biopsy. However, the pretest probability for polycythemia vera is virtually 100% and the patient should be treated accordingly.