Venous thromboembolism (VTE) results from clot formation in the venous circulation and is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE). Normal hemostasis maintains integrity of the circulatory system after blood vessel damage. Vascular injury allows components of the coagulation process to seal the breach through interaction of activated platelets and the clotting factor cascade initiated by tissue factor and culminating in formation of a fibrin clot.
In contrast to physiologic hemostasis, pathologic venous thrombosis occurs in the absence of gross vein wall disruption and may be triggered by microparticles bearing tissue factor rather than the tissue factor expressed in vessel walls.
Platelets are activated and contribute to thrombus formation by two pathways: (1) exposure of blood to subendothelial collagen after vascular injury; and (2) thrombin generation by tissue factor derived from the vessel wall or in blood. A platelet thrombus develops as activated platelets recruit unstimulated platelets. Platelet activation releases adenosine diphosphate (ADP), calcium ions, and P-selectin, an adhesion molecular that facilitates capture of microparticles bearing tissue factor. Accumulation of tissue factor in the platelet thrombus initiates fibrin clot formation via the coagulation cascade.
The tissue factor pathway triggers coagulation by generating a small amount of thrombin, which converts factors VIII and V to their active cofactor forms (VIIIa, Va), which then stimulates the tenase and prothrombinase complexes to generate a large burst of thrombin.
Finally, thrombin mediates conversion of fibrinogen to fibrin monomers, which precipitate and polymerize to form fibrin strands. Factor XIIIa covalently bonds these strands together. Fibrin deposition forms a meshwork that encases aggregated platelets to form a stabilized clot that seals the site of vascular injury and prevents blood loss.
Hemostasis is controlled by antithrombotic substances secreted by intact endothelium adjacent to damaged tissue. Thrombomodulin modulates thrombin activity by converting protein C to its activated form (aPC), which joins with protein S to inactivate factors Va and VIIIa. This prevents coagulation reactions from spreading to uninjured vessel walls. In addition, circulating antithrombin inhibits thrombin and factor Xa. Heparan sulfate is secreted by endothelial cells and accelerates antithrombin activity. Heparin cofactor II also inhibits thrombin.
The fibrinolytic system dissolves formed blood clots; plasminogen is converted to plasmin by tissue plasminogen activator and urokinase plasminogen activator. Plasmin degrades the fibrin mesh into soluble end products (fibrin split products or fibrin degradation products).
Many patients never develop symptoms from the acute event.
• Symptoms of DVT: Unilateral leg swelling, pain, tenderness, erythema, and warmth. Physical signs may include a palpable cord and a positive Homan sign.
• Symptoms of PE: Cough, chest pain or tightness, shortness of breath palpitations, hemoptysis, dizziness, or lightheadedness. Signs of PE include tachypnea, tachycardia, diaphoresis, cyanosis, hypotension, shock, and cardiovascular collapse.
• Postthrombotic syndrome may produce chronic lower extremity swelling, pain, tenderness, skin discoloration, and ulceration.
Assessment should focus on identifying risk factors (eg, increased age, major surgery, previous VTE, trauma, malignancy, hypercoagulable states, and drug therapy). Radiographic contrast studies (venography, pulmonary angiography) are the most accurate and reliable method for VTE diagnosis. Noninvasive tests (eg, compression ultrasound, computed tomography scan, ventilation-perfusion scan) are often used for initial evaluation of patients with suspected VTE.
Elevated d-dimer blood levels occur in acute thrombosis but also with other conditions (eg, recent surgery or trauma, pregnancy, cancer). Therefore, a negative test can help exclude VTE, but a positive test is not conclusive evidence of the diagnosis. Clinical assessment checklists can be used to determine whether a patient has a high, moderate, or low probability of DVT or PE.
Anticoagulation is usually initiated with an injectable anticoagulant (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux) and then transitioned to warfarin maintenance therapy. Injectable anticoagulants can be administered in the outpatient setting in most patients with DVT and in carefully selected hemodynamically stable patients with PE. Alternatively, oral rivaroxaban may be initiated in select patients.
• The acute phase (~7 days) requires rapidly-acting anticoagulants (UFH, LMWH, fondaparinux, rivaroxaban) to prevent thrombus extension and embolization.
• The early maintenance phase (7 days to 3 months) consists of continued anticoagulation to reduce risk of long-term sequelae (e.g., post-thrombotic syndrome) by allowing formed clot to be slowly dissolved by endogenous thrombolysis.
• Anticoagulation beyond 3 months is aimed at long-term secondary prevention of recurrent VTE.
Graduated compression stockings and intermittent pneumatic compression (IPC) devices improve venous blood flow and reduce risk of VTE. Inferior vena cava filters can provide short-term protection against PE in very highrisk patients with contraindications to anticoagulation therapy or in whom anticoagulant therapy has failed.
Encourage patients to ambulate as much as symptoms permit. Consider thrombectomy in life- or limb-threatening DVT. For acute PE, catheterbased embolectomy might be suitable for patients who have contraindications to thrombolytic therapy, have failed thrombolytic therapy, or in whom death is likely before onset of thrombolysis. Reserve surgical embolectomy for massive PE and hemodynamic instability when thrombolysis is contraindicated, has failed, or will have insufficient time to take effect.
Unfractionated heparin (UFH) prevents growth and propagation of a formed thrombus and allows endogenous thrombolytic systems to degrade the clot. Because some patients fail to achieve an adequate response, IV UFH has largely been replaced by LMWH or fondaparinux. UFH continues to have a role in patients with creatinine clearance less than 30 mL/min (0.5 mL/s).
When immediate and full anticoagulation is required, a weight-based IV bolus dose followed by a continuous IV infusion is preferred. Fixed dosing (eg, 5000-unit bolus followed by 1000-units/h continuous infusion) produces similar clinical outcomes. Weight-based subcutaneous (SC) UFH (initial dose 333 units/kg SC followed by 250 units/kg every 12 hours) without coagulation monitoring is a less costly option for select patients; warfarin therapy is overlapped for at least 5 days and continued after UFH is discontinued.
The activated partial thromboplastin time (aPTT) with a therapeutic range of 1.5 to 2.5 times the mean normal control value is generally used to determine the degree of therapeutic anticoagulation. Measure aPTT prior to initiation of therapy and 6 hours after the start of therapy or a dose change. Adjust the heparin dose promptly based on patient response.
Bleeding is the primary adverse effect associated with anticoagulant drugs. The most common bleeding sites include the gastrointestinal (GI) tract, urinary tract, and soft tissues. Critical areas include intracranial, pericardial, and intraocular sites, and adrenal glands. Symptoms of bleeding include severe headache, joint pain, chest pain, abdominal pain, swelling, tarry stools, hematuria, or the passing of bright red blood through the rectum. Minor bleeding occurs frequently (eg, epistaxis, gingival bleeding, prolonged bleeding from cuts, bruising from minor trauma).
If major bleeding occurs, discontinue UFH immediately and give IV protamine sulfate by slow IV infusion over 10 minutes (1 mg/100 units of UFH infused during the previous 4 hours; maximum 50 mg).
Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated problem that requires immediate intervention. Thrombocytopenia is the most common clinical manifestation, but serologic confirmation of heparin antibodies is required for making the diagnosis. Use of a clinical prediction rule, such as the four Ts score (Thrombocytopenia, Timing of platelet count fall or thrombosis, Thrombosis, oTher explanation for thrombocytopenia), can improve the value of platelet count monitoring and heparin antibody testing in predicting HIT. Discontinue all heparin if new thrombosis occurs in the setting of falling platelets in conjunction with a moderate or high four Ts score. Then initiate alternative anticoagulation with a parenteral direct thrombin inhibitor.
Long-term UFH has been reported to cause alopecia, priapism, hyperkalemia, and osteoporosis.
Advantages of LMWHs over UFH include: (1) predictable anticoagulation dose response, (2) improved SC bioavailability, (3) dose-independent clearance, (4) longer biologic half-life, (5) lower incidence of thrombocytopenia, and (6) less need for routine laboratory monitoring.
LMWH given SC in fixed or weight-based doses is at least as effective as UFH given IV for VTE treatment. Efficacy and safety are similar with inpatient or outpatient LMWH administration, once- or twice-daily dosing, and use of different LMWH preparations.
Stable DVT patients who have normal vital signs, low bleeding risk, and no other comorbid conditions requiring hospitalization can be discharged early or treated entirely on an outpatient basis. Some patients with PE may also be managed safely as outpatients with LMWH or fondaparinux. Patients who are unsuitable candidates for outpatient treatment should be hospitalized.
Recommended doses (based on actual body weight) of LMWH for treatment of DVT with or without PE include the following:
✓ Enoxaparin (Lovenox): 1 mg/kg SC every 12 hours or 1.5 mg/kg every 24 hours
✓ Dalteparin (Fragmin): 100 units/kg every 12 hours or 200 units/kg every 24 hours (not approved by the U.S. FDA [Food and Drug administration] for this indication)
✓ Tinzaparin (Innohep): 175 units/kg SC every 24 hours
• Acute treatment with LMWH can be transitioned to long-term warfarin after 5 to 10 days.
Because LMWH anticoagulant response is predictable when given SC, routine laboratory monitoring is unnecessary. Prior to initiating therapy, obtain a baseline complete blood cell count (CBC) with platelet count and serum creatinine. Check the CBC every 5 to 10 days during the first 2 weeks of LMWH therapy and every 2 to 4 weeks thereafter to monitor for occult bleeding. Measuring anti–factor Xa activity is the most widely used method to monitor LMWH; routine measurement is unnecessary in stable and uncomplicated patients.
As with other anticoagulants, bleeding is the most common adverse effect of LMWH therapy, but major bleeding may be less common than with UFH. If major bleeding occurs, administer protamine sulfate IV, although it cannot neutralize the anticoagulant effect completely. The recommended dose of protamine sulfate is 1 mg per 1 mg of enoxaparin or 1 mg per 100 anti–factor Xa units of dalteparin or tinzaparin administered in the previous 8 hours. A second dose of 0.5 mg per 1 mg or 100 anti– factor Xa units can be given if bleeding continues. Smaller protamine doses can beused if the LMWH dose was given in the previous 8 to 12 hours. Protamine sulfate is not recommended if the LMWH was given more than 12 hours earlier.
• Thrombocytopenia can occur with LMWHs, but the incidence of HIT is three times lower than with UFH.
Fondaparinux sodium (Arixtra) prevents thrombus generation and clot formation by indirectly inhibiting factor Xa activity through its interaction with antithrombin. It is approved for prevention of VTE following orthopedic (hip fracture, hip and knee replacement) or abdominal surgery and for the treatment of DVT and PE (in conjunction with warfarin).
Fondaparinux is a safe and effective alternative to LMWH for treatment of DVT or PE. Fondaparinux is dosed once daily via weight-based subcutaneous injection: 5 mg if less than 50 kg, 7.5 mg if 50 to 100 kg, and 10 mg if greater than 100 kg. Fondaparinux is contraindicated if creatinine clearance is less than 30 mL/min (0.5 mL/s).
For VTE prevention, the dose is 2.5 mg SC once daily starting 6 to 8 hours after surgery.
• Patients receiving fondaparinux do not require routine coagulation testing. Measure CBC at baseline and periodically thereafter to detect occult bleeding. Monitor for signs and symptoms of bleeding daily. There is no specific antidote to reverse the antithrombotic activity of fondaparinux.
Direct Anti-Xa Inhibitors
Rivaroxaban (Xarelto) and apixaban (Eliquis) are selective inhibitors of both free and clot-bound factor Xa that do not require antithrombin to exert their anticoagulant effect. Neither agent is FDA approved for VTE treatment in the United States, but rivaroxaban is approved for prevention of VTE following hip or knee replacement surgery; the rivaroxaban dose is 10 mg orally once daily with or without food. Rivaroxaban should be initiated at least 6 to 10 hours after surgery once hemostasis has been established and continued for 12 days (knee replacement) or 35 days (hip replacement).
Routine laboratory monitoring and dose adjustment are not required because of predictable pharmacokinetics. Bleeding is the most common adverse effect; patients should be observed closely for signs or symptoms of blood loss.
Warfarin inhibits enzymes responsible for cyclic interconversion of vitamin K in the liver. Reduced vitamin K is a cofactor required for the carboxylation of the vitamin K–dependent coagulation proteins prothrombin (II); factors VII, IX, and X; and the endogenous anticoagulant proteins C and S. By reducing the supply of vitamin K, warfarin indirectly slows their rate of synthesis. By suppressing the production of clotting factors, warfarin prevents initial formation and propagation of thrombi.
Warfarin has no direct effect on previously circulating clotting factors or previously formed thrombi. The time required to achieve its anticoagulant effect depends on the elimination half-lives of the coagulation proteins. Because prothrombin has a 2- to 3-day half-life, warfarin’s full antithrombotic effect is not achieved for 8 to 15 days after initiation of therapy.
Start warfarin concurrently with UFH or LMWH therapy. For patients with acute VTE, UFH, LMWH, or fondaparinux should be overlapped for at least 5 days, regardless of whether the target international normalized ratio (INR) was achieved earlier. The UFH or LMWH can then be discontinued once the INR is within the desired range for 2 consecutive days.
Thrombolytic agents are proteolytic enzymes that enhance conversion of plasminogen to plasmin, which subsequently degrades the fibrin matrix.
Removal of the occluding thrombus by fibrinolytic therapy (or surgical means) is rarely warranted. Patients who present within 14 days of symptom onset with extensive proximal DVT, good functional status, low bleeding risk, and a life expectancy of a year or more are candidates for thrombolysis.