An investigator is conducting a phase 1 trial for a novel epoxide reductase inhibitor with favorable pharmacokinetic properties for cerebrovascular accident prophylaxis. Two days after the trial starts, a subject begins to notice pain and erythema over the right thigh. It rapidly progresses to a purpuric rash with the development of necrotic bullae over the next 24 hours. Laboratory studies show a partial thromboplastin time of 29 seconds, prothrombin time of 28 seconds, and INR of 2.15. Which of the following best describes the pathogenesis of the disease process in the patient?

Question

Quizplus · Accepted Answer

Eductional Objective: Epoxide reductase results in the formation of reduced vitamin K, which is essential for activation of both procoagulant factors II, VII, IX, X as well as the anticoagulants protein C and protein S. Of these vitamin K-dependent factors, factors IIa and Xa have long half-lives. Protein C and factor VIIa, on the other hand, have the shortest half-lives and are thus the first components to be depleted following epoxide reductase inhibition. Despite an early increase in PT and INR caused by decreased VIIa (extrinsic pathway factor), the patient is initially in a hypercoagulable state because decreased active protein C levels cause increased activity of VIIIa (intrinsic pathway factor) and Va (common pathway factor). This hypercoagulable state can result in intravascular microthrombosis, which can cut off blood supply to the skin and cause necrosis, as seen in this patient.

An Investigator Is Conducting a Phase 1 Trial for a Novel