Thomas Raife

Credentials: MD

Position title: Professor (CHS)


Phone: (608) 265-8492

1685 Highland Ave
Madison, WI 53705

(608) 265-7000 #1246
3148 MFCB
Research Interests

Microvascular thrombosis disorders; genetics of the RBC storage lesion

Research Details: A major focus of my research involves pathogenic mechanisms and treatment of microvascular thrombosis syndromes. The major forms of these rare but devastating diseases include thrombotic thrombocytopenic purpura (TTP), Shiga-toxin associated hemolytic uremic syndrome (HUS), and atypical HUS. In the past decade, major advances in the understanding of these disease entities have allowed investigators to better distinguish between these disorders and to more specifically tailor therapy. It is now understood that TTP is caused by deficiency of the blood metalloprotease ADAMTS13, which causes disordered regulation of platelet-von Willebrand factor (VWF) interactions and spontaneous microvascular thrombosis. At the BloodCenter of Wisconsin, we developed one of the first commercially applied assays for ADAMTS13 and characterized a large historical population of microvascular thrombosis patients. Later work conducted at the University of Iowa identified several proteases in leukocytes that cleave VWF in a manner very similar to ADAMTS13. These findings suggested a possible alternative proteolytic mechanism for regulating platelet-VWF interactions.

In another line of investigation, we hypothesized that Shiga-toxin associated HUS results from a thrombin-driven mechanism. To investigate this hypothesis we conducted a series of animal studies in which direct thrombin inhibitors were shown to prevent Shiga toxin HUS manifestations. These studies supported the hypothesis that Shiga toxin HUS results from thrombin generation, and suggested a possible avenue of therapeutic intervention using thrombin inhibition.

A more recent research interest is in genetic mechanisms of the red blood cell (RBC) storage lesion. The RBC storage lesion comprises a complex array of degenerative changes that occur during RBC storage. The RBC storage lesion significantly reduces in vivo recovery of transfused RBCs and is increasingly implicated in numerous adverse effects. Our collaborative group was motivated by historical studies of RBC storage showing that concentrations of adenosine triphosphate (ATP), a key molecule involved in RBC storage, are largely genetically determined. We hypothesized that this important component of the RBC storage lesion is heritable, and that the observed biological variability might be traceable to specific genetic variants. Our preliminary work utilizing classic twin studies demonstrated the heritability of ATP and many other RBC metabolites. Our current goal is to apply a combination of metabolomics and genome-wide association studies to pinpoint the principal genetic variants responsible for differences in RBC ATP levels. Identifying and understanding these genetic variants could markedly improve RBC storage methods and improve patient care.

Clinical Interests
Transfusion Medicine; Therapeutic Apheresis; and Immunohematology
My work encompasses a broad range of blood banking and transfusion medicine activities. Serving as medical director at both a large regional blood center and a comprehensive hospital-based transfusion service, I gained extensive experience all major aspects of transfusion medicine including blood collection and manufacturing, therapeutic apheresis, cytapheresis, photopheresis, adsorption apheresis, progenitor cell collection, red blood cell, platelet, and neutrophil immunohematology and transfusion therapeutics. While working in an intense regulatory environment, I developed a strong appreciation for team-based approaches to work-flow development and problem solving. My roles as educator, rotation director for residents, and fellowship program director have allowed me to develop multiple levels of mentorship and to participate in lifelong learning alongside undergraduate and postgraduate trainees. Serving as chair of a very active hospital transfusion committee, and as a member of the leadership team of a successful transfusion safety and blood management program, I developed an appreciation for the value of multidisciplinary, institution-wide patient care initiatives.
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