POLISITEMIA VERA

POLISITEMIA VERA

AKIMA R. TAHIR, DASRIL DAUD, NADIRAH RASYID RIDHA

DEPARTEMEN ILMU KESEHATAN ANAK FK-UNHAS / RSWS  MAKASSAR

PRELIMINARY
Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by increased Red Blood Cell (RCM) mass, or erythrocytosis, leading to hyperviscosity and an increased risk of thrombosis. Erythrocytosis (similar to polycythemia or polyglobulia) is a very rare group of diseases in pediatric and adolescent patients. 1
Polycythemia vera or true polycythemia is distinguished from polycythemia spuria or relative polycythemia or pseudoerythrocytosis which is an increase in erythrocytes in the blood, but the underlying cause is a decrease in plasma in the blood (burns, stress, allergic reactions and dehydration) which causes hemoconcentration.
The clinical picture of PV is due to a marked increase in the mass of RBC causing an increase in blood plasma due to hyperviscosity and increased metabolism. Polycythemia vera is classified as primary, secondary and a combination of the two. Primary (due to somatic/congenital mutations, primary familial (germline mutation) and very sensitive to EPO). Secondary (physiological: fetal period, exposure to altitude, pathological: due to ventilation disorders such as: cyanotic heart disease, lung disease and obesity), a combination of primary and secondary (such as Chuvash polycythemia, mutations in the HIF 2a gene and PHO2 gene). ,10
Common complaints include pruritus after bathing, burning pain in the distal extremities (erythromyalgia), gastrointestinal disturbances, or nonspecific complaints such as weakness, headache, or dizziness. Another patient was diagnosed after incidental findings of elevated hemoglobin and/or hematocrit levels on a complete blood count. PV is characterized by erythrocytosis and, in about 40% of patients, leukocytosis and thrombocytosis occur. Splenomegaly occurs in 30% of cases and is rarely very large. 2.9
However, after 10 decades of rigorous clinical and laboratory investigations, the cause of PV is still unknown and there is no consensus as to the optimal therapy for the myeloproliferative disorder.

Epidemiology
Based on recent studies in Europe, the incidence of PV is 0.4-2.8/100,000 population per year. Meanwhile, in previous studies, it was 0.68-2.6/100,000 population per year. Meanwhile, the prevalence according to WHO is around 0.7-2.6/100,000 PV population. PV disease mostly attacks the age of 50-70 although it can occur at all ages including young adults, children and adolescents. PV can occur in all ethnicities. The incidence of PV is approximately 10-20/1,000,000, with a median age at presentation of 60 years. Only 1% of patients present before the age of 25 years, and only 0.1% are younger than 20 years.3

Pathophysiology
Most investigations into the pathogenesis of PV have focused on erythropoiesis. The lifespan of red blood cells is not prolonged in the PV and the erythroid progenitor cell pool is increased by suppressing the myeloid progenitor cell pool. This paradoxical result is due to the ability of erythroid progenitor cells to proliferate in vitro in the absence of erythropoietin.1
JAK is a cytoplasmic enzyme of the tyrosine kinase group of enzymes. The Janus Kinase 2 (JAK2)/Signal Transducers and Activators of Transcription (STAT) pathway affects cell proliferation, activation, migration and apoptosis. Jak2 is a group / member of the Janus Tyrosine Kinase family that plays a role in signal transduction through the process of erythropoietin, thrombopoietin, stimulating factor for macrophage formation, and stimulating factor for granulocyte formation in hematopoietic cells, as well as signal transduction by various cytokine receptors, such as interleukin (IL). -3, IL-5, and IL-6).56 Janus Kinase (Jaks) occupies 4 functional domains: the FERM domain, the SH2 domain, the pseudotyrosine kinase domain, and the catalyzed active tyrosine kinase. myeloproliferative.4

Gambar 1. JH2 sebagai domain terjadinya mutasi Jak2V617F

Gambar 1. JH2 sebagai domain terjadinya mutasi Jak2V617F

Normally, Jak2 will be activated if the receptor is bound to the same ligand but in this mutation, there is a change in the substitution of valine and phenylalanine at codon 617 (Jak2V617F). The V617F mutation occurs in a multipotent hematopoietic progenitor cell resulting in an increase in erythroid and myeloid levels that regulate the defense function of non-mutated cells. 4
The presence of excessive reactivity to the Janus Kinase signal, namely tyrosine kinase which plays a role in the hematopoietic process causes excessive proliferation of hematopoietic cells and also stimulates the inflammatory process of blood vessels. Approximately 96% of patients with PV have a mutation in the Janus kinase 2 (JAK2) gene. JAK2 is directly involved in intracellular signaling in PV progenitor cells, a process that occurs after exposure to cytokines to which these cells are hypersensitive. 4
The JAK2 gene is located on the short arm of chromosome 9, and loss of heterozygosity on chromosome 9p to uniparental disomy is the most common cytogenic disorder in PV.
The JAK-STAT pathway, with appropriate levels of the JAK protein, is essential for normal hematopoiesis and immune function. Janus kinases, which include JAK1, JAK2, JAK3, and TYK2. The JAK protein encoded by the JAK gene interacts with various STAT molecules, which are signal transducers and transcriptional activators, to induce cellular responses. 4.5
Excessive proliferation of hematopoietic cells will cause abnormalities in the clinical assessment of patients such as abnormalities in complete blood count and inflammation will trigger clinical symptoms in patients. 4

Gambar 2. Mutasi JAK 2

Gambar 2. Mutasi JAK 2

When the ligand binds to the cytokine receptor, it triggers dimerization. Jaks, which binds to its receptor via the SH2 domain, is transphosphorylated and subsequently phosphorylated STAT. Activated STAT will dimerize and translocate to the nucleus, by activating the gene promoter. STAT can also be activated directly by Src kinase. In the image below, Jaks phosphorylates the receptor and creates a binding site for STAT. At the same time, cytokine receptors also activate additional signaling pathways involving proteins such as Akt and ERK that ultimately lead to cell proliferation.6

Gambar 3. Sinyal yang diperantarai oleh Jaks.

Gambar 3. Sinyal yang diperantarai oleh Jaks.

 

Clinical Manifestations
Symptoms of PV include plethora, gastroenteritis, Budd-Chiari Syndrome, headache, pruritus, tinnitus, dizziness, migraine, syncope, abdominal pain, weight loss, lethargy and fainting. Other symptoms such as impaired activity, impaired concentration, itching in addition to pruritus, bone pain, fever, and midnight sweats. Fatigue is the most common physical complaint in patients, while fever is a rare symptom.

TABEL 1SIGN AND SYMPTOMS POLYCYTHEMIA VERA

SIGN AND SYMPTOMS POLYCYTHEMIA VERA

Diagnosis
According to WHO in 2008, the criteria for polycythemia vera are as follows:
Major symptoms:
– Hb >18.5 in men, 16.5 g/dL in women
– Found Jak2V617F mutation or other mutations that are functionally similar.
– Hypercellularity of bone marrow, erythroid, granulocytes and megakaryocytes
– Serum EPO (Erythropoietin) below normal value
– Formation of endogenous erythroid colonies

Kriteria diagnostik PV menurut WHO.

Kriteria diagnostik PV menurut WHO.

PV can also be suspected if the Ht/Hb is below the diagnostic value, if there are symptoms of PV such as arterial/venous thrombosis especially in young patients or atypical PV (splanchnic vein thrombosis, Budd-Chiari syndrome, pruritus,
erythromelalgia) or symptoms of acral ischemia (splenomegaly, leukocytosis, thrombosis, microcytosis). Patients with typical PV have subnormal or below normal S-erythropoietin (S-EPO). 7
Laboratory examination of Jak2V617F is very sensitive (95%) and 100% specific for differentiating PV from other diseases with elevated hematocrit. Subnormal serum EPO values ​​and no Jak2V617F mutation were found, there is a 3% possibility of Jak2 mutation in exon 12, therefore further mutation analysis is needed in Jak2 exon 12 if Jak2V617F negative results are found in PV patients. Bone marrow examination is not essential for the diagnosis of PV. 38 In PV there will be a decrease in iron caused by the use of Fe by an increase in erythrocyte mass. 6

Algoritma diagnosis PV dari PVSG.

Algoritma diagnosis PV dari PVSG.

 

Electrocardiographic Features of Polycythemia Vera:
PV is usually characterized by hyperviscosity in which there is an increase in plasma volume and a decrease in oxygen saturation in erythrocytes. Hyperviscosity will increase myocardial workload and tissue ischemia. This will cause a prolonged repolarization, characterized by a significant lengthening of the repolarization parameters (QT-QTc, Tp-Te, Tp-Te/QT) and a prolonged Pwave is also obtained.

Gambar 4. Gambaran Elektrokardiografi pada Polisitemia Vera

Gambar 4. Gambaran Elektrokardiografi pada Polisitemia Vera

Complications and Risk Factors
Complications that are often caused by PV disease include:
1) Thrombosis
2) Bleeding
3) Transformation into leukemia
Thrombosis was the most frequent complication (34-39%). In thrombosis, Jak2 mutations cause activation and interaction of leukocytes and platelets that cause inflammation, causing vascular endothelial dysfunction. While Erythrocytosis causes blood hyperviscosity that triggers thrombosis.
Differential diagnosis
Jak2 mutations do not only occur in polycythemia vera, but also in other myeloproliferative malignancies such as Essential Thrombocythemia (ET)6 and myelofibrosis (MF). So that these three diseases have a unique relationship. 44 Jak2 mutation is positive in patients with polycythemia vera around 95%-100% while in other malignancies ET and MF ± 50-60%. Although erythrocytosis can differentiate PV from ET and MF, not all patients with symptomatic erythrocytosis with a Jak2 mutation will develop PV.
To distinguish PV and other myeloproliferative diseases, it can be assessed from the proportion of clinical manifestations and complications, as shown in the following figure.

Proporsi manifestasi klinis dan komplikasi pada keganasan mieloproliferatif positif Jak2

Proporsi manifestasi klinis dan komplikasi pada keganasan
mieloproliferatif positif Jak2

Complications and Risk Factors
Complications that are often caused by PV disease include:
1) Thrombosis
2) Bleeding
3) Transformation into leukemia
Thrombosis was the most frequent complication (34-39%). In thrombosis, Jak2 mutations cause activation and interaction of leukocytes and platelets that cause inflammation, causing vascular endothelial dysfunction. While Erythrocytosis causes blood hyperviscosity that triggers thrombosis.
Differential diagnosis
Jak2 mutations do not only occur in polycythemia vera, but also in other myeloproliferative malignancies such as Essential Thrombocythemia (ET)6 and myelofibrosis (MF). So that these three diseases have a unique relationship. 44 Jak2 mutation is positive in patients with polycythemia vera around 95%-100% while in other malignancies ET and MF ± 50-60%. Although eryrocytosis can differentiate PV from ET, the prognosis
PV disease has a good prognosis and if PV is detected early and treated, life expectancy can be >10 years longer in 80% of PV patients. The development of this disease will lead to diseases such as splenomegaly, anemia, myelodysplasia and/or acute myeloid leukemia (AML). Men have a better life expectancy than women. When compared with white people, black patients have a slightly lower life expectancy. Research shows that the higher the age, the lower the life expectancy, and vice versa.7
Governance
The main goal of therapy in patients with PV is to reduce the risk of thrombosis and bleeding, minimize the risk of developing PV towards acute leukemia and myelofibrosis. Therapies for PV include aspirin, phlebotomy, cytoreductive and JAK inhibitors. Aspirin plays a role in controlling bleeding. Phlebotomy works by controlling hematocrit levels to normal levels (<45). The first-line cytoreductive therapy is Hydroxyurea, which has been shown to reduce thrombotic complications by inhibiting the ribonucleotide diphosphate enzyme that plays a role in DNA synthesis, but it has not been proven whether this drug is potentially leukemia or not. Interferon alpha acts as anti-proliferative and cell differentiation. Further clinical and molecular research is needed to determine the sensitivity and resistance of IFN in PV patients
Examples of Jak inhibitors include erlotinib and ruxolitinib. Erlotinib is effective in inhibiting the growth of hematopoietic progenitor cells. The data showed that the hamatopoetic progenitor cells of Jak2V617F were sensitive to Erlotinib. However, a subsequent study stated that erlotinib was not effective as a PV therapy because of its high toxicity and low efficacy. Diarrhea is one of the most common side effects experienced by PV patients on erlotinib therapy. Meanwhile, recently, Ruxolitinib, one type of Jak inhibitor, is a very potent preparation in the process of inhibiting the proliferation of Jak2V6117F by reducing cellular proliferation and inducing apoptosis. Ruxolitinib potentially inhibited the ex vivo proliferation of erythroid progenitors in PV-positive Jak2V617F patients. Ruxolitinib is most effective in treating splenomegaly and reducing symptoms in PV and hydroxyurea-resistant PV. In low-risk patients, only phlebotomy and prophylactic anti-thrombosis are recommended, namely aspirin, while in high-risk patients, cytostatic therapy and other therapies are required.
an MF, but not all patients with symptomatic erythrocytosis with a Jak2 mutation will develop PV.
To distinguish PV and other myeloproliferative diseases, it can be assessed from the proportion of clinical manifestations and complications, as shown in the following figure.

Alur Tatalaksana Polisitemia Vera

Alur Tatalaksana Polisitemia Vera

CONCLUSION
1. Patients with Polycythemia Vera (PV) is a disease that is rarely found in children and adolescents.
2. Polycythemia vera or marked polycythemia is distinguished from polycythemia spuria or relative polycythemia is a marked increase in erythrocytes in the blood, but the underlying cause is reduced plasma in the blood (burns, stress, and dehydration).
3. The pathogenesis of PV focuses on erythropoiesis and overreactivity to Janus Kinase signals, namely tyrosine kinases that play a role in the hematopoietic process without erythropoietin receptors causing excessive proliferation of hematopoietic cells continuously.
4. First-line therapy is hydroxyurea and interferon alpha. In patients whose disease fails to respond to hydroxyurea, ruxolitinib is a safe choice.
5. PV disease has a good prognosis and if PV is detected early and treated early.

 

BIBLIOGRAPHY

  1. Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. 2004;69(9):2139-2144. doi:10.1053/j.seminhematol.2005.08.003
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  3. Lash RW, Nicholson JM, Velez L, Van Harrison R, McCort J. Diagnosis and Management of Osteoporosis. Prim Care Clin Off Pr. 2009;36(1):181-198. doi:10.1016/j.pop.2008.10.009
  4. Spivak JL. Review article Polycythemia vera : myths , mechanisms , and management. Blood. 2002;100(13):4272-4290. doi:10.1182/blood-2001-12-0349.Reprints
  5. O’Sullivan JM, Harrison CN. JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms. Mol Cell Endocrinol. 2017;451:71-79. doi:10.1016/j.mce.2017.01.050
  6. Britain G. Guidelines for the diagnosis and treatment of patients with polycythemia vera , essential thrombocythemia and primary myelofibrosis . 2009;(1):1-73. http://legeforeningen.no/pagefiles/5783/nordisk handlingsprogram for mpd 2.pdf.
  7. Maffioli M, Mora B, Passamonti F. Polycythemia vera: from new, modified diagnostic criteria to new therapeutic approaches. Clin Adv Hematol Oncol. 2017;15(9):700-707.

8.         Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J. 2018;8(1). doi:10.1038/s41408-017-0042-7

 

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