Arterial thrombosis in Factor V Leiden or activated protein C resistance: Clinical and experimental studies

Abstract

Our studies so far has shown a higher frequency of APC resistances in peripheral vascular patients compared with a control group. Although a large number of these patients have abnormal APC ratio and FVL mutation, a substantial number, 37% have abnormal APC ratio but normal gene. Our study has not yet answered this intriguing observation pertaining to other causes of APC resistance. Our studies has shown a significantly high frequency of APC resistance in patients with lower extremity peripheral vascular disease and failed reconstructions.

Table of Contents

Chapter One: Introduction4

Arterial thrombosis5

Pathophysiology9

Frequency10

United States10

Mortality/Morbidity10

Chapter Two: Literature Review13

The factor V mutation and APC resistance20

The factor V mutation test21

Prevalence of the factor V mutation and its effect on incidence of thrombosis21

Factor V mutation in women's health21

Diagnostic work-up of patients with inherited thrombosis22

How do patients benefit from factor V mutation testing?22

Management of factor V heterozygotes and homozygotes23

Chapter Three: Methodology29

Data Analysis29

Chapter Four: Results and Discussion31

STUDY 1: Activated Protein C resistance in patients with peripheral vascular disease31

Prevalence33

STUDY 2: The impact of factor V mutation on the risk for occlusion in patients undergoing peripheral vascular reconstructions.34

Factor V Leiden Mutation and Risk for Factor V Leiden34

STUDY 3: Arterial thrombosis in mice with factor V Leiden mutation36

Hypercoagulability and Coronary Heart Disease37

Role of Fibrinolysis39

Interaction with Concomitant Inherited Defects of Hemostasis42

Risk for Factor V Leiden during Pregnancy45

Risk for Recurrent Factor V Leiden45

Risk for Arterial Thromboembolism46

Screening for Factor V Leiden Mutation47

Chapter Five: Conclusion52

References61

Chapter One: Introduction

Since its discovery in 1994, Activated Protein C (APC) resistance and the subsequent mapping of the gene mutation has been established as the most frequently occurring cause of venous thromboembolism in humans. The gene mutation or Factor V Leiden (FVL), is a single point mutation resulting in an R506Q substitution at the activated protein C cleavage site. This mutation renders activated factor V resistant to proteolysis by the APC to stop the coagulation cascade, resulting in hypercoagulable state. FVL has been found to account for 90% to 95% of all cases of APC resistance. The incidence of APC resistance is up to 7% in the caucasian populations, and even higher in the Nordic countries, but almost absent in other ethnic groups. About 30-60 % of all cases of venous thrombosis have been found to be due to FVL.

In contrast, the role FVL in arterial thrombosis is still not well established. Recent studies have shown conflicting relationship between arterial thrombosis and FVL. Our project was set up to try to find answers to some these intriguing questions about any role played by FVL in arterial thrombosis.

A prospective study was set up to follow a cohort of peripheral vascular disease patients admitted to the department of vascular surgery, Malmo University Hospital. All our patients were screened for APC resistance with APC ratio and gene specific analyses, and subsequently analysed specifically for factor V mutation with PCR. Patients were followed after surgery to determine patency rates in their reconstructions. An experimental study was also undertaken in this regard ...