Polycythemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Debduti Mukhopadhyay, M.B.B.S[2]

Overview

• The main mechanism is a valine to phenylalanine substitution, particularly the JAK2V617F mutation which leads to increased red blood cells. Other mechanisms include platelets, endothelial compartment, leukocytes, and plasma factors.

Pathophysiology

Physiology

• Polycythemia is considered a diagnosis when hematocrit is >48% in women and >52% in men, and when hemoglobin is >16.5g/dL in women and >18.5g/dL in men.

• It is important that we know the similarities and differences between polycythemia and erythrocytosis.
• Similarities :

Both are characterized by an increase in red blood cells in the blood. Genetics may play a role in both disorders.

• Differences :

Polycythemia is the increase in red blood cells and hemoglobin above normal. Erythrocytosis is the increase in the mass of red blood cells. Polycythemia may show an increase in white blood cells and platelets as well. Increase in mass is limited to red blood cells only.

Pathogenesis

• The main mechanism by which polycythemia vera develops is a valine to phenylalanine substitution, precisely the JAK2V617F leading to constitutive activation of cytokine receptors. This mutation is present in over 90% of patients with PV, 50% to 60% in patients with primary myelofibrosis, and 50% with patients with essential thrombocythemia.
• Other factors contributing to the pathophysiology of polycythemia (amongst other myeloproliferative neoplasms) are blood cells, plasma factors, and the endothelial compartment.
• The role of platelets:

 - Several studies in people and in mouse models have shown the increase in platelet activation and coagulation by factors such as cell surface proteins namely; P-selectin (CD62P), or tissue factor(CD142), and circulating leuco-platelets aggregates.

An increase in CD40 ligand, beta-thromboglobulin, platelet factor 4, thromboxane A2, and an increased expression of surface phosphatidylserine has been noted.

• The role of leukocytes:

 - An increased expression of CD11, CD14, and leukocyte alkaline phosphatase, which is further amplified in the event of a JAK2V617F mutation. The mutated macrophages also produce pro-inflammatory cytokines leading to a further exaggeration of atherosclerosis which is responsible for myocardial infarction, cerebrovascular accidents, etc in these patients. The increase in adhesion of granulocytes in patients with the JAK2V617F mutation on integrin @4B1, the ligand of VLA4 (either attached to a support or in a soluble form) has been shown in recent studies. In the mononuclear mutated cells, inhibition of activated Ras-proximate-1(small G- protein Rap 1) showed a reduction in cell adhesion, thereby proving that the JAK2V167F mutation is the cause of increased integrin expression (@4B1).
 - NETs(Neutrophil Extracellular Traps): Decondensed DNA along with histones are responsible for activation of platelets, inhibition of anticoagulation molecules, and activation of the intrinsic coagulation pathway by factor XII activation. 

• The role of red blood cells:

 - The Cytoreductive therapy in PV (CYTO-PV) clinical trial showed there is an increase in the risk of cardiovascular events in patients with >45% hematocrit; consequences depend on arterial or venous territory involvement. An amplified interaction between Lu/BCAM (erythroid Lutheran/ Basal cell adhesion molecule) and laminin accounts for qualitative abnormalities in red blood cells.

• The role of endothelial cells:

 - Activation of endothelial cells leading to increased levels of thrombomodulin, von Willebrand factor, both E and P selectins, and circulating endothelial cells. Some studies have shown that the enzyme heparanase leads to tissue factor inhibitor dissociation leading to pro coagulation. Both heparanase and tissue factor inhibitor have been found in increasing quantities in bone marrow samples of patients suffering from PV.

• The role of plasma:

 - D-dimers, thrombin-anti-thrombin complexes, F1 and F2 fibrinogen fragments are found to be in increased quantities. A reduction in serum protein C and S along with increased resistance to activated protein C is also noted. Extracellular vesicles of cytoplasmic membrane remnants called microparticles isolated from patients with JAK2617F mutation have shown to increase thrombin production. 

Genetics

• Majority of cases of polycythemia are inherited through somatic gene mutations. Rarely, it can occur in germ cells, in which case the inheritance is autosomal dominant. It must be noted that the most common mutations such as JAK2 or TET2 merely increase the risk of one developing the disease, not every person that has or inherits the mutation will develop it.

The development of polycythemia is the result of multiple genetic mutations such as:

• JAK2V617F
• MPL
• CALR
• CSF3R

Associated Conditions

Conditions associated with polycythemia include:

• Hereditary hemochromatosis

Microscopic Pathology

• Peripheral blood smear findings are divided according to stages in the disease:

Pre and overt polycythemia- normochromic and normocytic red blood cells, hypochromic microcytic pattern if coexisting iron deficiency anemia. Elevation of platelets and leukocytes especially neutrophils. Post polycythemia- teardrop red blood cells, poikilocytosis, nucleated red blood cells.

• Bone marrow- increased cellularity with panproliferation.

Prepolycythemia- erythrocytosis Overt polycythemia- increased RBC mass Post polycythemia with fibrosis- increased reticulin deposition

Bone marrow histomorphology of essential thrombocythemia (ET) and masked polycythemia vera (PV). (A) Bone marrow morphology of ET shows normocellular marrow with an increased number of large and mature megakaryocytes. Note the hyperlobulated megakaryocytes without significant pleomorphism (bone marrow biopsy, hematoxylin, and eosin [H&E] stain, ×200). (B) Bone marrow morphology of masked PV (patient 1) shows a trilineage proliferation. Note the higher cellularity compared with that in (A) and an increased number of megakaryocytes displaying cytologic pleomorphism with mild atypia (bone marrow biopsy, H&E stain, ×200). Case courtesy by Daehyun Chu.