Polycythemia Vera is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets.
Polycythemia vera (PV) is a myeloproliferative neoplastic disorder involving uncontrolled red blood cell production resulting in elevated red blood cell (RBC) mass. There is often concurrent stimulation of myeloid and megakaryocytic lineages leading to increased white blood cell and platelet production, respectively. The current understanding of pathophysiology involves increased sensitivity to growth factors due to an abnormal hematopoietic cell clone. Signs and symptoms, including pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।" data-rx-term="headache" data-rx-definition="Headache means pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।">headache, dizziness, claudication, thrombosis, are a consequence of increased blood viscosity.
Pathophysiology
JAK2 kinase mutation likely leads to the signaling derangements resulting in Polycythemia vera. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors.[rx] This mutation is observed in over 90% of patients with PV, as well as 50% to 60% of primary myelofibrosis and 50% of essential thrombocythemia.[rx][rx] This process leads to increased production of RBCs and platelets with associated complications of thrombosis and bleeding.
Peripheral blood smear findings can be different based on the stage of the disease. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are seen. A hypochromic and microcytic pattern can accompany concomitant iron deficiency. Platelets and white blood cells can also be elevated. Leukocytosis, predominantly with neutrophils, can be seen without blast activity. In the post-polycythemic stage, myelofibrosis develops with teardrop red blood cells, poikilocytosis, and circulating nucleated red cells.
Bone marrow sampling typically shows hypercellularity with panproliferation. Again, histopathology is dependent on the stage of the disease. Erythrocytosis is seen with pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।" data-rx-term="fibrosis" data-rx-definition="Fibrosis means excess scar-like tissue formation after chronic injury or inflammation. সহজ বাংলা: অতিরিক্ত দাগের মতো টিস্যু তৈরি হওয়া।">fibrosis, ineffective production, and extramedullary hematopoiesis.[rx]
Causes of Polycythemia Vera
The etiology of the disease process appears to be neoplastic proliferation. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of PV.[rx]
Symptoms of Polycythemia Vera
People with polycythemia vera can be asymptomatic.[rx] A classic symptom of polycythemia vera is pruritus or itching, particularly after exposure to warm water (such as when taking a bath),[rx] which may be due to abnormal histamine release[rx][rx] or prostaglandin production.[rx] Such itching is present in approximately 40% of patients with polycythemia vera.[rx] Gouty pain, swelling, stiffness, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।" data-rx-term="arthritis" data-rx-definition="Arthritis means joint inflammation causing pain, swelling, stiffness, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।">arthritis may be present in up to 20% of patients.[rx] Peptic ulcer disease is also common in patients with polycythemia vera; most likely due to increased histamine from mast cells, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori.[rx] Another possible mechanism for the development of peptic ulcers is increased histamine release and gastric hyperacidity related with polycythemia vera.
A classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia.[rx] This is a burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin. Erythromelalgia is caused by an increased platelet count or increased platelet “stickiness” (aggregation), resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin.[rx][rx]
Patients with polycythemia vera are prone to the development of blood clots (thrombosis). A major thrombotic complication (e.g. heart attack, stroke, deep venous thrombosis, or Budd-Chiari syndrome) may sometimes be the first symptom or indication that a person has polycythemia vera. Headaches, lack of concentration, and fatigue are common symptoms that occur in patients with polycythemia vera as well.
Diagnosis of Polycythemia Vera
History and Physical
Physical complaints can include fatigue, pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।" data-rx-term="headache" data-rx-definition="Headache means pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।">headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, which occurs during or after a hot shower, is a complaint in 40% of patients.[rx][rx] The mechanism is likely from mast cell and basophil degranulation, causing a histamine surge. In a 2013 study with 1545 patients, pruritis was associated with better survival.[rx] Erythromelalgia is burning pain in the hands and feet with allergy, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।" data-rx-term="erythema" data-rx-definition="Erythema means skin redness, often from irritation, allergy, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।">erythema or pallor. This can be seen in PV or essential thrombocythemia and responds well to low-dose aspirin.[rx] Bleeding and thrombotic complications are each observed in 1% of patients. Bleeding events can include epistaxis, gum bleeding, and gastrointestinal (GI) bleeding. Thrombotic events can include deep venoust thrombosis (DVT), pulmonary ebmolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis.[rx] Early satiety occurs from impaired gastric filling due to splenomegaly. GI discomfort and peptic ulcer disease are common, likely from increased histamine from basophils and increased viscosity in gastrointestinal blood supply.[rx]
On physical exam, patients can display plethora and flushing of the face and palms, conjunctival injection, and skin excoriation from pruritus. Splenomegaly and hepatomegaly are also often observed.[rx]
Evaluation
In the 1970s, the Polycythemia Vera Study Group (PVSG) set the first diagnostic criteria for PV. The diagnosis can be made if all three category A criteria are met, or if A1, A2, and 2 from category B are met.[15]
Category A
- Total red blood cell mass ≥36 mL/kg in males or ≥32 mL/kg in females
- Arterial oxygen saturation ≥92%
- Splenomegaly
Category B
- Platelets >400,000/microliter
- White blood cell count >12,000/microliter
- Leukocyte alkaline phosphatase (ALP) >100 U/L
- Serum vitamin B12 >900 pg/mL or binding capacity >2200 pg/mL
Measuring the red blood cell mass requires labeling with the 51Cr isotope, which is no longer readily available. Therefore, the PVSG guidelines have fallen out of favor, and the World Health Organization (WHO) published revised guidelines for diagnosing PV in 2016. These criteria are composed of three major and one minor criterion. Diagnosis can be made if all 3 major or 2 major and minor criteria are met.[16]
Major
- Hg >16.5 g/dL or Hct >49% in men, Hg >16 g/dL or Hct >48% in women; or red blood cell mass >25% above mean normal predicted
- Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
- JAK2 V617For JAK2 exon 12 mutation
Minor
- Serum erythropoietin level below the reference range for normal
These criteria should only be applied for diagnosis after secondary causes of polycythemia have been ruled out.
A mutation in the JAK2 kinase (V617F) is strongly associated with polycythemia vera.[rx][rx] JAK2 is a member of the Janus kinase family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy.
Following history and examination, the British Committee for Standards in Haematology (BCSH)
Recommend the following tests are performed:
- full blood count/film (raised hematocrit; neutrophils, basophils, platelets raised in half of patients)
- JAK2 mutation
- serum ferritin
- renal and liver function tests
If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests:
- red cell mass
- arterial oxygen saturation
- abdominal ultrasound
- serum erythropoietin level
- bone marrow aspirate and trephine
- cytogenetic analysis
- erythroid burst-forming unit (BFU-E) culture
Other features that may be seen in polycythemia vera include a low ESR and a raised leukocyte alkaline phosphatase.
The diagnostic criteria for polycythemia vera have recently been updated by the BCSH. This replaces the previous Polycythemia Vera Study Group criteria.
JAK2-positive polycythemia vera – diagnosis requires both criteria to be present
| Criteria | Notes |
|---|---|
| A1 | High erythrocyte volume fraction (EVF or hematocrit) (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted) |
| A2 | Mutation in JAK2 |
JAK2-negative polycythemia vera – diagnosis requires A1 + A2 + A3 + either another A or two B criteria:
| Criteria | Notes |
|---|---|
| A1 | Raised red cell mass (>25% above predicted) OR hematocrit>0.60 in men, >0.56 in women |
| A2 | Absence of mutation in JAK2 |
| A3 | No cause of secondary erythrocytosis |
| A4 | Palpable splenomegaly |
| A5 | Presence of an acquired genetic abnormality (excluding BCR-ABL) in the hematopoietic cells |
| B1 | Thrombocytosis (platelet count >450 * 109/l) |
| B2 | Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers) |
| B3 | Radiological evidence of splenomegaly |
| B4 | Endogenous erythroid colonies or low serum erythropoietin |
Treatment of Polycythemia Vera
There is no cure for polycythemia vera; the goals of treatment are aimed at symptom relief and reducing the risk of disease complications, including thrombosis, bleeding, and hematologic transformation. There are currently no means for preventing transformation into myelofibrosis or acute leukemia/myelodysplastic syndrome, but there are known agents to avoid that can increase this risk.[rx]
Patients under the age of 60 without a history of thrombotic events are considered low risk and treatment recommendations include:
- Phlebotomy, target hematocrit to less than 45%
- Daily low-dose aspirin, if no contraindications
- Treat aspirin refractory symptoms
- Optimizing cardiovascular (CV) health such as weight loss, exercise, tobacco cessation, blood pressure control.
As the condition cannot be cured, treatment focuses on treating symptoms and reducing thrombotic complications by reducing the erythrocyte levels.
- Phlebotomy – is one form of treatment, which often may be combined with other therapies. The removal of blood from the body induces iron deficiency, thereby decreasing the hemoglobin/hematocrit level, and reducing the risk of blood clots. Phlebotomy is typically performed to bring their hematocrit (red blood cell percentage) down below 45 for men or 42 for women.[rx] It has been observed that phlebotomy also improves cognitive impairment.[rx]
- Low dose aspirin (75–81 mg daily) – is often prescribed. Research has shown that aspirin reduces the risk for various thrombotic complications.
- Chemotherapy for polycythemia – may be used, either for maintenance, or when the rate of bloodlettings required to maintain normal hematocrit is not acceptable, or when there is significant thrombocytosis or intractable pruritus. This is usually with a “cytoreductive agent” (hydroxyurea, also known as hydroxycarbamide). The tendency of some practitioners to avoid chemotherapy if possible, especially in young patients, is a result of research indicating a possible increased risk of transformation to acute myelogenous leukemia (AML). While hydroxyurea is considered safer in this aspect, there is still some debate about its long-term safety.[rx]
- Injection of radioactive isotopes (principally phosphorus-32) – was used as another means to suppress the bone marrow. Such treatment is now avoided due to a high rate of AML transformation.
- Other therapies include interferon injections – and in cases where secondary thrombocytosis (high platelet count) is present, anagrelide may be prescribed.
- Bone marrow transplants – are rarely undertaken in people with polycythemia; since this condition is non-fatal if treated and monitored, the benefits rarely outweigh the risks involved in such a procedure. There are indications that with certain genetic markers, erlotinib may be an additional treatment option for this condition.[rx] The JAK2 inhibitor, ruxolitinib, is also used to treat polycythemia.[rx]
Patients 60 years of age or older and/or who have a history of thrombosis are considered high risk, and recommendations are the same as for low-risk patients with the addition of cytoreductive therapy (hydroxyurea, interferon, busulfan) and treating disease-specific complications.[rx][rx]
References
- https://www.ncbi.nlm.nih.gov/books/NBK526081/
- https://www.ncbi.nlm.nih.gov/books/NBK557660/
- https://www.ncbi.nlm.nih.gov/books/NBK12495/
- https://www.ncbi.nlm.nih.gov/books/NBK395975/
- https://www.ncbi.nlm.nih.gov/books/NBK531464/
- https://www.ncbi.nlm.nih.gov/books/NBK65852/
- https://www.ncbi.nlm.nih.gov/books/NBK557660/
- https://en.wikipedia.org/wiki/Polycythemia
- https://medlineplus.gov/genetics/condition/polycythemia-vera/
- https://www.nhlbi.nih.gov/health-topics/polycythemia-vera
- https://www.cancer.gov/about-cancer/treatment/clinical-trials/
