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RiittaLassila

Prevention of Venous Thromboembolism

Essentials

  • Venous thromboembolism (VTE) may be asymptomatic in a patient confined to bed - pulmonary embolism (PE) may be the first symptom.
  • Hospital treatment is associated with several factors increasing the risk of thrombosis.
  • The risk is very high in patients undergoing hip or knee replacement surgery, patients hospitalised for cancer or severe cardiac failure, and patients with a history of VTE or with a predisposition to thrombosis themselves or in their families.
  • Every hospital and clinic should have recommendations for the prevention of VTE.
  • Early mobilisation after surgery, trauma or acute disease improves venous return and will decrease the susceptibility to thrombosis but not eliminate it.
  • Medication, mechanical devices such as venous foot pumps or anti-embolism stockings (if there is a risk of bleeding, for instance) or a combination of these can be used for the prevention of VTE.
  • As the risk of recurrence of an idiopathic VTE within a year is three times higher than the risk of recurrence of secondary VTE (17% vs. 5%), permanent anticoagulation is recommended after idiopathic VTE, provided that there are no contraindications to it and that no such contraindications develop.
  • For tests for hereditary coagulation disorders, see the article on investigation of risk of thrombosis by laboratory tests Evaluation of Thrombophilia.
  • Aspirin is mainly used for the prevention of arterial occlusion, but there is accumulating evidence on aspirin and statins in preventing recurrence of VTE and PE.
  • A patient who has a history of thrombosis, or is otherwise predisposed to thrombus formation must be provided with guidance for high risk situations.

Risk factors for VTE Low Molecular Weight Heparin in Patients with Lower-Leg Immobilization, Interventions for Increasing the Use of Thromboprophylaxis in Hospitalized Patients, Statins for Primary Prevention of Venous Thromboembolism

Permanent risk factors

  • History of VTE in any part of the body (e.g. upper extremity thrombosis, portal vein thrombosis, mesenteric venous thrombosis or cerebral venous sinus thrombosis)
  • Age over 60 years
  • Smoking (if smoking cessation is not succesful)
  • Obesity
  • Diabetes
  • Fatty liver, cirrhosis of the liver
  • Uraemia, nephrotic syndrome
  • Inflammatory bowel and rheumatic diseases (such as vasculitis, SLE)
  • Permanent obstacle to venous return (such as anomalies of the inferior vena cava or other veins)
  • Incurable cancer, adenocarcinoma, in particular
  • Hereditary or acquired thrombophilia
  • Abnormal susceptibility to thrombosis in the family even in the absence of thrombophilia shown by laboratory tests
  • Some haematological diseases

Transient risk factors

  • Acute disease requiring bed rest (e.g. cardiac failure, pulmonary disease, severe infection or dehydration)
  • Prolonged immobility (e.g. a flight)
  • Other cause of immobility (e.g. paralysis, spinal cord injury, [femoral or tibial] fracture or postsurgical condition, extensive tissue trauma, other injuries) for a period of about 3 months
  • Surgical procedures (particularly those of the hips or knees, other invasive procedures of bone tissue, cancer surgery in the abdominal or pelvic area, fractures, particularly pathological ones, neurosurgery, laparoscopy, extensive or complicated surgical procedures taking more than 2 h, or repeat operation)
    • The increased risk of thrombosis associated with the aforementioned operations usually continues for about one month and in the most susceptible patients for at least 3 months.
  • Temporary mechanical hindrance to venous return (tumour, urinary retention, pregnancy, plaster casts of the limbs, splints, tight bandage of the limbs)
  • Cancer treated curatively, radiotherapy, certain cytotoxic drugs and cytolysis caused by them
  • Pregnancy, childbirth and puerperium (6 weeks)
  • Hormonal contraception, hormonal replacement therapy, treatment of cancer with tamoxifen or other adjuvant therapies, androgens taken to improve performance or to increase muscle mass
  • Central venous catheter, venous injuries or venous surgery
  • Repeated minor trauma (contact sports), particularly in patients with thrombophilia
  • Clozapine or olanzapine medication
  • High-dose glucocorticoid therapy, haematological growth factors, erythropoietin and interferon

Thrombophilias

  • Hereditary or acquired disorders predisposing to thrombosis.
  • The development of thrombosis usually requires some other exposure.
  • Laboratory tests show no more than 60% of the causes of hereditary predisposition to thrombosis.
  • For indications for laboratory tests for thrombophilia, see the articles Deep vein thrombosis > Investigations > Other laboratory tests Deep Vein Thrombosis and Laboratory evaluation of thrombophilia Evaluation of Thrombophilia.
  • Diagnosed thrombophilia affects the duration of anticoagulation therapy after DVT or PE and subsequent thromboprophylaxis, which should be started in good time and usually continued for one month in the event of risks (such as major operations).

Drugs used to prevent VTE

  • See also the article Antithrombotic agents in primary health care Antithrombotic Agents in Primary Health Care.
  • Low molecular weight heparins (LMWH; dalteparin, enoxaparin, tinzaparin) are used for thromboprophylaxis; if long-term prophylaxis is needed, warfarin and, in special cases, fondaparinux (patients with high risk of thrombosis, heparin allergy, heparin-induced thrombocytopenia (HIT)) and danaparoid (HIT) can be used.
  • Tinzaparin is the most suitable preparation for thromboprophylaxis in severe renal failure because it is not significantly accumulated except in therapeutic doses and protamine neutralizes it well. It is not recommended for patients with liver failure.
  • Patients susceptible to thrombosis (e.g. those with cancer or severe thrombophilia) may be given LMWH instead of warfarin either long term or permanently to treat and prevent DVT or PE.
  • Apixaban, dabigatran and rivaroxaban are used for postoperative prophylaxis after elective hip or knee replacement surgery.
  • Apixaban, dabigatran, edoxaban and rivaroxabam can also be used for the treatment and secondary prevention of VTE and PE in uncomplicated cases.

Surgical patients Interventions for Preventing Venous Thromboembolism in Adults Undergoing Knee Arthroscopy, Prophylaxis Against Deep Vein Thrombosis and Pulmonary Embolism in Hip Fracture Surgery

  • Low risk (risks of thrombosis: distal DVT 2%, proximal DVT 0.4%, fatal PE 0.002%)
    • Minor surgery, age < 40 years, no risk factors
  • Moderate risk (risks of thrombosis: distal DVT 10-20%, proximal DVT 2-4%, fatal PE 0.1-0.4%)
    • Minor surgery, no risk factors, age > 60 years
    • Non-major surgery, risk factors
    • Major surgery, age < 40 years, no risk factors
  • High risk (risks of thrombosis: distal DVT 40-80%, proximal DVT 10-20%, fatal PE 0.5-5%)
    • Major surgery, age > 40 years and history of DVT/PE, cancer, caesarean section
    • Major surgery, age > 60 years, even if no risk factors
    • Thrombophilia, prosthetic knee or hip surgery, hip fracture
    • Major trauma, spinal cord injury
  • When a patient is classified as belonging to a risk group, the individual predisposing factors as well as family history and type of surgery should be considered.
    • In particularly sensitive patients, even the smallest procedures (such as endoscopic procedures of the knee or abdominal cavity/pelvic area and invasive bone procedures) may involve an increased risk of thrombosis.
  • Patients with moderate or high risk must be given prophylactic treatment against VTE unless contraindicated.
  • Thromboprophylaxis should last for at least 10 days in moderate-risk situations and 4-5 weeks in high-risk situations.
  • Thromboprophylaxis may need to be extended for a longer period, such as 3 months, if complications arise during recovery or if the risk of thrombosis is very high. LMWH is, usually, used in patients with cancer; otherwise warfarin may be started unless contraindicated. In the treatment of venous thrombosis, taking into account certain precautions, factor Xa inhibitors can be used, but gastrointestinal malignancies are problematic due to the associated bleeding risk.
  • Immobility, e.g. plaster cast treatment, increases the risk of thrombosis. In patients with moderate or high risk of thrombosis, thromboprofylaxis by LMWH is used.
  • For further treatment, it is important to enter it in the patient records if the patient develops a thrombosis after an operation despite thromboprophylaxis.

Implementation Combined Intermittent Pneumatic Compression and Pharmacological Prophylaxis for Prevention of Venous Thromboembolism, Graduated Compression Stockings in the Prevention of Postoperative Venous Thromboembolism, Prolonged Thromboprophylaxis with Low Molecular Weight Heparin for Abdominal or Pelvic Surgery, Dabigatran Versus Lmwhs for Thromboprophylaxis after Total Hip or Knee Replacement

  • The planning of thromboprophylaxis must consider the risk of both thrombosis and bleeding, related not only to the patient but also to the planned procedure and the patient's clinical condition.
  • Check local guidance on thromboprophylaxis in hospital patients.
  • Factors predisposing the patient to bleeding include:
    • uncontrolled hypertension
    • renal failure (slows down the elimination of medicines but this does not apply to unfractionated heparin)
    • liver failure
    • anaemia (haematocrit < 30% or Hb < 100 g/l)
    • thrombocytopenia (platelet count < 50 × 109 /l)
    • medication (particularly antithrombotic therapy, NSAIDs, SSRIs, SNRIs, omega-3)
    • injuries.
  • If the risk of bleeding is high, pharmaceutical prophylaxis should be avoided, but mechanical methods of prophylaxis must not be forgotten.
  • Compression bandages or anti-embolism stockings are the most common and easiest mechanical methods of thromboprophylaxis, and are sometimes sufficient as the sole method of prophylaxis in patients with a low thrombosis but a high bleeding risk. Evidence of their benefit exists in surgical and obstetric patients but not in haematological patients. Venous foot pumps and intermittent pneumatic compression devices offer similar benefit.
  • Immobilization (long, over 6-hour flights, for example) should be avoided before and after the surgery or after a severe infection for about 1-4 weeks.
  • The surgery-associated increased risk of thrombosis continues for 1-3 months even if the patient were ambulatory.
  • Warfarin is also suitable for long-term prophylaxis as it is inexpensive and effective (e.g. pelvis fracture followed by a long period of immobility). Warfarin is associated with a risk of bleeding, drug interactions and the need for regular monitoring.
  • Low molecular weight heparins (LMWH) are administered subcutaneously once daily and routinely used in thromboprophylaxis.
    • The chosen LMWH preparation should not be unnecessarily changed to another preparation during the treatment period, and it is advisable to stay with the same preparation during future treatment in order to avoid immunological activation.
    • Usual prophylactic doses: 40 mg enoxaparin, 5 000 IU dalteparin or 3 500-4 500 IU tinzaparin subcutaneously once daily; for more detailed information see the respective summaries of product characteristics.
    • The individual risk factors, weight and renal function should be considered in dosage.
    • In renal failure, tinzaparin is best suitable for prophylactic use, but it may accumulate in therapeutic doses and, as necessary, its effect can best be reversed by protamine (effect neutralized by 65-80%, whereas the effect of other drugs is neutralized by 40-60%). It is not recommended for patients with liver failure.
    • Prophylactic treatment with LMWH is safe, and the treatment can often be self-administered or administered by a home nurse.
    • The duration of prophylactic treatment is 10 days in knee arthroplasty (longer if there are other factors increasing the risk of thrombosis), 4 weeks in hip arthroplasty and cancer surgery. During pregnancy according to a specific consultation and 6 weeks during the puerperium.
  • Fondaparinux can be used in high-risk patients, particularly if heparin is contraindicated.
  • Direct oral anticoagulants (apixaban, dabigatran, rivaroxaban) are only suitable for postoperative prophylaxis after elective hip or knee arthroplasty.
  • Adverse effects
    • Postoperative and post-traumatic bleeding (see contraindications and warnings in the summaries of product characteristics).
    • LMWH products are not indicated if the patient has a history of heparin-induced thrombocytopenia (HIT), which is associated with a paradoxical risk of thrombosis triggered by heparin due to immunological platelet activation.
    • Caution should be exercised in renal failure and minimal dosage used.

Bridging therapy for patients on warfarin

  • Bridging therapy for patients on warfarin must be planned in advance, as necessary Warfarin Therapy.
  • Check local guidance on pausing antithrombotic therapy in the context of surgical procedures.
  • Minor procedures can be carried out if the INR is at the lower end of the therapeutic range, but in major surgery requiring accurate haemostasis, or if potential bleeding may cause permanent organ damage, or if uncontrolled bleeding is a potential complication, warfarin should be paused (INR < 1.5). In patients with high risk of thrombosis, LMWH is started, as necessary, preoperatively as an alternative anticoagulant according to the operative policy.
  • The dose of LMWH should be chosen according to the patient's risk of thrombosis as well as the bleeding risk associated with the surgical operation; prophylactic doses are usually sufficient until the target INR has been achieved by warfarin therapy.
  • In high-risk patients (mechanical mitral valve, history of stroke, atrial fibrillation [CHA2DS2VASc score ≥ 2] and heart disease or other high risk of thrombosis, PE or any VTE during the preceding 3 months), bridging therapy should be planned individually and near therapeutic doses of LMWH are used as long as haemostasis is confirmed.
    • A prophylactic dose of LMWH can be administered on the day of surgery and the day after but the dose should then be increased, the patient's condition allowing.
    • A therapeutic dose of LMWH can usually be introduced about 48(-72) hours after surgery in patients with adequate postprocedural haemostasis.
    • Highly detailed individual planning and monitoring is needed for patients undergoing neurosurgery or surgery involving the liver or thoracic cavity, repeat surgery in particular, all of which entail a high risk of bleeding, and in renal failure.
    • During bridging therapy it is important to ensure that in association with a high bleeding risk the INR value is normal (1.0), otherwise below 1.5.
    • Anaemia in association with anticoagulant therapy (regardless of the strategy applied) predisposes the patient to bleeding; its cause should therefore be defined and it should be treated preoperatively. Iron deficiency is the most common cause.
  • Warfarin therapy should not be reintroduced until it is ascertained that no complications have arisen, that there is no need for repeat surgery and that no drug interactions are likely to complicate the re-establishment of warfarin therapy.

Medical and neurological patients Heparin for the Prevention of Venous Thromboembolism in General Medical Patients (Excluding Stroke and Myocardial Infarction)

  • The use of LMWH should be considered in all patients who are confined to bed for more than 3 days and have one or more of the above-mentioned risk factors here. COVID-19 infection is a topical example.
  • Anti-embolism stockings enhance venous return. If the patient has a high risk of both thrombosis and bleeding and pharmacological prophylaxis is not indicated, mechanical methods of prophylaxis (venous foot pumps or intermittent pneumatic compression devices) can be considered.
  • If a patient on warfarin or some other oral anticoagulant is admitted to hospital, it is recommended to change the anticoagulant over to LMWH. This decision is further justified in the case of concomitant drug treatment that has interactions (e.g. broad-spectrum antimicrobials), parenteral nutrition, septicaemic conditions and cancer, as well as if the planned procedures are extensive or there is a need to perform repeated procedures, e.g. punctures or revision surgery.
    • Heparin has anti-inflammatory properties, and parenteral administration is reliable compared to oral administration.
    • LMWH therapy is associated with lower frequency of bleeding complications than the direct FXa inhibitors (rivaroxaban and apixaban) in the thromboprophylaxis of medical patients as well, and hence direct FXa inhibitors are not indicated for thromboprophylaxis of medical patients.
    • The dose of thromboprophylaxis should be adjusted according to the clinical situation: therapeutic dose in special patients (e.g. bridging therapy in a patient with a heart valve prosthesis) and in patients who have an especially high risk of thrombosis but a low risk of bleeding.
  • The most recent recommendation concerning LMWH therapy in patients hospitalized because of COVID-19 infection is to use therapeutic dose of LMWH, provided that there are no contraindications for it. In intensive care, LMWH therapy is defined on an individual basis.
  • Prophylactic dose is chosen for patients whose risk of thrombosis is not significant and their condition is associated with some risk of bleeding.
  • Long-term (1 month) prophylaxis with LMWH may be beneficial in medical patients with high risk of thrombosis, but it is not used routinely.
  • LMWH can be replaced by warfarin in cases where there is a prolonged need for thromboprophylaxis.
  • Direct oral anticoagulants are unsuitable for thromboprophylaxis in medical patients as they increase the risk of bleeding.

Cancer patients Primary Prophylaxis for Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy, Anticoagulation for Thrombosis Prophylaxis in Cancer Patients with Central Venous Catheters

  • Patients with active cancer, metastatic cancer in particular, are at an increased risk of thrombosis.
  • Cancer and its treatment (chemotherapy, radiotherapy, surgery) may cause a bleeding risk concomitantly with a risk of thrombosis. Thromboprophylaxis should be considered individually in each case by weighing potential risks against benefits.
  • Warfarin may often interact with drugs used in cancer treatment, and LMWH is therefore a safer and more effective method of prophylaxis. The principles of choice of LMWH dose are the same as listed above. In patients with atrial fibrillation, increased or divided prophylactic doses are recommended; full therapeutic doses are unnecessary unless warranted by other risk factors.
  • Certain types of cancer surgery (of the brain, gastrointestinal or pelvic area, skeletal metastases) require thromboprophylaxis of at least one month.
    • The risk of VTE is highest in cancer surgery involving the lower abdomen, in adenocarcinomas, cancers spread via the circulatory system, brain tumours and in cancers that mechanically obstruct the flow of blood.
    • In association with surgical treatment, prophylaxis is carried out by administering LMWH by subcutaneous injection for one month: 40 mg enoxaparin, 5 000 units dalteparin or 3 500-4 500 units tinzaparin once daily.
  • The risk is also increased in patients who have a history of venous thrombosis or who have additional risk factors for VTE. Thromboprophylaxis is usually indicated for 10 days in patients confined to bed.
  • The risk of thrombosis is increased in patients with thrombocytosis (> 350 × 109 /l), leucocytosis (> 11 × 109 /l) or elevated concentrations of CRP and D dimer (Khorana score).
  • New anticoagulants are an approved alternative in the treatment of thrombosis and, associated with chemotherapy, as prophylaxis.
  • In patients with cancer of the gastrointestinal tract, the bleeding risks may reduce the benefits of direct anticoagulants. Of FXa inhibitors, apixaban has the least bleeding problems in this context.
  • Drug interactions must be excluded, and the patient's anaemia/thrombocytopenia is taken into account and corrected to the extent possible

Pregnant women

  • Anticoagulant treatment is provided in specialised care.
  • LMWH is safe in the prophylaxis and treatment of thromboses during pregnancy.
  • Direct oral anticoagulants are unsuitable for use during pregnancy or lactation.
  • Warfarin is not recommended for use during pregnancy because it affects fetal organogenesis during the first trimester. It may be used, however, during the second trimester (e.g. severe antithrombin deficiency or prosthetic heart valve or congenital heart defect) and during lactation.
  • Pregnancy in a patient who requires permanent anticoagulant therapy needs to be discussed and planned with a specialist (cardiologist, neurologist, haematologist).
    • The thrombotic risk is greatest during late pregnancy when the doses of LMWH approach therapeutic doses and their dosage should be determined by measuring anti-factor Xa activity (the target reading is 0.3-0.5 measured 12 hours after injection or 0.7-1.2 measured 3-4 hours after injection).
    • Thromboprophylaxis should continue for 6 weeks after delivery, but after the delivery warfarin may be introduced even though it is contraindicated in early and late pregnancy.
  • Vaginal delivery is associated with a lower risk of thrombosis than caesarean section.

Special groups

  • Patients with high risk of thrombosis
    • Thromboprophylaxis should be started at the very beginning of pregnancy.
  • Patients with a prior episode of VTE associated with a transient risk factor
    • Follow-up and imaging during pregnancy as required by the symptoms
    • Thromboprophylaxis for 6 weeks after delivery
  • A history of a single thrombosis in a patient with thrombophilia or of idiopathic VTE in a patient not on continuous anticoagulant therapy.
    • Thromboprophylaxis throughout the pregnancy and for 6 weeks after delivery
  • Thrombophilia alone without a history of VTE
    • LMWH prophylaxis should be started towards the end of the pregnancy or right after delivery, at the latest, and continued for no less than 6 weeks after delivery.
  • Antithrombin deficiency
    • The risk is so high that LMWH prophylaxis must always be given (even if the patient has no history of thrombosis). Dosage is individual and usually higher than ordinary prophylactic doses.
    • Antithrombin replacement therapy is given with LMWH prophylaxis in association with operations and delivery (consult a specialist in coagulation disorders). LMWH prophylaxis both during pregnancy and for at least 6 weeks following it, depending on laboratory response to antithrombin and LMWH.
    • If the case of thrombosis, in a patient with severe antithrombin deficiency, warfarin may be used during second trimester.
  • Acquired coagulation disorders with a high risk of VTE include antiphospholipid syndrome and myeloproliferative diseases.
    • A haematologist should always be consulted in the case of haematological diseases.

Air travellers Air Travel and Prevention of Venous Thromboembolism by Medication, Compression Stockings for Preventing Deep Vein Thrombosis in Airline Passengers

  • The risk of thrombosis is increased by such factors as a history of DVT, active cancer, pregnancy, use of oestrogen, age over 60 years, injury impairing mobility, significant obesity, thrombophilia and trauma, dehydration, surgical procedure or severe infection less than one month before travelling.
  • During long-haul flights (over 6 hours), all passengers are recommended to avoid wearing tight clothes, to drink sufficient amounts of water and to keep bending their ankles to contract their calf muscles and to speed up venous blood flow.
    • The same applies to long car and train journeys, but the cabin air pressure in an aeroplane and dryness of the air increase the risk of VTE.
  • Patients susceptible to thrombosis should additionally wear anti-embolism stockings.
  • LMWH may also be used in patients with known thrombophilia, other high risk of thrombosis or a history of VTE but no long-term anticoagulant therapy (a single prophylactic dose half an hour before the flight will protect the patient for about 12 hours).
  • There is no evidence on the effectiveness of aspirin or direct anticoagulants.

Heparin-induced thrombocytopenia (HIT) Risk for Heparin-Induced Thrombocytopenia (HIT) with Either Low-Molecular-Weight Heparin (Lmwh) or Unfractionated Heparin (Ufh)

  • Early thrombocytopenia (1-2 days after the heparin dose) is benign and reversible (HAT, heparin-associated thrombocytopenia).
  • Severe immune-mediated thrombocytopenia (heparin-induced thrombocytopenia, HIT) activates platelets and causes endothelial damage and subsequent vascular thrombi formation. Typically, thrombocytopenia appears within 5-10 days after starting heparin therapy. A so-called spontaneous HIT, appearing without heparin use, has been observed with COVID-19 adenovirus vaccines. Similar phenomenon may occur, rarely, in inflammatory conditions and immunological disorders.
    • The platelet count decreases by at least 50% of the baseline count (or fewer than 150 platelets in a single reading) but there is usually no bleeding.
    • Another venous or arterial thrombosis may occur, or the treatment may lose its efficacy.
  • If the probability of HIT is assessed to be higher than 1%, platelet levels should be monitored (every 2-3 days on days 4-14 of treatment).
    • If unfractionated heparin is used, the probability of HIT in patients who have undergone operative treatment (particularly major orthopaedic or cardiac surgery) is > 1%. In other patients, its probability is ≤ 1%.
    • In patients on LMWH, the probability of HIT is ≤ 1%.
  • A haematologist must always be consulted as regards the diagnosis and treatment.
  • HIT is diagnosed based on the clinical picture and laboratory tests (thrombocytopenia and detection of heparin antibodies). So-called 4T scoring is used for diagnostic assessment.
  • Platelet transfusion is contraindicated.
  • All forms of heparin (including LMWH) should be avoided.
  • Alternative anticoagulants: fondaparinux (may cause cross reactions), danaparoid (may cause cross reactions; only available for compassionate use), argatroban and bivalirudin
    • Prophylactic treatment should continue for at least one month.
    • Asymptomatic VTE in the lower limbs should be checked for because the dose of anticoagulant (prophylactic or therapeutic) depends on the finding.
  • Warfarin therapy must not be introduced until the platelet count has normalised. Instead of heparin, parenteral anticoagulant therapy should be given parallel to warfarin until stable therapeutic INR levels have been achieved.
  • If HIT is diagnosed during warfarin treatment, it should be reversed by giving vitamin K, and the above options should be used for anticoagulation.
  • There is preliminary evidence on the effectiveness of direct anticoagulants in the further treatment of HIT.
  • The history of HIT must be recorded in the patient's risk data, and they should not be given heparin in the future other than for fast-track cardiac anaesthesia.

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