Essential thrombocythaemia and myelofibrosis

• Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are two of the three common Philadelphia-chromosome-negative myeloproliferative neoplasms (MPN), alongside polycythaemia vera. All are clonal disorders of the haematopoietic stem cell driven by constitutive activation of JAK signalling. ^[1][3]
• ET presents with a persistently raised platelet count and a marrow rich in large mature megakaryocytes. PMF presents with clonal myeloproliferation plus progressive bone marrow fibrosis, extramedullary haematopoiesis, splenomegaly and anaemia. ^[1][3]
• The three "driver" mutations are JAK2 V617F, CALR exon 9 mutations and MPL W515 (and rarer) mutations. They are usually mutually exclusive. A patient without any of them is "triple-negative". ^[3][4]
• ET is mainly dangerous because of thrombosis. Risk is scored with IPSET-thrombosis, and a raised platelet count alone is not enough to decide on cytoreduction. ^[2][4]
• PMF is the more serious disease. Its only potentially curative treatment is allogeneic stem cell transplantation, offered to transplant-eligible patients in intermediate-2 or high risk, with modern drugs (ruxolitinib, fedratinib, momelotinib) controlling splenomegaly and symptoms. ^[2][3]

By the end of this page you should be able to:

1. Define ET, prefibrotic PMF and overt PMF, and place them among the Philadelphia-chromosome-negative MPNs, cross-checking with polycythaemia vera. ^[1][3]
2. Name the three driver mutations, their relative frequencies, what each does to the blood picture, and what "triple-negative" implies. ^[3][4]
3. Apply the WHO 2022/ICC 2022 diagnostic criteria for ET and for pre-PMF, overt PMF and post-ET myelofibrosis. ^[1][3]
4. Stratify thrombotic risk in ET with IPSET-thrombosis, and MF risk with DIPSS, MIPSS70+ v2.0 and the MYSEC score. ^[2][3]
5. Plan management of ET by risk category, including aspirin, cytoreduction and bleeding precautions, and of MF by risk and symptom profile, including JAK inhibitors, transplant and splenectomy. ^[2][3]
6. Counselling for pregnancy, older adults and low-resource settings. ^[2][4]

The 5th edition of the WHO classification of haematolymphoid tumours (2022, based on the 4th edition revised in 2016) and the parallel International Consensus Classification (ICC, 2022) divide the classic Philadelphia-chromosome-negative MPNs into essential thrombocythaemia, polycythaemia vera and primary myelofibrosis (prefibrotic and overtly fibrotic). Both 2022 systems agree that bone marrow morphology stays central to separation of ET from prefibrotic PMF, supported by JAK2, CALR and MPL mutational testing. ^[1][3] A number of authors regard the two 2022 systems as diagnostically almost identical for these entities; the main practical differences concern the place of leukoerythroblastosis among the minor criteria and the quality of guidance on specimen handling. ^[3]

For reference alongside this page, the polycythaemia vera topic covers the same family from the red cell side: the same JAK2 mutation, the same age and thrombosis risk factors, and a parallel classification. Where this page crosses into PV management (phlebotomy, haematocrit targets) it defers to that topic and to the ELN consensus. ^[2]

ET is uncommon but not rare. Western estimates give an annual incidence of about 0.2 to 2.5 cases per 100,000 and a prevalence of 38 to 57 per 100,000. Women are affected roughly twice as often as men, and the median age at diagnosis is around 60 years. ^[4] Incidence is hard to measure accurately because platelet counts are checked incidentally and reactive thrombocytosis is far commoner; in one series of 801 adults with thrombocytosis, only 5.2% proved to have a primary (clonal) cause. ^[4]

Myelofibrosis is rarer. Its estimated annual incidence is 0.22 to 0.99 per 100,000. The median age at diagnosis is about 65 years, roughly one in five patients is under 56, and men are affected more often (about 65%). About 15% of people with ET or PV eventually develop a myelofibrotic phenotype. ^[3] Life expectancy in ET is close to the general population (estimated 18 to 19.8 years), whereas PMF behaves as an aggressive haematological cancer (median survival around 5.9 years in historical series). ^[4]

There is no single modifiable cause of either disease. Both are acquired clonal disorders of a haematopoietic stem cell. A familial tendency exists: familial clustering is described and the JAK2 46/1 haplotype increases susceptibility to JAK2-mutant clonal haematopoiesis. ^[3][4]

Thrombosis, not the platelet count, is the main clinical danger in ET. The established risk factors are age over 60, a previous thrombosis or major haemorrhage, and cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidaemia, obesity). ^[2][4] In one large study of 1,297 people with WHO-defined ET, 17.8% had thrombosis before or at the time of diagnosis. ^[4] Moderate leucocytosis and high JAK2 mutant allele burden have also been linked with thrombosis, and mutated MPL appears to add risk beyond JAK2 alone. ^[2][4]

The mechanism is the same three-step story in every MPN.

1. A somatic mutation hits a haematopoietic stem cell and constitutively activates JAK-STAT signalling, usually through loss of the normal auto-inhibitory control of JAK2, thrombopoietin receptor (MPL) or calreticulin (CALR) - endoplasmic reticulum chaperone protein.
2. The mutant stem cell expands and produces one or more myeloid lineages autonomously, that is, without normal dependence on erythropoietin or thrombopoietin.
3. The marrow and spleen are remodelled: in ET this means large megakaryocytes and platelets; in PMF it means cytokine-driven marrow fibrosis, osteosclerosis, neoangiogenesis and extramedullary haematopoiesis, with ineffective erythropoiesis causing anaemia.

CALR mutations deserve separate explanation, because their mechanism is indirect. Mutant calreticulin does not signal on its own; instead, the altered C-terminal tail of the mutant protein loses negative charge and physically binds to the extracellular domain of MPL, the thrombopoietin receptor, and activates it. Because CALR-mutated megakaryocytes express less MPL on the cell surface, they also remove thrombopoietin from the blood less efficiently. The result is thrombocytosis with a lower risk of thrombosis than JAK2-mutated ET (higher platelet counts, lower haemoglobin and leucocyte counts). Type 1 and type 1-like CALR mutations more often precede myelofibrotic transformation; type 2 and type 2-like mutations tend to stay indolent. ^[4]

The three driver mutations are usually mutually exclusive. Their approximate distribution differs by disease:

• ET: JAK2 V617F in about 50 to 60% (one consecutive single-centre series reported 72%); CALR in about 9%; MPL in about 5%; 14 to 17% triple-negative. ^[4]
• PMF: JAK2 V617F in about 60%; CALR in 20 to 25%; MPL in a minority; about 10% triple-negative. ^[3]

About one in ten people with PMF carries none of the three drivers ("triple-negative"), which carries a worse prognosis. ^[3]

Additional non-driver ("passenger") mutations are common in PMF and are the engine of progression: ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 Q157 and TP53 are regarded as high-molecular-risk (HMR) mutations. In ET the presence of ASXL1, TET2, DNMT3A and similar mutations is common in sequencing studies but is not yet routine in practice and does not yet change standard therapy decisions. ^[3][4]

ET is often found incidentally. Many patients are asymptomatic for years. When symptoms occur they fall into three groups.

• Microvascular disturbance: headache, dizziness, visual disturbance, paraesthesiae in the fingers and toes, erythromelalgia (burning pain, warmth and erythema of the extremities), atypical chest pain or transient ischaemic symptoms. These are thought to be platelet- and neutrophil-mediated and often respond to aspirin. ^[2][4]
• Constitutional symptoms: fatigue, pruritus, night sweats, bone pain, low-grade fever, weight loss. Fatigue is the commonest symptom in contemporary surveys. ^[4]
• Thrombotic or bleeding events: stroke, TIA, myocardial infarction, splanchnic vein thrombosis, deep vein thrombosis, pulmonary embolism, or gastrointestinal or genitourinary bleeding with extreme thrombocytosis. ^[4]

On examination the spleen is usually not enlarged or only mildly so; splenomegaly should make you think of prefibrotic PMF instead. The blood count shows thrombocytosis (at least 450 × 10^9/L on two occasions) with normal or near-normal haemoglobin and white cell count. ^[1][2]

Pre-PMF is the earliest stage. It clinically resembles ET: isolated thrombocytosis, often no symptoms, frequently an unexpected finding. Compared with ET it has more often mild anaemia, raised LDH, palpable splenomegaly (about 64%), leukocytosis and a higher JAK2 allele burden (median around 46% versus about 25% in ET). Pre-PMF has a 15-year survival of about 59%, worse than ET but better than overt PMF. ^[3] Many patients progress over years or decades to overt fibrotic disease. ^[3]

The classic triad is anaemia, splenomegaly and constitutional symptoms (weight loss over 10%, night sweats, fever above 37.5 °C). Initial presentation may be incidental when a blood count is abnormal or splenomegaly is found. ^[3] Serious complications include splanchnic or other venous thrombosis (estimated 1.7% per patient per year, half in atypical sites), portal hypertension, and non-hepatosplenic extramedullary haematopoiesis causing organ compression (for example spinal cord compression). ^[3] The blood smear is leukoerythroblastic with teardrop poikilocytes and nucleated red cells; LDH is raised. ^[3]

Secondary (post-ET and post-PV) myelofibrosis uses the same clinical words but is diagnosed by the IWG-MRT criteria requiring a prior MPN, grade 2 or higher marrow fibrosis, and at least two additional features (such as a fall in haemoglobin, leukoerythroblastic blood, new or increasing splenomegaly, or constitutional symptoms). ^[2][3]

• Reactive (secondary) thrombocytosis: infection, inflammation, iron deficiency, recent surgery or splenectomy, haemorrhage, malignancy, pregnancy. Usually self-limited, lower peaks, raised acute-phase reactants; marrow lacks megakaryocyte clustering and atypia. ^[4]
• Prefibrotic PMF mimicking ET: the commonest diagnostic trap, separated by marrow morphology plus driver mutation testing and clues (anaemia, raised LDH, splenomegaly, higher JAK2 allele burden). ^[1][3]
• Myelodysplastic syndrome with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): SF3B1 mutation, dysplasia, ring sideroblasts. ^[1]
• Chronic myeloid leukaemia: BCR::ABL1-positive; excluded in every suspected MPN. ^[1][3]
• Familial thrombocytosis / germline JAK2, MPL, THPO mutations: young age, family history, normal marrow; rare. ^[4]

• Acute myelofibrosis (acute megakaryoblastic leukaemia) with pancytopenia and no organomegaly. ^[3]
• Myelodysplastic syndrome with fibrosis, systemic mastocytosis, hairy cell leukaemia, autoimmune or infectious (for example tuberculosis) fibrosis, metastatic or granulomatous infiltration, radiation exposure. ^[3]

• Full blood count with repeat platelet count. Sustained count of at least 450 × 10^9/L. ^[1][2]
• Blood film. No leukoerythroblastosis, no significant dysplasia. ^[1]
• Exclusion of reactive thrombocytosis: iron studies (including ferritin), CRP, ESR, screening for infection and inflammatory disease. ^[4]
• Molecular testing in order: JAK2 V617F first; if negative, CALR (types 1 and 2) then MPL; if all negative and PV suspected, JAK2 exon 12. For persistent diagnostic doubt in ET or MF, BCR::ABL1 once only, to exclude CML. ^[2]
• Bone marrow aspirate and trephine biopsy. Mandatory for ET unless all clinical and laboratory clues clearly fit; specifically mandatory to separate ET from prefibrotic PMF. A good-quality trephine core, taken at right angles to the cortical bone with properly processed smears, interpreted by a pathologist who reads MPN regularly. ^[1][2][3]
• von Willebrand assays (ristocetin cofactor and factor VIII activity) with marked thrombocytosis or any bleeding, to look for acquired von Willebrand syndrome before giving aspirin or anagrelide. ^[4]

• Blood count and film: anaemia, raised white cells sometimes, platelets high/normal/low, leukoerythroblastosis, teardrop cells. ^[3]
• LDH (raised), urate, liver function, bilirubin, haptoglobin and Coombs test, because some anaemia is haemolytic. ^[3]
• Abdominal ultrasonography for spleen and liver size and extramedullary haematopoiesis. ^[3]
• Molecular tests: JAK2, CALR, MPL plus at least the high-molecular-risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 Q157, TP53), together with cytogenetics (conventional karyotype or, failing that, FISH). ^[2][3]
• Bone marrow biopsy is mandatory: reticulin and collagen fibrosis grade, megakaryocyte morphology, cellularity and iron stores. ^[3]

Major criteria: platelet count at least 450 × 10^9/L; bone marrow with megakaryocyte proliferation with large mature morphology, no significant left shift of granulopoiesis or erythropoiesis and at most grade 1 reticulin fibrosis; exclusion of CML, PV, PMF, MDS or other myeloid neoplasms; JAK2, CALR or MPL mutation. Minor criterion: a clonal marker or no evidence of reactive thrombocytosis. The diagnosis requires all four major criteria, or the first three major plus the minor. ^[1][2][4]

Pre-PMF requires all three major criteria plus at least one minor criterion confirmed on two consecutive measurements: megakaryocytic proliferation and atypia without significant (grade 0 or 1) reticulin fibrosis, with granulocytic proliferation and decreased erythropoiesis; exclusion of other myeloid neoplasms; and a driver mutation (JAK2, CALR, MPL) or another clonal marker or exclusion of reactive fibrosis. Minor criteria are anaemia not otherwise explained, leukocytes at least 11 × 10^9/L, palpable splenomegaly or a raised LDH. ^[2][3]

Overt PMF requires megakaryocytic proliferation and atypia with grade 2 or 3 fibrosis, the same exclusions and mutational criteria, plus at least one minor criterion (the pre-PMF list plus leukoerythroblastosis). ^[2][3] In over-fibrotic PMF the marrow is usually depleted of cells, osteosclerosis is common and the smear is leukoerythroblastic. ^[3]

Post-ET MF requires a prior ET, grade 2 or 3 bone marrow fibrosis, and at least two of: anaemia with a haemoglobin drop greater than 2 g/dL, leukoerythroblastosis, an increase in splenomegaly of over 5 cm or new palpable splenomegaly, raised LDH, or two constitutional symptoms. ^[3]

ET (thrombosis): IPSET-thrombosis assigns 2 points for previous thrombosis, 2 for JAK2 V617F, 1 for age over 60 and 1 for cardiovascular risk factors. Low risk scores 0 to 1, intermediate 2 and high 3 or more. ^[2][4] The revised IPSET (r-IPSET) re-arranges these into four groups, from very low to high, using age, thrombosis history and JAK2 status only; the r-IPSET is preferred when deciding on aspirin in low-risk disease, because it separates JAK2-mutated and unmutated young patients. ^[4] Conventional high-risk ET (age over 60 and/or previous thrombosis) remains the simplest frame and is still used to trigger cytoreduction. ^[2]

IPSET as a survival (rather than thrombosis) score gives 2 points for age over 60, 1 for previous thrombosis and 2 for leucocytes above 11 × 10^9/L, with low, intermediate and high prognostic groups. ^[4]

MF (survival): IPSS for newly diagnosed patients (age over 65, constitutional symptoms, haemoglobin less than 100 g/L, white cells over 25 × 10^9/L, circulating blasts at least 1%; low 0, intermediate-1 1, intermediate-2 2, high 3 or more); DIPSS for any point in the disease course (anaemia weighted at 2 points); and DIPSS-plus, which adds transfusion dependence, platelets under 100 × 10^9/L and unfavourable cytogenetics. ^[2] Mutation-based scores (MIPSS70 for patients 70 or under, the more recent MIPSS70+ v2.0 for all ages with modern cytogenetics, and the MYSEC-PM score for secondary MF) are preferred when a treatment decision depends on long-term prognosis or on whether to transplant. ^[3] In very young patients or when NGS is unavailable, IPSS/DIPSS/DIPSS-plus is acceptable; the important thing is to apply one score and to re-apply DIPSS whenever the clinical state changes. ^[2][3]

Use a standardised tool (MPN-10 or MPN-SAF) at diagnosis and at every visit in every MPN, particularly in MF, because physicians consistently under-estimate symptom burden. A total symptom score of 10 or more is often used in MF studies to define symptomatic disease (for example momelotinib eligibility). ^[3]

Management has two separate questions: whether to give antiplatelet therapy, and whether to give cytoreductive therapy.

Antiplatelet therapy. Low-dose aspirin is recommended for all high-risk ET, and for low or intermediate risk when the patient is at least 60, has uncontrolled cardiovascular risk factors, or has a JAK2 V617F mutation. In CALR-mutated, low-risk disease, antiplatelet therapy can increase bleeding without clearly preventing thrombosis and should be individualised. ^[2][4]

Cytoreduction. For those who need it, the agreed first-line agents are hydroxyurea and recombinant or pegylated interferon alpha. Anagrelide is second line in most European guidance; it is an alternative single agent in selected centres but has a less certain risk-benefit profile. ^[2][4] Cytoreduction is indicated in high-risk disease, when platelets are above 1500 × 10^9/L, when there is progressive splenomegaly or uncontrolled symptoms, in severe tissue iron deficiency from frequent phlebotomy (this point applies to PV), and when a patient enters the high-risk category by turning 60 or having a major event. ^[2][4]

Aspirin cautions. Extreme thrombocytosis (above about 1 to 1.5 million platelets per microlitre) can cause acquired von Willebrand syndrome and paradoxical bleeding. Check von Willebrand factor antigen and ristocetin cofactor activity before starting aspirin or anagrelide in that range, and use cytoreduction first. ^[4] Avoid anagrelide in patients with cardiac disease or significant liver disease and keep aspirin or anticoagulant decisions to the prescriber. ^[2]

Monitoring. Blood count regularly in stable low-risk disease, more often after starting cytoreduction; check spleen, symptoms and cardiovascular risk at every visit. ^[2][4]

The aim splits by context: cure where possible, symptom control and quality of life elsewhere. The 2025 German ONKOPEDIA guideline organises treatment by the ICC/WHO 2022 disease subtype and by MIPSS70+ v2.0 risk. ^[3]

Watchful waiting. Asymptomatic patients with low or very low MIPSS70+ v2.0 risk have a favourable prognosis and do not need disease-specific drug therapy; use problem-based treatment (transfusions, erythropoietin, low-dose aspirin or hydroxyurea for counts) as needed. ^[3]

Low or intermediate-1 risk with symptoms. Hydroxyurea remains the first-line cytoreductive agent when reduction of leukocytosis or thrombocytosis or symptomatic splenomegaly is needed in lower risk. ^[2] Anagrelide or interferon may be used where appropriate. ^[2]

Splenomegaly and symptoms in intermediate-2 or high risk. Ruxolitinib is the first-line JAK inhibitor for adults with PMF, post-PV MF or post-ET MF who have disease-related splenomegaly or symptoms. ^[2][3] Benefits appear within about 12 weeks, though a first assessment should not be made before 6 months. The starting dose is 5 to 20 mg twice daily, guided chiefly by the platelet count; 20 mg twice daily is the usual target for durable splenic response, while counts below 50 × 10^9/L call for pausing or very close monitoring. Ruxolitinib should never be stopped suddenly because of the risk of a life-threatening withdrawal (ruxolitinib discontinuation) syndrome. Anaemia caused by the drug is not the same as disease-related anaemia and is not a reason to stop. ^[2][3]

After ruxolitinib failure. Fedratinib (400 mg once daily) and momelotinib (200 mg once daily) are licensed alternatives. Fedratinib is used second line when disease progresses on ruxolitinib, or first line in JAK-inhibitor-naive disease; thiamine must be normalised and monitored because of a rare risk of Wernicke encephalopathy. Momelotinib is especially useful when anaemia is moderate to severe. ^[3] A joint German consensus position states that after ruxolitinib the choice is between fedratinib and momelotinib; other combinations are off-label. ^[3]

MF-related anaemia. Options with modest evidence include erythropoiesis-stimulating agents, danazol, androgens and prednisolone, lenalidomide (particularly with del(5q)), thalidomide with prednisolone in patients without neuropathy, and transfusion support. ^[2] No drug has strong evidence for survival benefit, and the choice should follow the toxicity profile and comorbidities. ^[2]

Allogeneic stem cell transplantation. This is the only potentially curative treatment and should be discussed for transplant-eligible patients with intermediate-2 or high-risk disease (by DIPSS, IPSS or MYSEC, or high or very high MIPSS70+ v2.0), and for selected intermediate-1 patients with refractory transfusion-dependent anaemia, circulating blasts above 2%, adverse cytogenetics or high-risk mutations. ^[2][3] Transplant-related mortality is 10 to 30% and relapse within 5 years is about 29%, so selection and counselling are deliberate. MIPSS70+ v2.0 is the preferred risk score for decision-making in transplant-age (under about 70) patients. ^[3] Drug reduction of bulk disease before transplant (ruxolitinib, spleen irradiation where the spleen is very large, and, in some settings, splenectomy) is planned with the transplant team. ^[3] After the JAK inhibitor, drug choice and timing of transplant should be reviewed at 6 months using the ruxolitinib response (RR6) model, because high-risk RR6 patients need a switch and transplant evaluation rather than continued ruxolitinib. ^[3]

Splenectomy remains a palliative option for symptomatic, drug-refractory splenomegaly, particularly when drug-induced cytopenias block effective JAK-inhibitor dosing; it is not routinely done before transplant. ^[2][3]

• Thrombosis is the dominant source of illness and death in ET and remains common in MF. Splanchnic (portal, splenic, hepatic) and cerebral venous thrombosis are over-represented in all MPNs and may be the first clue. ^[3][4]
• Bleeding, usually from extreme thrombocytosis with acquired von Willebrand syndrome in ET, and from thrombocytopenia in advanced MF. ^[4]
• Transformation to myelofibrosis (about 13% cumulative at 10 to 15 years in ET if the diagnosis was made with the WHO system; about 21% in PV). ^[4]
• Blast/leukaemic transformation: roughly 2 to 5% over 15 years in ET and around 9% over 10 years in PMF. ^[4]
• Infections, cytopenias, cachexia and hospitalisation dominate advanced MF. The most common causes of death in MF are blast transformation (20%), infection (10%) and cardiovascular events (12%). ^[3]

ET has an excellent prognosis with the WHO (2016 or later) criteria: life expectancy close to normal, particularly in the low-risk group, and a low rate of transformation when the diagnosis was rigorous. Prognosis in MF is heterogeneous and is read from a modern risk score: by MIPSS70+ v2.0 the 10-year overall survival ranges from above 90% in the very low risk group to under 5% in the very high risk group (for patients 70 or under, median survivals 16.4 and 1.8 years respectively). ^[3][4] Prefibrotic disease behaves better than overt PMF (about 59% survival at 15 years compared with about 7 years median for overt PMF). ^[3] Secondary MF is scored with MYSEC-PM. ^[3]

There is no population screening. Targeted testing is worth offering in three situations:

• Unexplained or recurrent splanchnic or cerebral venous thrombosis in a young person: screen for JAK2 V617F regardless of the full blood count, plus CALR and MPL. ^[4]
• Persistent thrombocytosis: confirm with a bone marrow biopsy rather than presuming ET, so that prefibrotic PMF is not missed. ^[1][3]
• Familial MPN: take a family history of thrombocytosis or MPN. ^[4]

Prevention otherwise means controlling cardiovascular risk (smoking cessation, blood pressure, diabetes, lipids, weight) and giving appropriate thromboprophylaxis around surgery, pregnancy and delivery. ^[2][4]

Pregnancy. Risk in ET pregnancy is defined by prior complications. Low-risk women are managed with low-dose aspirin through pregnancy, plus prophylactic low molecular weight heparin from the day after delivery to 6 weeks postpartum; high-risk women (previous major thrombosis or severe pregnancy complication) should have LMWH throughout pregnancy, aspirin stopped if bleeding becomes problematic, and cytoreduction added only if platelets exceed about 1.5 million per microlitre (rIFN alpha). ^[2][4] MF in pregnancy is rare and should be managed jointly with obstetrics, cardiology and haematology. ^[2]

Older adults. Age is itself the main risk variable; management thresholds remain the same and drug choices should weigh renal function, bone marrow reserve and comorbidity. ^[2][3]

Children and young adults. MPN is rare under 40, and a triple-negative or atypical presentation should raise the possibility of germline disease; a haematology specialist is needed. ^[3][4]

Immunocompromised and people with cytopenias. HMR mutations add prognostic information but should not on their own delay transplant discussion. ^[2][3]

• Where bone marrow biopsy is limited, remember that a JAK2 V617F test plus CALR/MPL panels, applied with clinical and cardiovascular risk assessment, will correctly triage many patients, because reactive thrombocytosis remains the commonest diagnosis. ^[1][4]
• Sustained microvascular symptoms and thrombocytosis in a young patient are often "vasculitis" or "functional" in settings without diagnostics. Repeat the count, look for iron deficiency and infection, then refer.
• Hydroxyurea, aspirin and LMWH are widely available and are the realistic first-line agents in most settings. ^[2]
• Modern JAK inhibitors, NGS and transplantation are not universally available; for MF beyond primary centres, identify the nearest transplant centre early and refer before blast transformation. ^[3]
• Send every marrow biopsy, even a short one, for reticulin staining and morphology review by an expert if possible. ^[3]

• ET and PMF are the other two common Philadelphia-chromosome-negative MPNs, next to polycythaemia vera, and share the same JAK-STAT-driven clonal stem cell mechanism. ^[1][3]
• The three driver mutations are JAK2 V617F (about 50 to 60% in ET, about 60% in PMF), CALR (about 9% in one ET series, 20 to 25% in PMF) and MPL (about 5% in ET, a minority in PMF); roughly 10 to 17% are triple-negative. ^[3][4]
• Most ET is asymptomatic and thrombosis, not the platelet count, is the real risk. Score with IPSET-thrombosis; treat high risk with hydroxyurea or interferon plus aspirin. ^[2][4]
• Extreme thrombocytosis (over 1 to 1.5 million platelets per microlitre) can cause bleeding from acquired von Willebrand syndrome: check before giving aspirin or anagrelide. ^[4]
• Prefibrotic PMF is the commonest mimic of ET and is separated by marrow morphology; missing it understates the risk of fibrotic and blast transformation. ^[1][3]
• PMF ranges from a slowly progressive Prefibrotic phase to aggressive overt disease with constitutional symptoms, splenomegaly, anaemia and leukoerythroblastosis. ^[3]
• JAK inhibitor therapy controls splenomegaly and symptoms (ruxolitinib first line in intermediate-2 or high risk; fedratinib or momelotinib after or when anaemia dominates); allogeneic stem cell transplantation is the only cure and should be planned early for suitable patients. ^[2][3]
• Risk stratification tools differ: IPSET for ET; IPSS, DIPSS, DIPSS-plus, MIPSS70/MIPSS70+ v2.0 and MYSEC-PM for MF. Pick one and re-stage as the disease changes. ^[2][3]
• In low-resource settings, basic tools (aspirin, hydroxyurea, LMWH, repeated marrow review and early referral) capture most of the benefit. ^[2][3]