Thrombocytopenia in patients with proved antiphospholipid antibodies or with antiphospholipid syndrome

Czech version

Authors: A. Buliková ¹; D. Haruštiaková ²; J. Zavřelová ¹; L. Dušek ²; M. Penka ¹
Authors‘ workplace: Oddělení klinické hematologie FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Miroslav Penka, CSc. ¹; Institut biostatistiky a analýz Lékařské a Přírodovědecké fakulty MU Brno, přednosta doc. RNDr. Ladislav Dušek, CSc. ²
Published in: Vnitř Lék 2010; 56(Supplementum 1): 81-90
Category: 16th Parizek's Days, Ostrava-Poruba, March 25th –26th 2010

Overview

Thrombocytopenia in patients with antiphospholipid antibodies (APA) is relative common finding which is found in approximately 20–40% of cases. There are likely different mechanisms resulting in thrombocytopenia in these situations. Authors summarise current knowledge of pathophysiology, clinical manifestations and management of APA-associated thrombocytopenia and other causes of decreased value of peripheral blood platelets in APA positive persons.

Key words:
thrombocytopenia – antiphospholipid antibodies – pathophysiology – treatment

Sources

1. Harris EN, Asherson RA, Gharavi AE et al. Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibodies. Br J Haematol 1985; 59: 227–230.

2. Harris EN, Cahn JKH, Asherson RA et al. Thrombosis, recurrent fetal loss, and thrombocytopenia. Arch Intern Med 1986; 146: 2153–2156.

3. Asherson RA, Khamashta M, Ordi-Ros J. The “primary” antiphospholipid syndrome. Major clinical and serological features. Medicine 1989; 68: 366–375.

4. Alacrón-Segovia D, Pérez-Vézquez ME, Villa AR et al. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Sem Arthr Rheumat 1992; 21: 275–285.

5. Pierangeli SS, Chen PP, Raschi E et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenetic mechanisms. Semin Throm Hemost 2008; 34: 236–250.

6. Pennings MTT, Derksen RHWM, van Lummel M et al. Platelet adhesion to dimeric β₂-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibα and apoliporotein E receptor 2’. J Thromb Haemost 2007; 5: 369–377.

7. Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.

8. McNeil HP, Simpson RJ, Chesterman CN et al. Anti-phospholipid antibodies are directed a complex antigen that includes a lipid-binding inhibitor of coagulation. Proc Natl Acad Sci 1990; 87: 4120–4124.

9. Galli M, Comfurius P, Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990: 335: 1544–1547.

10. Matsuura E, Igarashi Y, Fujimoto M et al. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177–178.

11. Roubey RAS. Mechanisms of autoantibody-mediated thrombosis. Lupus 1998; 7: 114–119.

12. Pierangeli SS, Chen PP, Gonzalez EB. Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms. Curr Opin in Hematology 2006; 13: 366–375.

13. Giannakopoulos B, Passam F, Rahgozar S et al. Current concepts on the pathogenesis of the antiphospholipd syndrome. Blood 2007, 109; 422–430.

14. Meroni PL. Pathogenesis of the antiphospholipid syndrome: An additional example of the mosaic of autoimmunity. Blod 2008; 30: 99–103.

15. Raschi E, Testoni C, Bosisio D et al. Role of the MyD66 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 2003; 101: 3495–3500.

16. Vega-Ostertag M, Casper K, Swerlick Ret al. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheumat 2005; 52: 1545–1554.

17. Holers VM, Girardi G, Mo L et al. C3 activation is required for anti-phospholipid antibody-induced fetal loss. J Ex Med 2002; 1995: 211–220.

18. Redecha P, Tilley R, Tencati M et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blod 2007; 110: 2423–2431.

19. Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induces thrombocytopenia. Thromb Haemost 1996; 75: 536–541.

20. Vermylen J, Hoylaerts MF, Arnout J. Antibody-mediated thrombosis. Thromb Haemost 1997; 78: 420–426.

21. Arnout J, Vermylen J. Current status and implication of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Throm Haemost 2003; 1: 931–942.

22. Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996; 78: 420–426.

23. Pennings MTT, Derksen RHWM, van Lummer M et al. Platelet adhesion to dimeric β₂-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibα and apoliprotein E receptor 2‘. J Throm Haemost 2007; 5: 369–377.

24. Urbanus RT, Pennings MTT, Derksen RHWM et al. Platelet activation by dimeric β₂-glycoprotein I requires signaling via both glycoprotein Ibα and apolipoprotein E receptor 2’. J Thromb Haemost 2008; 6: 1405–1412.

25. Lutters BCH, Derksen RHWM, Tekelenburg WL et al. Dimers of β₂-Glykoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2’. J Biolog Chem 2003; 278: 33831–33838.

26. van Lummel M, Pennings MTT, Derksen RHWM et al. The binding site in β₂-glycoprotein I for ApoER2’ on platelet is located in domain V. J Biological Chem 2005; 280: 36729–36736.

27. Shi T, Giannakopoulos B, Yan X et al. Anti-β₂-glykoprotein I antibodies in complex with – β₂-glykoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Artritis Rheumat 2006; 54: 2558–2567.

28. Vega-Ostertak ME, Ferrata DE, Romay-Penabad Z et al. Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation. J Thromb Haemost 2007; 5: 1828–1834.

29. Hulstein JJJ, Lenting PJ, de Laat B et al. β₂-glycoprotein I inhibits von Willebrand factor-dependent platelet adhesion and aggregation. Blood 2007; 110: 1483–1491.

30. Hulstein JJJ, de Groot PG, Silence K at al. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Blood 2005; 106: 3035–3042.

31. Stasi R, Stipa E, Masi M et al. Prevalence and clinical significance of elevated antiphospholipid antibodies in patients with idiopatic thrombocytopenic purpura. Blood 1994; 84: 4203–4208.

32. Diz-Kücükkaya R, Hacihanefioglu A, Yenerel M et al. Antiphospholipid antibodies and antiphospholipid syndome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood 2001; 98: 1760–1764.

33. Bidot CJ, Jy W, Horstman LJ et al. Antiphosholipid antibodies in immune thrombocytopenic purpura tend to emerge in exacerbation and decline in remission. British J Haematol 2004; 128: 366–372.

34. Atsumi T, Furukawa S, Amengual O et al. Antiphospholipid antipody associated thromocytopenie and the paradoxical risk of thrombosis. Lupus 2006; 14: 499–504.

35. Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheumat 1999; 42: 1309–1311.

36. Macchi L, Rispal P, Clofent-Sanchez G et al. Anti-platelet antibodies in patients with systemic lupus erythematosus and primary antiphopholipid antibody syndrome: their relationship with observed thromocytopenia. British J Haematol 1997; 98: 336–341.

37. Jimenez JJ, Jy W, Mauro LM et al. Transendothelial migration of leukocytes is promoted by plasma from a subgroup if immune thrombocytopenic purpura patients with small-vessel ischemic brain disease. Am J Hematol 2008; 83: 206–211.

38. Dunoyer-Geindre S, Bochlen F, Favier R et al. Endothelial cell activation by immunuglobulins from patients with immune thromobcytopenic purpura or with antiphopholipid syndrome. Haematologica 2008; 84: 635–636.

39. Bizzato N, Brandaliase M. EDTA-dependent pseudothrombocytopenia. Association with antiplatelet and antiphospholipid antibodies. Am J Clin Patol 1995; 103; 103–107.

40. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002; 346: 995–1008.

41. Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response to intravenous immunoglobulin G in the treatment of patients with immune thromobcytopenie. Haematologica 2007; 92: 283–284.

42. Ollsson B, Andersson PD, Jernas M et al. T-cell mediated lysis of autologous platelets in chronic thromocytopenic purpura. Nat Med 2003; 9: 1123–1124.

43. Zang F, Chu X, Wang L et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76: 427–431.

44. McMillian R, Wang L, Tomer A et al. Suppression of in vitro megakaryocyte production by antiplatetet autoantibodies from adult patients with chronic ITP. Blood 2004; 103: 1364–1369.

45. Cervera R, Khamashta MS, Font J et al. Systemic lupus erythematosus: Clinical and immunological patterns of disease expression in a cohort of 1000 patients. Medicine 1993; 72: 113–124.

46. Cuadrado MJ, Mujic F, Muňoz E et al. Thrombocytopenia in the antiphospholipid syndrome. Ann Rheum Dis 1997; 56: 194–196.

47. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl Med 2007; 357: 580–587.

48. Gruel Y, Rupin A, Watier H et al. Anticardiopipin antibodies in heparin-associated thrombocytopenia. Thromb Res 1992; 67: 601–606.

49. Socher I, Kroll H, Jorsk S et al. Heparin-independent activation of platelet by heparin-induced thrombocytopenia antibodies: a common occurrence. J Thromb Haemost 2008; 6: 197–200.

50. Pauzner R, Greinacher A, Selleng K et al. False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Tromb Haemost 2009; 7: 1070–1074.

51. Martion-Toutain I, Piette JC, Diewmert MC et al. High prevalence of antibodies to platelet factor 4 heparin in patients with antiphospholipid antibodies in absence of heparin induced thromocytopenia. Lupus 2007; 16: 79–83.

52. Lo GK, Sigouin ChS, Warkentin TE. What is the potential overdiagnosis of heparin-induced thrombocytopenia. Am J Hematol 2007; 82: 1037–1043.

53. Warkentin TE. Antiphospholipid and anti-PF4 antibodies: an association affecting anti-PF4/heparin assay analysis. J Thromb Haemost 2009; 7: 1067–1069.

54. Espinosa G, Bucciarelli S, Cervera R et al. Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Ann Rheum Dis 2004; 63: 730–736.

55. Fojtík Z, Kořístek Z, Klabussay M et al. Recidivující trombotická trombocytopenická purpura u nemocné se systémovým lupus erythermatodes. Čes Revmatol 2003; 11: 157–160.

56. Cervera R, Font J, Gómez-Puerta JA et al. Validation of the preliminary criteria for the classification of catastrophic antiphosholipid syndrome. Ann Rheum Dis 2005; 64: 1205–1209.

57. Asherson RA, Pierangeli S, Cervera R. Is there a microangiopathic antiphospholipid syndrome? Ann Rheum Dis 2007; 66: 429–432.

58. Asherson RA, Pierangeli S, Cervera R. Microangiopathic antiphospholipid-associated syndromes revisited – new concepts relating to antiphospholipid antibodies and syndromes. J Rheumatol 2007; 34: 1793–1795.

59. Galli M, Finazzi G, Barbui T. Thromocytopenia in the antiphospholipid syndrome. Br J Haematol 1996; 93: 1–5.

60. Finazzi G. The Italian registry od antiphospholipid antibodies. Haematologica 1997; 82: 101–105.

61. Vianna JL, Khamashta MA, Ordi-Ros J et al. Comparison of the primary and secondary antiphospholipid syndrome: European multicentre study of 114 patients. Am J Med 1994; 96: 3–9.

62. Buliková A, Haruštiaková D, Zavřelová J et al. Long-term follow-up in patients with positive antiphospholipid antibodies – single centre experience. J Thromb Haemost 2009; Suppl. 2: PP–MO–259.

63. Leuzzi RA, Davis GH, Cowchock FS et al. Management of immune thromobocytopenic purpura associated with the antiphospholipid antibody syndrome. Clin Exp Rhematol 1997; 15: 197–200.

64. Galli M, Barbui T. Management of thrombocytopenia in Hughes syndrome. In: Khamashta MA (Ed.) Hughes syndrome. London: Springer Verlag 2000; 408–418.

65. Lim W. Antiphospholipid syndrome. Hematology (Am Soc Hematol Edu Program) 2009: 233–239.

66. Galindo M, Khamashta MA, Hughes GRV. Splenectomy for refractory thrombocytopenia in the antiphospholipid syndrome. Rheumatology 1999; 38: 848–853.

67. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Heaematol 2008; 141: 149–169.

68. Ruckert A, Glimm H, Lubbert M et al. Successful treatment of life-threatening Evans syndrome due to antiphospholipid antibody syndrome by rituximab-based regimen: a case with long-term follow-up. Lupus 2008; 17: 757–760.

69. Snowden JA, Martin-Rendon E, Watt SM. Clinical stem cell therapies for severe autoimmune diseases. Transfusion medicine 2009; 19: 223–234.

70. Orita T, Tsunoda H, Yabuta N et al. A novel therapeutic approach for thrombocytopenia by miniantibody agonist of the thrombopeitein receptor. Blood 2005; 105: 562–566.

71. Kavanaugh A. Danazol therapy in throm-bocytopenia associated with the antiphospholipid antibody syndrome. Ann Int Med 1994; 121: 767–768.

72. Durand JM, Lefevre P, Kaplanski G et al. Correction of thromocytopenia with dapson in the primary antiphospholipid syndrome. J Rheumatol 1993; 20: 1777–1778.

73. Dunoyer-Geindre S, Kruithof EKO, Boehledn F et al. Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies. J Throm Haemost 2004; 2: 1176–1181.

74. Erkan D, Harrison MJ, Levy R et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome. Arthritis and rheumatism 2007; 56: 2382–2391.

75. Alliot C, Messouak D, Albert F. Correction of thromocytopenia with aspirin in the primary antiphospholipid syndrome. Am J Hematol 2001; 68: 215–217.

76. Rand JH, Wu X-X, Quinn AS et al. Hydrochloroquine directly reduces the binding of antiphospholipid antibody-β₂-glycoprotein I complex to phospholipid bilayers. Blood 2008; 112: 1687–1695.

77. Suarez IM, Diaz RA, Aguayo CD et al. Correction of severe thrombocytopenia with choroquine in the primary antiphospholipid syndrome. Lupus 1996; 25: 81–83.

78. Hotlan SG, Knox SK, Terreri A. Use of fondaparinux in patient with antiphospholipid syndrome and heparin-associated thrombocytopenia. J Thromb Haemost 2006; 4: 1632–1634.

79. Athar U, Husain J, Hudson J et al. Prolonged half-life od argatroban in patients with renal dysfunction and antiphospholipid antibody syndrome being treated for heparin-induced thrombocytopenia. Am J Hematol 2007; 83: 245–246.