Studies are proposed to better understand the pathogenesis of drug-induced immune conditions that affect blood platelets and to improve their diagnosis and management.
Aim 1 concerns drug-induced immune thrombocytopenia (DITP) of the ?quinine-type? (Qn-DITP), so-called because quinine is the prototypic trigger for this condition, which can be induced by at least 100 different medications. A curious aspect of Qn-DITP is that the responsible antibodies (abs) are harmless unless drug is present, in which case they bind to a platelet glycoprotein (GP) and cause platelet destruction. We produced monoclonal abs (mAbs) that mimic the behavior of abs from patients with Qn-DITP and have used them to show that Qn promotes binding of these mAbs to their targets by reconfiguring ab binding domains so they recognize an autologous GP. The findings suggest a previously un-described mechanism for drug-induced immune injury in DITP that could be applicable to other types of idiosyncratic drug reactions (IDRs), an important cause of morbidity and mortality in industrialized nations.
Aim 1 describes studies to generalize the new findings by producing platelet-reactive mAbs specific for drugs other than Qn utilizing protocols designed to improve the efficiency of ab induction and to develop a mouse model that mimics the human disease, DITP. A successful outcome could define a new paradigm for induction of certain types of IDRs and have important implications for new drug development. The widely used drugs clopidogrel, ceftriaxone and piperacillin are being implicated as triggers for DITP with increasing frequency, but serologic testing for abs is often negative in such patients. A likely reason for this is that a drug metabolite, rather than unmodified drug is the sensitizing agent. A second goal of Aim 1 is to define the extent to which metabolites of these three drugs trigger DITP and to identify the responsible metabolites. Other drugs will be similarly studied if time and resources permit. Findings will define the extent to which drug metabolites cause DITP and other IDRs and will yield improved diagnostic tools for identifying patients with thrombocytopenia caused by sensitivity to a drug metabolite.
Aim 2 concerns heparin-induced immune TP (HIT), a major case of morbidity and mortality in patients treated with heparin. Our recent findings suggest that a key aspect of HIT pathogenesis is antibody recognition of platelet factor 4 (PF4) in a complex with platelet membrane glycosaminoglycans (GAGs), leading to platelet activation, thrombocytopenia and predisposition to thrombosis.
In Aim 2, PF4-dependent priming of platelets for recognition by pathogenic abs will be characterized at the molecular level and findings made will be applied to development and validation of improved methods for identifying heparin-treated patients who are at high risk for thrombosis that can be performed ?on-demand? in patients suspected of having HIT.
Using drug-induced immune thrombocytopenia (low blood platelets) as a model, studies proposed in Aim 1 will seek to validate a new concept explaining how medications induce unpredictable immunological side effects and will examine the extent to which drug metabolites cause sensitization leading to immune thrombocytopenia. Aim 2 studies will further define the pathogenesis of heparin-induced thrombocytopenia ? a serious complication of treatment with the anticoagulant heparin ? and devise new tools for early identification and treatment of patients with this condition.
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