Aspirin cures erythromelalgia and cerebrovascular disturbances in JAK2-thrombocythemia through platelet-cycloxygenase inhibition

Figure 2 Dutch design by Michiels and Van Vliet on membrane phospholipid - arachidonic acid metabolism in platelets as compared to endothelial cells conceptualize in 1976, three years before the Moncada and Vane[13] publication in the NEJM. Arachidonic acid (AA) is metabolized by lipoxygenase into (12-HPETE) and 12 HETE, and by platelet cyclooxygenase into prostagandin endoperoxides G2 and H2, which consist of PGE2, PG2alpha, PGD2, malondialdehyde (M.D.A.) and HHT. Prostaglandin endoperoxides in platelets are metabolized by thromboxane synthetase into thromboxane A2. Thromboxane A2 is potent inducer of platelet aggregation and smooth muscl cell contraction. AA induced prostaglandin endoperoxides in endothelial cells are metabolized by prostacyclin synthethase into prostacycline. Endothelial cell (EC) derived prostacyclin causes vasodilatation and prevents platelet aggregation and platelet derived thromboxane causes vasoconstriction and platelet aggregation. Prostacyclin is continuously produced by endothelial cells, which have a nucleus to synthesize cyclo-oxygenase and prostacyclin. The biological half life times of prostacycline and thromboxne A2 are short and broken down to the inactived metabolites 6-keto-PGF-1-alpha and thromboxane B2, which are sereceted by the kidneys into the urine (Figure 15). Ticlopedine and clopidogrel inhibit ADP induced platelet aggregation without affecting platelet cyclo-oxygenase (Figure 13). Upon platelet activation of constitutively activated JAK2-platelets by shear stress starts the membrane phospholipids → phopspholipase A2 → arachidonic acid (AA) → cyclooxygenase biochemical pathway induced prostaglandin endoperoxides G2 and H2 production by platelets are the cause of the inflammatory signs erythromelalgia (Figure 4) featured by fibromuscular intimal proliferation and occlusive platelet thrombi (Figures 9 and 10). Release of platelet derived growth factor accounts for the fibromuscular intimal proliferation (Figures 6, 9 and 10) followed by von Willebrand (VWF) rich occlusive platelet thrombi (Figure 15). As platelets do not have a nucleus, irreversible inhibition of platelet cyco-oxygenase (COX-1) persist for the rest of platelet life time in the circulation and cures erythromelagia and migraine-like cerebrovascular ischemic manifestations[37,52,53].