Idiosyncratic drug reactions (IDR), occur unpredictably in persons taking medication, affect various organs, can have a devastating effect on individual patients and are an important cause of morbidity and mortality in the general population. However, causative mechanisms are very poorly understood and an animal model is unavailable. This grant addresses IDR pathogenesis in the context of drug-induced immune thrombocytopenia (DITP), an IDR triggered by hundreds of widely used medications through several different mechanisms.
Aim 1 : Our recent findings suggest a previously unsuspected mechanism by which drug-dependent antibodies (DDAbs) cause platelet destruction upon exposure of a patient to a sensitizing drug. This mechanism will be more fully characterized and the concept will be applied to development of an animal model of DITP. DITP is a heterogeneous disease. Other ways in which widely used drugs such as RGD-mimetic platelet inhibitors trigger this condition will be defined at the molecular level. Findings made will improv understanding of this important group of conditions and enable identification of the agents responsible for reactions experienced by individual patients.
Aim 2 : Drug-dependent, platelet-reactive antibodies (DDAbs) are often not detected in patients with a history compelling for DITP. An important reason for this is that a drug metabolite can be the sensitizing agent. We will utilize a library of archived serum samples from """"""""antibody-negative"""""""" patients suspected of DITP to identify DDAbs specific for metabolites of widely used drugs such as NSAIDs, furosemide, and clopidogrel implicated as triggers for DITP. Findings made will facilitate identification of metabolite-specific antibodies in individual patients and define the range of drug metabolites that can trigger DITP and other IDRs.
Aim 3 will address yet another IDR affecting platelets: heparin-induced thrombocytopenia/thrombosis (HIT), an important side effect of heparin treatment that can have catastrophic consequences for patients. Recent reports claim that only IgG HIT antibodies are pathogenic. We have evidence that IgA and IgM HIT antibodies can also cause thrombocytopenia and thrombosis and will examine the responsible mechanisms. Achievement of Aims 1-3 will be facilitated by several unique resources developed previously under this grant: 1) A new animal model that permits destruction of human platelets by human antibodies to be studied in the NOD/scid mouse;2) Archived serum samples from 4,000 patients suspected of having DITP;3) Relationships with referring hematologists throughout the US that ensure referral of new and interesting cases.

Public Health Relevance

Idiosyncratic (unpredictable) drug reactions (IDR) are a major cause of morbidity and mortality in the general population but the responsible mechanisms are very poorly understood, no reliable tools are available with which to identify the causative agent in an individual patient and there is no generally accepted animal model in which to study this group of conditions. This grant will address each of these issues in the context of a commonly encountered IDR - drug-induced immune thrombocytopenia (low blood platelet levels). Findings made are expected to validate a newly identified mechanism by which drugs induce IDRs, provide new tools with which to identify the drug that caused an IDR, identify causative antibodies and, it is hoped, establish an animal model for studying how IDRs are induced by individual drugs and what factors predispose to development of these reactions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-J (02))
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Kindzelski, Andrei L
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Bloodcenter of Wisconsin, Inc.
United States
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Bougie, Daniel W; Nayak, Dhirendra; Aster, Richard H (2016) Immune destruction of human platelets in the NOD/scid mouse. Transfusion 56:2648-2649
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