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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL013629-43
Application #
8666784
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Kindzelski, Andrei L
Project Start
1970-06-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
43
Fiscal Year
2014
Total Cost
$505,900
Indirect Cost
$202,966
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
Bougie, Daniel W; Nayak, Dhirendra; Aster, Richard H (2016) Immune destruction of human platelets in the NOD/scid mouse. Transfusion 56:2648-2649
Padmanabhan, Anand; Jones, Curtis G; Curtis, Brian R et al. (2016) A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis. Chest 150:506-15
Fuentes, Rudy E; Zaitsev, Sergei; Ahn, Hyun Sook et al. (2016) A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation. J Clin Invest 126:483-94
Falk, Gavin; Winans, Charles G; Bowens, Krista et al. (2016) An unexpected development after surgery-post-transfusion purpura! Am J Hematol 91:848-51
Comstock, Ioanna A; Longmire, Michelle; Aster, Richard H et al. (2015) Drug-Induced Thrombocytopenia following a Transvaginal Oocyte Retrieval for In Vitro Fertilization. Case Rep Obstet Gynecol 2015:890610
Zheng, Yongwei; Yu, Mei; Padmanabhan, Anand et al. (2015) Critical role of CD4 T cells in PF4/heparin antibody production in mice. Blood 125:1826-9
Bougie, Daniel W; Peterson, Julie; Rasmussen, Mark et al. (2015) Mechanism of quinine-dependent monoclonal antibody binding to platelet glycoprotein IIb/IIIa. Blood 126:2146-52
Padmanabhan, Anand; Jones, Curtis G; Bougie, Daniel W et al. (2015) Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis. Blood 125:155-61
Reese, Jessica A; Bougie, Daniel W; Curtis, Brian R et al. (2015) Drug-induced thrombotic microangiopathy: Experience of the Oklahoma Registry and the BloodCenter of Wisconsin. Am J Hematol 90:406-10
Khawandanah, Mohamad O; Weiss, Susan M; Cherry, Mohamad A et al. (2015) Autoimmune hemolytic anemia and thrombocytopenia attributed to an intrauterine contraceptive device. Transfusion 55:657-60

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