Jan Jacques Michiels is is the Professor of Nature Medicine and Health, Clinical and Molecular Genetics, Blood and Coagulation Research at the University Hospitals Antwerp,Brussels. He is the Editor of Journal of Hematology & Thromboembolic Diseases, World Journal of Hematology and Editor in Chief of World Journal of Clinical Cases.
Hypersensitive (sticky) platelets in JAK2-mutated essential thrombocythemia (ET) and polycythemia vera (PV) with thrombocythemia spontaneously activate at high shear in arterioles, secrete their infl ammatory prostaglandin endo-peroxides and induce plateletmediated arteriolar fi bromuscular intimal proliferation. Increased production of prostaglandin endoperoxides E2 and thromboxae A2 released by activated sticky platelets in arterioles account for redness warmth and swelling of erythromelalgia and platelet derived growth factor (PDGF) can readily explain the arteriolar fi bromuscular intimal proliferation. Th e von Willebrand factor (VWF) platelet rich occlusive thrombi in arterioles are the underlying etiopathophysiology of erythromelalgic acrocyanosis, migraine-like transient cerebral attacks (MIAs) and the coronary and abdominal microvascular ischemic events. Th e irreversible platelet cyclooxygenase inhibition by aspirin cures the erythromelalgia, MIAs and microvascular events, corrects shortened platelet survival to normal, and returns increased plasma levels of beta-TG, platelet factor 4, thrombomodulin and urinary thromboxane B2 excretion to normal in symptomatic JAK2- thrombocythemia patients. In vivo activation of sticky platelets and VWF-platelet aggregates account for endothelial cell activation to secrete thrombomodulin and sVCAM followed by occlusion of arterioles by VWF-rich platelet thrombi in patients with erythromelalgic thrombotic thrombocythemia (ETT) in ET and PV patients. ETT is complicated by spontaneous hemorrhagic thrombocythemia (HT) or paradoxical ETT/HT due to acquired von Willebrand disease type 2A at platelet counts above 1000x109/L, which disappear by correction of platelets to normal (<400x109/L). A new set of International Clinical, Laboratory, Molecular and Pathological (CLMP) criteria for myeloproliferative neoplasms (MPN) defi ne the JAK2V617F trilinear MPNs as a broad continuum of essential thrombocythemia (ET), polycythemia vera (PV), masked PV and post-ET or post-PV myelofi brosis (MF). Normal vs increased erythrocyte counts (5.8x1012/L) on top of bone marrow histology separate JAK2V617F ET and prodromal PV from early and classical PV are diagnostic for JAK2V617F trilinear MPN obviating the need of red cell mass measurement. The JAK2V617F trilinear MPNs, JAK2 exon 12 PV, MPL515 thrombocythemia and calreticulin (CALR) thrombocythemia and MF mutually exclude each other. JAK2, MPL and CALR MPN disease burden is best refl ected by the degree of anemia, splenomegaly, mutation allele burden, bone marrow cellularity and myelofi brosis. Bone marrow histology of the JAK2 V617F trilinear MPNs show variable degrees of erythrocytic (E), megakaryocytic (M), and granulocytic (G) myeloproliferation, peripheral cytoses and splenomegaly related to low intermediate and high JAK2 allele burden. MPL515 thrombocythemia displayed predominantly normocellular megakaryocytic (M) proliferation. CALR thrombocythemia initially presents with megakaryocytic (M) followed by dual granulocytic and megakaryocytic (GM) myelo-proliferation without features of PV. CALR thrombocythemia is featured by dense clustered large immature dysmorphic megakaryocytes with bulky (bulbous) hyperchromatic nuclei, which are never seen in JAK2V617F, JAK2 exon 12 MPN and MPL515 thrombocythemia. Low dose aspirin in thrombocythemia and on top of phlebotomy in PV patients is mandatory for thrombosis reduction and pegylated interferon, hydroxyurea or ruxolitinib for control of MPN burden. Reduction of platelets and leukocytes to normal by pegylated interferon to postpone or eliminate the use of hydroxyurea does reduce and even can eliminate the thrombotic risk and reduce MPN burden in JAK2V617F prodromal PV and in JAK2, CALR and MPL thrombocythemia.