Thompson & Thompson Genetics in Medicine, 8th Edition

Case 46. Thrombophilia (FV and PROC Mutations, MIM 188055 and MIM 176860)

Autosomal Dominant


• Gain-of-function mutation (factor V Leiden)

• Loss-of-function mutation (protein C mutations)

• Incomplete penetrance

• Genetic modifiers

• Environmental modifiers

• Heterozygote advantage

• Founder effect

Major Phenotypic Features

• Age at onset: Adulthood

• Deep venous thrombosis

History and Physical Findings

J.J., a 45-year-old businessman of French and Swedish descent, suddenly developed shortness of breath on the day after a trans–Pacific Ocean flight. His right leg was swollen and warm. Subsequent studies identified a thrombus in the popliteal and iliac veins and a pulmonary embolus. Both of his parents had had leg venous thromboses, and his sister had died of a pulmonary embolus during pregnancy. Based on his age and family history, J.J. was believed to have inherited a predisposition to thrombophilia. Screening for inherited causes of thrombophilia identified that J.J. was a carrier of factor V Leiden. Subsequent studies of other family members identified the same heterozygous mutation in J.J.'s father, deceased sister, and unaffected older brother. J.J. and his mother, deceased sister, and unaffected older sister were all found to be heterozygous for a frameshift mutation (3363insC) in PROC, the gene encoding protein C. Thus J.J. is a double heterozygote for two variants—in two unlinked genes—that predispose to thrombosis.


Disease Etiology and Incidence

Venous thrombosis (MIM 188050) is a panethnic multifactorial disorder (see Chapter 8); its incidence increases with age and varies among races. The incidence is low among Asians and Africans and higher among whites. Major predisposing influences are stasis, endothelial damage, and hypercoagulability. Identifiable genetic factors, present in 25% of unselected patients, include defects in coagulation factor inhibition and impaired clot lysis. Factor V Leiden occurs in 12% to 14%, prothrombin mutations in 6% to 18%, and deficiency of antithrombin III or protein C or S in 5% to 15% of patients with venous thromboses.

Factor V Leiden, an Arg506Gln mutation in the FV gene, has a prevalence of 2% to 15% among healthy European populations; it is highest in Swedes and Greeks and rare in Asians and Africans. Factor V Leiden apparently arose from a mutation in a white founder after the divergence from Africans and Asians.

Protein C deficiency (MIM 176860) is a panethnic disorder with a prevalence of 0.2% to 0.4%. Mutations of PROC are usually associated with activity levels of less than 55% of normal.


The coagulation system maintains a delicate balance of clot formation and inhibition; however, venous thrombi arise if coagulation overwhelms the anticoagulant and fibrinolytic systems. The proteases and protein cofactors of the clotting cascade must be activated at the site of injury to form a fibrin clot and then be inactivated to prevent disseminated coagulation (see Fig. 8-8). Activated factor V, a cofactor of activated factor X, accelerates the conversion of prothrombin to thrombin. Factor V is inactivated by activated protein C, which cleaves activated factor V at three sites (Arg306, Arg506, and Arg679). Cleavage at Arg506 occurs first and accelerates cleavage at the other two sites; cleavage at Arg506 reduces activated factor V function, whereas cleavage at Arg306 abolishes its function. Protein S, a cofactor for protein C, both accelerates the inactivation of activated factor V by protein C and enhances cleavage at Arg306.

The factor V Leiden mutation removes the preferred site for protein C proteolysis of activated factor V, thereby slowing inactivation of activated factor V and predisposing patients to thrombophilia. The risk for thrombophilia is higher for patients homozygous for factor V Leiden; the lifetime risks for venous thrombosis for factor V Leiden heterozygosity and homozygosity are approximately 10% and 80%, respectively.

Inherited deficiency of protein C arises from mutations in the PROC coding and regulatory sequences. Many mutations are sporadic, although some, such as the French-Canadian mutation 3363insC, entered populations through a founder. Unlike the gain-of-function factor V Leiden mutation, PROC mutations impair protein C function, thereby slowing inactivation of activated clotting factors V and VIII and predisposing to thrombus formation. Inheritance of two mutant PROC alleles usually results in purpura fulminans, a form of disseminated intravascular coagulation that is often fatal if it is not treated promptly. Heterozygous protein C mutations predispose to thrombophilia and carry a 20% to 75% lifetime risk for venous thrombosis.

In general, for patients heterozygous for the factor V Leiden polymorphism or a PROC mutation, progression from a hypercoagulable state to venous thrombi requires coexisting genetic or environmental factors. Associated nongenetic factors include smoking, pregnancy, oral contraceptive use, surgery, advanced age, neoplasia, immobility, and cardiac disease. Tobacco and oral contraceptive use act synergistically and increase the risk 8.8-fold over those who do not use either. Associated genetic abnormalities include other disorders of coagulation factor inhibition and impaired clot lysis.

Phenotype and Natural History

Although thrombi can develop in any vein, most arise at sites of injury or in the large venous sinuses or valve cusp pockets of the legs. Leg thrombi are usually confined to the veins of the calf, but approximately 20% extend into more proximal vessels. Obstruction of the deep leg veins can cause swelling, warmth, erythema, tenderness, distention of superficial veins, and prominent venous collaterals, although many patients are asymptomatic (Fig. C-46).


FIGURE C-46 Autopsy picture of the cardiac right ventricle from a 58-year-old man who had had a cervical laminectomy and decompression. He complained of right calf pain 33 days after surgery, and Homans sign was present. Venous ultrasonography detected a thrombus extending from the post-tibial and popliteal veins into the femoral vein. Despite anticoagulation with heparin, the patient was found 2 days later unresponsive and with a low oxygen saturation; he did not respond to cardiopulmonary resuscitation and died. Autopsy showed a thromboembolus in the right ventricle occluding the pulmonary artery. See Sources & Acknowledgments.

Once formed, a venous thrombus can propagate along the vein and eventually obstruct other veins, give rise to an embolus, be removed by fibrinolysis, or be organized and possibly recanalized. Embolism is serious and can be acutely fatal if it obstructs the pulmonary arterial system; pulmonary embolism occurs in 5% to 20% of patients presenting initially with deep calf vein thrombosis. In contrast, organization of proximal vein thrombi chronically impedes venous return and causes post-thrombotic syndrome, characterized by leg pain, edema, and frequent skin ulceration.

With the possible exception of an increased risk for recurrence, the symptoms, course, and outcomes of patients with PROC mutations and factor V Leiden are similar to those of other thrombophilia patients. In general, untreated patients with proximal vein thrombosis have a 40% risk for recurrent venous thrombosis.


The diagnosis of deep venous thrombosis of the calf is difficult because patients are often asymptomatic and most tests are relatively insensitive until the thrombus extends proximal to the deep calf veins. Duplex venous ultrasonography is used most often to diagnose deep venous thrombosis; the thrombus is detected either by direct visualization or by inference when the vein does not collapse on compressive maneuvers. Doppler ultrasonography detects flow abnormalities in the veins.

Factor V Leiden can be diagnosed directly by DNA analysis or can be suspected on the basis of activated protein C resistance. Protein C deficiency is diagnosed by measuring protein C activity; PROCmutations are identified by analysis of the PROC gene.

Acute treatment focuses on minimizing thrombus propagation and associated complications, especially pulmonary embolism; it usually involves anticoagulation and elevation of the affected extremity. Subsequent therapy focuses on prevention of recurrent venous thrombosis through identification and amelioration of predispositions, and anticoagulant prophylaxis. Treatment recommendations for patients with protein C deficiency and factor V Leiden are still evolving. All patients should receive standard initial therapy followed by at least 3 months of anticoagulant therapy. It is unclear which patients with a single mutant allele should receive prolonged, perhaps lifelong anticoagulation, but long-term anticoagulation is generally prescribed for patients with a second episode of deep venous thrombosis. In contrast, homozygous factor V Leiden patients as well as those who are homozygous for other mutations or are combined carriers (like J.J.) are placed on long-term anticoagulation after their initial episode.

Inheritance Risk

Each child of a couple in which one parent is heterozygous for factor V Leiden has a 50% risk for inheriting a mutant allele. Assuming 10% penetrance, each child has an a priori 5% lifetime risk for development of a venous thrombosis.

Each child of a couple in which one parent is heterozygous for a PROC mutation also has a 50% risk for inheriting a mutant allele. Estimates for penetrance of protein C deficiency range from 20% to 75%; therefore each child has an a priori 10% to 38% lifetime risk for development of a venous thrombosis.

Because of the incomplete penetrance and availability of effective therapy for factor V Leiden and heterozygous PROC mutations, prenatal diagnostic testing is not routinely used except for detection of homozygous or compound heterozygous PROC mutations. Prenatal detection of homozygous or compound heterozygous PROC mutations is helpful because of the severity of the disease and the need for prompt neonatal treatment.

Questions for Small Group Discussion

1. Some studies of oral contraceptives suggest that such drugs decrease the blood levels of protein S. How would this predispose to thrombosis? At a molecular level, why would this be expected to enhance the development of venous thromboses in women with the factor V Leiden mutation? Should such women avoid the use of oral contraceptives? Should women be tested for factor V Leiden before using oral contraceptives?

2. Testing of asymptomatic relatives for the factor V Leiden mutation is controversial. For it to be of clear utility, what should presymptomatic testing allow?

3. Synergism is the multiplication of risk with the co-occurrence of risk factors. Illustrate this with factor V Leiden and protein C deficiency (the family of J.J. is an example), factor V Leiden and oral contraceptive use, and factor V Leiden and hyperhomocystinemia.

4. Factor V Leiden is thought to reduce intrapartum bleeding. How would this lead to a heterozygote advantage and maintenance of a high allele frequency in the population?


Kujovich JL. Factor V Leiden thrombophilia. [Available from]

Varga EA, Kujovich JL. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012;81:7–17.