Management of Venous Thromboembolism

K. Pavithran*
Mathew Thomas*

* Assistant Professor in hematology
**Professor of Medicine

Medical college hospital

Address for Correspondence:
Dr. K. Pavithran,
Department of Hematology
Medical College Hospital,

See also Thromobopoetin by Pavithran

Management of Venous Thromboembolism


Venous thrombosis is the third most common cardiovascular disease after ischemic heart disease and stroke.1 It is common in whites, affecting 1 in 1,000 individuals every year, and is strongly associated with life-threatening pulmonary embolism (PE). Though the exact incidence is not known in India it is becoming a common clinical problem because the physicians and the surgeons are now more aware of venous thrombosis.
In addition to circumstantial predisposing factors, pregnancy, or immobilization), genetic abnormalities, molecular abnormalities of components of the coagulation pathway leading to hypercoagulability and, in turn, to thrombophilia have been found in subjects who have had thromboembolic disease (Table 1).2
Venous thrombosis occur most commonly in the lower limbs though it can occur in any vein in the body. Thrombosis of superficial veins (as occurring in varicosities) is benign and self-limiting. Thrombosis of deep vein is a serious condition. Thrombi localized to the deep veins of the calf are less serious than those involving the proximal veins (popliteal, femoral or iliac veins) because they are often smaller and therefore less commonly associated with long term disability or clinically important pulmonary embolism (PE). On the other hand PE frequently complicates proximal vein thrmbosis. Asymptomatic PE is detected by perfusion lung scanning in about 50% of patients with documented proximal vein thrombosis. Asymptomatic venous thrombosis is found in 70% of patients who present with confirmed PE.

Clinical approach -
A. Diagnosis of venous thrombosis

1. Clinical Diagnosis of venous thrombosis

Clinical diagnosis of venous thrombosis in symptomatic patients lacks both sensitivity and specificity. It is insensitive because many potentially dangerous thrombi do not totally obstruct the veins nor produce inflammation of the vessel wall and therefore produce minimal clinical manifestations. It is non-specific because none of the signs and symptoms is unique to this condition.
Other conditions frequently confused with venous thrombosis include muscle strain or tear, superficial thrombophlebitis, lymphangitis, lymph edema, cellulitis and post-phlebitic syndrome.
Maneuvers formerly recommended for diagnosis of DVT, such as Homan sign (pain provoked by forced dorsiflexion of the foot) or the Lowemberg sign (pain provoked by the application on the calf of the sphygmomanometer cuff at relatively low pressure) are totally useless and even dangerous as is any other maneuver exerted on the calf at the time of a recent DVT.

2. Imaging

The standard diagnostic test for deep-vein thrombosis of the lower extremities is ascending phlebography. Phlebography can detect both distal thrombi (in the calf veins, a common site of inception of deep-vein thrombosis) and proximal thrombi (in the popliteal, femoral, and iliac veins), which are the source of most large pulmonary emboli.
Other objective diagnostic methods include impedance plethysmography 3 and various forms of real-time B-mode ultrasonography,4 most of which are more sensitive for the detection of proximal than distal thrombosis. With impedance plethysmography, one measures the electrical impedance between two electrodes wrapped around the calf. Venous obstruction proximal to the electrodes decreases the impedance as the leg becomes engorged with blood, an electrical conductor, and delays the characteristic increase in calf impedance when a thigh tourniquet is deflated.
The introduction of real-time B-mode ultrasonography has provided a promising alternative to impedance plethysmography, with a sensitivity for proximal thrombi that approaches 100 percent in patients with symptomatic deep-vein thrombosis 4,5. In symptomatic outpatients with suspected deep-vein thrombosis, serial compression ultrasonography had a positive predictive value of 94 percent, superior to the positive predictive value of 83 percent for serial impedance plethysmography 6.
In duplex scanning, real-time B-mode ultrasonography is supplemented by Doppler flow-detection ultrasonic imaging, which allows detection of blood flow in any vessel seen. In symptomatic patients with proximal deep-vein thrombosis, its overall sensitivity in a meta-analysis of four well-designed studies was 93 percent, with a specificity of 98 percent7.
The sensitivity of d-dimer measured by enzyme-linked immunosorbent assay is 97 percent. Venous thrombosis is unlikely to be present if d-dimer concentrations are not elevated, but a positive result requires confirmation by more specific tests based on imaging.
Magnetic resonance venography has 100% sensitivity and over 96% specificity for diagnosis of deep vein thrombosis but this is done only in exceptional cases. Radio nucleotide venography is under development.

B. Etiology

1. Detailed clinical history: One should suspect thrombophilia in the following situations8 (Table.2).

Age - young vs old. In most patients with inherited thrombophilia, thrombotic event occurs before the age of 45 years. In the elderly except Factor V Leiden all others are rare.
Race - Factor V Leiden and prothrombin gene mutation (G20210A) are common among healthy whites but are extremely rare among Asians and Africans.
Arterial vs venous: In addition to venous thrombosis occurrence arterial thrombosis is also seen with Protein S deficiency and hperhomocystinemia and antiphospholipd antibody syndrome.
Site - unusual site, multiple sites occurs more often with inherited thrombophilia.
Drugs - history of oral contraceptive and tamoxifen use.

Hereditary thrombophilia
The term "thrombophilia" refers to a tendency to have recurrent venous thromboembolism. Hereditary abnormalities that are associated with initial and recurrent venous thromboembolism include congenital deficiencies of antithrombin III, protein C, protein S, or plasminogen; congenital resistance to activated protein C (APC resistance or Factor V Leidin defect), mutation of prothrombin and hyperhomocysteinemia. The most common hereditary condition is APC resistance. Lifetime prevalence of venous thromboembolism in patients with antithrombin III, protein C, protein S is over 50 percent. Initial episodes of venous thromboembolism are rare before the age of 18 years and uncommon after the age of 50.

Acquired thrombophilias
As with the hereditary thrombophilias, acquired disorders vary widely in their propensity to cause venous and arterial thrombotic disease. Mucin secreting carcinomas have very high potential for thrombosis. Antiphospholipid antibody syndrome may manifest solely as a laboratory abnormality or present with venous and arterial thrombosis, stroke or recurrent abortion. Patients with myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria may present with thrombosis at unusual sites9.



The main objectives of treatment of DVT are 1) to prevent (both fatal and non-fatal) PE and thrombus extension in the acute phase of the disease 2) to prevent recurrences of venous thromboembolism (VTE) 3) to prevent late sequelae (post phlebitic syndrome)
In highly selected cases of deep vein thrombosis it may be possible to restore the venous patency by surgical thrombectomy with dramatic early results.
Antithrombotic regimens modify one or more of these abnormalities. These regimens include drugs that inhibit blood coagulation, such as the various heparins and heparinoids; warfarin; direct thrombin inhibitors; drugs that inhibit platelet function, such as aspirin and dextran; and techniques that counteract venous stasis, such as compression stockings and pneumatic compression devices.
Once venous thromboembolism is diagnosed, heparin should be given for four to seven days and warfarin therapy should be initiated. Thrombolytic therapy is reasonable in selected patients with extensive proximal-vein thrombosis or pulmonary embolism. In patients with acute venous thromboembolism and active bleeding or a high potential for bleeding, those who are noncompliant, and those with a history of heparin-induced thrombocytopenia, a filter should be inserted in the inferior vena cava. After an initial bolus of 5000 U, at least 30,000 U per day of UFH should be infused. Lower doses result in higher rates of recurrence10, 11. An APTT value 1.5 to 2.5 times the control value is commonly recommended as a target therapeutic range for heparin. To ensure a continuous antithrombotic effect in patients with venous thromboembolism, heparin should be given for at least four days and not discontinued until the INR has been in the therapeutic range for two consecutive days. In patients with extensive proximal-vein thrombosis or pulmonary embolism, a longer course of heparin should be considered12,13.

LMW Heparin or Unfractionated Heparin?

Both unfractionated (UFH) and low molecular weight heparins have been found to be equally effective for the management of VTE. Data from four meta-analyses suggest that low-molecular-weight heparins are more effective than unfractionated heparin in preventing recurrence (risk reduction, 34 to 61 percent) and cause less major bleeding (risk reduction, 35 to 68 percent) 14- 17. LMWH are also found to provide a survival advantage in those with malignancy.
LMW heparin is effective in most patients when given in weight-based doses (anti-Xa U/kg body weight) without subsequent laboratory monitoring or dose adjustment. The kidneys clear all LMW heparins and caution should be exercised when the creatinine clearance is < 30 mL/min. The correct dose for massively obese persons has not been established, and laboratory monitoring (plasma anti-Xa activity) may be useful in such patients.
Doses of various LMWH preparations are dalteparin sodium 200 anti-Xa IU/kg/d subcutaneous, enoxaparin sodium 1 mg/kg q12h subcutaneous or enoxaparin sodium 1.5 mg/kg/d subcutaneous, nadroparin calcium 86 anti-Xa IU/kg bid subcutaneous or nadroparin calcium 171 anti-Xa IU/kg subcutaneous daily, tinzaparin sodium 175 anti-Xa IU kg/d subcutaneous daily.
Warfarin or other coumarins should be started within 24 hours after the initiation of heparin therapy, with a target INR of 2.0 to 3.0; higher values are associated with more bleeding but no greater efficacy 18. Therapy should be continued at least for 3 to 6 months. Patients with metastatic cancer are candidates for long-term therapy because they probably have high rates of recurrence. Patients with recurrent disease should receive long-term therapy - for those who had two episodes one year and life long for those who had three episodes or having multiple risk factors.

Other newer antithrombotic drugs.
Hirudin a new molecule is a potent inhibitor of thrombin but unlike heparin its action is independent of AT III and it has very little effect on platelets. Other newer molecules are 7 E3 a murine monoclonal antibody fragment that competes with fibrinogen for its platelet receptor and recombinant human Factor Xa. Drugs that target factor VIIa/tissue factor (tissue factore pathway inhibitor and NAPc2), block factor Xa (synthetic pentasaccaride and DX9065a), inhibitors of factor VA and VIIIa oral formulation of heparin. Anisoylated plasminogen-streptokinase activator complex or single chain urokinase like plasminogen activator is under investigation.

Management of complications of anticoagulant therapy


The management of bleeding associated with anticoagulant treatment should be individualized, with therapy depending on the location and severity of bleeding, laboratory-test results, and the risk of recurrent venous thromboembolism. If urgent treatment is needed, vitamin K and plasma or factor IX concentrates should be administered to warfarin-treated patients; protamine should be administered to heparin-treated patients who have a prolonged APTT. In patients who have bleeding while receiving a low-molecular-weight heparin, protamine should be given because it neutralizes the heparin molecules thought to be most responsible for bleeding.
Heparin Induced thrombocytopenia
Frequency of heparin-induced thrombocytopenia (HIT) is < 1% when either unfractionated heparin or LMW heparin is given for no more than 5 to 7 days. Because of this finding, a platelet count should be checked between day 3 and day 5 of therapy. When the platelet count falls precipitously or in a sustained fashion, heparin therapy should be stopped. The syndrome of HIT is unusual after 14 days of heparin therapy. Recombinant hirudin (lepirudin) has been specifically approved for HIT accompanied by thrombosis. In this setting, lepirudin should be used for temporary anticoagulation and warfarin therapy delayed until the platelet count has risen to > 100,000/muL20.

Failure of Anticoagulation

The failure of anticoagulant therapy results in symptomatic recurrent venous thromboembolism. Treatment failure despite adequate anticoagulation occurs in patients with overt or occult cancer and possibly in patients with antiphospholipid antibodies.

Post-phlebitic syndrome.

This is a syndrome occurring in patients after acute deep vein thrombosis. It occurs in about one third of patients during long-term follow up. This is usually due to valve destruction but can also be due to large proximal vein thrombi that block the overflow. As a result the venous pressure increases during exercise and blood flow is directed from deep to superficial veins resulting in edema, impaired viability of subcutaneous tissue and venous ulcerations. Use of graduated compression stockings may reduce the risk of the syndrome.

Venous Thromboembolism during Pregnancy

The risk of venous thromboembolism is five times higher in a pregnant woman than in a nonpregnant woman of similar age. Unfractionated and low-molecular-weight heparins do not cross the placenta and are very safe for the fetus, 21,22 whereas coumarin derivatives can cause fetal bleeding and are teratogenic. Low-molecular-weight heparins are suitable substitutes for unfractionated heparin and probably cause less bleeding and osteoporosis, but they are more expensive and the clinical experience with the drug is still limited. Some authorities recommend the use of warfarin during pregnancy for specific patients, such as women with mechanical heart valves, those who have a recurrence while receiving heparin, and those with contraindications to heparin therapy. If venous thrombosis is diagnosed during pregnancy intravenous heparin is given for 5-10 days followed by subcutaneous heparin for the rest of pregnancy. After delivery, warfarin, which is safe for infants and nursing mothers, should be given (with initial heparin overlap) for four to six weeks23,24.

Prognosis of venous thrombosis

Untreated or inadequately treated venous thrombosis is associated with the high complication rate, which can be reduced by adequate anticoagulant therapy. About 30% of untreated silent or symptomatic calf thrombi extend into popliteal vein and is associated with 40-50% risk of clinically detectable PE. Patients with proximal vein thrombosis who are inadequately treated have a 47% frequency of recurrent thrombo embolism over three months. If properly treated the recurrence rate is only 2% in the first 3 months and 5-10% in the subsequent year.
Prevention of Venous Thromboembolism
The goal of prophylactic therapy in patients with risk factors for deep-vein thrombosis is to prevent both its occurrence and its consequences. Detection of deep-vein thrombosis is likely to be delayed, as many of the affected patients are asymptomatic. Preventing deep-vein thrombosis in patients at risk is clearly preferable to treating the condition after it has appeared, a view that is supported by cost-effectiveness analysis. The presence of clinical risk factors identifies patients with the most to gain from prophylactic measures, as well as patients who should receive antithrombotic prophylaxis during periods of increased susceptibility, such as postoperatively or post partum. For example a patient with Homocysteinemia should get folic acid supplements as a preventive measure and antithrombotic prophylaxis during surgery.

For prophylactic treatment the following risk categories are identified for inpatients.
Risk category Risk of VT % Calf vein T Proximal vein T PE

High risk

1.Gen. Surgery-patient >40 years with
recent DVT or PE
2.Extensive pelvic or abd surgery for 40-80 10-20 1-5
malignant disease
3. Major ortho surgery of lower

Low risk

1.General surgery-patient >40 years
lasting 30 minutes or more
2.Immobilization with medical illness 10-40 2-10 0.1-0.7
cardiac disease, stroke, chronic resp
disease, bowel disease & malignancy
VT- venous thromboembolism, PE - pulmonary embolism, DVT- deep vein thrombosis
The methods used for prophylaxis in these patients are early ambulation, low dose unfractionated heparin, intermittent pneumatic compression, graduated compression stockings, oral anticoagulants, dextran and low molecular weight heparin. These methods are used alone or in combination, the choice depending upon the risk stratification. A simple regimen of low dose unfractionated heparin is 5000 U given 2 hours prior to surgery and is continued post operatively at a dose of 5000 U for every 12 hours.
6th ACCP Recommendations24

Treatment of VTE

1 Patients with DVT or PE should be treated acutely with LMW heparin, unfractionated IV heparin, or adjusted-dose subcutaneous heparin.
2. When unfractionated heparin is used, the dose should be sufficient to prolong the APTT to a range that corresponds to a plasma heparin level of 0.2 to 0.4 IU/mL by protamine sulfate or 0.3 to 0.6 IU/mL by an amidolytic anti-Xa assay.
3. LMW heparin offers the major benefits of convenient dosing and facilitation of outpatient treatment. LMW heparin treatment may result in slightly less recurrent VTE and may offer a survival benefit in patients with cancer.

Initial Anticoagulation With Heparin

1. Treatment with heparin or LMW heparin should be continued for at least 5 days and that oral anticoagulation should be overlapped with heparin or LMW heparin for at least 4 to 5 days. For most patients, treatment with warfarin can be started together with heparin or LMW heparin. The heparin product can be discontinued on day 5 or day 6 if the INR has been therapeutic for 2 consecutive days.
2. For massive PE or severe iliofemoral thrombosis, longer period of heparin therapy of approximately 10 days is required.

Long-term Anticoagulation

1. Oral anticoagulant therapy should be continued for at least 3 months to prolong the prothrombin time to a target INR of 2.5 (range, 2.0 to 3.0). When oral anticoagulation is either contraindicated or inconvenient, a treatment dose of LMW heparin or unfractionated adjusted-dose heparin to prolong the APTT to a time that corresponds to a therapeutic plasma heparin level for most of the dosing interval should be used.
2. Patients with reversible or time-limited risk factors should be treated for at least 3 months.
3. Patients with a first episode of idiopathic VTE should be treated for at least 6 months.
4. Patients with recurrent idiopathic VTE or a continuing risk factor such as cancer, antithrombin deficiency, or anticardiolipin antibody syndrome needs treatment for 12 months or longer.
5. Symptomatic isolated calf vein thrombosis should be treated with anticoagulation for at least 6 to 12 weeks.
Thrombolytic Therapy

Patients with hemodynamically unstable PE or massive iliofemoral thrombosis, who are at low risk to bleed, are the most appropriate candidates.
Inferior Vena Caval Procedures

Placement of an inferior vena caval filter when there is a contraindication or complication of anticoagulant therapy in an individual with or at high risk for proximal vein thrombosis or PE. Placement of an inferior vena caval filter is also useful for recurrent thromboembolism that occurs despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy.


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