Activated Protein C Resistance (Factor V Leiden)

I. Review of Protein C and Factor V

Factor V is a proenzyme that is activated to Factor Va, whose function is to catalyze the activation of prothrombin to thrombin. Therefore, FVa is a potent procoagulant.
Protein C is a Vitamin K-dependent protease that functions as an anticoagulant by inactivating Factor Va.
In intact vessels, thrombin binds thrombomodulin (an endothelial cell transmembrane protein). This binding converts thrombin from a procoaglulant to anticoagulant protease which can now cleave and activate Protein C.
Activated Protein C in conjunction with a cofactor called Protein S inactivates both Factor Va and VIIIa.

II. History

Prior to 1993, the diagnostic evaluation of patients with inherited hypercoagulable states included Proteins C&S, Antithrombin III and the rare dysfibrinogenemias. However, this evaluation yielded positive results only about 25% of the time. In the remaining cases, no further information regarding the etiology of the condition could be ascertained.

Then in 1993 in Holland, Dahlback et al. made a significant discovery. In their experiments to determine the cause of many of these unexplained thrombotic events, they administered exogenous activated protein C (APC) to patients' plasma and then measured the aPTT. In normal healthy men, when exogenous APC was given, the aPTT was substantially prolonged. This was expected given the role of Protein C in inhibiting factors Va and VIIIa. However, when many men with history or family history of unexplained thrombosis were given APC, the aPTT was not prolonged nearly as much. With this novel finding in mind, they proposed mechanisms that could account for this APC resistance. Their hypotheses included: autoantibody against Protein C, antiphospholipid antibodies inhibiting APC function, fast-acting inhibitor of APC, and Protein S Deficiency. They excluded all of these possibilities experimentally, leaving mutation in the genes for Factors V and VIII as possible mechanisms. Through their experiments they eventually found that adding normal Factor V corrected the abnormality and actually prolonged the aPTT to expected levels. This led to studies searching for mutations in the gene for Factor V as the cause for APC resistance.

III. APC Resistance

A. Inheritance - autosomal dominant

B. Epidemiology

1. APC resistance is estimated to occur in 25-40% of patients with family history of thrombosis.

2. It also occurs in 3-5% of apparently normal individuals.

C. Mechanism

1. Inactivation of normal Factor Va occurs through an ordered series of cleavages at arginine residues.

2. In APC resistance, the arginine at position 506 is substituted with glutamine. This renders the Factor Va molecule resistant to cleavage by APC.

3. Thrombosis occurs because this altered Factor Va still has the same procoagulant activity as normal Factor Va.

D. Risk of thrombosis

1. There is a 7.9 fold increase in the relative risk for thrombosis with the Factor V mutation.

2. Homozygous and heterozygous individuals for the Factor V mutation can develop thrombosis.

3. Homozygotes have a 91 fold increase in thrombotic events.

4. Mean onset of thrombotic symptoms

In heterozygotes, the mean age of onset is 44.
In homozygotes, the mean age of onset is 31.

5. There is no increased risk of myocardial infarction or stroke.

E. Clinical Features - smiliar to Antithrombin III, Protein C, and Protein deficiencies.

1. Increased risk of venous thrombosis and pulmonary embolism. Venous thrombosis occurs most frequently in the deep veins of the lower extremities.

2. Thrombotic events begin in mid-late teenage years.

3. Mesenteric veins, IVC, renal veins are all susceptible.

4. Cerebral vein thrombosis can occur.

5. Thrombosis may be precipitated by surgery, trauma, pregnancy, OCP use, or infection.

6. Arterial thrombosis is not increased.

F. Laboratory Evaluation

1. Functional test

a. Similar to Dahlback's experiments.

b. Measure aPTT before and after addition of APC to patient's plasma.

c. Compute ratio of aPTT with APC:aPTT without APC. Ratio less than two indicates that aPTT is not being signifcantly prolonged with addition of APC and therefore suggests APC resistance.

d. Note that if the patient is on anticoagulant therapy or has lupus anticoagulant, the aPTT will be prolonged as a result. Therefore, the functional assay will not be useful. In this setting, perform the molecular assay instead.

2. Molecular assay via polymerase chain reaction for detection of arginine mutation at position 506.

3. Screen with the functional test and confirm APC resistance with the molecular assay.

G. Treatment of APC resistance

1. Acute thrombosis should be treated with intravenous heparin.

2. Long term prophylaxis should be undertaken with warfarin.

3. Long term low dose subcutaneous heparin can be used as an alternative to warfarin.

4. Peri-operative prophylaxis with intravenous heparin.

Go to Antithrombin III Deficiency

Go to Protein C Deficiency

Go to Protein S Deficiency

Go to Antiphospholipid Syndrome

Go Back to Hypercoagulable States

Go to Prothrombin 20210 Defect

Go back to Table of Contents