Aspirin responsive erythromelalgia in JAK2-thrombocythemia and incurable inherited erythrothermalgia in neuropathic Nav1.7 sodium channelopathy: from Mitchell 1878 to Michiels 2017

ABSTRACT

Introduction: The article reports on the nosologic classification and common etiologic pathways of aspirin responsive erythromelalgia in clonal JAK2 thrombocythema and incurable inherited autosomal dominant erythrothermalgia in Nav1.7 channelopathy.

Areas covered: Aspirin responsive platelet-mediated erythromelalgic arteriolar inflammation and thrombotic manifestations in thrombocythemia are 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 (sticky platelet syndrome). Incurable inherited erythrothermalgia is a rare autosomal dominant neuropathy due to gain function mutations in the SCN9A gene that result in warmth-induced burning pain of the body and both legs sparing the toes and fingers caused by hyperexcitable action potentials firing of the Nav1.7 mutated small C-fiber DRG nociceptive sensory neurons of the skin.

Expert opinion: Acetyl salicylic acid (aspirin) is a wonder drug in the treatment of symptomatic thrombocythemia patients with erythromelalgia but not sodium salicylate, coumadin and the platelet inhibiting agents ticlopedin and dipyridamole. The JAK2, MPL, CALR or TPO gain of function mutations constitutively activate megakaryopoesis and increase the production of hypersensitive platelets as the cause of aspirin responsive erythromelalgia. Incurable inherited erythrothermalgia is a congenital autosomal dominant neuropathic Nav1.7 channelopathy of the afferent C-fibers neurons and blood flow regulating system in the arteriole venule shunt of the skin caused by a gain-of-function mutation in the SCN9A gene.

KEYWORDS:

• Erythromelalgia
• aspirin
• primary erythermalgia
• inherited erythrothermalgia
• congenital insensitivity for pain
• thrombocythemia
• platelet cyclo-oxygenase
• SCN9A gene
• Nav1.7 sodium channel
• JAK2 gene

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Corrigendum

Article highlights

• Aspirin responsive erythromelalgia is caused by spontaneous activation and aggregation of hypersensitive JAK2-mutated platelets at high shear stress rate in the arteriolar endarterial circulation of the peripheral, cerebral, ocular and coronary circulation and can easly explain the occurrence of migraine-like cerebral ischemic attacks (MIAs) in clonal myeloproliferative 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 did not inhibit platelet cyclo-oxygenase and had no effect at all on erthromelalgia indicating that activation of prostagandin metabolism by JAK2-mutated platelets at high shear stress in arterioles is necessary for erthromelalgia to develop.

• Erythromelalgia and its subsequent microvascular ischemic complications in JAK2, CALR, TPO and MPL mutated clonal myeloproliferative thrombocythemias is relieved and cured by aspirin due to irreversible inhibition of platelet cyclo-oxygenase activity but not by anticoagulation with coumarin, unfractionated heparin (UFH) or low molecular heparin (LMWH).

• Incurable erythrothermalgia is a rare dominantly inherited neuropathy caused by gain function mutations in the SCN9A gene that result in warmth-induced burning pain of the body and both legs sparing the toes and fingers caused by spontaneous inducition of action potentials firing of the Nav1.7 mutated small C-fiber DRG nociceptive neurons of the neurosensory-vasomotor arteriolar-capillary-AVS function unit in the skin.

• Inherited erythrothermalgia in Nav1.7 channelopathy induced burnig pain, like fire in severe cases, and red congestion of the skin of legs and body with sparing of the toes and fingers. Neuropathic erythrothermalgia remains incurable and therefore recently labeled as the ‘Man on Fire Syndrome’.

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Acknowledgments

The author is very grateful to Prof Johan Abels, my teacher in Hematology and Bloodcoagulation (1974-1981) and to Dr Drenth and Dr Van Genderen for their significant contributions and publications in scientific friendship during so many years since 1990.

Declaration of interest

The author is a founder of the Goodheart Intitute & Foundation in Nature Medicine & Health, Rotterdam, The Netherlands, Freedom of Science and Education, European Free University. JJ Michiels serves as consultant professor in the Bloodcoagulation, Hemostasis Research Laboratory (co-founder VWF-VWD research program) at the department of Hematology University Hospital, Antwerp; as consultant professor in Hematology and Bloodcoagulation, Comenius University, Bratislava and Martin, Slovakia; as consultant professor in Hematology, Romania MPN Working Group, University Hospital Bucharest; consultant to the Dutch Society of Internal Medicine and Ministery of Public Health; consultant of Industrial and Pharmaceutical Medicine; as an editor of 3 Medical Journals and as a guest editor on request and by self initiation. Writing assistance was utilised in the preparation of this manuscript, it was carried out at the Goodheart Institute and Foundation in Nature Medicine and Health, Rotterdam, The Netherlands. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.