The molecular etiology and pathophysiology of platelet-mediated aspirin responsive erythromelalgia and microascular thrombosis in JAK2, CALR and MPL mutated thrombocythemia

J. J. Michiels1,2 (1Antwerp, Belgium, 2Rotterdam, The Netherlands)

Arterial thrombosis
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Introduction. This insight review article decribes the sequential steps between 1975 and 2016 in the discovery of aspirin responsive platelet-mediated erythromelalgic inflammation followed by microvascular thrombosis in thrombocythemia patients caused by prostaglandin endoperoxides released from spontaneous activation, release reaction and aggregagation of hypersensitive constitutively activated platelets due to gain of function mutations in the JAK2, TPO, MPL and CALR genes (Acquired and Congenital Sticky Platelet Syndrome).


Results: Results. The initial stages of platelet-mediated aspirin erythromelalgia in clonal thrombocythemia are featured by livido reticularis of the skin, acroparesthesias of prickling ‘needles’ sensations and caused by shear stress induced activation of hypersensitive JAK2 mutated platelets in the endarterial microcirculation followed by platelet mediated arteriolar occlusive thrombosis if left untreated. The release of prostaglandin endoperoxides, serotine, adenosine account for the inflammatory signs, burning pain and red congestion of typical erythromelalgia. In this ongoing proces of platelet activation, platelet aggregation and platelet-endothelial interactions, the endothelial cells release thrombomoduline indicating endothelial cell activation and damage. Release of platelet derived growth factor (PDGF) by activated platelets account for the fibromuscular intimal proliferation. The analgetic effect of aspirin immediately and completely relieves the inflammatory, burning painful vasomotor manifestations for a few days by irreversible inhibition of platelet cyclo-oxygenase (COX-1) and subsequently will prevent the erythromelagic microvascular complications through maintained irreversible inhibition of platelet cyclooxygenase (COX-1) by low dose aspirin 50 to 75 mg daily. The analgesic agents sodium salicylate and paracetamol and anticoagulation with coumadin and heparin do not inhibit platelet cyclo-oxygenase and are ineffective to relief the pain and inflammatory manifestations of erythromelalgia. The high shear rate of blood flow in arterioles as compared to that in arteriolar circulation contributes to the location of erythromelalgia and MIAs in the endarterial circulation in thrombocythemia caused by a gain of function mutation in the JAK2, CALR, MPL or TPO gene. Spontaneous activation and reversible aggregation of hypersensitive JAK2, TPO, CALR or MPL-mutated thrombocythemic platelets in the arteriolar circultation is a pathophysiological process which transforms platelet membrane phopholopid by phopholipase A2 into achidonic acid as the source for cyclooxygenases (COX-1) to produce prostaglandin endperoxides and the release by platelet of serotonin, platelet factor 4, beta-thrombglobulin, platelet derived growth factor (PDGF), adenosine diphosphonate. The inflammatory mediators, such as prostaglandin, adenosine and serotonin directly affect the afferent (pain-signalling) nociceptive C-fiber neurons of the vasomotor-neurosensory arterilar-capillary-AVS functional unit in the skin and induce erythromelalgic pain and inflammatory manifestations of red warm and congested skin. This can only be reversed by irreversibly inhibition of platelet COX-1with asirin as the explanation of relief of erythromelagic pain and inflammatory manifestation in JAK2, CALR, MPL and TPO mutated thrombocythemia (‘one molecular cause etiology of asprin responsive erythromelalgia’). Other platelet inhibiting drugs like sulfinpyrazon, dipyridamol, ticlopedine, and clopidrogrel do not inhibit platelet COX-1 activity and consequently have no effect on erythromelalgia in thrombocythemia.

Conclusion: Discussion. Aspirin responsive erythromelalgia is caused by spontaneous activation and aggregation of hypersensitive JAK2, TPO, CALR or MPL-mutated platelets at high shear stress rate in the end-arterial circulation of the peripheral, cerebral, ocular and coronary circulation and can easly explain the occurrence of migraine-like cerebral ischemic attacks (MIAs) in clonal thrombocthemia. Irreversible inhibition of platelet cyclooxygenase by aspirin (acetylsalicylic acid) completely relieved erythromelalgia for the duration of treatment, but sodium salicylate, dazoxyben, dipirydamol and ticlopedin had no effect at all. Erythromelalgia and its microvascular ischemic complications in JAK2, TPO, CALR and MPL mutated clonal myeloproliferative thrombocythemias is relieved and cured by aspirin but not by anticoagulation with counarin or heparin.