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Phd Thesis Master Document Antibody and Antigen in Heparin-Induced Thrombocytopenia Peter M. Newman Submitted as part of the requirement for the degree of Doctor of Philosophy School of Pathology University of New South Wales 1999 Table of Contents Table of Figures............................................................................................................... 7 Acknowledgments ......................................................................................................... 10 Publications arising from this thesis............................................................................ 11 Abbreviations ................................................................................................................ 12 Summary........................................................................................................................ 15 Chapter 1 - Literature Review ................................................................... 17 Heparin-induced thrombocytopenia ........................................................................... 17 Historical aspects ........................................................................................................ 17 Type I HIT................................................................................................................... 19 Type II HIT.................................................................................................................. 20 Clinical observations................................................................................................... 21 Thrombocytopenia .................................................................................................. 21 Incidence of HIT ..................................................................................................... 21 Thrombosis.............................................................................................................. 23 Clinical diagnosis........................................................................................................ 25 Normal platelet physiology ......................................................................................... 27 Pathophysiology of HIT .............................................................................................. 29 An immune basis for HIT ....................................................................................... 29 A HIT antibody ....................................................................................................... 30 Role of the platelet FcγRII in HIT........................................................................... 30 Fc-receptor polymorphism ...................................................................................... 31 Heparin is not the HIT antigen................................................................................ 32 Platelet HIT antigens............................................................................................... 33 HIT antibodies against PF4-heparin........................................................................ 34 Are anti-PF4-heparin antibodies pathogenic?......................................................... 37 HIT antibodies against IL-8, NAP-2 ....................................................................... 38 Epitopes on PF4 ...................................................................................................... 38 Role of T cells in HIT ............................................................................................. 40 Mechanism of thrombosis....................................................................................... 40 2 A paradigm for HIT................................................................................................. 42 Dissenting views ..................................................................................................... 45 Laboratory diagnosis of HIT ....................................................................................... 46 Platelet aggregation................................................................................................. 46 14C-Serotonin Release Assay .................................................................................. 48 Variations of functional assays eg. HIPAA, Platelet Microparticles ...................... 48 ELISA...................................................................................................................... 49 Comparisons of HIT assays..................................................................................... 50 Prevention of HIT........................................................................................................ 51 Prevention through early diagnosis ......................................................................... 51 Prevention by using alternative anticoagulants....................................................... 51 Treatment of HIT ........................................................................................................ 52 Treatment with LMWH........................................................................................... 53 Treatment with Oral Anticoagulants....................................................................... 53 Treatment with Orgaran .......................................................................................... 54 Treatment with Ancrod ........................................................................................... 55 Heparin .......................................................................................................................... 57 Clinical use of heparin ................................................................................................ 57 Other side effects......................................................................................................... 58 Structure and synthesis of heparin............................................................................... 58 Mode of anticoagulant action...................................................................................... 61 Pharmacokinetics of heparin ....................................................................................... 62 Effect of heparin on platelets ...................................................................................... 63 PF4.................................................................................................................................. 64 PF4 in the Plasma........................................................................................................ 65 Plasma Kinetics of PF4 ........................................................................................... 65 Physiological role of PF4 ............................................................................................ 66 PF4 in Inflammation and Immune regulation ......................................................... 66 PF4 and coagulation................................................................................................ 67 Regulation of Platelet production by PF4 ............................................................... 68 Platelet associated PF4............................................................................................ 68 Endothelial associated PF4 ..................................................................................... 69 3 PF4 and Angiogenesis............................................................................................. 70 Structure of PF4 .......................................................................................................... 70 Interaction between PF4 and heparin......................................................................... 74 In vitro molecular interactions .................................................................................... 74 In vivo release of PF4 by heparin................................................................................ 76 Other drug-induced and immune thrombocytopenias .............................................. 77 Quinine/quinidine induced thrombocytopenia (QIT).................................................. 77 Idiopathic/Immune thrombocytopenic purpura (ITP) ................................................. 78 Insights into the HIT antigen offered by the antiphospholipid syndrome................... 78 Key Questions................................................................................................................ 80 Why does HIT only occur in a few percent of patients? ............................................. 80 How does the HIT antibody bind and activate platelets?............................................ 81 What is the best way to diagnose HIT?....................................................................... 81 What is the best way to treat HIT?.............................................................................. 81 Are the anti-PF4-heparin antibodies pathogenic? ....................................................... 82 What is the HIT epitope(s) ? ....................................................................................... 82 Chapter 2 - IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid................................................................................................... 83 Introduction ................................................................................................................
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