Canadian Medical Association Journal 1996; 155: 296-298
© 1996 Canadian Medical Association (text and abstract/résumé)
The recent discovery of factor V Leiden has expanded considerably the proportion of patients with a familial predisposition to venous thrombosis in whom a specific heritable abnormality can be identified. The initial observation by Dahlbäck and associates[1] of a resistance to activated protein C in a large proportion of patients with familial thrombophilia was quickly confirmed by other researchers.[2] In almost all patients this functional abnormality, as detected in a clotting assay, corresponds to the mutation known as factor V Leiden.[3] The single substitution of glutamine for arginine at position 506 renders activated factor V resistant to proteolysis by its natural inhibitor, activated protein C. This mutation accounts for up to 40% of patients with familial venous thrombosis[1-3] and thus is more frequent in this group than deficiencies in antithrombin III, protein C and protein S combined. There is evidence that people who are heterozygous for factor V Leiden have a 5- to 10-fold increase in risk for venous thrombosis.[5] Resistance to activated protein C was found in 21% of an unselected group of patients presenting with a first episode of deep venous thrombosis, a higher frequency than was reported for other heritable risk factors.[6]
Although factor V Leiden increases the relative risk of thrombosis, we might infer from the impact of other mutations that can lead to venous thrombosis that this risk is not invariable. People with a family history of venous thrombosis who have mutations such as antithrombin III, protein C or protein S deficiency are reported to have a 50% to 60% chance of experiencing a thrombotic event by age 50;[4,7] such rates may overestimate the risk, however.[8] Thromboses, when they occur, may either be idiopathic or associated with a clinical risk factor such as surgery, immobilization or pregnancy. Venous thrombosis is frequent in clinical circumstances that give rise to stasis, injury and hypercoagulability.
The plasmatic imbalance of procoagulant and anticoagulant factors can be critical in promoting a relative hypercoagulable state. The more the perturbations in this balance, the higher the likelihood of clinical thrombotic manifestations. People who are homozygous for factor V Leiden are at a much greater risk for venous thrombosis than those who are heterozygous, having close to a 100% lifetime risk of a thrombotic event.[5,10,11] People with familial protein C deficiency who also carry factor V Leiden are also at higher risk of thrombosis than those with only one or the other defect.[12] The concurrence of hereditary homocystinuria and factor V Leiden has also been shown to confer a high risk of venous and arterial thrombosis.[13] The risk of thrombosis among women taking oral contraceptives who were also heterozygous for factor V Leiden was reported to be eight times higher than the risk among women taking oral contraceptives who did not have the mutation.[9] The impact of other clinical variables such as surgery, immobilization or an associated malignant disease on the risk of thrombosis in people who are heterozygous for factor V Leiden is not yet known.
Lee and associates document a relatively high prevalence rate of factor V Leiden in a Canadian blood donor population. The rate is in the same range as that reported in most other countries where similar studies have been conducted. Although in the present study the participants found to have the mutation could not be traced to obtain information on any history of venous thrombosis, they appear to represent a cross-section of the general population. A similar prevalence rate for factor V Leiden was found in the control arm of the Leiden Thrombophilia Study, which was composed of people with no history of venous thrombosis.[6] The question has been raised whether a beneficial effect of factor V Leiden has maintained its relatively high frequency in the gene pool through some selective advantage.[14] Perhaps a slight prothrombotic tendency provides some survival or reproductive advantage that allows this genetic variance to persist despite the potential thrombotic consequences. The observations of Lee and associates closely parallel the findings of a study of protein C deficiency in a normal population.[15] Although occurring far less frequently than factor V Leiden, decreased protein C levels in a normal blood donor population were not found to be associated with any excess risk of venous thrombosis.
These findings are somewhat paradoxical. Whereas significant increases in the risk of venous thrombosis have been found among people with a family history of thrombosis who have factor V Leiden or protein C deficiency, there seems to be little excess risk of thrombosis when these mutations occur in people with no family history of thrombosis. This discrepancy, along with the known variability of the actual magnitude of the thrombotic risk in different families with an underlying mutation, strongly suggests that other factors influence the clinical expression of a thrombophilic tendency in such kindreds.[15] Factors modulating the expression of venous thrombosis probably include numerous other genetic variables that determine endothelial cell function and control the regulation of blood coagulation, for example. Acquired risks such as immobilization and the use of oral contraceptives are superimposed on the genetic polymorphisms present in a population. The impact of an acquired risk factor in provoking venous thrombosis may very well depend on the unique genetic profile of the patient.
The management of patients at high risk for venous thrombosis, such as those with combined genetic defects, should include vigorous thrombosis prophylaxis when clinical circumstances warrant. Early consideration should be given to long-term anticoagulation therapy for patients in this category who have experienced a serious or an idiopathic thrombotic event.[4] Although the optimal length of anticoagulation therapy for patients with a history of thrombosis and an intermediate underlying heritable risk or single genetic defect is unclear, thrombosis prophylaxis should always be instituted as required for this group. Although long-term anticoagulation therapy is recommended by some centres, most advocate a more conservative approach in which patients with an inherited defect who have had one thrombotic event are managed similarly to those with no identified heritable risk.[4] The development of more precise recommendations will depend on the results of clinical trials that address such questions.
The question of routine testing for factor V Leiden before the prescription of oral contraceptives will need to be resolved. It would seem appropriate to screen women who have experienced a thrombotic event while using oral contraceptives and to consider screening any woman with a family history of thrombosis. As many as one in five patients with a history of venous thrombosis may carry factor V Leiden.[6] One could argue that all patients who have experienced a thrombotic event should be tested for the purposes of risk counselling. However, in the absence of prospective studies involving such patients, no definitive guidelines can be established. Neither can definite recommendations be made with respect to the risk of recurrent thrombotic events or the optimal length of anticoagulation therapy for patients with a history of thrombosis who are heterozygous for factor V Leiden. None the less, laboratory screening for the purposes of thrombosis prophylaxis of asymptomatic members of thrombosis-prone families with an identified heritable defect appears to be justified.
Laboratory screening for factor V Leiden is most readily available in the form of the functional clotting test for activated protein C resistance. Direct testing for the factor V mutation may be offered in centres with expertise in DNA testing. A small proportion of patients with a functional resistance to activated protein C do not carry the factor V Leiden mutation and are presumably carriers of an unknown defect. Activated protein C resistance cannot be tested in the usual way in patients taking warfarin, nor can it be interpreted in patients with a lupus anticoagulant, for example. No such limitation would apply to genetic testing for factor V Leiden. Furthermore, identification of homozygotes is most reliable in DNA testing. Commercial kits for factor V Leiden detection will undoubtedly increase the availability of testing; in the meantime, however, screening for activated protein C resistance remains an effective alternative.
Lee and associates establish factor V Leiden as an important variable to consider in the design, interpretation and analysis of clinical studies on the prevention and management of venous thrombosis. More precise clinical practice guidelines that address the specific needs of people who are heterozygous for factor V Leiden are anticipated. Given the prevalence of this mutation in the general population, Canadian physicians will await further studies on this intriguing condition with interest.