Review: Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera,” by Jan Jacques Michiels, et al., World Journal of Hematology, May 6, 2013,  doi:10.5315/wjh.v2.i2.20

This sprawling, carefully annotated study of the role of aspirin-responsive MIciels WJH 2013thrombophilia (coagulability) in ET and PV is a comprehensive and sometimes daunting review of cellular and vascular impacts of essential thrombocythemia and polycythemia vera and the means to assess and modify the risk of hemorrhage and thrombosis.

Its 24 pages, illustrated with slides, tables, and figures painstakingly describe the molecular and hematological effects of ET and PV and biologic pathways involved in reducing erythromelalgia  (pain, inflammation) and risk of vascular or cardiac events. Our review focuses narrowly on the impact of aspirin in reducing both thrombotic complications     and erythromelalgia although the paper itself , as indicated by the Michiels’ outline, goes much further afield in near encyclopedic review of therapeutic options, lavishly footnoted.


Abstract and Introduction

Histopathology of erythromelalgia in thrombocythemia

Involvement of platelets as the cause of erythromelalgia in ET

Migraine-like microvascular cerebral ischemic attacks in ET

 Activated platelets, leukocytes and endothelial cells in ET and PV

Thrombotic and hemorrhagic risk stratification in ET

Thrombohemorrhagic ET risk and the need to reduce platelet count without leukemogenic agents

Thrombosis and hemorrhage in thrombocythemia related to von Willebrand factor.  

The role of hematocrit and platelets in thrombosis risk.

Assessment in PV: Reversal by phlebotomy and low dose aspirin

Induction of complete hematological remission by IFN in early PF and ET

Molecular etiology of platelet mediated arteriolar thrombosis in ET and PV

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 “Erythromelalgia is the main pathognomonic and presenting symptom in patients with essential thrombocythemia and  thrombocythemia associated with polycythemia vera.”

Michiels immediately focuses on the painful swelling and burning frequently affecting extremities of patients with chronic MPNs.  The condition described in 1878 by Silas Weir Mitchell, who supplied a manuscript footnote tracing the etymological roots of the condition i.e.,  The “burning painful and red congestion of the foot and hand disorder might conveniently be labeled erythromelalgia, (From the Greek: erthyros=red, melos=extremity and algos=pain.)”

At the time the condition, then called Mitchell’s Disease, was not separated into the more common form of erythromelalgia that arises from a disease state and primary or congenital idiopathic erythromelalgia.

L.A. Smith in the American Heart Journal (1938)  first described aspirin’s effect in promptly relieving erythromelalgic pain over a period of  approximately three days.  Michiels established the involvement of platelets’ role in erythromelalgia through evidence of platelet consumption, platelet proliferation and increased platelet activation markers obtained through skin biopsy of swollen red areas. It was Michiels and his associates who. during the 1975-1981 period, discovered “the specific subset of patients with burning painful red extremities, who experienced clinical relief with aspirin, all had elevated platelet counts associated with thrombocythemia…or associated with polycythemia vera.”

Thrombophilia, a state of hypercoagulability, is a blood coagulation abnormality that increases the risk of thrombosis or blood clots in blood vessels.  A core contention of this paper and an earlier Michiels  publication (2002) is his observation:   “Complete relief of erthyromelalagic …pain is obtained with the cyclooxygenase inhibitor aspirin…”   (Cyclooxygenase (COX) is an enzyme that is responsible for the formation of prostanoids. The three main groups of prostanoids — prostaglandins, prostacyclins, and thromboxanes — are each involved in the inflammatory response.)

“Aspirin sensitive erythromelalgia is characterized by warm, red, congested extremities and painful burning sensations and causally linked to thrombcythemia in various myeloproliferative disorders….

“Acroparaesthesias (tingling, numbness, stiffness) “usually preceed the disabling red, swollen burning distress. Warmth intensifies the discomfort and cold provides relief …The long lasting effect of a single dose of aspirin is so specific for erythromelalgia that it can be used as a diagnostic criterion.”

Although he couldn’t contribute patients to the European Collaboration on Low Dose Aspirin in PV (ECLAP) “because nearly all PV patients in…The Netherlands were on low dose aspirin,” Michiels could call on ECLAP  data to support his contention that aspirin control of platelet function—coupled with normalizing platelet levels through use of platelet lowering agents “are effective in the prevention of platelet- mediated microvascular circulatory disturbances in thrombocythemia vera.

Treatment  with  low  dose  aspirin  significantly reduced the overall risk of  a combined end point of  microvascular and major vascular complications, including cardiac death, non-fatal myocardial infarction and stroke
and major venous thrombosis from 15.5% to 6.7% during 2.7 years follow-up. Absolute risk reduction was 8.4%. These significant risk reductions in major thrombosis were seen very soon after randomization. Major  total  and  gastro-intestinal  bleeding  were  slightly increased without reaching statistical significance.

Michiels ECLAP

THE COX-1 inhibition effect.

“Erythromelalgia in ET and PV,” writes Michiels,” is caused by platelet mediated arteriolar thrombosis and inflammation that can only be relieved by selective inhibition of  platelet COX1.  This platelet- mediated thrombotic disease (platelet thrombophilia) in the end-arterial circulation of  thrombocythemia (ET and PV)  patients,  first  described  by  Michiels et  al was confirmed by the Rotterdam MPD Study Group in a series
of  prospective histopathological, platelet kinetic, experimental  and  aspirin  intervention  studies  in  symptomatic and asymptomatic ET patients.”

Two Forms of Cyclooxygenase (COX)

In the 1990s, researchers discovered that two different COX enzymes existed, now known as COX-1 and COX-2. Cyclooxygenase-1 (COX-1) is  present in most tissues. In the gastrointestinal tract, COX-1 helps in maintaining the  stomach lining and is also critically involved in platelet and kidney  function. Cyclooxygenase-2 (COX-2) is found largely at inflammation sites. COX-1 and COX-2 convert arachidonic acid to prostaglandin, resulting in pain and inflammation.  Their biological functions make indiscriminate inhibition of COX-1 undesirable while COX-2 is targeted for inhibition.

Based on skin punch biopsies in erythromelalgic areas, Michiels “conceptualized that the symptoms of  platelet-mediated erythromelalgia, including migraine-like cerebral ischemic attacks and visual disturbances, are the result of  platelet activation and aggregation in vivo, which preferentially takes place in the arterioles….The  sustained  relief of  erythromelalgia and MIAs by aspirin is correlated with inhibition of  ADP, epinephrine, collagen and AA-induced platelet  aggregation,  which  is  the  result  of   irreversible inhibition of  platelet COX1, as can be measured by the MDA  in  PRP (platelet rich plasma).”
Michiels concludes his paper with a discussion of the ability of the interferons to effect complete hematological remission and a discussion of the molecular etiology of platelet mediated thrombosis in ET and PV in light of the new JAK2 mutation findings.
Michaelis Kiladjian chart 2
Basing his conclusions on the international Polycythemia Study Group (PVSG)  clinical studies and a few clinical studies from Silver, Kiladjian and Quintas-Cardama et al Michiels finds: “The rational for using IFN-α as the first-line treatment option in newly diagnosed PV-patients include its  effectiveness  to abate  constitutional  symptoms and to induce a  complete  remission, thereby avoiding phlebotomy, iron deficiency and macrocytosis associated with hydroxyurea.
IFN-α may  prevent  myelofibrosis  if used early in the early prefibrotic stage of  prodromal and overt PV disease.

“Clinicians .” conclude Michiels, “will be reluctant to postpone the use of hydroxyurea in early stage PV as long as it is a conservative approach using phlebotomy aiming at a hematocrit below 0.45, on top of  low dose aspirin for the control platelet function, and if  indicated, anagrelide for the control of platelet[ levels.]”.

Along with the Hasselbalch bone marrow biopsy slides (see cover, MQJ, Winter) Michiels provided this dramatic representation of Jean Jacques Kiladian’s work showing progressive reduction of the JAK2 mutation allele burden under interferon therapy.
-Zhenya Senyak
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© MPN Quarterly Journal, 2013. This work is licensed under a Creative Commons Attribution-NonCommercial No-Derivs 3.0 Unported License.