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without the mutation had an approximate 1.6-fold increase in the risk of recurrent thrombosis [56]. When this was restricted to patients with an unprovoked event, this decreased to a 1.2-fold increase in risk that was no longer statistically signicant. The same analysis found a borderline signicant 1.4-fold increase in risk of recurrent venous thrombosis in patients heterozygous for the prothrombin gene mutation. This data suggests heterozygosity for the FVL or PGM should not be used by itself to determine duration of anticoagulation.

There is less data regarding the impact of antithrombin, protein C and protein S deciency on the risk of recurrent venous thrombosis, and due to their lower incidence, data tends to be pooled for all three conditions. Data from prospective cohort studies of unselected patients with venous thrombosis has suggested an approximate twofold increase in the risk of recurrence in patients with deciencies of these proteins in comparison to patients with normal levels [8]. A retrospective study of thrombophilic families found that individuals with AT, PC and PS deciency had a cumulative incidence of recurrent thrombosis of 55% by 10years after ceasing anticoagulation, in comparison to a gure of 25% in patients with FVL, PGM or elevated FVIII levels [57]. These data suggest that patients with conrmed AT, PC or PS deciency may benet from long-term anticoagulation. It is important to stress that the levels of these proteins may be spuriously low, for example in the case of recent extensive thrombosis, or, in the case of protein C and S, recent warfarin therapy. Therefore, repeat testing in the absence of confounding factors should be performed to conrm the diagnosis prior to therapeutic decisions being made. While data is lacking on clinical factors that can be used to reliably identify patients with venous thrombosis that will have a deciency of one of the natural inhibitors of coagulation, it would appear reasonable to focus testing on patients with unprovoked events, younger age (<50 years of age), unusual site of thrombosis, or a strong family history (>1 rst degree relative) of venous thrombosis. If testing is to be performed it is suggested that it be performed at either the time cessation of anticoagulation is being considered, or one month after cessation.

As previously mentioned, patients with APLAS have been demonstrated to have an increased risk of recurrent thrombosis, with estimates of risk ranging from 10 to 60% perannum [

44]. In addition, patients with antiphospholipid antibody syndrome

have been demonstrated to have an increased risk of death after ceasing anticoagulation, contributed to by the fact that this patient group is at increased risk of not only recurrent venous thrombosis but also arterial complications. Therefore, long-term anticoagulation is generally recommended for patients who meet the diagnostic criteria for this condition.

10.3.1.4 Determining theNeed forPrimary Prophylaxis inAsymptomatic

Family Members

Another possible role for thrombophilia testing is determined if the baseline risk of venous thrombosis is sufcient to warrant primary prophylaxis with anticoagulation. Given the lack of evidence supporting a role for anti-platelet therapy in the

226

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Table 10.2 Risk of venous thrombosis in asymptomatic family members with inherited thrombophilia

AT deciency

Overall risk (risk/year) 1.5–2.0% 1.0–1.5% 1.5–2.0% 0.5% 0.3–0.4% Oral contraception

(risk/year exposure) Pregnancy (risk/

pregnancy 95% CI) Antepartum risk 7.3%

Postpartum risk 11.1%

Refers to heterozygote state

4–5% (pooled data) 0.3–2.0% 0.2–2.0%

16.6% (0.0–45.1)

(1.8–15.6)

(3.7–21.0)

Protein C deciency

7.8% (0.0–33.8)

3.2% (0.6–8.2)

5.4% (0.9–13.8)

Protein S deciency

4.8% (0.0–20.0)

0.9% (0.0–3.7)

4.2% (0.7–9.4)

FVL mutation

1.1% (0.3–0.9)

0.4% (0.1–0.9)

2.0% (0.9–3.7)

PGM

mutation

0.9% (0.2–2.0)

0.0% (0.0–0.2)

0.9% (0.2–2.0)

primary prevention of venous thromboembolism, at present this would require an estimate of risk that was sufciently high to justify exposure to the 1–2% annual risk of major haemorrhage associated with ongoing oral anticoagulant therapy.

As shown in Table 10.2, the annual risk of venous thrombosis in previously asymptomatic patients varies from approximately 0.3% with the PGM to up to 2% in patients with AT or protein S deciency [8, 9, 57]. This is against a background rate of approximately 0.1% perannum in the general population, with incidence increasing with age. It is generally accepted that given the risk associated with oral anticoagulation, that primary prophylaxis is therefore not justied in patients with any of the known inherited thrombophilias. It has been shown that between 50 and 60% of episodes of venous thrombosis in previously asymptomatic family members with thrombophilia will occur in the context of an additional environmental risk factor such as surgery. While not clearly demonstrated in clinical trials, it is possible that more aggressive thromboprophylaxis may be justied particularly in patients with type 1 thrombophilic conditions [9]. Again, if testing is performed for this indication, care must be taken to avoid over-interpretation of the test result by both patient and other clinicians.

10.3.1.5 Making Decisions Regarding theUse oftheOral

Contraceptive Pill

Knowledge of whether a previously asymptomatic individual is a carrier of a known inherited thrombophilia may inuence decision-making regarding exposure to the pro-thrombotic effects of oral contraception. Estimates of the annual risk of thrombosis with the use of a combined oestrogen/progesterone oral contraceptive (OCP) in previously asymptomatic relatives identied due to a family history of thrombosis [8, 58] are shown in Table10.2. Generally women of child bearing age have a low annual risk of thrombosis of approximately 1–2/10,000/year. The increase in annual risk of venous thrombosis with OCP use is higher in previously asymptomatic individuals with type 1 thrombophilic states, and most clinicians would accept

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that the magnitude of risk justies avoidance of the combined OCP and use of other contraceptive measures, including progesterone only pills or intrauterine devices, that do not increase the risk of thrombosis. Estimates of the risk with OCP use in family members heterozygous for FVL and PGM vary, and decisions may be inuenced by patient perception of the benet obtained from OCP use, and the presence of other risk factors for venous thrombosis such as obesity.

It is worth emphasising that negative testing for an underlying thrombophilia may provide false reassurance in this setting. Family members testing negative for the thrombophilia identied in the proband have still been shown to have a risk of venous thrombosis signicantly higher than the remainder of the community possibly due to unidentied inherited factors [58].

10.3.1.6 Determining theNeed forThromboprophylaxis

During Pregnancy

The risk of venous thrombosis during pregnancy in women with no prior history of thrombosis associated with the presence of common inherited thrombophilic conditions, derived from a meta-analysis of available studies, is shown in Table10.2 [59]. Two-thirds to three-quarters of pregnancy related episodes of venous thrombosis will occur during the post-partum period. Estimates for type 1 conditions are derived from family studies and therefore cannot be extrapolated to women diagnosed incidentally. The case for prophylactic anticoagulation during pregnancy can be made most strongly for women with type 1 conditions, particularly for antithrombin deciency and, to a lesser extent, protein C deciency. Other risks factor such as obesity, other medical conditions and the strength of family history of thrombosis are likely to inuence decision making. As a minimum, post-partum prophylaxis should be administered for 6–8weeks. In FVL and PGM heterozygotes ante-partum prophylaxis is generally not recommended in women with no prior history of events. Post-partum prophylaxis should be considered, again particularly in women with additional risk factors.

227

10.4 Patients withArterial Thrombosis

The association between inherited thrombophilic conditions and arterial disease has not been clearly demonstrated. Case reports and small studies have linked antithrombin, protein C and protein S deciency to arterial disease, however the data are inconclusive [8]. Larger studies have evaluated the link between the FVL and PGM mutations with both coronary artery disease, myocardial infarction and stroke. Generally the ndings have been of either no link or a weak association with odds ratios of <1.5 [8, 9], with some data suggesting a stronger association with myocardial infarction in younger patients with the additional risk factor of smoking. There is also no conclusive evidence supporting an association of thrombophilia with

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peripheral arterial disease. Based on the lack of a clear association of inherited thrombophilia with arterial disease, and no data supporting that a change in management based on the knowledge of the presence of a thrombophilic conditions improves patients outcome, it is recommended that testing for inherited thrombophilia should not be performed in patients with arterial disease outside clinical studies.

As stated above, the association of antiphospholipid antibodies with an increased risk of arterial disease is more denitive. It is generally recommended that patients with APLAS and arterial disease should be treated with warfarin rather than antiplatelet agents, although the evidence supporting this approach remains minimal [44]. Myeloproliferative disorders can also be associated with arterial disorders, and should be considered in patients with unexplained arterial thrombotic events in the absence of traditional risk factors.

The clinical utility of measuring homocysteine levels in patients with arterial disease at present remains unclear. While a number of trials have shown benet of B-vitamin supplementation on surrogate end-points of arterial disease, a metaanalysis found no reduction in clinical end-points in patients with mild hyperhomocysteinemia and either cardiovascular disease or stroke with supplementation therapy [60]. This should be distinguished from patients with severe hyperhomocysteinemia who constitute a small proportion of patients with thrombosis (~0.2%), who may present with premature arterial disease [61].

S. J. McRae

10.5 Potential Detrimental Effects ofThrombophilia Testing

A small number of studies have examined the potential psychological impact on patients of performing thrombophilia testing [62]. While the general conclusion was that the impact was low, it was clear that many patients were unclear that they had been tested, and the knowledge of having a thrombophilia did cause signicant distress in some individuals. Other potential drawbacks to testing for inherited thrombophilia may include difculty with obtaining or changes to the cost of lifeinsurance, and questionable cost-effectiveness [8].

Perhaps due to the uncertainty about the clinical implications of the nding of the presence of a low risk thrombophilic condition, studies have found that patients tested for these conditions show a low degree of satisfaction with no impact on quality of life [63].

10.6 Conclusion

It can be concluded that, despite the ability to detect an underlying thrombophilia in up to 50% of patients with venous thrombosis, it is doubtful that performing laboratory testing for thrombophilias has a positive effect on patient outcome in the

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majority of patients. The strongest case for testing for inherited thrombophilia can be made for type 1 conditions, although these conditions will be detected in only approximately 5% of patients with venous thrombosis. The evidence that testing for FVL and the PGM abnormalities improves patient outcome is limited.

Widespread testing for inherited thrombophilia in unselected patients is recommended against, with a stronger case for testing able to be made for patients with previously-asymptomatic female rst-degree relatives of child-bearing age particularly with type 1 conditions. Prior to any testing being performed, the clinician involved in test-ordering should counsel the patient regarding the implications of both a positive and negative test result, and how this will change patient management. If it is unclear how the test result will change treatment for the individual or relatives, then testing should not be performed. Clinicians have been shown to adhere poorly to guidelines that recommend against widespread thrombophilia testing, and continuing education is required in this area [63].

Testing for acquired thrombophilic conditions, including APLAS, MPN and HIT is more likely to impact clinical decision making, and should be performed in patients with suggestive clinical features.

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