Do we need antiplatelet therapy in thrombocytosis? Contra

Rüdiger E. Scharf

doi:10.5482/HAMO-16-06-0016

Hämostaseologie, Table of Contents

Hamostaseologie 2016; 36(04): 241-260
DOI: 10.5482/HAMO-16-06-0016

Review

Schattauer GmbH

Do we need antiplatelet therapy in thrombocytosis? Contra

Proposal for an individualized risk-adapted treatmentBrauchen wir eine antithrombozytäre Therapie bei Thrombozytose? ContraVorschläge zur individualisierten risiko-adaptierten Behandlung

Rüdiger E. Scharf

¹Dept. of Experimental and Clinical Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University Medical Center, Düsseldorf

²Hemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf

³Biological Medical Research Center, Heinrich Heine University, Düsseldorf

› Author Affiliations

Abstract

Summary

Thrombocytosis is a frequent laboratory finding but not a diagnosis. Therefore, elevated platelet counts (>450 × 10⁹/l) require careful diagnostic work-up to differentiate between reactive thrombocytosis (RT), caused by various conditions, and essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN). In either setting, aspirin is widely used in clinical practice. However, RT (even at platelet counts >1000 × 10⁹/l) has never been shown to cause thrombosis or bleeding due to acquired von Willebrand factor defects in association with high platelet counts. Identification of reactive conditions and appropriate therapy of the underlying disorder are most relevant. By contrast to RT, ET and related MPN can be associated with thrombosis and/or hemorrhage. Current recommendations suggest the use of low-dose aspirin in all patients with ET unless contraindicated. However, the strength of this recommendation is weak, i. e. evidence level IIb grade B. A potential benefit of aspirin used for primary thromboprophylaxis in ET is mostly derived from the ECLAP study in polycythemia vera (PV). However, translating study results from PV to ET appears to be highly questionable and may be biased. In the absence of robust data regarding the benefit-risk balance of aspirin in ET, it appears reasonable (1) to stratify patients according to their individual thrombotic and bleeding risk, (2) to restrict the use of aspirin to high-risk categories and patients with microcirculatory disturbances, (3) to test for pharmacological efficacy (COX-1 inhibition; measurement of TXB₂), and (4) to modify the aspirin dosing regimen (twice instead of once daily) if required.

Zusammenfassung

Thrombozytose ist ein häufiger Laborbefund, aber keine Diagnose. Erhöhte Thrombozytenwerte (>450 × 10⁹/l) erfordern daher eine Differenzierung zwischen reaktiver Thrombozytose (RT) bei verschiedenen Erkrankungen und essenzieller Thrombozythämie (ET), einer myeloproliferativen Neoplasie (MPN). In beiden Fällen wird Aspirin breit eingesetzt. Allerdings wurde nie belegt, dass eine RT (selbst bei Thrombozytenwerten >1000 × 10⁹/l) Thrombosen oder Blutungen als Folge eines erworbenen von-Willebrand-Syndroms bei ausgeprägter Thrombozytose hervorruft. Bei RT bleiben Nachweis auslösender Ursachen und Behandlung der Grunderkrankung maß-geblich. Im Gegensatz dazu treten bei ET und anderen MPN Thrombosen und/oder Blutungen auf. Sofern keine Kontraindikation besteht, wird derzeit bei allen Patienten mit ET eine niedrig dosierte Aspirin-Behandlung empfohlen. Die Beweislage hierfür ist aber schwach (Evidenzklasse IIb Grad B). Ein möglicher Nutzen von Aspirin zur antithrombotischen Primärprophylaxe bei ET wird hauptsächlich aus der ECLAP-Studie bei Polycythaemia vera (PV) abgeleitet. Eine Übertragung der PV-Studienergebnisse auf ET-Patienten erscheint jedoch äußerst fragwürdig, da potenziell irrtumsbelastet. Auf Grund fehlender verlässlicher Daten zur Nutzen-Risiko-Bewertung von Aspirin bei ET wird vorgeschlagen, 1) die Patienten entsprechend ihrem individuellen Thrombose- und Blutungsrisiko zu stratifizieren, 2) eine Aspirin-Behandlung auf die Hochrisikogruppe und Patienten mit akuten Mikrozirkulationsstörungen zu beschränken, 3) die pharmakologische Wirksamkeit von Aspirin zu prüfen (COX-1-Hemmung; TXB₂-Spiegel-Bestimmung) und 4) das Aspirin-Dosierungsintervall (2-mal statt 1-mal tgl.) gegebenenfalls zu anzupassen.

Keywords

Reactive thrombocytosis - essential thrombocythemia - von Willebrand factor - bleeding - thrombosis - aspirin - personalized medicine

Schlüsselwörter

Reaktive Thrombozytose - essenzielle Thrombozythämie - von-Willebrand-Faktor - Blutungen - Thrombosen - individualisierte Medizin

Full Text

References

References
1 Harrison CN, Bareford D, Butt N. et al. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 2010; 149: 352-375.
2 Harrison CN, Butt N, Campbell P. et al. Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia. Br J Haematol 2014; 167: 421-423.
3 Kreher S, Ochsenreither S, Trappe RU. et al. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (OGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). Ann Hematol 2014; 93: 1953-1963.
4 Beer PA, Erber WN, Campbell PJ, Green AR. How I treat essential thrombocythemia. Blood 2011; 117: 1472-1482.
5 Cervantes F. Management of essential thrombocythemia. Hematology 2011; 2011: 215-221.
6 Harrison CN, Garcia NC. Management of MPN beyond JAK2. Hematology 2014; 2014: 348-354.
7 Barbui T, Barosi G, Birgegard G. et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29: 761-770.
8 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90: 162-173.
9 Spiviak JL. Polycythemia vera and other myeloproliferative diseases. In: Kasper DL, Braunwald E, Fauci AS. et al. (eds). Harrison‘s Principles in Internal Medicine. 16th edn. New York: McGraw-Hill; 2005. pp 626-631.
10 Girodon F, Bonicelli G, Schaeffer C. et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica 2009; 94: 865-869.
11 Griesshammer M, Bangerter M, Sauer T. et al. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999; 245: 295-300.
12 Schafer AI. Thrombocytosis. N Engl J Med 2004; 350: 1211-1219.
13 Alberio L. Do we need antiplatelet therapy in thrombocytosis? Pro. Diagnostic and pathophysiologic considerations for making a treatment choice. Hämostaseologie. 2016 36. __-__.
14 Budde U, Scharf RE, Franke P. et al. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma. Blood 1993; 82: 1749-1757.
15 James C, Ugo V, Le Couedic JP. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-1148.
16 Baxter EJ, Scott LM, Campbell PJ. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-1061.
17 Rumi E, Pietra D, Guglielmelli P. et al. Acquired copy-neutral loss of heterozygosity of chromo-some 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood 2013; 121: 4388-4395.
18 Klampfl T, Gisslinger H, Harutyunyan AS. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379-2390.
19 Nangalia J, Massie CE, Baxter EJ. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391-2405.
20 Milosevic Feenstra JD, Nivarthi H, Gisslinger H. et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 2016; 127: 325-332.
21 Cabagnols X, Favale F, Pasquier F. et al. Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood 2016; 127: 333-342.
22 Beer PA, Campbell PJ, Scott LM. et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008; 112: 141-149.
23 Vannucchi AM, Antonioli E, Guglielmelli P. et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 2008; 112: 844-847.
24 Rotunno G, Mannarelli C, Guglielmelli P. et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014; 123: 1552-1555.
25 Skoda RC. Hereditary myeloproliferative disorders. Haematologica 2010; 95: 6-8.
26 Teofili L, Larocca LM. Advances in understanding the pathogenesis of familial thrombocythaemia. Br J Haematol 2011; 152: 701-712.
27 Shim K, Anderson PJ, Tuley EA. et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008; 111: 651-657.
28 Buss DH, Cashell AW, O’Connor ML. et al. Occur-rence, etiology, and clinical significance of extreme thrombocytosis: a study of 280 cases. Am J Med 1994; 96: 247-253.
29 Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104: 2822-2829.
30 Simanek R, Vormittag R, Ay C. et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Hae-most 2010; 8: 114-120.
31 Yee DL, Sun CW, Bergeron AL. et al. Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106: 2723-2739.
32 Scharf RE, Rahman MM, Seidel H. The impact of acquired platelet dysfunction. Hamostaseologie 2011; 31: 28-40.
33 Scharf RE, Zotz RB. Blood platelets and myocardial infarction: do hyperactive platelets really exist?. Transfus Med Hemother 2006; 33: 189-199.
34 Ay C, Simanek R, Vormittag R. et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008; 112: 2703-2708.
35 Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005; 128: 275-290.
36 Falanga A, Marchetti M. Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost 2014; 40: 348-358.
37 Adams BD, Baker R, Lopez JA, Spencer S. Myeloproliferative disorders and the hyperviscosity syndrome. Hematol Oncol Clin North Am 2010; 24: 585-602.
38 Cortelazzo S, Finazzi G, Ruggeri M. et al. Hydro-xyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332: 1132-1136.
39 Budde U, van Genderen PJ. Acquired von Wille-brand disease in patients with high platelet counts. Semin Thromb Hemost 1997; 23: 425-431.
40 Tefferi A, Gangat N, Wolanskyj AP. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter?. Blood 2006; 108: 2493-2494.
41 Landolfi R, Rocca B, Patrono C. Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment. Crit Rev Oncol Hematol 1995; 20: 203-222.
42 Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost 2013; 11: 1215-1227.
43 Passamonti F, Randi ML, Rumi E. et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 2007; 110: 485-489.
44 Bazzan M, Tamponi G, Schinco P. et al. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol 1999; 78: 539-543.
45 Passamonti F, Rumi E, Pungolino E. et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004; 117: 755-761.
46 Mesa RA, Silverstein MN, Jacobsen SJ. et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: Olmsted County Study, 1976–1995. Am J Hematol 1999; 61: 10-15.
47 Tefferi A, Guglielmelli P, Larson DR. et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124: 2507-2513.
48 Papadakis E, Hoffman R, Brenner B. Thrombohemorrhagic complications of myeloproliferative disorders. Blood Rev 2010; 24: 227-232.
49 Scharf RE. Acquired disorders of platelet function. In: Gresele P, Lopez JA, Kleiman N. Page CP (eds). Platelets in Thrombotic and Non-Thrombotic Disorders – an Update. Berlin, Heidelberg, New York: Springer; 2016. (in press).
50 Patrono C, Rocca B, De Stefano V. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood 2013; 121: 1701-1711.
51 Reimers HJ, Scharf RE, Baker RK. Thrombin pre-treatment of human platelets impairs thromboxane A₂ synthesis from endogenous precursors in the presence of normal cyclooxygenase activity. Blood 1984; 63: 858-865.
52 Scharf RE. Funktionelle und biochemische Char-akterisierung aktivierter Blutplättchen. Sekretions-muster, Aggregationsverhalten und Zyklooxygenaseaktivität nach vorausgegangener Thrombinex-position. In: Thrombozyten und Mikrozirkulationsstörungen. Stuttgart: Schattauer; 1986. pp 199-212.
53 Wehmeier A, Fricke S, Scharf RE, Schneider W. A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders. Eur J Haematol 1990; 45: 191-197.
54 Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood 1984; 64: 1-12.
55 Gresele P. Subcommittee on Platelet Physiology of the International Society on Thrombosis and Haemostasis.. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 314-322.
56 Kaywin P, McDonough M, Insel PA, Shattil SJ. Platelet function in essential thrombocythemia. Decreased epinephrine responsiveness associated with a deficiency of platelet alpha-adrenergic receptors. N Engl J Med 1978; 299: 505-509.
57 Panova-Noeva M, Marchetti M, Spronk HM. et al. Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera. Am J Hematol 2011; 86: 337-342.
58 Panova-Noeva M, Marchetti M, Buoro S. et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood 2011; 118: 2599-2601.
59 Pascale S, Petrucci G, Dragani A. et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119: 3595-3603.
60 Hobbs CM, Manning H, Bennett C. et al. JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Blood 2013; 122: 3787-3797.
61 Landolfi R, Di Gennaro L, Barbui T. et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109: 2446-2452.
62 Carobbio A, Finazzi G, Guerini V. et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007; 109: 2310-2313.
63 Carobbio A, Antonioli E, Guglielmelli P. et al. Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol 2008; 26: 2732-2736.
64 Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor?. Blood 2009; 114: 759-763.
65 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
66 Smedly LA, Tonnesen MG, Sandhaus RA. et al. Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest 1986; 77: 1233-1243.
67 Del Maschio A, Zanetti A, Corada M. et al. Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J Cell Biol 1996; 135: 497-510.
68 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
69 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123: 2768-2776.
70 Hurtado-Nedelec M, Csillag-Grange MJ, Boussetta T. et al. Increased reactive oxygen species production and p47phox phosphorylation in neutrophils from MPD patients with JAK2 (V617F) mutation. Haematologica 2013; 98: 1517-1524.
71 Fuchs TA, Abed U, Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176: 231-241.
72 Isermann B, Hendrickson SB, Zogg M. et al. Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. J Clin Invest 2001; 108: 537-46.
73 Falanga A, Marchetti M, Vignoli A. et al. V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. Exp Hematol 2007; 35: 702-711.
74 Marchetti M, Castoldi E, Spronk HM. et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera. Blood 2008; 112: 4061-4068.
75 Barbui T, Finazzi G, Carobbio A. et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 2012; 120: 5128-5133.
76 Passamonti F, Thiele J, Girodon F. et al. A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 2012; 120: 1197-1201.
77 Finazzi G. How to manage essential thrombocythemia. Leukemia 2012; 26: 875-882.
78 Harrison CN, Barbui T. Aspirin in low-risk ET, not so simple after all?. Leukemia Res 2011; 35: 286-289.
79 Landolfi R, Marchioli R, Kutti J. et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114-124.
80 Finazzi G, Carobbio A, Thiele J. et al. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia 2012; 26: 716-719.
81 Harrison CN, Campbell PJ, Buck G. et al. Hydro-xyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33-45.
82 Alvarez-Larrán A, Cervantes F, Pereira A. et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010; 116: 1205-1210.
83 Ruggeri M, Finazzi G, Tosetto A. et al. No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 1998; 103: 772-777.
84 Gisslinger H, Gotic M, Holowiecki J. et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013; 121: 1720-1728.
85 Squizzato A, Romualdi E, Middeldorp S. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 2008; CD006503.
86 Patrono C, Baigent C, Hirsh J, Roth G. American College of Chest P. Antiplatelet drugs: American College of Chest P hysicians Evidence-Based Clinical Practice Guidelines (8^th ed). Chest 2008; 133: 199S-233S.
87 Catella-Lawson F, Reilly MP, Kapoor SC. et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809-1817.
88 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372.
89 Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330: 1287-1294.
90 Patrono C, Garcia Rodriguez LA, Landolfi R, Bai-gent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
91 Dragani A, Pascale S, Recchiuti A. et al. The contribution of COX-1 and –2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy. Blood 2010; 115: 1054-1061.
92 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscl Thromb Vasc Biol 2004; 24: 1980-1987.
93 Scharf RE, Suhijar D, Del Zoppo GJ. Analysis of platelet aggregation defects: characterization of dysfunctional GPIIb-IIIa using conformation-specific antibodies. Thromb Haemost 1993; 69: 1018.
94 Wehmeier A, Tschope D, Esser J. et al. Circulating activated platelets in myeloproliferative disorders. Thromb Res 1991; 61: 271-278.
95 Rocca B, Ciabattoni G, Tartaglione R. et al. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 1995; 74: 1225-1230.
96 Jensen MK, de Nully Brown P, Lund BV. et al. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol 2000; 110: 116-124.
97 Viallard JF, Solanilla A, Gauthier B. et al. Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis. Blood 2002; 99: 2612-2614.
98 Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC. et al. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol 2009; 84: 102-108.