Download PDF
Thromb Haemost 1996; 76(05): 774-779
DOI: 10.1055/s-0038-1650659
Original Article
Schattauer GmbH Stuttgart

The Mechanism of Platelet Aggregation Induced by HLA-Related Antibodies

John T Brandt
The Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA
,
Carmen J Julius
The Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA
,
Jeanne M Osborne
1   The Department of Pathology, Ohio State University, Columbus, Ohio, USA
,
Clark L Anderson
1   The Department of Pathology, Ohio State University, Columbus, Ohio, USA
› Author Affiliations
Further Information

Publication History

Received 08 February 1996

Accepted after revision 19 August 1996

Publication Date:
11 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Immune-mediated platelet activation is emerging as an important pathogenic mechanism of thrombosis. In vitro studies have suggested two distinct pathways for immune-mediated platelet activation; one involving clustering of platelet FcyRIIa, the other involving platelet-associated complement activation. HLA-related antibodies have been shown to cause platelet aggregation, but the mechanism has not been clarified. We evaluated the mechanism of platelet aggregation induced by HLA-related antibodies from nine patients. Antibody to platelet FcyRIIa failed to block platelet aggregation with 8/9 samples, indicating that engagement of platelet FcyRIIa is not necessary for the platelet aggregation induced by HLA-related antibodies. In contrast, platelet aggregation was blocked by antibodies to human C8 (5/7) or C9 (7/7). F(ab’)2 fragments of patient IgG failed to induce platelet activation although they bound to HLA antigen on platelets. Intact patient IgG failed to aggregate washed platelets unless aged serum was added. The activating IgG could be adsorbed by incubation with lymphocytes and eluted from the lymphocytes. These results indicate that complement activation is involved in the aggregation response to HLA-related antibodies. This is the first demonstration of complement-mediated platelet aggregation by clinical samples. Five of the patients developed thrombocytopenia in relationship to blood transfusion and two patients developed acute thromboembolic disease, suggesting that these antibodies and the complement-dependent pathway of platelet aggregation may be of clinical significance.

 

  • References

  • 1 Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995; 89: 431-439
    CrossrefPubMedGoogle Scholar
  • 2 Lellouche F, Martinuzzo M, Said P, Maclouf J, Carreras LO. Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 1991; 78: 2894-2899
    PubMedGoogle Scholar
  • 3 Martinuzzo ME, Maclouf J, Carreras LO, L’vy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70: 667-671
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Campbell AL, Pierangeli SS, Welhausen S, Harris EN. Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. Thromb Haemost 1995; 73: 529-533
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Anderson CL, Chacko GW, Osborne JM, Brandt JT. The Fc receptor for immunoglobulin G (FcγRII) on human platelets. Semin Thromb Haemost 1995; 21: 1-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Anderson GP, Anderson CL. Signal transduction by the platelet Fc receptor. Blood 1990; 76: 1-8
    PubMedGoogle Scholar
  • 7 Anderson GP, van de Winkel JGJ, Anderson CL. Anti-GPIIb/IIIa (CD41) monoclonal antibody-induced platelet activation requires Fc receptor-dependent cell-cell interaction. Br J Haematol 1991; 79: 75-83
    CrossrefPubMedGoogle Scholar
  • 8 Rubinstein E, Boucheix C, Worthington RE, Carroll RC. Anti-platelet antibody interactions with Feγ receptor. Semin Thromb Haemost 1995; 21: 10-22
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Horsewood P, Hayward CPM, Warkentin TE, Kelton JG. Investigation of the mechanisms of monoclonal antibody-induced platelet activation. Blood 1991; 78: 1019-1026
    PubMedGoogle Scholar
  • 10 Worthington RE, Carroll RC, Boucheix C. Platelet activaiton by CD9 monoclonal antibodies is mediated by the Fcgammall receptor. Br J Haematol 1990; 74: 216-222
    CrossrefPubMedGoogle Scholar
  • 11 Osborne JM, Brandt JT, Chacko GW, Anderson CL. CDw32-dependence of antibody mediated platelet aggregation. In: Leukocyte Typing V Oxford: 1994
  • 12 Tomiyama Y, Kunicki TJ, Zipf TF, Ford SB, Aster RH. Response of human platelets to activating monoclonal antibodies: importance of FcgRII (CD32) phenotype and level of expression. Blood 1992; 80: 2261-2268
    PubMedGoogle Scholar
  • 13 De Reys S, Blom C, Lepoudre B, Declerck PJ, De Ley M, Vermylen J, Deckmyn H. Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent. Blood 1993; 81: 1792-1800
    PubMedGoogle Scholar
  • 14 Sims PJ. Interaction of human platelets with the complement system. In Platelet Immunobiology: Molecular and Clinical Aspects Kunicki TJ, George JN. eds. JB Lippincott Co.; Philadelphia: 1989: 354-383
  • 15 Amiral J, Bridey F, Wolf M, Boyer-Neumann C, Fressinaud E, Vissac AM, Peynaud-Debayle E, Dreyfus M, Meyer D. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995; 73: 21-28
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994; 93: 81-88
    CrossrefPubMedGoogle Scholar
  • 17 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-930
    PubMedGoogle Scholar
  • 18 Chong BH, Castaldi PA, Berndt MC. Heparin-induced thrombocytopenia: effects of rabbit IgG, and its Fab and Fc fragments on antibody-hepar-in-platelet interaction. Thromb Res 1989; 55: 291-295
    CrossrefPubMedGoogle Scholar
  • 19 Christie DJ, Leja DN, Carlson DL, Swinehart CD. Characterization of platelet activation induced by HLA antibodies associated with alloimmune thrombocytopenia. J Lab Clin Med 1993; 121: 437-443
    PubMedGoogle Scholar
  • 20 Isenhart CE, Brandt JT. Platelet aggregation studies for the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1993; 99: 324-330
    CrossrefPubMedGoogle Scholar
  • 21 Coller BS. A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet GPIIb/IIIa complex. J Clin Invest 1985; 76: 101-108
    CrossrefPubMedGoogle Scholar
  • 22 Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C. Monoclonal antibody-specific immobilization of platelet antigens (MAIPA): a new tool for the identification of platelet-reactive antibodies. Blood 1987; 70: 1722-1726
    PubMedGoogle Scholar
  • 23 Kickler T, Kennedy SD, Braine HG. Alloimmunization to platelet-specific antigens on glycoproteins Ilb-IIIa and MX in multiply transfused thrombocytopenic patients. Transfusion 1990; 30: 622-625
    CrossrefPubMedGoogle Scholar
  • 24 Godeau B, Fromont P, Seror T, Duedari N, Bierling P. Platelet alloimmunization after multiple transfusions: a prospective study of 50 patients. Br J Haematol 1992; 81: 395-400
    CrossrefPubMedGoogle Scholar
  • 25 Bordin JO, Heddle NM, Blajchman MA. Biologic effects of leukocytes present in transfused cellular blood products. Blood 1994; 84: 1703-1721
    PubMedGoogle Scholar
  • 26 Horstman LL, Jy W, Schultz DR, Mao WW, Ahn YS. Complement-mediated fragmentation and lysis of opsonized platelets: gender differences in sensitivity. J Lab Clin Med 1994; 123: 515-525
    PubMedGoogle Scholar
  • 27 Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WH, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993; 82: 1192-1196
    CrossrefPubMedGoogle Scholar
  • 28 Wu K, Hoak JC, Thompson JS, Koepke JA. Use of platelet aggregometry in selection of compatible platelet donors. N Engl J Med 1975; 292: 130-133
    CrossrefPubMedGoogle Scholar
  • 29 Shulman NR. Posttransfusion purpura: clinical features and the mechanism of platelet destruction. In: Clinical and Basic Science Aspects of Immuno-hematology Nance SJ. ed. American Association of Blood Banks; Arlington, VA: 1991: 137-154