Heterogeneity of drug-dependent platelet antigens and their antibodies in quinine- and quinidine-induced thrombocytopenia: involvement of glycoproteins Ib, IIb, IIIa, and IX

Sl, Pfueller; Bilston, RA; Logan, Dana; Gibson, J. M.; Firkin, Barry G.

doi:10.1182/blood.v72.4.1155.bloodjournal7241155

Cited by 6 publications

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“…Preincubation of the patient's purified immunoglobulin with leupeptin (4.5 mM), soya bean trypsin inhibitor (0.03 mg/ml), trasylol (300 units/ml) or hirudin (3 units/ml) for 10 minutes did not affect its platelet aggregating activity. However, EDTA (15 mM) and benzamidine (24 mM) were effective inhibitors of SPAF mediated platelet aggregation (the indicated concentrations of the inhibitors represents their initial concentration during the preincubation with SPAE, in the aggregation cuvette the final concentration was reduced by a factor of three antibody. Solubilised ['H] labeled normal platelets were incubated with acid eluate from normal platelets pretreated with normal (N) or patient (P) serum as described in Methods.…”

Section: Resultsmentioning

confidence: 99%

“…The pellets were resuspended in 85 pl 0.125 M Tiis HCI pH 6.8 containing 2% sodium dodecyl sulfate and 8 M urea and boiled for 10 min. After centrifugation for 5 min at 10,000 x g 75 pl of the supernatant were analysed by SDS-PAGE carried out as described (13) using a 5-15Y" polyacrylamide gradient as the separating gel and 3% polyacrylamide as the sample loading gel (15). Some samples were reduced with 2% dithiothreitol.…”

Section: ^Gmentioning

confidence: 99%

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Arterial Thrombosis Associated with Immune Thrombocytopenia: Presence of a Platelet Aggregating IgG Synergistic with Thrombin and Adrenalin

et al. 1989

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SummaryWe report the case of a 50-year-old lady who presented with arterial thrombosis in the setting of thrombocytopenia. Investigations confirmed the diagnosis of idiopathic thrombocytopenic purpura. A spontaneous platelet aggregating factor (SPAF) was isolated from the immunoglobulin fraction of the patient's plasma. The isolated IgG irreversibly aggregated platelet-rich plasma and washed platelets, an effect abolished by pretreating the platelets with aspirin. The activity of the IgG was greatly enhanced by subaggregatory concentrations of thrombin and adrenalin and was localized to the F(ab')2 of the molecule. Plasmapheresis in combination with anti-platelet therapy resulted in an increase in the patient's platelet count, reduced platelet aggregating activity of plasma and significant clinical improvement.We suggest that the presence of this platelet aggregating IgG contributed to the development of thrombosis in our patient and postulate that a similar factor may explain the paradox of thrombosis observed in a select group of thrombocytopenic patients.

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Section: Resultsmentioning

confidence: 99%

Section: ^Gmentioning

confidence: 99%

Arterial Thrombosis Associated with Immune Thrombocytopenia: Presence of a Platelet Aggregating IgG Synergistic with Thrombin and Adrenalin

et al. 1989

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“…Serum from patients with Q .Ab and washed platelet suspensions were obtained and prepared as described (3). The presence of quininedependent IgG antibodies was detected by ELISA (19).…”

Section: Methodsmentioning

confidence: 99%

Expression of the Drug-Dependent Antigen for Quinine-Dependent Antiplatelet Antibodies on GP III a but not that on GPI b, II b or IX on Human Endothelial Cells

et al. 1990

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SummaryIn quinine- and quinidine-induced thrombocytopenic purpura IgG antibodies are known to react in a drug-dependent manner with different combinations of surface glycoproteins (GP) Ib , IIb, IIIa and IX. Because endothelial cells share a number of properties of platelets, including the presence of GP Ilia and GPIb-like proteins, we have compared these two cell types for their quinine-dependent IgG binding abilities. By immunoblotting of endothelial cells, quinine-dependent IgG binding from four patient sera was observed only to a 93 kDa component corresponding to GP Ilia. Strong IgG binding independent of the drug was found at 170–180 kDa. Thus endothelial cells express the GP Ilia quinine-dependent epitope on platelet GP IIIa , but not those on other platelet glycoproteins.

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“…Drug‐dependent antibodies can be diagnosed by a variety of assays (280). Both, whole platelet‐ (281, 282) and GP‐specific immunochemical techniques (283, 284) have been employed. Due to labile interaction of the drug and platelet GP, and due to the potential dependency of the determinant on protein conformation, assays which guarantee preservation of GP conformation are usually more sensitive than immunoblot.…”

Section: Drug‐induced Immune Thrombocytopeniasmentioning

confidence: 99%

DRUG‐INDUCEDAND DRUG‐DEPENDENT IMMUNE THROMBOCYTOPENIAS

Greinacher¹,

Eichler²,

Lübenow³

et al. 2001

Rev Clin Exp Hematol

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Thrombocytopenia is a frequent comorbid condition in many in hospital patients. In some patients, drugs are the cause of low platelet counts. While cytotoxic effects of anti-tumor therapy are the most frequent cause, immune mechanisms should also be considered. This review addresses thrombocytopenias in four groups. Heparin-dependent thrombocytopenia (HIT), by far the most frequent drug-induced immune-mediated type of thrombocytopenia, has a unique pathogenesis and clinical consequences. HIT is a clinicopathological syndrome in which antibodies mostly directed against a multimolecular complex of platelet factor 4 and heparin cause paradoxical thromboembolic complications. The mechanisms through which heparin can enhance thrombin generation are discussed and treatment alternatives for affected patients are presented in detail. It is of primary importance to recognize these patients as early as possible and to substitute heparin with a compatible anticoagulatory drug, such as hirudin, danaparoid or argatroban. Patients seem to benefit from therapeutic doses of alternative treatment rather than from low-dose prophylactic doses. With the increasing use of glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndromes, thrombocytopenias are increasingly recognized as an adverse effect of these drugs. Up to 4% of treated patients are affected. Most important, pseudothrombocytopenia, a laboratory artefact, is as frequent as real drug-induced thrombocytopenia and must be excluded before changes in treatment are considered. The pathogenesis of these thrombocytopenias is still debated; an immune mechanism involving preformed antibodies is likely. However, since these antibodies are also detectable in a high percentage of normal controls and of patients not developing thrombocytopenia, their impact is still unclear. Patients with real thrombocytopenia are at an increased risk of bleeding; treatment consists of cessation of the GP IIb/IIIa inhibitor and platelet transfusions in cases of severe hemorrhage. Classic immune thrombocytopenia can be induced by some drugs, e.g. gold, which trigger anti-platelet antibodies indistinguishable from platelet autoantibodies found in autoimmune thrombocytopenia. Drug-induced and drug-dependent immune thrombocytopenia is induced by antibodies recognizing an epitope on platelet GP formed after binding of a drug to a platelet glycoprotein. Still unresolved is whether antibody binding is the consequence of a conformational change of the antigen, the antibody, or both. These antibodies typically react with monomorphic epitopes on platelet GP, but only in the presence of the drug or a metabolite. Although several platelet GP have been identified as antibody target (GPIb/IX, GPV, GP IIb/IIIa), antibodies in an individual patient are highly specific for a single GP. Clinically, these patients present with very low platelet counts and acute, sometimes severe, hemorrhage. Treatment is restricted to withdrawal of the drug and symptomatic treatment of bleeding.

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Heterogeneity of drug-dependent platelet antigens and their antibodies in quinine- and quinidine-induced thrombocytopenia: involvement of glycoproteins Ib, IIb, IIIa, and IX

Cited by 6 publications

References 0 publications

Arterial Thrombosis Associated with Immune Thrombocytopenia: Presence of a Platelet Aggregating IgG Synergistic with Thrombin and Adrenalin

Arterial Thrombosis Associated with Immune Thrombocytopenia: Presence of a Platelet Aggregating IgG Synergistic with Thrombin and Adrenalin

Expression of the Drug-Dependent Antigen for Quinine-Dependent Antiplatelet Antibodies on GP III a but not that on GPI b, II b or IX on Human Endothelial Cells

DRUG‐INDUCEDAND DRUG‐DEPENDENT IMMUNE THROMBOCYTOPENIAS

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