Chapter 10 Venous Thromboembolism
Epidemiology
Venous thromboembolism (VTE) refers to deep vein thrombosis (DVT) and pulmonary embolism (PE). In the general population, VTE occurs in 1 per 1000 persons each year in the United States, although the frequency increases with advancing age. The risk of PE from proximal (above-the-calf) lower extremity DVT is approximately 50%, and the mortality rate from PE exceeds 15% in the first 3 months following diagnosis.
Pathophysiology
Virchow’s triad (venous stasis, vessel wall injury, and hypercoagulability) summarizes the mechanisms by which acquired and inherited risk factors (Table 10-1) predispose to VTE. Typically, lower-extremity thrombus develops in valve pockets of the calf veins. Although most of these thrombi lyse spontaneously, approximately one fourth of untreated calf vein thrombi extend into the proximal veins. Thrombus that sufficiently impairs venous return through the affected vein will lead to increased venous and capillary pressures and subsequently edema. Massive thrombosis can compromise venous outflow from the leg (phlegmasia cerulean dolens).
Table 10-1 Acquired and Inherited Risk Factors for Venous Thromboembolism
| Acquired Risk Factors | Inherited Risk Factors |
|---|---|
| Age | Antithrombin III deficiency |
| Antiphospholipid antibodies | Factor V Leiden |
| Cancer | Protein C deficiency |
| Central venous catheter | Protein S deficiency |
| Chronic care facility resident | Prothrombin gene mutation |
| Critical illness | |
| Heparin-induced thrombocytopenia | |
| Hormone replacement therapy | |
| Hyperhomocysteinemia* | |
| Hypertension | |
| Immobilization | |
| Long-haul flights | |
| Medical illness (e.g., CHF, COPD) | |
| Obesity | |
| Oral contraceptives | |
| Pregnancy | |
| Stroke with extremity paresis | |
| Surgery | |
| Thoracic outlet syndrome | |
| Tobacco use | |
| Trauma | |
| Varicose veins |
CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease.
* Hyperhomocysteinemia can be inherited (rare).
Adapted from Gelfand EV, et al. Venous Thromboembolism Guidebook, 4th ed. Crit Path Cardiol. 2003;2:247–265.
PE most commonly originates from veins of the pelvis and lower extremities. PE of sufficient size can increase right ventricular afterload, which may lead to right ventricular dilatation, tricuspid regurgitation, and right heart failure. Mechanisms of hypoxemia from PE include ventilation–perfusion mismatch, atelectasis (resulting from loss of surfactant and alveolar hemorrhage), and shunting (venous blood not passing through ventilated gas exchange units of the lung before returning to the arterial circulation). In acute PE, intracardiac shunting can occur through a patent foramen ovale when right atrial pressure exceeds left atrial pressure.
Risk Factors
The known major risk factors for VTE are summarized in the following text. Up to one half of patients who present with first-time VTE have no readily identifiable risk factors.
Surgery
Patients at high risk for post-operative VTE are over 40 years of age; undergoing surgery for cancer, neurosurgery, major vascular surgery, or orthopedic leg surgery lasting more than 30 minutes; or have a personal history of VTE or additional risk factors for VTE. DVT is usually diagnosed during the third to sixth postoperative days, but the risk for thrombosis persists for several months.
Cancer
Virtually any cancer can present with DVT, but typical sites of malignancy include the pancreas, ovary, liver, and brain. Idiopathic VTE probably increases the risk of a subsequent diagnosis of cancer, especially within the first year following the thrombotic event. The benefit of extensively searching for cancer in patients with primary VTE is uncertain and has not been shown to be cost-effective. Therefore, a complete medical history, physical examination, routine laboratory tests, chest x-ray, age-appropriate cancer screening are all that is currently recommended for these patients.
Medical Illness
Other medical illnesses associated with VTE include myocardial infarction, chronic obstructive pulmonary disease, heart failure, hypertension, nephrotic syndrome, stroke, and polycythemia vera. The highest incidence of VTE in critically ill patients not receiving prophylaxis occurs in acute spinal cord patients. More frequent use of central venous catheters for dialysis, parenteral nutrition, and chemotherapy has increased the incidence of upper extremity DVT, which has been reported in up to one-fourth of patients with these catheters.
Oral Contraceptives and Hormone Replacement Therapy
Hormone replacement therapy (HRT), raloxifene (selective estrogen receptor modulator), and oral contraceptives are risk factors for VTE. Oral contraceptives and HRT substantially increase the risk of VTE in women with a coexisting thrombophilia, such as Factor V Leiden. However, routine screening for thrombophilia is not recommended prior to initiating these medications because the absolute risk for VTE in these patients is low. A history of VTE is an absolute contraindication to exogenous estrogen use.
Antiphospholipid Antibodies
Antiphospholipid antibodies may occur as a primary thrombotic or obstetrical disorder known as the antiphospholipid antibody syndrome or can be seen in association with other medical disorders, such as systemic lupus erythematosus. Antiphospholipid antibodies predispose to arterial and venous thrombosis and recurrent pregnancy loss. A definitive diagnosis of the antiphospholipid antibody syndrome requires the presence of clinical criteria (such as recurrent, spontaneous abortions and arterial or venous thrombosis) in the setting of persistent laboratory abnormalities (lupus anticoagulant antibodies or moderate-to-high levels of IgG or IgM anticardiolipin antibodies detected on two occasions at least 6 weeks apart).
Hyperhomocysteinemia
Hyperhomocysteinemia, typically defined as fasting homocysteine levels greater than 15 μmol/L (greater than the 95th percentile of the general population), is a risk factor for arterial and venous thrombosis. The mechanism of thrombosis is unknown. Hyperhomocysteinemia is most commonly caused by folate deficiency exacerbated by vitamin B12 or vitamin B6 deficiencies. Other causes of hyperhomocysteinemia include genetic defects in the methylenetetrahydrofolate reductase and methionine synthase enzymes, folate antagonists (such as methotrexate and phenytoin), and renal insufficiency (homocysteine is metabolized predominantly by the kidneys). Regardless of etiology, most patients with hyperhomocysteinemia respond to multivitamin treatment. Folic acid is the most effective therapy and will reduce homocysteine levels even when patients are not obviously folate deficient. Clinical trials are currently underway to determine whether these therapies ultimately reduce the frequency of subsequent thrombosis.
Factor V Leiden
Factor V Leiden refers to an abnormal factor V protein resulting from a point mutation in the factor V gene. This mutation, which is most prevalent in people of northern European descent, renders the protein relatively resistant to degradation by the endogenous anticoagulant, protein C. As a result, factor V remains active, increases thrombin generation, and predisposes to VTE. Factor V Leiden increases the risk for a first episode of VTE and is the most common known inherited cause of VTE. There is conflicting data as to whether patients with Factor V Leiden have an increased risk of recurrent VTE.
Prothrombin Gene Mutation
The prothrombin gene mutation is the second most common genetic abnormality predisposing to VTE. Prothrombin (factor II) is a precursor of thrombin. A point mutation in an untranslated region of the prothrombin gene results in higher plasma prothrombin levels and increases the risk for a first episode of VTE.
Antithrombin III Deficiency
Antithrombin III (ATIII) is a naturally occurring anticoagulant that limits thrombosis by inactivating procoagulant factors. ATIII deficiency can be acquired (e.g., in cirrhosis), but only the inherited form appears to carry a risk for initial and recurrent VTE. The risk of VTE in surgical patients with ATIII deficiency is extremely high, in part, because surgery further reduces ATIII levels. Heparin and acute VTE lower ATIII levels; therefore, ATIII deficiency cannot be diagnosed in these settings.
Protein C and Protein S Deficiencies
Protein C is a naturally occurring anticoagulant that requires protein S as a cofactor for its reactions. More than 100 mutations in the protein C or protein S genes have been detected that reduce protein level or function and predispose to VTE. Protein C and S deficiencies are rare causes of VTE. Warfarin inhibits the synthesis of all vitamin K–dependent proteins, including protein C and S; therefore, protein C or S deficiency cannot be diagnosed during concurrent warfarin use.
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