The Paradox of Platelet Activation and Impaired Function: Platelet-von Willebrand Factor Interactions, and the Etiology of Thrombotic and Hemorrhagic Manifestations in Essential Thrombocythemia and Polycythemia Vera

ABSTRACT

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased β-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 × 10⁹/L). Despite strong evidence of in vivo platelet activation, the ex vivo platelet function tests are impaired. Platelet dysfunction in ET and PV typically is characterized by a missing second-wave adrenaline aggregation, an increased adenosine diphosphate aggregation threshold, and reduced secretion products, but a normal arachidonic acid or collagen-induced aggregation. The proposed concept is that platelets in thrombocythemia (ET and PV) are hypersensitive. Due to the existing high shear stress in the microvasculature (end-arterial circulation), platelets spontaneously activate, secrete their products, form aggregates mediated by von Willebrand factor (vWF) that transiently plug the microcirculation, deaggregate, and then recirculate as exhausted defective platelets with secondary storage pool disease on ex vivo analysis. At increasing platelet counts from below to above 1000 × 10⁹/L, the thrombotic condition changes into an overt spontaneous bleeding tendency as a result of a functional vWF deficiency that is caused by proteolysis of large vWF multimers. This is consistent with acquired type 2 von Willebrand syndrome (AvWS). AvWS is reversible by reduction of the platelet count to normal. The acquired JAK2 V617F gain of function mutation is the cause of trilinear myeloproliferative disease with the sequential occurrence of ET and PV. Heterozygous JAK2 V617F mutation with slightly increased kinase activity is enough for the induction of spontaneous megakaryopoiesis and erythropoiesis, and an increase of hypersensitive platelets is the cause of aspirin-sensitive, platelet-mediated microvascular ischemic and thrombotic complications in ET and early PV mimicking ET. Homozygous JAK2 mutation with pronounced increase of kinase activity is associated with pronounced trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, with the most frequent clinical picture of classical PV complicated by major thrombosis, in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia.

KEYWORDS

Platelets - aspirin - thrombosis - bleeding - acquired von Willebrand syndrome - essential thrombocythemia - polycythemia vera - myeloproliferative disorders

REFERENCES

• 1 Gunz F W. Hemorrhagic thrombocythemia. A critical review.  Blood. 1960;  15 706-723
• 2 Michiels J J. Erythromelalgia and Thrombocythemia [thesis]. Rotterdam, The Netherlands; Erasmus University Rotterdam 1981
• 3 Van Genderen P JJ, Michiels J J. Erythromelalgic, thrombotic and hemorrhagic thrombocythemia.  Presse Med. 1994;  23 73-77
• 4 Michiels J J, van de Velde A, van Vliet H HDM, van der Planken M, Schroyens W, Berneman Z. Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications.  Semin Thromb Hemost. 2002;  28 111-131
• 5 Michiels J J, Gadisseur A, Budde U et al.. Characterization, classification and treatment of von Willebrand diseases: a critical appraisal of the literature and personal experiences.  Semin Thromb Hemost. 2005;  31 577-601
• 6 Michiels J J, Abels J, Steketee J, van Vliet H HDM, Vuzevski V D. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.  Ann Intern Med. 1985;  102 466-471
• 7 Michiels J J, van Genderen P JJ, Lindemans J, van Vliet H HDM. Erythromelalgic, thrombotic and hemorrhagic thrombocythemia.  Leuk Lymphoma. 1996;  22(suppl 1) 47-56
• 8 Michiels J J, Koudstaal P J, Mulder A H, van Vliet H HDM. Transient neurologic and ocular manifestations in primary thrombocythemia.  Neurology. 1993;  43 1107-1110
• 9 Scheffer M G, Michiels J J, Simoons M L, Roelandt J RTC. Thrombocythemia and coronary artery disease.  Am Heart J. 1991;  122 573-576
• 10 Michiels J J, van Genderen P JJ, Jansen P HP, Koudstaal P J. Atypical transient ischemic attacks in thrombocythemia of various myeloproliferative disorders.  Leuk Lymphoma. 1996;  22(suppl 1) 65-70
• 11 Michiels J J. Platelet dependent and aspirin responsive arterial thrombophilia in essential thrombocythemia.  Thorax J. 1996;  8 1-3
• 12 Van Genderen P JJ, Michiels J J. Erythromelalgia: a pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera.  Semin Thromb Hemost. 1997;  23 357-363
• 13 Koudstaal P J, Koudstaal A. Neurologic and visual symptoms in essential thrombocythemia.  Semin Thromb Hemost. 1997;  23 365-370
• 14 Griesshammer M, Bangerter M, van Vliet H HDM, Michiels J J. Aspirin in essential thrombocythemia: status quo and quo vadis.  Semin Thromb Hemost. 1997;  23 371-383
• 15 Michiels J J. Erythromelalgia and vascular complications in polycythemia vera.  Semin Thromb Hemost. 1997;  23 441-454
• 16 Schafer A I. Bleeding and thrombosis in the myeloproliferative disorders.  Blood. 1984;  64 1-12
• 17 Ravandi-Kashani F, Schafer A I. Microvascular disturbances, thrombosis and bleeding in thrombocythemia: current concepts and perspectives.  Semin Thromb Hemost. 1997;  23 479-488
• 18 Michiels J J. Erythromelalgia and thrombocythemia. A disease of platelet prostaglandin metabolism.  Semin Thromb Hemost. 1997;  23 335-338
• 19 Van Genderen P JJ, Mulder P GH, Waleboer M, van de Moesdijk D, Michiels J J. Prevention from treatment of thrombotic complications in essential thrombocythemia: efficacy and safety of aspirin.  Br J Haematol. 1997;  97 179-184
• 20 Epstein E, Goedel A. Hämorrhagische thrombozythämie.  Virchows Arch. 1934;  293 233-247
• 21 De La Chapelle A, Traskelin A L, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.  Proc Natl Acad Sci USA. 1993;  90 4495-4499
• 22 Berk P, Wasserman L R, Fruchtman S M, Goldberg J D. Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group. In: Wasserman LR, Berk PD, Berlin NI Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, PA; WB Saunders 1995: 166-194
• 23 Fruchtman S M, Mack K, Kaplan M E, Peterson P, Berk P D, Wasserman L R. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera.  Semin Hematol. 1997;  34 17-23
• 24 Lawrence J H. The control of polycythemia vera by marrow inhibition.  JAMA. 1949;  141 13-18
• 25 Pearson T C, Wetherley-Mein G. Vascular occlusive episodes and venous hematocrit in primary proliferative polycythaemia.  Lancet. 1978;  2 1219-1222
• 26 Thomas D J, Marshall J, Russell R WR et al.. Cerebral blood-flow in polycythemia.  Lancet. 1977;  2 161-163
• 27 Thomas D J, du Boullat G H, Marshall J et al.. Effect of haematocrit on cerebral blood flow in man.  Lancet. 1977;  2 941-943
• 28 Messinezy M, Pearson T C, Pochazka A, Wetherley-Mein G. Treatment of primary proliferative polycythemia by venesection and low dose busulphan. Retrospective study from one centre.  Br J Haematol. 1985;  61 657-666
• 29 Barabas A P, Offen H D, Meinhari E A. The arterial complications of polycythemia vera.  Br J Surg. 1973;  60 183-187
• 30 Landolfi R, Marchioli R. European collaboration on low-dose aspirin in polycythemia vera (ECLAP): a randomized trial.  Semin Thromb Hemost. 1997;  23 473-478
• 31 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low-dose aspirin in polycythemia vera: results of the ECLAP trial.  N Engl J Med. 2004;  350 114-124
• 32 Huijgens P C, Van Den Berg C AM, Van Der Meer C, Imandt L MFM, Langenhuizen M MAC. Dosage of acetylsalicylic acid for inhibition of platelet function.  Scand J Haematol. 1980;  25 76-80
• 33 Kalmann R, Nieuwenhuis H K, de Groot P G, van Gijn J, Sixma J J. Effects of low dose aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF-1 excretion in healthy subjects.  Thromb Res. 1987;  45 355-361
• 34 The Dutch TIA Study Group . Protective effects of low dose aspirin and atenolol in patients with transient ischemic attacks or nondisabling stroke.  Stroke. 1988;  19 512-517
• 35 Patrono C. Aspirin and human platelets: from clinical trials yto acetylation of cyclooxygenase and back.  Trends Pharmacol Sci. 1989;  10 453-458
• 36 Patrono C. Aspirin as an antiplatelet drug.  N Engl J Med. 1994;  330 1287-1294
• 37 Michiels J J. Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 247-251
• 38 Michiels J J. Acquired von Willebrand disease due to increasing platelet count can readily explain the paradox of thrombosis and bleeding in thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 147-151
• 39 Bellucci S, Michiels J J. Spontaneous proliferative megakaryopoiesis and platelet hyperactivity in essential thrombocythemia: is thrombopoietine the link?.  Ann Hematol. 2000;  79 51-58
• 40 Michiels J J, Ten Kate F WJ, Vuzevski V D, Abels J. Histopathology of erythromelalgia in thrombocythemia.  Histopathology. 1984;  8 669-678
• 41 Van Genderen P JJ, Lucas I S, van Strik R et al.. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.  Thromb Haemost. 1996;  76 333-338
• 42 Van Genderen P JJ, Michiels J J, van Strik R, Lindemans J, van Vliet H HDM. Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.  Thromb Haemost. 1995;  73 210-214
• 43 Van Genderen P JJ, Prins F, Michiels J J, Schrör K. Thromboxane-dependent platelet activation in vivo precedes arterial thrombosis in thrombocythaemia: a rationale for the use of low-dose aspirin as an antithrombotic agent.  Br J Haematol. 1999;  104 438-441
• 44 Landolfi R, Ciabattoni G, Patrinani P et al.. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo.  Blood. 1992;  80 1965-1971
• 45 Rocca B, Ciabattoni G, Tartaglione R et al.. Increased thromboxane biosynthesis in essential thrombocythemia.  Thromb Haemost. 1995;  74 1225-1230
• 46 Karakantza M, Giannakoulas N C, Zikos P et al.. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia vera.  Int J Hematol. 2004;  79 253-259
• 47 Finazzi G, Budde U, Michiels J J. Bleeding time and platelet function in essential thrombocythemia and other myeloproliferative disorders.  Leuk Lymphoma. 1996;  22(suppl 1) 71-78
• 48 Rao A K. Molecular and biochemical basis for the platelet dysfunction in myeloproliferative disorders.  Semin Hematol. 2004;  41 6-9
• 49 Cesar J M, de Miguel D, Garcia Avello A, Burgaleta C. Platelet dysfunction in primary thrombocythemia using the platelet function analyzer, PFA-100.  Am J Clin Pathol. 2005;  123 772-777
• 50 Michiels J J, Berneman Z, Schroyens W, Koudstaal P J, Lindemans J, van Vliet H HDM. Platelet-mediated thrombotic complications in patients with ET: reversal by aspirin, platelet reduction, and not by coumadin.  Blood Cells Mol Dis. 2006;  36 199-205
• 51 Michiels J J, Berneman Z, Van Bockstaele D, VanDer Planken M, De Raeve H, Schroyens W. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera.  Semin Thromb Hemost. 2006;  32 174-207
• 52 Stuart M, Miller M, Davey F, Wolk J. The post-aspirin bleeding time: a screening test for evaluating haemostatic disorders.  Br J Haematol. 1979;  43 649-659
• 53 Barbui T, Buelli M, Cortelazzo S, Viero P, De Gaetano G. Aspirin and the risk of bleeding in patients with thrombocythemia.  Am J Med. 1987;  83 265-268
• 54 Van Genderen P JJ, van Vliet H HDM, Prins F J et al.. The excessive prolongation of the bleeding time by aspirin in essential thrombocythemia is related to a decrease of large von Willebrand factor multimers in plasma.  Ann Hematol. 1997;  75 215-220
• 55 Troost M M, van Genderen P JJ. Excessive prolongation of the Ivy bleeding time after aspirin in essential thrombocythemia is also demonstrable in vitro in the high shear stress system PFA-100.  Ann Hematol. 2002;  81 352-353
• 56 Fabris F, Casonato A, Del Ben M G, De Marco L, Girolami A. Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis.  Br J Haematol. 1986;  63 75-83
• 57 Mohri H. Acquired von Willebrand disease in patients with polycythemia vera.  Am J Hematol. 1987;  26 135-146
• 58 Lopez-Fernandez M F, Lopez-Berges C, Martin R, Pardo A, Ramos F J, Battle J. Abnormal structure of von Willebrand factor in myeloproliferative syndrome is associated to either thrombotic or bleeding diathesis.  Thromb Haemost. 1987;  58 753-757
• 59 Tatewaki W, Takahashi H, Shibata H. Multimeric composition of plasma von Willebrand factor in chronic myeloproliferative disorders.  Clin Lab Haematol. 1988;  10 417-425
• 60 Castaman G, Lattuada A, Ruggeri M, Tosetto A, Mannucci P M, Rodeghiero F. Platelet von Willebrand factor abnormalities in myeloproliferative syndromes.  Am J Hematol. 1995;  49 289-293
• 61 Van Genderen P JJ, Budde U, Michiels J J, van Strik R, van Vliet H HDM. The reduction of large von Willebrand factor multimers in plasma in essential thrombocythemia is related to the platelet count.  Br J Haematol. 1996;  93 962-965
• 62 Van Genderen P JJ, Prins F J, Lucas I S, van de Moesdijk D, van Vliet H HDM, Michiels J J. Decreased half-life time of plasma von Willebrand factor collagen binding activity in essential thrombocythemia: normalization after cytoreduction of the increased platelet count.  Br J Haematol. 1997;  99 832-836
• 63 Budde U, Scharf R E, Franke P, Hartmann-Budde K, Dent F, Ruggeri Z M. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma.  Blood. 1993;  82 1749-1757
• 64 Budde U, Dent J A, Berkowitz S D, Ruggeri Z M, Zimmerman ThS. Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome.  Blood. 1986;  68 1213-1217
• 65 Van Genderen P JJ, Michiels J J, van der Poel-van de Luitgaarde S CPAM, van Vliet H HDM. Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemiawith platelet count.  Ann Hematol. 1994;  69 81-84
• 66 Budde U, van Genderen P JJ. Acquired von Willebrand disease in patients with high platelet counts.  Semin Thromb Hemost. 1997;  23 425-431
• 67 Van Genderen P JJ, Leenknegt H, Michiels J J. The paradox of bleeding and thrombosis in thrombocythemia: is von Willebrand factor the link?.  Semin Thromb Hemost. 1997;  23 385-389
• 68 Leupin L, Beck E A, Furlan M, Bucher U. Hämostasestörung mit verminderter Aktivität des von Willebrand-Faktors bei myeloproliferativen Syndromen.  Schweiz Med Wschr. 1993;  113 713-716
• 69 Budde U, Schaefer U, Mueller N et al.. Acquired von Willebrand's disease in the myeloproliferative syndrome.  Blood. 1984;  64 981-985
• 70 Raman B KS, Sawdyk M, Saeed A M. Essential thrombocythemia with acquired von Willebrand's disease.  Am J Clin Pathol. 1987;  88 102-106
• 71 Murakawa M, Okamura T, Tsutsumi K et al.. Acquired von Willebrand's disease in association with essential thrombocythemia: regression following treatment.  Acta Haematol. 1992;  87 83-87
• 72 James C, Ugo V, Le Couedic P F et al.. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera.  Nature. 2005;  434 1144-1148
• 73 Kaushanky K. On the origin of the chronic myeloproliferative disorders: it makes all sense.  Blood. 2005;  105 4187-4190
• 74 Goldman J M. A unifying mutation in chronic myeloproliferative disorders.  N Engl J Med. 2005;  352 1744-1745
• 75 Cazzola M, Skoda R. Gain of function, loss of control. A molecular basis for chronic myeloproliferative disorders.  Haematologica. 2005;  90 871-874
• 76 Geddis A E, Linden H M, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine.  Cytokine Growth Factor Rev. 2002;  13 61-73
• 77 Tong W, Zhang J, Lodish H F. Lnk inhibits erythropoiesis and EPO-dependent JAK2 activation and downstream signalling pathways.  Blood. 2005;  105 4604-4612
• 78 Levine R L, Wadleigh M, Cools J et al.. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis.  Cancer Cells. 2005;  7 387-397
• 79 Kralovics R, Passamonti F, Buser A S et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
• 80 Baxter E J, Scott L M, Campbell P J et al.. Acquired mutation of the tyrosine kinase in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
• 81 Zhao R, Xing S, Li Z et al.. Identification of an acquired JAK2 mutation in polycythemia vera.  J Biol Chem. 2005;  , In press
• 82 Jones A V, Kreil S, Xoi K et al.. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.  Blood. 2005;  106 2162-2168
• 83 Wolanskyj A P, Lasho T L, Schwager S M et al.. JAK2 V617 mutation in essential thrombocythaemia: clinical associations and long-term relevance.  Br J Haematol. 2005;  131 208-213
• 84 Antonioli E, Guglielmelli P, Pancrazzi A et al.. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia.  Leukemia. 2005;  19 1847-1849
• 85 Lu X, Levine R, Wernig G, Pikman Y, Zarnegar S, Gilliland D G. Expression of a homodimeric type I cytokine receptor is required for JAK2 V617F-mediated transformation.  Proc Natl Acad Sci USA. 2005;  102 18962-18967
• 86 Goerttler P S, Steimle C, Maerz E et al.. The JAK2 V617F mutation, PRV-1 over expression and EEC formation define a similar cohort of MPD patients.  Blood. 2005;  106 2862-2864
• 87 Kralovics R, Teo S S, Buser A S et al.. Altered gene expression in myeloproliferative disorders correlates with activation of signalling by the V617F mutation of JAK2.  Blood. 2005;  106 3374-3376
• 88 Passamonti F, Pietra D, Malabarba L et al.. Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders.  Br J Haematol. 2004;  126 650-656
• 89 Passamonti F, Rumi E, Pietra D et al.. Relation between JAK2 V617F mutation status, granulocyte activation, and constitutive mobilization of CD34 ⁺ cells into peripheral blood in myeloproliferative disorders.  Blood. 2006;  107 3676-3682
• 90 Michiels J J, Berneman Z, Schroyens W, Van Vliet H HDM. Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythemia and polycythemia vera.  Platelets. 2004;  15 67-84
• 91 Michiels J J, De Raeve H, Berneman Z et al.. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications.  Semin Thromb Hemost. 2006;  32 174-207
• 92 Villeval J L, James C, Pisani D F, Casadevall N, Vainchenker W. New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences in the management of patients.  Semin Thromb Hemost. 2006;  , In press
• 93 James C, Ugo V, Casadevall N, Constantinescu S N, Vainchenker W A. JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.  Trends Mol Med. 2005;  11 546-554
• 94 Schlemper R J, van der Maas A PC, Eikenboom J CJ. Familial essential thrombocythemia: clinical characteristics of 11 cases in one family.  Ann Hematol. 1994;  68 153-158
• 95 Ding J, Komatsu H, Wakita A et al.. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes the receptor for thrombopoietin.  Blood. 2004;  103 4198-4200
• 96 Wiestner A, Schlemper R J, van der Maas A PC, Skoda R C. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythemia.  Nat Genet. 1998;  18 49-52
• 97 Campbell P, Scott L M, Buck G et al.. Definition of essential thrombocythemia and relation of essential thrombocythemia to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.  Lancet. 2005;  366 1945-1953
• 98 Arellano-Rodrigo E, Alvarez-Larran A, Reverter J C, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status.  Haematoligica. 2006;  91 169-175