Download PDF
Thromb Haemost 1994; 71(05): 641-645
DOI: 10.1055/s-0038-1642496
Review Article
Schattauer GmbH Stuttgart

Heparin-Associated Thrombocytopenia: The Effects of Various Intravenous lgG Preparations on Antibody Mediated Platelet Activation - A Possible New Indication for High Dose i.v. IgG

A Greinacher
1   The Institute for Clinical Immunology and Transfusion Medicine, Giessen, FRG
,
U Liebenhoff
2   Rudolf-Buchheim-Institut für Pharmakologie, Justus Liebig University, Giessen, FRG
,
V Kiefel
1   The Institute for Clinical Immunology and Transfusion Medicine, Giessen, FRG
,
P Presek
2   Rudolf-Buchheim-Institut für Pharmakologie, Justus Liebig University, Giessen, FRG
,
C Mueller-Eckhardt
1   The Institute for Clinical Immunology and Transfusion Medicine, Giessen, FRG
› Author Affiliations
Further Information

Publication History

Received 01 June 1993

Accepted after revision 28 January 1994

Publication Date:
26 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

The immunologic type of heparin-associated thrombocytopenia (HAT) is caused by antibodies which activate platelets via the Fc-re- ceptor in the presence of polysulfated oligosaccharides. The antigen is formed by a releasable platelet protein (in many cases PF4) complexed to heparin. Since the role of GP Ilb/IIIa in platelet activation by HAT antibodies is controversial, we investigated platelet activation by antibodies related to HAT. We used normal platelets and platelets from a patient with Glanzmann’s thrombasthenia (GT) lacking GP Ilb/IIIa. Heparin and sera from patients with HAT stimulated GT platelets in the same manner as determined by 14C-serotonin release and the changes in phosphorylation of p20 and p47. Platelet activation could be inhibited by an anti FcRII monoclonal antibody (IV. 3, Fab-fragments), and by Fc-fragments, but not by F(ab’)2-fragments of human IgG. The effect of four different, commercially available preparations of intact i.v. IgG on the platelet activation by six HAT sera was investigated by 14C-seroto- nin release. The inhibitory effect was strongly dependent upon the manufacturing process. At a concentration of 20 mg/ml only IgG that had been subjected to low pH and traces of pepsin sufficiently inhibited platelet activation. IgG treated with polyethylenglycol or sulfitolysis was less effective, whereas beta-propiolactone-treated IgG almost completely lost the ability to inhibit platelet activation by antibodies related to HAT. We conclude that inhibition of GP Ilb/IIIa-fibrinogen interaction is insufficient for preventing platelet activation in HAT. This is, however, possible by high dose i.v. IgG, whereby inhibition of FcRII on platelets strongly depends upon the process by which the i.v. IgG preparation was manufactured.

 

  • References

  • 1 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Progress in Hemostasis and Thrombosis 1991; 10: 1-34
    PubMedGoogle Scholar
  • 2 Greinacher A, Michels I, Liebenhoff U, Presek P, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulfated oligosaccharide. British Journal of Haematology 1993; 84: 711-716
    CrossrefPubMedGoogle Scholar
  • 3 Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M. et al Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: 247-252
    PubMedGoogle Scholar
  • 5 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C. et al Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-930
    PubMedGoogle Scholar
  • 6 Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. British Journal of Haematology 1989; 73: 235-40
    CrossrefPubMedGoogle Scholar
  • 7 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545-549
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Anderson GP. Insights into heparin-induced thrombocytopenia. British Journal of Haematology 1992; 80: 504-8
    CrossrefPubMedGoogle Scholar
  • 9 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. New England Journal of Medicine 1987; 316: 581-9
    CrossrefPubMedGoogle Scholar
  • 10 Chong BH, Castaldi PA. Heparin-induced thrombocytopenia: further studies of the effects of heparin-dependent antibodies on platelets. British Journal of Haematology 1986; 64: 347-354
    CrossrefPubMedGoogle Scholar
  • 11 Adelman B, Sobel M, Fujimura Y, Ruggeri ZM, Zimmerman TS. Heparin-associated thrombocytopenia: observation on the mechanism of platelet aggregation. Journal of Laboratory and Clinical Medicine 1989; 113: 204-210
    PubMedGoogle Scholar
  • 12 Demers C, Ginsberg JS, Brill-Edwards P, Panju A, Warkentin TE, Anderson DR. et al Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia. Blood 1991; 78: 2194-2197
    PubMedGoogle Scholar
  • 13 Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66: 734-736
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
    PubMedGoogle Scholar
  • 15 Chong BH, Grace CS, Rozenberg MC. Heparin-induced thrombocytopenia: effect of heparin platelet antibody on platelets. British Journal of Haematology 1981; 49: 531-40
    CrossrefPubMedGoogle Scholar
  • 16 Bux J, Sohn M, Hachmann R, Mueller-Eckhardt C. Quantification of granulocyte antibodies in sera and determination of their binding sites. British Journal of Haematology 1992; 82: 20-25
    CrossrefPubMedGoogle Scholar
  • 17 Reuter C, Findik D, Presek P. Characterization of purified pp60 c-src tyrosine kinase from human platelets. European Journal of Biochemistry 1990; 190: 343-350
    CrossrefPubMedGoogle Scholar
  • 18 Sachs L. Applied statistics A handbook for techniques Heidelberg:. Springer 1982
    Google Scholar
  • 19 Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69: 344-350
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Nader HB, Buonassisi V, Colburn P, Dietrich CP. Heparin stimulates the synthesis and modifies the sulfation pattern of heparan sulfate proteoglycan from endothelial cells. Journal of Clinical Pathology 1989; 140: 305-310
    PubMedGoogle Scholar
  • 21 Warkentin TE, Hayward CP, Smith CA, Kelly PM, Kelton JG. Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia. Journal of Laboratory and Clinical Medicine 1992; 120: 371-379
    PubMedGoogle Scholar
  • 22 Chong BH, Pilgrim RL, Cooley MAS, Chesterman CN. Increased expression of platelet IgG Fc-receptors in immune heparin-induced thrombocytopenia. Blood 1993; 81: 988-93
    PubMedGoogle Scholar
  • 23 Chong BH, Castaldi PA, Berndt MC. Heparin-induced thrombocytopenia: effects of rabbit IgG and its Fab and Fc fragments on antibody-heparin- platelet interaction. Thrombosis Research 1989; 55: 291-295
    CrossrefPubMedGoogle Scholar
  • 24 Nurden AT, Laroche-Traineau J, Jallu V, Broult J, Durrien C, Besse P. et al Heparin-induced thrombocytopenia: observations on the nature of the antibody activities and on the use of gammaglobulin concentrates in a patient with thrombotic complications. Thromb Haemost 1991; 65: 796
    PubMedGoogle Scholar
  • 25 Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Annals of Internal Medicine 1989; 111: 946-947
    CrossrefPubMedGoogle Scholar
  • 26 Grau E, Linares M, Olaso MA, Ruvira J, Sanchis J. Heparin-induced thrombocytopenia-response to intravenous immunoglobulin in vivo and in vitro. American Journal of Hematology 1992; 39: 312-313
    CrossrefPubMedGoogle Scholar
  • 27 Vender JS, Matthew EB, Silverman IM, Konowitz H, Dau PC. Heparin-associated thrombocytopenia: alternative managements. Anesthesia and Analgesia 1986; 65: 520-522
    PubMedGoogle Scholar
  • 28 Jungi TW, Santer M, Lerch PG, Barandun S. Effect of various treatments of gamma-globulin (IgG) for achieving intravenous tolerance on the capacity to interact with human monocyte Fc receptors. Vox Sanguinis 1986; 51: 18-26
    CrossrefPubMedGoogle Scholar
  • 29 Jungi TW, Eiholzer J, Lerch PG, Barandun S. The capacity of various types of immunoglobulin for intravenous use to interact with Fc receptors on human monocytes and macrophages. Blut 1986; 53: 321-332
    CrossrefPubMedGoogle Scholar
  • 30 Landsperger WJ, Gallagher MJ, Branch DR. Biological activity of intravenous immunoglobulins (letter). Lancet 1987; 1: 1035
    PubMedGoogle Scholar
  • 31 Medgyesi GA, Kovacs J, Jenei B, Fust G, Meretey K. Safety aspects of intravenous immunoglobulins. Immunological Investigations 1988; 17: 121-133
    CrossrefPubMedGoogle Scholar
  • 32 Boshkov LK, Kelton JG. Use of intravenous gammaglobulin as an immune replacement and an immune suppressant. Transfusion Medicine Reviews 1989; 3: 82-120
    CrossrefPubMedGoogle Scholar
  • 33 Blanchette VS, Sacher RA. Intravenous immunoglobulin: more questions than answers. Transfusion Medicine Reviews 1991; 5: 165-170
    CrossrefPubMedGoogle Scholar
  • 34 Dwyer JM. Manipulating the immune system with immune globulin. New England Journal of Medicine 1992; 326: 107-116
    CrossrefPubMedGoogle Scholar