Overview

The overarching goal of the Zimowski laboratory is to further elucidate the intricacies of coagulation regulation.  This research focus began by exploring the effects of a novel deletion in exon 13 of the coagulation factor V gene, with encodes the B-domain of the factor V (FV) protein. This novel deletion was identified in a patient with an unexplained bleeding disorder and is unique in that it should result in a terminal frameshift and premature stop codon leading to a functionally null allele. Yet, this patient’s FV activity level was normal. This deletion is thought to drive the production of alternatively-spliced truncated FV transcripts capable of binding to the C-terminal tail of tissue factor pathway inhibitor alpha with high affinity, ultimately increasing the plasma concentration of this natural anticoagulant protein.  Similar shortened FV protein have been shown to exist naturally in the form of platelet FV and FV activation intermediates, suggesting a physiologic role for these truncated FV isoforms in regulating the initiation of coagulation. This work authenticates the presence of additional processes governing the fine balance within our hemostatic system and highlights its complexity.

We are actively working to uncover the elements and mechanisms involved in the unconventional FV alternative splicing event and to correlate changes in FV splicing with altered tissue factor pathway inhibitor (TFPI) levels. Furthermore, we hope to correlate these changes in FV and TFPI in vivo with both abnormal bleeding as well as venous thrombosis.

Dr. Zimowski is also a member of the clinical hemostasis and thrombosis team at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta. Dr. Zimowski maintains a strong interest in clinical research regarding patients with disorders of hemostasis and thrombosis including the hemophilia and the rare bleeding disorders.

Julie Wechsler

Education: Undergraduate student, Emory University 

Fun Fact: 2020 Emory SURE Program Recipient

Batsuli G, Zimowski KL, Tickle K, Meeks SL, and Sidonio RF. Immune tolerance induction in paediatric patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019; 00: 18. https://doi.org/10.1111/hae.13819

Sidonio RF and Zimowski KL. TFPI blockade: removing coagulation’s brakes. Blood. 2019; 134 (22): 1885-1887.

Zimowski KL, Ho MD, Shields JE, Denning G, Petrillo T, Jhita N, Rivera AA, Escobar MA, Kempton CL, Doering CB, and Camire RM. Factor V Atlanta: a novel mutation in the F5 gene reveals potential new cis-acting elements involved in regulating FV-short and TFPI levels. ASH 59th annual meeting, Atlanta, GA. December 2017.

Pfizer 2018 ASPIRE Gene and anti-TFPI Therapies for Hemophilia Global Research Award

Regulation of TFPIα through alternative splicing of coagulation factor V

Role: PI