Considerations Prior to Seeing the Patient

What we know so far:

  1. 68 year-old woman with extreme thrombocytosis (defined below)
  2. Inpatient setting

Definitions:

  1. Thrombocytosis = platelet count > 450 x 109/L
  2. Extreme thrombocytosis = platelet count > 1000 x 109/L

Patients with extreme thrombocytosis are sometimes called “platelet millionaires”. Why? Because the platelet count in extreme thrombocytosis can be written in one of two ways:

  1. > 1000 x 109/L
  2. > 1 x 106/microliter (ul) or > 1 million/ul

What is the most important question to address from an etiologic standpoint?

a
Is this primary or secondary (reactive) thrombocytosis?
Correct. Primary thrombocytosis is associated with an increased risk of thrombosis (and sometimes bleeding) and may require anti-platelet or cytoreductive therapy, whereas reactive thrombocytosis is not.
b
Does the patient have iron deficiency or inflammatory bowel disease?
Both may cause secondary (reactive) thrombocytosis but the question is too granular at this early stage.
c
Is the patient postop?
This is a great question regarding an inpatient with de novo thrombocytosis, but we don’t yet know whether the elevated platelet count is acute or chronic. Moreover, surgery is just one of many causes of secondary (reactive) thrombocytosis.

Without knowing anything else about the patient, what is the most likely diagnosis?

a
Primary thrombocytosis
b
Secondary (reactive) thrombocytosis

Correct. Secondary (reactive) thrombocytosis accounts for 80% of cases of thrombocytosis (including those with platelet counts >1000 x 109/L).

What is the mechanism underlying primary thrombocytosis?

a
Defect in the bone marrow microenvironment
This is a cause of secondary thrombocytosis, not primary thrombocytosis..
b
Excessive platelet growth factors, especially thrombopoietin
This is a cause of secondary thrombocytosis, not primary thrombocytosis.
c
Autonomous growth of platelet precursors in the bone marrow
Correct. Mutations in genes responsible for megakaryocyte growth and differentiation are responsible for primary thrombocytosis. The most well known example is the JAK2 V617F mutation in essential thrombocythemia.
d
Jak2 mutation
Jak2 mutation is causative in some, but not all cases of primary thrombocytosis.

What is the mechanism underlying secondary thrombocytosis?

a
Process extrinsic to the platelet and its precursors
Correct. In secondary thrombocytosis, extrinsic processes, such as elevated levels of growth factors and cytokines, are responsible for increasing the platelet count.
b
Defective intracellular signaling in platelet precursors
c
Jak2 mutation

MECHANISMS OF THROMBOCYTOSIS

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 they 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 growth factors (primarily thrombopoietin) and cytokines (primarily interleukin-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.

What is the main growth factor that controls proliferation of megakaryocytes and the platelet count?

a
Interleukin-6 (IL-6)
IL-6 increases platelet production indirectly through induction of thrombopoietin expression.
b
Thrombopoietin
Yes! Platelet production is directly regulated by thrombopoietin (TPO), a hormone predominantly synthesized in the liver. TPO regulates the proliferation and differentiation of megakaryocytes in the bone marrow by binding to its receptor, c-Mpl (TPO-R), which is expressed on the surface of both megakaryocytes and circulating platelets.
c
Interleukin-11 (IL-11)
IL-11 has a minor effect on megakaryopoiesis and platelet counts.
d
G-CSF

Can stimulate megakaryocyte growth in vitro.

e
Stem cell factor (SCF)
Can stimulate megakaryocyte growth in vitro.in vitro.

True or false: if you were to find that the patient’s thrombocytosis was longstanding (say it was present for months or years before admission to hospital), the diagnosis is, by definition, primary, not secondary thrombocytosis.

a
True
b
False
Secondary (reactive) thrombocytosis, while often acute and transient, can also be chronic in nature, depending on the underlying condition that is driving the high platelet count. Acute insults may cause transient elevation in platelet counts (e.g., trauma or infection) while more chronic conditions may present with sustained thrombocytosis (e.g., iron deficiency anemia, malignancy, or chronic inflammatory conditions).

True or false: secondary thrombocytosis resolves when the underlying causative condition is addressed.

a
True
b
False

As you prepare to see the patient, you are now armed with information that she has extreme thrombocytosis and you have considered the possibility that the elevated platelet count is primary (autonomous, clonal) or secondary (reactive to extracellular signals). Beyond diagnostic considerations, what are your most pressing concerns for the patient?

a
That she may be at high risk for thrombosis
Patients with primary thrombocytosis have an increased risk of thrombosis. Although there are case reports/series of thrombosis events associated with secondary thrombocytosis, there is no evidence that secondary thrombosis is generally associated with a higher thrombotic risk. In this case, you are not sure whether the patient has primary or secondary thrombocytosis, so the concern about thrombotic risk remains relevant. And even if you are convinced the patient has secondary thrombocytosis, you should always remain vigilant about the possibility of clot, especially in those with extreme thrombocytosis.
b
That she may be at high risk for bleeding
Patients with primary thrombocytosis have an increased risk of bleeding. The chief mechanism is excessive binding of platelet GPIb receptors to circulating von Willebrand factor, leading to acquired von Willebrand disease (other causes include quantitative and qualitative platelet defects and endothelial dysfunction). This complication is much less common in secondary thrombocytosis.
c
That she may need psychological counseling

Before taking a history, it helps to consider the questions you will ask the patient. Such questions are guided by the differential diagnosis of thrombocytosis. To that end, which of the following questions are relevant?

a
Does the patient have a history or symptoms of iron deficiency?

Yes, iron deficiency is a common cause of secondary (reactive) thrombocytosis, though typically with platelet counts < 1000 x 109/L.

b
Is the patient postop?
Correct. Surgery may be associated with postoperative thrombocytosis.
c
Does the patient have a history of hypertension?
Hypertension is not normally associated with thrombocytosis (though it may be present in patients with polycythemia vera, who often have high platelet counts).
d
Has the patient lost weight in the past 6 months, or are they complaining of night sweats and fever?
Hypertension is not normally associated with thrombocytosis (though it may be present in patients with polycythemia vera, who often have high platelet counts).
e
Has the patient had a splenectomy?
Correct. Splenectomy is a cause of chronic secondary (reactive) thrombocytosis.

What are some other causes of secondary (reactive) thrombocytosis?

a
Acute bleeding
b
Hemolysis
c
Drugs
d
Infections
e
Inflammatory disorders

Below is a table of representative symptoms associated with different underlying causes of secondary thrombocytosis:

Cause of secondary thrombocytosisSymptoms
BleedingMelena, hematochezia, surgical blood loss, traumatic blood loss, hemoptysis, hematuria, epistaxis, menorrhagia, hematoma.
HemolysisJaundice, history of gall stones, history of extracorpuscular or intracorpuscular causes of hemolysis.
Iron deficiencyHistory of iron deficiency or supplementation, bleeding history, pica, hair loss, brittle nails, restless legs.
AspleniaHistory of splenectomy or sickle cell disease.
InfectionsHistory of chronic infections, especially abscesses, empyema.
Inflammatory disordersHistory or symptoms of inflammatory bowel disease, rheumatological disorders.
SurgeryRecent surgery.
DrugsUse of thrombopoietin receptor agonists, epinephrine, glucocorticoids.
CancerFocal or constitutional symptoms.

Regarding primary thrombocytosis, which of the following questions is/are relevant?

a
Do you have painful and burning sensation in your hands or feet?
These are symptoms of erythromelalgia, a manifestation of vasomotor disturbance associated with primary thrombocytosis.
b
Do you have bruising, hematomas, ecchymoses, epistaxis, or gingival bleeding
Primary thrombocytosis is associated with increased risk of bleeding.
c
Do you have pruritus?
Pruritus is classically found in polycythemia vera, but occurs in up to 50% of patients with primary thrombocytosis.
d
Have you noticed any change in vision?
Vasomotor disturbance associated with primary thrombocytosis.
e
Do suffer from headaches?
Vasomotor disturbance associated with primary thrombocytosis.

Now you are ready to see the patient!