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

Pfueller, Sharron L.; Bilston, Robyn A.; Jane, Stephen; J, Gibson

doi:10.1055/s-0038-1645209

Cited by 13 publications

(3 citation statements)

References 11 publications

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“…The mechanisms of formation are thought to be by two methods: (i) the formation of new or altered antigenic sites secondary to the binding of quinine (drug dependent) and (ii) the stimulation of true autoantibody formation without the need for drug (drug independent) [18]. It has been shown that endothelial cells share the glycoprotein IIIa quinine-dependent epitope found on platelets [19,20]. Presumably, it is the antibody damage to endothelial cells which leads to the formation of the thrombotic microangiopathy and microangiopathic hemolytic anemia.…”

Section: Discussionmentioning

confidence: 98%

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy

Park

Hay

King

et al. 2009

J of Clinical Apheresis

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Thrombocytopenia with or without microangiopathy following quinine is often referred to as quinine "hypersensitivity." When schistocytes are present it is frequently termed "quinine-associated TTP/HUS." A severe deficiency of the vWF-cleaving protease, ADAMTS13, is associated with idiopathic TTP. A previous study of patients with "quinine-associated TTP/HUS" found that ADAMTS13 activities were not abnormal in 12/12 patients. A retrospective review of TTP patients with quinine-associated thrombotic microangiopathy (TMA) for whom ADAMTS13 was measured before plasma exchange was performed. Six patients were identified. All were females (age range: 43 to 73, mean = 61.7 years) and had taken quinine for leg cramps. Four of the six experienced renal failure requiring dialysis. Five of the patients had D-Dimers levels measured, all were elevated. In four patients the levels were > or = 18 times the upper limit of normal. ADAMTS13 was normal in four patients and mildly decreased in two patients. We conclude that while thrombocytopenia and schistocytosis can be seen in quinine-associated TTP/HUS, the pathophysiology seems to be distinct from that seen in most cases of idiopathic TTP (i.e., severely decreased ADAMTS13 with an inhibitor). We recommend that a TMA in association with quinine be consistently referred to as quinine-associated thrombotic microangiopathy (quinine-TMA) to better distinguish this entity from idiopathic TTP. The use of plasma exchange in quinine-TMA is called into question.

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Section: Discussionmentioning

confidence: 98%

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy

Park

Hay

King

et al. 2009

J of Clinical Apheresis

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“…DDTP 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 in DDTP (GPIb/IX (263–265), GPV (266), GPIIb/IIIa (267–271)) antibodies in an individual patient are highly specific for a single GP. Kroll et al (272) investigated sera of 5 patients with carbimazole‐dependent platelet reactive antibodies.…”

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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“…We have re cently observed that it also carries one of the drug-dependent antigens involved in quinine-induced thrombocytopenia [4]. Be cause the quinine-dependent antigen is ex pressed on GPIIIa on platelets which do not react with anti-PlA1 antibodies, these anti gens are distinct from one another [4], Both these epitopes are present on endothelial cells [5] which express a glycoprotein which is probably identical to GPIIIa [6] on plate lets. The P1A1 epitope lies on a 17-kDa poly peptide obtained after tryptic digestion of GPIIIa [7], This polypeptide is located somewhere within a 66-kDa fragment of GPIIIa which remains associated with platelets after digestion with chymotrypsin [8],…”

Section: Introductionmentioning

confidence: 99%

Location of the Quinine-Dependent Epitope on Platelet Glycoprotein IlIa

Sl¹,

Wf²,

J³

et al. 1991

Pathophysiol Haemos Thromb

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Quinine-dependent (Q) IgG antibodies (Q.Ab) in drug-induced immune thrombocytopenia are heterogeneous and bind to different platelet surface glycoproteins (GP), namely GPIb, IX, lIb, IlIa and an unidentified 57-kDa membrane proteins. Although both the Q-dependent epitope on GPIIIa and the P1^A1 antigen require intact disulphide bonds for their expression, they are distinct because Q.Ab bind to GPIIIa lacking P1^A1. Epitopes for both antigens were examined on Western blots of either intact washed human platelets or purified GPIIIa. When intact platelets were digested with trypsin and washed and solubilised prior to electrophoresis, membrane-associated fragments of GPIIIa of 78 kDa were found to be reactive with both antibodies. In addition, 60- and 68-kDa fragments bound anti-P1^A1 but not Q.Ab. Similar digestion with chymotrypsin produced only 60-kDa fragments containing both epitopes. Digestion of purified GPIIIa with chymotrypsin produced 60-kDa peptides reactive with Q.Ab and anti-P1^A1 in immunoblotting studies. Similar digestion with elastase produced 58-kDa fragments also containing the epitopes for both antibodies. Longer digestion times or sequential digestion with different enzymes did not reveal extra fragments. However, immunoprecipitation of trypsin-digested ¹²⁵I-labelled GPIIIa with affinity-purified Q.Ab produced a 17-kDa fragment containing the Q-dependent epitope.

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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

Cited by 13 publications

References 11 publications

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy

DRUG‐INDUCEDAND DRUG‐DEPENDENT IMMUNE THROMBOCYTOPENIAS

Location of the Quinine-Dependent Epitope on Platelet Glycoprotein IlIa

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