Primary Prevention of Venous Thromboembolism

Chapter: Primary Prevention of Venous Thromboembolism
McMaster Section Editor(s): James Douketis
Section Editor(s) in Interna Szczeklika: Krystyna Zawilska†, Anetta Undas, Wiktoria Leśniak
McMaster Author(s): James Douketis
Author(s) in Interna Szczeklika: Krystyna Zawilska†, Rafał Niżankowski
† Deceased.
Additional Information

Methods of Prevention Top

The choice of the method depends on the patient’s characteristics (risk of venous thromboembolism [VTE], of bleeding, and of other complications) as well as the feasibility of the method (availability, cost, ability to monitor the anticoagulant effect).

1. Early mobilization.

2. Mechanical treatment:

1) Graduated compression stockings (or appropriately applied short-stretch bandages).

2) An intermittent pneumatic compression device, which facilitates outflow of venous blood from the lower extremities. The device consists of a cuff applied to the lower or upper extremity and an electrical pneumatic pump, which periodically fills segments of the cuff with compressed air.

3. Anticoagulant terminology (contraindications and complications: see Anticoagulant Treatment):

1) Heparins: Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs).

2) Selective factor Xa inhibitors: Fondaparinux, rivaroxaban, apixaban, edoxaban, betrixaban (in the United States).

3) Direct thrombin inhibitors: Dabigatran (oral; the other are parenteral), bivalirudin, argatroban, desirudin.

3) Vitamin K antagonists (VKAs): Acenocoumarol, warfarin.

4) Direct oral anticoagulants (DOACs): Apixaban, edoxaban, rivaroxaban, dabigatran.

Patients after Surgery or Trauma Top

Prevention of VTE is usually started before the surgery or within 24 hours afterwards and is continued until the patient is completely mobilized; in the case of major orthopedic surgery, prevention continues for ≥10 to 14 days.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to indirectness (asymptomatic deep vein thrombosis) and imprecision in some of the critical outcomes. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S. doi: 10.1378/chest.11-2404. PubMed PMID: 22315265; PubMed Central PMCID: PMC3278063.

Because of high incidence of VTE after discharge from the hospital, it is suggested to continue the VTE prophylaxis, typically with a LMWH, for up to 35 days in patients after major orthopedic surgeryEvidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to imprecision. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-325S. doi: 10.1378/chest.11-2404. PubMed PMID: 22315265; PubMed Central PMCID: PMC3278063. and it is recommended to continue prophylaxis up to 4 weeks in high-risk patients (eg, with prolonged immobilization) after abdominal or pelvic cancer surgery, as long as these patients are not at high risk of bleeding.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to imprecision, indirectness, and potential bias (unclear blinding and concealment). Gould MK, Garcia DA, Wren SM, et al; American College of Chest Physicians. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S. doi: 10.1378/chest.11-2297. Erratum in: Chest. 2012 May;141(5):1369. PubMed PMID: 22315263; PubMed Central PMCID: PMC3278061. The choice of the prevention method depends on the individual risk of thrombosis (Table 3.19-7).

After elective hip or knee replacement surgery, prophylaxis with a DOAC can be considered, with apixaban 2.5 mg bid, dabigatran 150 mg to 220 mg daily, or rivaroxaban 10 mg daily. An alternative option involves a hybrid approach comprising 5 days of rivaroxaban 10 mg daily followed by 14 to 28 days of acetylsalicylic acid (ASA) 75 to 100 mg daily.

Also see Perioperative DOAC Management.

Medical Patients Top

Risk factors: Table 3.19-8.

Principles of prevention: Table 3.19-9.

Drug dosage: Table 3.19-10.

Patients with Cancer Top

1. The risk of VTE in patients with cancer is approximately 6-fold higher than in patients without cancer; this concerns in particular patients with malignant brain tumors and adenocarcinomas of the ovary, pancreas, colon, stomach, lung, prostate, or kidney, as well as with hematologic malignancies. It is further increased by immobilization, hospitalization, treatment with angiogenesis inhibitors (thalidomide, lenalidomide, bevacizumab), erythropoietin, darbepoetin, chemotherapy (particularly with platinum analogues), and surgical procedures. VTE in patients with cancer can be asymptomatic (so-called incidental VTE) and it is diagnosed as a result of imaging performed for the staging of cancer or evaluation of the effects of cancer therapy. Both incidental and symptomatic thrombosis are independent risk factors for recurrent VTE and reduced survival of the patients. Risk score: Table 3.19-11.

2. Recommended prevention of VTE in outpatients with solid tumors: VTE prophylaxis can be considered in selected high-risk outpatients with solid tumors who are receiving chemotherapy. Treatment options include LMWH or selected DOACs:

1) Consider a prophylactic-dose anticoagulant in the following patients:

a) Patients with additional risk factors of VTE (see above) or risk factors included in the Khorana score (Table 3.19-11), and at low risk of bleeding (do not use prophylactic anticoagulant treatment in patients with none of these features).

b) Patients receiving chemotherapy for pancreatic cancer or lung cancer who are at low risk of bleeding (such prophylactic treatment is ineffective in patients with metastatic breast cancer, and it increases the risk of intracranial hemorrhage in patients with brain tumors).

c) Patients treated with angiogenesis inhibitors combined with glucocorticoids or doxorubicin (other therapeutic options in this group of patients include low-dose ASA (eg, 80-100 mg/d) or a VKA at a low dose or at a dose maintaining the international normalized ratio [INR] in the range of 2.0-3.0).

2) Do not use routine prophylactic anticoagulant treatment to prevent central venous catheter-associated thrombosis in patients with no additional risk factors for VTE.

3. Recommended prevention of VTE in hospitalized patients:

1) In medical patients: Table 3.19-9.

2) In surgical patients: Table 3.19-7.

Long-Distance Travel Top

Overall, there is only low-quality evidence regarding the use of intervention to prevent VTE during long-distance travel (>6 hours) and all statements below represent suggestions.

1. For long-distance air travelers, suggest wearing loose-fitting clothing that does not compress the lower extremities or the waist, drinking plenty of nonalcoholic beverages, avoiding alcohol and caffeinated beverages, frequent tightening of the muscles of the calf during the flight, flexing the toes or standing on tiptoes, and avoiding sleeping in a sitting position.

2. For long-distance air travelers at increased risk for VTE, suggest frequent ambulation, calf muscle exercises, or sitting in an aisle seat, if feasible. The use of knee-high graduated compression socks with 15 to 30 mm Hg compression at the ankle level is suggested in the following groups: individuals with a history of VTE, recent (<6 weeks) trauma, or surgery; patients with cancer; women who are pregnant or receive estrogens; elderly persons; physically handicapped or obese persons; patients with thrombophilia. A single prophylactic dose of a LMWH before departure can be used in selected patients at increased risk for VTE (eg, VTE within the past year). The prophylactic use of antiplatelet agents is not recommended.

3. For long-distance travel by car, bus, or train, in addition to the above-mentioned propositions we suggest periodic ambulation during car stops or while travelling.

PREGNANCYTop

1. Appropriate prevention of VTE in pregnant patients is very important. In developed countries, PE is the most common cause of death in women during pregnancy and the postpartum period.

2. Recommended methods of prevention in pregnant women at increased risk of VTE: Table 3.19-12.

3. LMWHs are the drugs of choice (agents: Table 3.19-2, dosage: Table 3.19-10), but UFH may also be used (5000 IU administered subcutaneously every 12 hours), because—unlike VKAs—heparins do not cross the placenta and do not cause fetal malformations or bleeding. New oral anticoagulants (factor Xa inhibitors and thrombin inhibitors) have not been studied in pregnant women and thus are not recommended.

4. The use of LMWHs, UFH, or VKAs by a mother is not a contraindication to breastfeeding; however, fondaparinux, oral factor Xa inhibitors, and thrombin inhibitors should not be administered during lactation.

5. In women receiving long-term VKA treatment who plan to become pregnant, frequent pregnancy testing is recommended. Once the patient becomes pregnant, she should be switched from VKAs to UFH or LMWHs. An alternative approach is to switch from a VKA to an LMWH before attempting to become pregnant. This does not apply to women with implanted mechanical heart valves, who should be referred to a specialist center.

6. DOACs should be avoided during pregnancy because they cross the placenta and their effects on the developing fetus are uncertain.

TablesTop

Table 3.19-7. A modified Caprini risk assessment score

Risk factor

Score

Age

 

41-60 years

1

61-74 years

2

≥75 years

3

BMI >25 kg/m2

1

Women

 

Oral contraceptives or HRT

1

Pregnancy or postpartum

1

History of unexplained or recurrent miscarriage/stillborn infant

1

Thrombophilia

 

Elevated serum homocysteine

3

Positive factor V Leiden

3

Positive prothrombin 20210A

3

Positive lupus anticoagulant

3

Positive anticardiolipin antibodies

3

Positive anti–beta2-GPI antibodies

3

HIT

3

Other congenital or acquired thrombophilia

3

Venous disease

 

Lower limb edema

1

Varicose veins of lower limb

1

History of VTE

3

Family history of VTE

3

Immobilization

 

 

Medical patient currently at bed rest

1

Patient confined to bed (>72 h)

2

Limb immobilized in plaster cast

2

Surgery

 

Minor surgery planned

1

Arthroscopic surgery

2

Major surgery (>45 min)

2

Laparoscopic surgery (>45 min)

2

Elective arthroplasty

5

Hip, pelvis, or leg fracture

5

Other

 

Sepsis (<1 month)

1

Serious lung disease, including pneumonia (<1 month)

1

Abnormal pulmonary function

1

Acute myocardial infarction

1

Onset or exacerbation of heart failure (<1 month)

1

History of inflammatory bowel disease

1

Central venous access

2

Malignancy

2

Stroke (<1 month)

5

Acute spinal cord injury (<1 month)

5

Interpretation of risk level:

Score 0: Very low risk

Score 1-2: Low risk

Score 3-4: Moderate risk

Score ≥5: High risk

Adapted from Chest. 2012;141(2 Suppl):e227S-e277S.

Anti–beta2-GPI, anti–beta2-glycoprotein I; BMI, body mass index; HIT, heparin-induced thrombocytopenia; HRT, hormone replacement therapy; VTE, venous thromboembolism.

Table 3.19-8. Risk factors for venous thromboembolism in hospitalized patients: the Padua risk assessment score
Baseline features Score

Active cancer (patients with regional lymph node involvement or distant metastases who received chemotherapy or radiotherapy in the prior 6 months)

3

A history of VTE (except for superficial vein thrombosis)

3

Immobilization (bed rest with bathroom privileges, either due to patient’s limitations or physician order, for at least 3 days)

3

Previous diagnosis of thrombophilia (deficiencies of antithrombin, protein C, protein S, or factor V Leiden, prothrombin gene G20210A mutation, or antiphospholipid syndrome)

3

Recent (≤1 month) trauma or surgery

2

≥70 years of age

1

Heart failure or respiratory failure

1

Acute myocardial infarction or ischemic stroke

1

Acute infection or rheumatologic disorder

1

Obesity (BMI ≥30 kg/m2)

1

Hormonal therapy

1

Interpretation:

Score ≥4: High risk of VTE

Adapted from J Thromb Haemost. 2010;8(11):2450-7.

BMI, body mass index; VTE, venous thromboembolism.

Table 3.19-9. Prevention of venous thromboembolism in medical patients

Clinical condition

Recommended prevention

Ischemic stroke with impaired mobilitya

Options:

– Adequate prophylactic dose of LMWHb (preferred);

– SC UFH 5000 IU every 12 hours;

– IPC and/or graduated compression elastic stockings in patients with contraindications to anticoagulant treatment.

Note: You can safely use a prophylactic dose of heparin in combination with ASA. Do not use heparin in the first 24 hours after thrombolytic treatment of stroke.

Hemorrhagic strokea

– Use IPC in early treatment;

– In clinically stable patients at very high risk of VTE you may use LMWH at an adequate prophylactic doseb (preferred dose) or SC UFH 5000 IU every 12 h starting on day 2-4 after the bleeding if considered safe (documented cessation of bleeding).

Note: The time for starting heparin administration depends on the evaluation of the risk of thrombosis and the risk of recurrent bleeding in the patient.

Hospitalized acutely ill medical patients at high risk of VTE (Padua Score ≥4)c

Options:

– Adequate prophylactic dose of LMWHb;

– SC UFH 5000 IU every 12 h;

– SC fondaparinux 2.5 mgd SC every 24 h;

– In the case of bleeding or high risk of bleedinge use IPC and/or graduated compression elastic stockings at least in early treatment until the risk of bleeding is reduced.

Use pharmacologic prophylaxis during the patient’s immobilization or hospitalization.

Long-term immobilized patients remaining at home or in an institution

Do not use VTE prevention routinely.

a Recommendations for the management of patients with stroke apply to VTE prophylaxis only, and not to the anticoagulant and thrombolytic treatment of stroke.

b Agents: see Deep Vein Thrombosis. Dosage: see Table 3.19-10.

c See Table 3.19-8.

d 1.5 mg in patients with a creatinine clearance <50 mL/min.

e The risk of bleeding is highest in patients with active gastric or duodenal ulcers, a history of severe bleeding within the prior 3 months, platelet counts of <50 × 109/L, or liver failure (INR >1.5). Other risk factors of bleeding: ≥85 years of age (vs <40 years), severe renal failure (GFR <30 mL/min/1.73 m2), admission to an intensive care unit or coronary care unit, insertion of a central venous catheter, chronic arthritis, cancer, male sex. The coexistence of several of these factors indicates a significant increase in the risk of bleeding. Moreover, these factors often increase the risk of VTE. Hence the decision to start anticoagulant treatment should be based on a joint evaluation of all these risks.

ASA, acetylsalicylic acid; GFR, glomerular filtration rate; INR, international normalized ratio; IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin; SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism.

Table 3.19-10. Prophylactic doses of low-molecular-weight heparin in medical patients and pregnant women

Low-molecular-weight heparin

Prophylactic doses

Medical patients

Pregnant women

Dalteparin

5000 IU every 24 h

5000 IU SC every 24 h

Enoxaparin

40 mg every 24 h

40 mg SC every 24 ha

Nadroparin

2850 IU every 24 h

3800 IU SC every 24 h

a Dose adjustment may be necessary in the case of extremely low or extremely high body weight.

SC, subcutaneous.

Table 3.19-11. Risk assessment score for venous thromboembolism in outpatients with cancer treated with chemotherapy (Khorana score)

Clinical features

Score

Type of cancer

Stomach, pancreas (very high risk)

2

Lung, lymphoma, gynecologic, genitourinary (high risk)

1

Platelet count before chemotherapy ≥350,000/microL

1

White blood cell count before chemotherapy >11,000/microL

1

Hemoglobin level before chemotherapy <10 g/dL and/or planned use of erythropoiesis stimulating agents

1

Body mass index ≥35 kg/m2

1

Interpretation:

Score 0: Low risk

Score 1-2: Intermediate risk

Score ≥3: High risk

Adapted from Blood. 2008;111(10):4902-7.

Table 3.19-12. Prevention of venous thromboembolism in high-risk pregnant women

Clinical setting

Recommended prevention

During pregnancy

Postpartum

History of 1 VTE episode associated with a transient risk factor (except pregnancy and estrogen use)

Careful monitoringa

LMWHb or VKAc

History of 1 VTE episode associated with pregnancy or estrogen use

LMWHd/UFHd

LMWHb or VKAc

History of 1 idiopathic VTE episode (in a patient without thrombophilia and currently not receiving long-term anticoagulant treatment)

LMWHd/UFHd or careful monitoringa

LMWHb or VKAc

History of 1 VTE episode in a patient with low-risk thrombophiliae (currently not receiving long-term anticoagulant treatment)

LMWHd/UFHd or careful monitoringa

LMWHb or VKAc

History of 1 VTE episode in a patient with high-risk thrombophiliaf (currently not receiving long-term anticoagulant treatment)

LMWHg/UFHg

LMWHb or VKAc or LMWH/UFHh

Negative history of VTE in a patient with low-risk thrombophilia

Careful monitoringa

Careful monitoringa or anticoagulant treatment if positive family history of VTE (LMWHb or VKAc)i

Negative history of VTE in a patient with high-risk thrombophiliag

LMWHd/UFHd

LMWHb or VKAc

History of ≥2 VTE episodes in a patient receiving long-term anticoagulant treatment

LMWHj/UFHj

Continuation of long-term treatment used before pregnancy

History of ≥2 VTE episodes (currently not receiving long-term anticoagulant treatment)

LMWHg/UFHg

LMWHb or VKAc or LMWH/UFHh

a Plus prompt diagnostic workup in patients with suspected DVT/PE.

b At a prophylactic dose (see Table 3.19-10) for 4-6 weeks. Do not reduce the dose of LMWH used during pregnancy.

c For 4-6 weeks, INR 2.0-3.0 (initially together with LMWH/UFH until the INR is ≥2.0 for 2 consecutive days).

d At a prophylactic dose.

e Heterozygotes for factor V Leiden, heterozygotes for the prothrombin G20210A gene, deficiency of protein C or protein S.

f Antithrombin deficiency, double heterozygotes for the prothrombin G20210A gene and factor V Leiden, homozygotes for factor V Leiden or homozygotes for the prothrombin G20210A gene.

g Adjusted or prophylactic dose.

h Adjusted dose for 6 weeks.

i If additional risk factors are present (a first-degree relative with an episode of VTE before 50 years of age or other major risk factors for thrombosis, eg, obesity, prolonged immobilization).

j Adjusted dose.

Note: In patients with a history of DVT, use adequately fitted graduated compression stockings during pregnancy, labor, and postpartum.

DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

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