Polycythemia

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

Polycythemia first came into notice by a French physician in the late 1800’s. It was not until 2005 that the main genetic mutation JAK2V617F was implicated in its pathogenesis. William Dameshek was responsible for its inclusion in the group “myeloproliferative disorders”.

• Polycythemia vera was first mentioned in 1892 in the medical literature by a French physician Louis Henri Vaquez.^[1][2][3]

• In 1899 and 1900 two additional cases of polycythemia vera were described by Richard Clark Cabot both with increased erythrocytes and leukocytes and one with marked splenomegaly. ^[4]
• In 1951, William Dameshek grouped together chronic myelogenous leukemia (CML), polycythemia vera, essential thrombocythemia, primary myelofibrosis, and erythroleukemia and coined the term “myeloproliferative disorders”. ^[5]
• In 2005, a gain of function mutation in JAK2 (JAK2V617F) was first implicated in the pathogenesis of BCR–ABL negative myeloproliferative disorders. A liquid culture system was used to culture PV erythroid cells without exogenous cytokines. it was noted that PV erythroid proliferation was inhibited with inhibition of JAK2.

• In 1960, Peter Nowell and David Hungerford published data on an abnormally small chromosome that looked like a Y chromosome, the data came from two male patients with CML. Eventually, seven more cases were discovered, with the presence of a specific chromosomal abnormality.
• Nowell and Hungerford further noticed that these abnormal cells coexisted with normal karyotype, and, thus concluded that the abnormally small chromosome might be a cause of CML rather than coincidental.
• This abnormally small chromosome was named the Philadelphia chromosome, after the city it was discovered in.
• Polycythemia Vera Study Group: Louis Wasserman in 1967 created a group with clinicians from all over the country to study PV in detail. A major significance of this was to study the leukemogenicity of radioactive phosphorus which was one of the major agents used at that time for the treatment of PV.
• Prior to this, the mainstay of treatment was phlebotomy and IV P-32. Other modalities included the following : skeletal radiation therapy, acetyl phenylhydrazine, potassium arsenite, lead acetate, nitrogen mustard, hydroxyurea, melphalan, etc.

The following are a few famous cases of polycythemia vera:

• Phyllis George – A former Miss America and sportscaster, passed away at age 70, due to complications from polycythemia vera on May 14, 2020.

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

Mainly classified into primary and secondary causes based on the presence or absence of genetic mutations and underlying disorders.

Once the diagnosis of absolute erythrocytosis has been established, red cell mass (RCM > 125% of predicted), classification can be done accordingly:^[1][2][3][4]

• Primary erythrocytosis^[5][6]

– Polycythemia vera

• Secondary erythrocytosis^[7]

Congenital:

         - Erythropoietin receptor-mediated
         - High oxygen affinity hemoglobin
         - Bisphosphoglycerate mutase deficiency  
         - VHL (Von Hippel-Lindau) gene mutation (Chuvash erythrocytosis)
         - PHD2 (prolyl hydroxylase domain) mutations
         - HIF-2 alpha mutations

Acquired:

         - Hypoxia driven
             - Central hypoxic process:
                 - Chronic Lung disease
                 - Right-to-left cardiopulmonary vascular shunts
                 - Carbon monoxide poisoning
                 - Smoker's erythrocytosis
                 - Hypoventilation syndromes including sleep apnea (high-altitude habitat)
             - Local renal hypoxia:
                 - Renal Artery Stenosis
                 - End Stage Renal Disease
                 - Hydronephrosis
                 - Renal cysts (polycystic kidney disease)
                 - Postrenal transplant erythrocytosis
             - Pathologic EPO production:
                 - Tumors
                    - Cerebellar hemangioblastoma
                    - Meningioma
                    - Parathyroid carcinoma/adenomas
                    - Hepatocellular carcinoma
                    - Renal cell cancer
                    - Pheochromocytoma
                    - Uterine leiomyomas
              - Exogenous EPO:
                  - Drug associated 
                    - EPO administration
                    - Androgen administration

Idiopathic erythrocytosis ^[8][9][10]

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

• 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.

• 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. ^[1]

• 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. ^[2]

• 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.^[3]
• 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. [4]

• 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. ^[5]

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

• JAK2V617F
• MPL
• CALR
• CSF3R ^[6]

Conditions associated with polycythemia include:

• Hereditary hemochromatosis ^[7]

• 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 ^[8]

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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]

Divided into primary and secondary causes based on underlying genetic mutations and other factors(refer to classification).

Common causes of polycythemia may include:

• Primary erythrocytosis^[1][2]

Polycythemia vera

• Secondary erythrocytosis

Congenital

• Erythropoietin receptor-mediated
• High oxygen affinity hemoglobin^[3]
• Bisphosphoglycerate mutase deficiency^[4]
• VHL(Von Hippel-Lindau) gene mutation (Chuvash erythrocytosis)^[5][6][7]
• PHD2 mutations
• HIF-2 alpha mutations^[8][9]

Acquired

• Hypoxia driven
  • Central hypoxic process:
    • Chronic Lung disease
    • Right-to-left cardiopulmonary vascular shunts
    • Carbon monoxide poisoning
    • Smoker’s erythrocytosis
    • Hypoventilation syndromes including sleep apnea (high-altitude habitat)
• Local renal hypoxia:
  • Renal Artery Stenosis
  • End-Stage Renal Disease
  • Hydronephrosis
  • Renal cysts (polycystic kidney disease)
  • Postrenal transplant erythrocytosis

Pathologic EPO production:^[10]

• Tumors
  • Cerebellar hemangioblastoma
  • Meningioma
  • Parathyroid carcinoma/adenomas
  • Hepatocellular carcinoma
  • Renal cell cancer
  • Pheochromocytoma
  • Uterine leiomyomas

Exogenous EPO:

• Drug associated
  • EPO administration
  • Androgen administration^[11]

Idiopathic erythrocytosis ^{[12][13] [14]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Polycythemia manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary and secondary polycythemia must be differentiated from each other. Primary polycythemia might be seen in patients with various mutations. Iatrogenic causes including medications, athletic drugs, and smoking might cause primary polycythemia. Secondary polycythemia must be differentiated in patients with chronic hypoxemia, erythropoietin producing tumors, or arteriovenous malformations.

Polycythemia must be differentiated from a variety of other conditions.^[1][2][3]

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

• Not usually diagnosed in individuals below 60 years of age. Slightly more prevalent in men than in women according to some studies.

• The incidence of polycythemia vera is approximately 1.9 per 100,000 individuals in the United States.^[1][2][3]
• Taking into account all races and ethnicities, the incidence is approximately 2.8 per 100,000 males and 1.3 per 100,000 in females.

• The prevalence of polycythemia vera in the 7 MM countries was 283,442 in 2017.
• Prevalence of polycythemia vera was the highest in the US in 2017 at 157,290, out of which 62,916 cases were asymptomatic and 94,374 were symptomatic.
• 22 cases per 100,000 people.

• 4-year mortality rate is >10%.
• On average patients lived with the disease for 8.6 years (mean), the cases that were fatal were approximately 77.1 years of age on average.
• Comorbidities such as cardiovascular diseases, other blood, and lymphatic disorders, vascular disorders, mass occupying lesions in the thorax, respiratory system, infections, etc. accounted for more deaths more often.^[4]
• Thrombotic complications were the most common cause of death followed by hematologic malignancy.

• It has been noted that PV is more common in the age group >75.^[5]
• Median age of diagnosis is 60.^[6]

• Jews of Eastern European descent have a higher number of cases as compared to other Europeans or Asians.

• Generally, there is no sex predilection.^[7]
• In the analysis for the 7 MM countries, the percentage of prevalent males was higher than prevalent females.

• Incidence of cases is higher in the United States and Europe than in Japan.^[8][9]

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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]

There are no established risk factors for developing polycythemia vera except for the genetic abnormality JAK2V617F.

• One of the most common and most dangerous complications of polycythemia vera is thrombus formation. The risk factors are as follows:^[1][2][3][4]
• Women- usually younger at the time of diagnosis, have a higher risk of arterio-venous thrombosis.
• Mutation– the higher burden of JAK2V617F allele
• Inflammatory markers- Pentraxins play an important role: increased hs-CRP and a lower PTX3 have a higher risk of thrombosis.
• Presence of microparticles- responsible for decreased thrombin inhibition, increased CD41, and an increased chance of splenomegaly.
• Neutrophil Extracellular Trap formations- NETosis and apoptosis.

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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]

There is insufficient evidence to recommend routine screening for polycythemia vera.

There is insufficient evidence to recommend routine screening for polycythemia.

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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]; Zaida Obeidat, M.D.

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

• The symptoms of (disease name) usually develop in the first/ second/ third decade of life, and start with symptoms such as ___.
• The symptoms of (disease name) typically develop ___ years after exposure to ___.
• If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

• Common complications of polycythemia vera include:^[1]
  • Post-PV myelofibrosis (PPMF) in 10% of PV patients.
  • Leukemic transformation, the most serious complication, can develop in chronic phase, but more frequently during PPMF, spontaneously or associated with chemotherapy or irradiation, particularly in patients age ≥60 years.

• Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [–]%.
• Depending on the extent of the [tumor/disease progression] at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor/good/excellent.
• The presence of [characteristic of disease] is associated with a particularly [good/poor] prognosis among patients with [disease/malignancy].
• [Subtype of disease/malignancy] is associated with the most favorable prognosis.
• The prognosis varies with the [characteristic] of tumor; [subtype of disease/malignancy] have the most favorable prognosis.

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