Objectives

1. To understand the definition of thrombophilia and its limitations.
2. To identify individuals who may have an underlying thrombophilic state, either primary or secondary.
3. To identify the tests used to detect thrombophilia and their limitations.
4. To discuss the optimal duration of therapy for unprovoked venous thromboembolic disease.
5. To understand how the thrombophilia workup may impact the recommended duration of therapy.

Key words

anticoagulation therapy; deep venous thrombosis; genetic testing; hypercoagulable states; pulmonary embolus; thrombophilia

Abbreviations

APC = activated protein C; AT = antithrombin; DIC = disseminated intravascular coagulation; DVT = deep venous thrombosis; MTHFR = methylenetetrahydrofolate reductase; PC = protein C; PE = pulmonary embolus; PS = protein S; VTE = venous thromboembolic disease

The term thrombophilia implies an ongoing stimulus that predisposes an individual to thrombosis. This stimulus may be genetic (primary) in nature or acquired. Unfortunately, the genetic risk factors that characterize thombophilia are not uniform in their effects. Many individuals who carry thrombophilic conditions remain asymptomatic. Others who carry one or more of the genetic markers for a thrombophilic condition demonstrate a tendency for thrombosis, spontaneously or disproportionately to the thrombogenic stimulus. Finally, some individuals demonstrate an ongoing predisposition to recurrent thrombosis, yet have no identifiable thrombophilic defect. Individuals in these latter two categories may develop venous thromboembolic disease (VTE) at an early age, may suffer from recurrent deep venous thrombosis (DVT) and pulmonary embolus (PE), and may have family members who are similarly affected. Thrombophilia can be a particularly useful clinical concept in these instances.

The prothrombotic states may be acquired, inherited, or a combination of both. Acquired defects may be further categorized as intrinsic to the individual, such as cancer or presence of the lupus anticoagulant, or exogenous, such as estrogen therapy and surgery. These secondary risk factors may further interact with an individual's genetic predisposition, potentially enhancing the risk for thrombosis.

Secondary Causes

Secondary causes of thrombophilia (Table 1) are important to recognize and may be modifiable. Oral contraceptive agents or hormone replacement therapy, high-risk surgery, obesity, and the presence of a central venous catheter are potentially reversible risk factors for VTE and, if modified, will lower the patient's likelihood of recurrent VTE. Cancer, with or without evidence of disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria, and the lupus anticoagulant are likely to be persistent risk factors associated with a significant risk of recurrent VTE.

Primary Causes

The primary causes of thrombophilia (Table 2) are genetic in nature and imply an ongoing risk factor for developing VTE that may or may not manifest itself in an individual's lifetime. These genetic variants are independent risk factors for the development of a first episode of "unprovoked" DVT and PE, but their impact on the risk of recurrent disease is less certain for some of the more common mutations. The inherited disorders of thrombophilia pertain to either a quantitative or qualitative abnormality of the natural anticoagulant system. Deficiencies of the natural anticoagulants antithrombin (AT), protein C (PC), and protein S (PS) will be found in only 5% of patients presenting with an unprovoked DVT, although each deficiency on its own is associated with a high relative risk of first episode and recurrent DVT.^1,2 In other words, these are uncommon but potent thrombotic risk factors. In contrast, the factor V Leiden and prothrombin 20210 mutations and hyperhomocysteinemia will be found in 40 to 60% of patients presenting with an unprovoked DVT. However, these defects have a modest impact on the absolute risk of both initial and recurrent DVT.^2,3

Antithrombin

AT inactivates thrombin and factors Xa, IXa, XIa, and XIIa. The anticoagulant activity toward activated factors II (thrombin) and X is enhanced by the presence of heparin. The inheritance pattern of AT deficiency is autosomal dominant. Symptomatic AT deficiency in the general population is not rare, with an estimated frequency between 1:2,000 and 1:5,000, but it is still an uncommon abnormality. However, the majority of individuals with AT deficiency will develop VTE by their third decade of life. In unselected patients with a history of VTE (first episode of unprovoked DVT), the frequency of AT deficiency is 1.1%. In selected patients with a history of recurrent VTE and/or familial history, the frequency is approximately 2.4%. The majority of affected individuals are heterozygotes, with AT levels between 40 and 70% of normal. There are three types of AT deficiency among individuals with the disorder, and the vast majority of cases can be diagnosed by determination of the functional AT level, a widely available clinical test.

Protein C and S

PC and PS are vitamin K-dependent glycoproteins that are involved in the inactivation of activated factors V and VIII. PC is slowly activated to activated protein C (APC) by thrombin. PS, in and of itself, has no intrinsic anticoagulant activity. Instead, it enhances the affinity of APC for negatively charged phospholipids, such as those found on the platelet surface, forming a membrane-bound APC-PS complex that renders factors Va and VIIIa more easily accessible to APC-mediated cleavage.

Deficiencies in PC and PS are transmitted as autosomal-dominant traits. Homozygous PC deficiency is associated with neonatal purpura fulminans and warfarin-induced skin necrosis. The frequency of symptomatic PC and PS deficiencies is somewhat greater than that of AT deficiency, but it is still uncommon, being 2.2 to 3.2% in unselected patients with venous thrombosis (first unprovoked DVT) and 3 to 3.8% in selected patients (recurrent VTE with or without family history of VTE).

Factor V Leiden

The factor V Leiden mutation is a single-point mutation in the gene encoding coagulation factor V, resulting in the replacement of arginine by glutamine at a key proteolytic site on the activated factor V protein. The mutated molecule cannot be cleaved by activated protein C—hence the so-called APC resistance. Factor V clotting activity is normal in in vitro coagulation assays. Rather, factor V is resistant to inactivation in vivo. The factor V Leiden mutation is found in 2 to 5% of the asymptomatic Caucasian population, making it a far more common abnormality overall than the AT, PC, and PS deficiencies combined. The factor V Leiden mutation is very uncommon in the African-American and Asian populations. For asymptomatic individuals, the relative risk for developing unprovoked VTE is increased about sevenfold for heterozygotes and 80-fold for homozygotes. Nonetheless, < 50% of heterozygous individuals will develop VTE in their lifetime. In unselected patients who do present with a first unprovoked DVT, approximately 40% will be identified as heterozygotes for the factor V Leiden mutation. The presence of the factor V Leiden mutation has also been associated with an increased risk for venous thrombosis during use of oral contraceptives, during pregnancy, and when combined with other genetic and acquired abnormalities of anticoagulation, such as PC and PS deficiencies.

Prothrombin 20210

The prothrombin gene mutation is the second most common genetic predisposition to thrombosis in the Caucasian population. It is characterized by a G-to-A transition in the 3'-untranslated region of the prothrombin (factor II) gene. This mutation is associated with mild increases in plasma prothrombin levels and thus with an increased risk of venous thrombosis. In one study, the FII 20210A polymorphism was found in 18% of selected patients with a personal and family history of venous thrombosis, in 6.2% of unselected consecutive patients presenting with their first unprovoked DVT, and in 2.3% of normal control subjects. As with the factor V Leiden mutation, the prothrombin mutation is relatively rare in African-American and Asian populations. Heterozygotes of the 20210A allele have a three- to fourfold increased risk of VTE, which is further increased by the use of estrogen therapy, pregnancy, and the concomitant presence of the factor V Leiden mutation.

Hyperhomocysteinemia

The early descriptions of patients with hyperhomocysteinemia involved homozygous mutations in genes encoding for enzymes of homocysteine metabolism resulting in a severe multisystem disease with neurologic and vascular manifestations. Severe elevations in plasma homocysteine are also associated with homozygous defects of the methylenetetrahydrofolate reductase (MTHFR) gene or of various enzymes that participate in the vitamin B₁₂ cycle. However, these mutations are uncommon. The more common causes of hyperhomocysteinemia are subtle in presentation and may be caused by less severe defects in genes encoding for enzymes or from inadequate status of those vitamins that are involved in homocysteine metabolism. Inadequate folate, vitamin B₁₂, or pyridoxine may result in a substantial increase in plasma homocysteine concentrations. More recently, a thermolabile polymorphism of the MTHFR gene was found to be associated with elevated homocysteine levels in the setting of folate deficiency.

Mild (16 to 24 mmol/L) and moderate (25 to 100 mmol/L) hyperhomocysteinemia both have been shown to be independent risk factors for stroke, myocardial infarction, peripheral arterial disease, and extracranial carotid artery stenosis. Hyperhomocysteinemia has also been shown to be a risk factor for venous thromboembolic disease. Furthermore, it appears to augment the independent risk of VTE associated with oral contraceptive use, pregnancy, trauma, surgery, immobilization, and other disorders of thrombophilia, most notably factor V Leiden mutation and the lupus anticoagulant.

Other Abnormalities

More recently, persistently elevated levels of factor VIII have been associated with a higher risk of recurrent venous thrombosis.⁴ There are likely to be other genetically related abnormalities that remain to be identified, especially among non-Caucasian racial groups.

Clinical Presentation

The clinical manifestations of patients with PC, PS, and AT deficiencies and the factor V Leiden and prothrombin mutations are all very similar. Upwards of 90% of patients will present with venous thrombosis of the lower extremity, with or without accompanying PE. A minority of patients (generally 5%) will present with venous thrombosis in an unusual location, such as cerebral veins or the mesenteric venous system. Rarely, these disorders are associated with arterial thrombosis.

Venous thromboembolism develops in 60 to 80% of individuals heterozygous for AT, PC, or PS deficiency, typically before the age of 40 to 45 years. Approximately 50% of patients suffer from recurrent disease.² Individuals with the factor V Leiden and prothrombin mutations have a less marked tendency for thrombosis, and often the first episode of thrombosis occurs at a more advanced age. However, the combined presence of factor V Leiden mutation together with AT, PC, or PS deficiency greatly enhances an individual's risk of thrombosis beyond a purely additive effect.

Approximately 50% of patients with AT, PS, PC, factor V Leiden, or prothrombin mutations will have no inciting event as the cause of their DVT. In the remaining patients, thrombosis may be associated with minor trauma, pregnancy, oral contraceptive use, or recent surgery or immobilization.^2,5,6 The frequency of thrombosis during pregnancy and the peripartum period is 31 and 44%, respectively, for AT deficiency; 10 and 19% for PC + PS deficiency; and 28% for the factor V Leiden mutation. The frequency of postoperative thrombosis has been shown to be high in patients with AT, PC, or PS deficiencies: 21% of patients after abdominal surgery and 37% of patients following high-risk orthopedic or cancer surgery. The incidence of postoperative thrombosis attributable to the presence of the factor V Leiden and prothrombin mutations is unknown. Patients with factor V Leiden mutation, if treated with pharmacologic prophylaxis during high-risk surgeries such as joint replacements, do not appear to have an increased risk of thrombosis compared with patients who do not have the factor V Leiden mutation.⁷

Approach to the Patient With an Unprovoked DVT/PE

Approximately 250,000 patients are diagnosed annually with acute VTE disease. The major morbidity relates to acute PE, the postphlebitic syndrome (characterized by intermittent pain, swelling, or recurrent skin ulceration), and recurrent disease with renewed risk for both of these complications on a repeated basis. The initial assessment of a patient with an unprovoked DVT/PE should include a thorough evaluation of the medical history, physical findings, and initial laboratory screening results. Hormonal therapy, the incidental finding of a mass, a prolonged prothrombin time, evidence of a myeloproliferative disease, or nephrotic syndrome should alert the clinician to the presence of a secondary thrombophilia risk factor. A history of recurrent unprovoked VTE in either the patient or the patient's biological family raises suspicion for the presence of an underlying genetic risk factor. Presence of a DVT or PE should be confirmed with the appropriate radiographic tests, including ultrasound, venogram, ventilation/perfusion study, or chest spiral CT scan.⁸

Identification of a thrombophilic risk factor during the acute presentation of VTE disease rarely influences the initial approach to therapy.^3,8 However, many clinicians are in the habit of ordering a variety of tests before initiating therapy (Table 3). DNA-based tests, such as factor V Leiden and prothrombin gene testing, can be performed at any time. Testing for AT, PC, and PS deficiencies may be affected by the acute thrombotic event due to consumption of these factors as an effect rather than a cause of the disease process. Additionally, these levels are lowered in the setting of liver disease and DIC. AT levels may be lowered in the setting of heparin therapy as a result of binding to either unfractionated heparin or low–molecular weight heparin. PC and PS levels are lowered by warfarin therapy, as their synthesis is dependent on vitamin K, and PS levels may be lowered in pregnancy, with the use of estrogen therapy, or in the presence of the lupus anticoagulant. Homocysteine levels rise with advancing age, renal insufficiency, smoking, certain medications such as phenytoin, and B vitamin deficiency. Homocysteine levels are best measured in the fasting state. A methionine load may identify a subset of patients at risk for hyperhomocysteinemia missed by random screening.

Treatment of Thrombotic Disorders

Once acute VTE disease is confirmed, therapy is initiated with an immediate-acting agent, such as heparin. The patient then transitions to warfarin therapy for a duration of 3 to 6 months.^8,9 Recent studies evaluating the recurrence rate after a longer duration of therapy, such as 1 or 2 years, demonstrate similar recurrence rates once anticoagulant therapy is stopped.^10,11 The risk of recurrent VTE after a treated, unprovoked event is 10 to 25% for the first 2 years after therapy is stopped. The yearly risk appears to decrease thereafter. Patients who have DVT after surgery, trauma, or another clearly predisposing event have a much lower risk for recurrence after anticoagulant treatment is stopped. Patients who experience recurrent episodes of VTE, regardless of whether they have an identifiable underlying thrombophilic defect or not, generally receive lifelong therapy. Nonetheless, the potential benefits of prolonged warfarin therapy must be balanced against the risks of major hemorrhage, estimated to be 2 to 3% per year.⁸

Who To Test?

After a patient presents with an unprovoked DVT, many clinicians advocate evaluation for a genetic thrombophilic state. However, the utility of information gleaned from such an evaluation remains controversial.^12-14 The ultimate goals of testing are to elucidate why an individual patient developed VTE, define the patient's risk for recurrence, and implement an optimally effective and safe duration of therapy. Unfortunately, our knowledge of and insight into these disorders is insufficient to meet these goals currently. The available data do strongly suggest that individuals in whom lupus anticoagulant persists are at increased risk for both recurrent arterial and venous disease if therapy is discontinued.¹⁵ Thus, many advocate that all patients presenting with an unprovoked VTE event should be evaluated for the persistent presence of a lupus anticoagulant. Persons with AT deficiency who have had a DVT appear to be at increased risk for recurrence. This may also be true for deficiencies of PC and PS.¹⁶ However, the prevalence of these deficiencies is low and screening strategies are less likely to identify affected individuals. In contrast, individuals with the factor V Leiden and prothrombin mutations are more likely to be identified, but the data suggest that these individuals do not predictably experience recurrent VTE.¹¹ Individuals with double defects or homozygous states have a very high relative risk for recurrent VTE, but the prevalence of these two genetic conditions is uncommon.^11,17 Thus, only small numbers of these patients have been enrolled in clinical trials, making a determination of the absolute risk of recurrent disease elusive. Finally, the impact of hyperhomocysteinemia on recurrence among patients with minimal or moderate elevation is unclear, especially if the homocysteine level can be normalized with vitamin supplementation.

In summary, an increasing number of genetic mutations predispose individuals to venous thromboembolic disease. Detection of these inherited thrombophilic defects is not generally useful in guiding clinical decision making regarding the choice of anticoagulant therapy or the intensity and duration of therapy. Testing of asymptomatic or unselected individuals (those with a first episode) should be done by a clinician who can provide informed counseling on the limitations of testing and the impact on risk. Unfortunately, our tools to identify the majority of individuals who will develop recurrent disease are limited at present, and the identification of individuals who would benefit from long-term anticoagulant therapy remains a major clinical research objective.

References

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