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World J Hematol. May 6, 2013; 2(2): 20-43
Published online May 6, 2013. doi: 10.5315/wjh.v2.i2.20
Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera
Jan Jacques Michiels, Fibo WJ Ten Kate, Peter J Koudstaal, Perry JJ Van Genderen
Jan Jacques Michiels, Department of Medicine, Erasmus Medical Center, Erasmus University Rotterdam, 3015 GE, Rotterdam, The Netherlands
Jan Jacques Michiels, Department of Hematology University Hospital Antwerp, B-2650 Edgem, Antwerp, Belgium
Jan Jacques Michiels, European Working Group on Myeloproliferative Neoplasms, Goodheart Institute and Foundation, 3069 AT, Rotterdam, The Netherlands
Fibo WJ Ten Kate, Department of Pathology, Erasmus Medical Center, Erasmus University Rotterdam, 3015 GE, Rotterdam, The Netherlands
Peter J Koudstaal, Department of Neurology, Erasmus Medical Center, Rotterdam, Erasmus University Rotterdam, 3015 GE, Rotterdam, The Netherlands
Perry JJ Van Genderen, Department of Internal Medicine, Haven Hospital, 3011 TD, Rotterdam, The Netherlands
Perry JJ Van Genderen, Erasmus Medical Center, Rotterdam, 3015 GE, Rotterdam, The Netherlands
Author contributions: Michiels JJ wrote the manuscript, discovered the platelet-mediated microvascular disturbances in thrombocythemia and conducted the studies on the etiology of platelet thrombophilia in thrombocythemia; Ten Kate FWJ performed the pathology study on skin biopsies from erythromelalgic areas and bone marrow histology for detection of early stage essential thrombocythemia and polycythemia vera; Van Genderen PJJ performed the platelet kinetic, platelet function and coagulation studies; Koudstaal PJ analyzed and interpreted the neurological, ocular and visual manifestations as part of the broad spectrum of aspirin responsive microvascular disturbances in thrombocythemia.
Correspondence to: Jan Jacques Michiels, MD, PhD, European Working Group on Myeloproliferative Neoplasms, Goodheart Institute and Foundation, Erasmus Tower, Veenmos 13, 3069 AT, Rotterdam, The Netherlands.
Telephone: +31-62-6970534 Fax: +31-10-4212054
Received: August 12, 2012
Revised: December 21, 2012
Accepted: January 5, 2013
Published online: May 6, 2013

Essential thrombocythemia (ET) and polycythemia vera (PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks (MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive platelet-rich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombomoduline (TM), increased urinary thromboxane B2 (TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase (COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complications, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression (not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2V617F mutated compared to JAK2 wild type ET.

Keywords: Erythromelalgia, Migraine-like cerebral transient ischemic attacks, Platelets, β-thromboglobulin, Thrombomoduline, Thrombosis, Aspirin, Anticoagulation, Arterial platelet thrombophilia, Essential thrombocythemia, Polycythemia vera