Published online Aug 6, 2017. doi: 10.5315/wjh.v6.i3.32
Peer-review started: March 24, 2017
First decision: April 18, 2017
Revised: July 3, 2017
Accepted: July 17, 2017
Article in press: July 17, 2017
Published online: August 6, 2017
Hypersensitive (sticky) platelets in JAK2-mutated essential thrombocythemia (ET) and polycythemia vera (PV) with thrombocythemia spontaneously activate at high shear in arterioles, secrete their inflammatory prostaglandin endoperoxides and induce platelet-mediated arteriolar fibromuscular intimal proliferation. Constitutively activated JAK2 mutated hypersensitive (sticky) platelets spontaneously aggregate at high shear in the endarteriolar circulation as the cause of aspirin responsive erythromelalgia and platelet arterial thrombophilia in JAK2-mutated thrombocythemia patients. Increased production of prostglandin endoperoxides E2 and thromboxane A2 released by activated sticky platelets in arterioles account for redness warmth and swelling of erythromelalgia and platelet derived growth factor can readily explain the arteriolar fibromuscular intimal proliferation. Von Willebrand factor (VWF) platelet rich occlusive thrombi in arterioles are the underlying pathobiology of erythromelalgic acrocyanosis, migraine-like transient cerebral attacks (MIAs), acute coronary syndromes and abdominal microvscular ischemic events. Irreversible platelet cyco-oxygenase 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, thrombomoduline 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 thrombomoduline 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 1000 × 109/L and disappears by cytoreduction of platelets to normal (< 400 × 109/L).
Core tip: About seventy years after the synthesis by Hoffmann, acetyl salicylic acid (aspirin) has been discovered in the late 1970s as a wunder drug that cures erythromelalgia and migraine-like cerebral microvascular disturbances by irreversible blockage of platelet cyclo-oxygenase mediated arteriolar inflammation and thrombosis in JAK2-mutated thrombocythemia of patients with essential thrombocythemia (ET) and polycythemia vera (PV). The ADP (P2Y12) receptor inhibtors ticlopedin and clopidogrel, other platelet inhibitors that do not affect platelet cycooxygenase, and coumarin are ineffective in the treatment of erythromelalgia and cerebral vascular thrombotic complications in ET and PV.