Thromb Haemost 1992; 67(05): 545-549
DOI: 10.1055/s-0038-1648491
Original Articles
Schattauer GmbH Stuttgart

Heparin-Associated Thrombocytopenia: The Antibody Is Not Heparin Specific

A Greinacher
The Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Gießen, FRG
,
I Michels
The Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Gießen, FRG
,
C Mueller-Eckhardt
The Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Gießen, FRG
› Author Affiliations
Further Information

Publication History

Received 15 August 1991

Accepted after revision 15 November 1991

Publication Date:
03 July 2018 (online)

Summary

In this study the hypothesis was assessed whether heparin-associated thrombocytopenia (HAT) may be caused by an antibody dependent on polysulfated oligosaccharide epitopes, present not only on heparin but also on different polysulfated substances such as dextran sulfate and pentosan polysulfate. We found that the major factor for eliciting platelet activation with sera of HAT type II patients is neither the structure nor the AT III binding capacity of an oligosaccharide, but rather its grade of sulfation. This was shown by in vitro crossreactivity studies with 40 sera of HAT type II patients using unfractionated heparins, LMW heparins (Fragmin, Fraxiparin), enoxaparin, LMW heparinoid (Org 10172 and its subfractions), de-N-sulfated heparin, dermatan sulfate, dextran sulfate, pentosan polysulfate and dextran. Platelet activation was measured by the heparin induced platelet activation (HIPA) assay and the serotonin release assay (SRA). The platelet activating factor was isolated with the IgG fraction, but did not bind to heparin and dextran sulfate fixed to a solid phase. By isoimmune fixation electrophoresis a monoclonal gammopathy was ruled out in the three sera assessed. The in vivo effect of different LMW heparins and the heparinoid Org 10172 was observed in 10 patients with HAT type II. In a prospective study, a compatible heparin-like anticoagulant was selected for 10 HAT patients for whom further parenteral anticoagulation was required. The only substance that showed no crossreactivity in vitro was the LMW heparinoid Org 10172, which differs from heparin and LMW heparins by its low-grade sulfation. Upon treatment with the heparinoid, all 10 patients had a good clinical outcome, even if they had previously developed thromboembolic complications under LMW heparin administration. As Org 10172 contains a small amount of a LMW heparin-like substance (3%) this heparinoid should not be used in HAT patients without prior in vitro testing. We conclude that heparin-associated thrombocytopenia is not caused by a heparin-specific antibody and that a major factor contributing to the pathomechanism is the high grade of sulfation present in a variety of polysulfated oligosaccharides.

 
  • References

  • 1 King DJ, Kelton JG. Heparin associated thrombocytopenia. Ann Intern Med 1984; 100: 535-540
  • 2 Chong BH, Fawaz I, Chesterman CN, Bemdt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-240
  • 3 Kelton JG, Sheridan D, Santos A, Smith J. et al Heparin-induced thrombocytopenia: Laboratory studies. Blood 1988; 72: 925-930
  • 4 Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing Heparin-associated thrombocytopenia. Thromb Haemostas. 1991 (in press)
  • 5 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
  • 6 Hotchkiss AJ, Leissinger CA, Smith ME, Jordan JV, Kautz CA, Shulman NR. Evaluation by quantitative acid elution and radioimmunoassay of multiple classes of immunoglobulins and serum albumin associated with platelets in idiopathic thrombocytopenic purpura. Blood 1986; 67: 1126-1131
  • 7 Kiefel V, Jager S, Mueller-Eckhardt C. Competitive enzyme-linked immunoassay (CELIA) for the quantitation of platelet-associated immunoglobulins (IgG, IgM, IgA) and complement (C3c, C3d) with polyclonal and monoclonal reagents. Vox Sang 1987; 53: 151-156
  • 8 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-589
  • 9 Gouault-Heilmann M, Payen D, Contant G, Intrator L, Huet Y, Schaeffer A. Thrombocytopenia related to synthetic heparin analogue therapy. Thromb Haemostas 1985; 54: 557
  • 10 Follea G, Hamandjian I, Trzeciak M-C, Nedey Ch, Streichenberger R, Dechavanne M. Pentosane polysulphate associated thrombocytopenia. Thromb Res 1986; 42: 413-418
  • 11 Levy DE, Horner AA, Solomon A. Immunoglobulin-sulfated polysaccharide interactions. J Exp Med 1981; 153: 883-896
  • 12 Addonizio VP, Fisher CA, Kappa JR, Ellison N. Prevention of heparin induced thrombocytopenia during open heart surgery with iloprost (ZK 36374). Surgery 1987; 102: 796-807
  • 13 Kappa JR, Cottrell ED, Berkowitz HD, Fisher CA, Sobel M, Ellison N, Addonizio VP. Carotid endarterectomy in patients with heparin-induced platelet activation: Comparative efficacy of aspirin and iloprost (ZK 36374). J Vase Surg 1987; 5: 693-701
  • 14 Gouault-Heilmann M, Huet Y, Adnot S, Contant G, Bonnet F, Intrator L, Payen D, Levent M. Low molecular weight heparin fractions as an alternative therapy in heparin-induced thrombocytopenia. Haemostasis 1987; 17: 134-140
  • 15 Horellou MH, Conard J, Lecrubier C, Samana M, Roque-D’Orbcas-tel O, de Fenoyl O, Di Maria G, Bemadeu A. Persistent heparin-induced thrombocytopenia despite therapy with low molecular weight heparin. Thromb Haemostas 1984; 5: 134
  • 16 Leroy J, Leclerc MH, Delahousse B, Guerois C, Foloppe P, Gruel Y, Toulemonde F. Treatment of heparin-associated thrombocytopenia and thrombosis with low molecular weight heparin. Semin Thromb Hemostas 1985; 11: 326-329
  • 17 Eichinger S, Kyrle PA, Brenner B, Wagner B, Kapiotis S, Lechner K, Kominger HC. Thrombocytopenia associated with low-molecular-weight heparin. Lancet 1991; 377: 1425-1426
  • 18 Chong BH, Ismail F, Cade J, Gallus AS, Gordon S, Chesterman CN. Heparin-induced thrombocytopenia: Studies with a new low molecular weight heparinoid, Org 10172. Blood 1989; 73: 1592-1596
  • 19 Blockmans D, Bounameaux H, Vermylen J, Verstraete M. Heparin-induced thrombocytopenia. Platelet aggregation studies in the presence of heparin fractions or semi-synthetic analogues of various molecular weights and anticoagulant activities. Thromb Haemostas 1986; 55: 90-93
  • 20 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Annu Rev Med 1989; 40: 31-44
  • 21 Meuleman DG. Synopsis of the anticoagulant and antithrombotic profile of the low molecular weight heparinoid Org 10172 in experimental models. Semin Thromb Hemostas 1989; 15: 370-372
  • 22 Magnani HN. Compassionate use of Lomoparan® in patients with HIT. Br J Haematol 1991; 77: 65