Approximately 30 conditions that increase the risk of venous thromboembolism (VTE), known as thrombophilias, have been identified. Some are relatively common and likely to be within the realm of primary care, whereas others are difficult to diagnose and require referral to a specialist. This variability and the risk involved with misdiagnosis demonstrate the need for primary care clinicians to be aware of these conditions as well as determine which patients should be referred to a hematologist.
This article reviews the diagnostic tests for the seven most common genetic thrombophilic conditions, the pitfalls of testing, and the follow-up for patients who test positive for one or more of the thrombophilias. A discussion of drug management is limited because of the complexity and individualization required when treating patients with thrombophilia. In addition, acquired causes of VTE are discussed only in their roles as aggravating factors in patients with thrombophilia.
CASE
A previously healthy 23-year-old woman began to notice pain behind her left knee in February 2007. She was an avid basketball player and frequently experienced trauma to her legs when playing, but she could not recall any specific injury to account for this pain. Further history disclosed that she was a nonsmoker, had a paternal grandmother who suffered a fatal pulmonary embolism (PE), and had recently started taking oral contraceptives. She had no other significant history. Physical examination revealed a Baker's cyst-like lesion in the left popliteal space. Venous Doppler ultrasound revealed a deep venous thrombosis (DVT) of the left popliteal vein. CBC, prothrombin time (PT), and partial thromboplastin time (PTT) were within normal limits. She was prescribed low molecular weight heparin and warfarin (Coumadin, Jantoven, generics) for 8 days, followed by warfarin alone when the international normalized ratio (INR) became therapeutic. She was also placed on bed rest and told to discontinue oral contraceptives. The DVT resolved with treatment. Follow-up venous Doppler ultrasound 6 months later showed no abnormality. The warfarin was replaced with a daily dose of adult aspirin (325 mg).
In September 2007, however, the woman experienced another episode of seemingly unprovoked calf pain in her left leg. No history of trauma existed, nor had she resumed oral contraceptives. Her physical examination was unremarkable, including minimal difference in the circumference of her calves, normal pulses, and no calf or thigh tenderness. Nevertheless, a venous Doppler ultrasound revealed another DVT in the same popliteal vein. Because of the recurrence of seemingly unprovoked DVT, the woman was evaluated for hypercoagulability; she was found to be heterozygous for factor V Leiden and had protein S deficiency. Once again, she was treated with low molecular weight heparin and warfarin with the same target INR of 2.0 to 3.0. Furthermore, she was advised that she would need lifelong warfarin therapy to prevent DVT recurrences, was referred for genetic and prepregnancy counseling, and was given a follow-up appointment with a hematology specialist. A year later, the woman remains anticoagulated and thrombosis-free.
HEMOSTASIS AND VENOUS THROMBOSIS
The coagulation-antithrombotic system consists of a complex interaction of positive and negative feedback loops that work simultaneously to ensure equilibrium. The coagulation cascade is essential to complement primary hemostasis to prevent life-threatening bleeding following vessel damage (see Figure 1). The antithrombotic system simultaneously limits fibrin formation and abnormal clotting, or thrombosis. Thus, both prothrombotic and antithrombotic efforts must be intact to avoid hemorrhage or VTE.
Incidence of VTE is approximately 1 per 1,000 adults per year. VTE is responsible for approximately 296,000 deaths per year in the United States.1-3 About two-thirds of patients present with DVT; and the rest present with PE.2 Virchow's triad, first published in the late 1800s, illustrates the combination of blood flow stasis or turbulence; endothelial injury; and plasma alterations, referred to as hypercoagulability, that cause VTE (see Figure 2).
For unknown reasons, the incidence of DVT increases after age 50 years. Other acquired risk factors for VTE are well-established, including obesity, defined as body mass index higher than 30 kg/m2; surgery, especially orthopedic surgery; pregnancy; malignancy; trauma; use of oral contraceptives or hormone replacement therapy; immobility from bed rest or prolonged sitting; and conditions such as heart failure, myeloproliferative disorders, inflammatory bowel disease, nephrotic syndrome, hyperviscosity syndrome, multiple myeloma, and sickle cell anemia.4,5 In addition, a number of genetic thrombophilias predispose patients to VTE6 (see Table 1). Thrombophilias significantly increase the risk of VTE when combined with an acquired risk factor. Not only does the prevalence of the thrombophilias vary among ethnic groups, but so do the acquired risk factors.4 Thrombophilias may not be suspected until a VTE develops in association with an acquired risk factor.7
VTE caused by thrombophilias is no different than that associated with acquired risk factors. Therefore, a complete personal and family history and physical examination are essential for identifying a person with a thrombophilic disorder. Indeed, history is the more important component and should include a three-generation pedigree or family tree. Some of the factors to look for include a family history of VTE, a VTE developing in an unusual location or shortly after starting oral contraceptives, and an MI in a female smoker younger than 50 years. Table 2 is a complete list of the factors to keep in mind when taking a patient's history. Doppler ultrasonography is the test of choice to confirm the diagnosis.