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AinoLepäntalo
RiittaLassila

Evaluation of Thrombophilia and Prevention of Thrombosis

Essentials

  • History, clinical examination, imaging and laboratory tests should be used to find out whether the cause of thrombosis is local or generalized tendency for thrombosis. These may coexist.
    • Local causes include a (pseudo)aneurysm obstructing or invading a blood vessel, an atherosclerotic plaque, a vascular anomaly or an extravascular cause of obstruction, such as a tumour, enlarged lymph nodes, pregnancy or urinary retention.
    • Generalized thrombophilia may be either hereditary or acquired; combinations of the two also exist.
  • Clinical investigation of thrombophilia is indicated to be able to decide on the duration of anticoagulant therapy and subsequent thromboprophylaxis.
    • Unnecessary examinations not affecting the duration or choice of treatment should be avoided.
  • In young patients (below 50 years) with idiopathic thrombosis, malignancies and thrombophilia should be excluded.

Transient factors predisposing to thrombosis

  • Medication
    • Combined oral contraceptives
    • Hormone replacement therapy and ovulation induction
    • Hormonal or antiangiogenic adjuvant cancer treatment (e.g. tamoxifen)
    • Certain psychotropic drugs, such as clozapine
  • Sequelae of surgical treatment, in particular: orthopaedic surgery, cancer surgery, gastrosurgery or pelvic surgery, multiple injuries
  • Unexpected postsurgical thrombosis
  • Pregnancy, caesarean section and puerperium (6 weeks)
  • Immobilization associated with an underlying disease, i.e. severe infections, lung and heart diseases or paralyses
  • Uraemia
    • May cause a haemorrhagic disorder due to platelet dysfunction and anaemia.
  • Central venous catheter
  • Dehydration
  • Long-haul flights
  • Smoking and overweight
  • Recurring minor trauma (e.g. contact sports).

Factors suggesting permanent thrombophilia

  • History of venous thrombosis Deep Vein Thrombosis or pulmonary embolism Pulmonary Embolism, particularly if idiopathic
    • Idiopathic thrombosis recurs in about 20% of patients.
  • Both venous and arterial thrombosis
  • Thrombosis at a young age (before the age of 50)
  • Family history of venous thrombosis or early arterial thrombosis
  • Thrombosis at an atypical site, such as venous sinuses or abdominal veins, unless there is a local cause for this
  • Recurring problems with vascular access in patients undergoing dialysis
  • Recurring miscarriage Recurrent Miscarriage
    • Fetal death
    • Infertility
  • Anatomical anomalies may cause a risk of thrombosis.
    • Varicose veins Venous Insufficiency of the Lower Limbs may suggest a history of asymptomatic venous thrombosis.
    • Anomalies in the vena cava or other vascular structures involve a risk of thrombosis (in about 5% of young patients).
    • Thrombosis in the central retinal vein or in upper limb veins are most commonly due to local blood flow obstruction.

Hereditary thrombophilia

  • Hereditary thrombophilia detectable by blood tests
    • Factor V mutation (FV Leiden associated with activated protein C resistance; in about 20-30% of patients with thrombosis)
    • Prothrombin mutation, in about 5%
    • Antithrombin deficiency
    • Protein C deficiency
    • Protein S deficiency
      • The latter three hereditary factors in about 1-3% in total.
    • High factor VIII level (hereditary or acquired forms in about 10-15%)
  • Thrombophilia not detectable by laboratory tests can be detected based on patient or family history.

Acquired thrombophilia

Particularly severe thrombophilia

  • Recent (within the last 1-3 months) pulmonary embolism Pulmonary Embolism, venous or arterial thrombosis Deep Vein Thrombosis
  • Generalized atherothrombosis
    • Cardiac, cerebrovascular and lower limb manifestations
  • Prosthetic valve, particularly in mitral or tricuspid position Heart Valve Operation: Patient Follow-Up and Complications
  • Malignancies (solid tumours and haematological malignancies)
  • Paroxysmal nocturnal haemoglobinuria (PNH)http://www.orpha.net/en/disease/detail/447
  • Sequelae of major orthopaedic operations
  • Patient with multiple injuries
  • Several concomitant states predisposing to thrombosis
  • Certain syndromes, such as DIC or thrombotic thrombocytopenias, may involve haemorrhage.
    • Thrombus formation is usually predominant, requiring accurate planning, timing and monitoring of antithrombotic treatment in association with procedures or plasma exchange, for example.

Timing of laboratory tests

  • Laboratory tests should be done for patients with features of permanent thrombophilia, such as patients or families with thrombosis before the age of 50, thrombosis at atypical sites (abdominal area or venous sinuses), arterial and venous thrombosis in the same patient.
  • Available laboratory tests
    • Basic blood count with platelet count
    • Evaluation of thrombophilia (laboratories have extensive test packages for investigation of a bleeding diathesis )
    • JAK2 gene mutation analysis and PNH test (extensive analysis of erythrocytes, granulocytes and monocytes) for patients with a history of venous sinus thrombosis or idiopathic abdominal thrombosis
  • Thrombosis as such or its treatment may affect the results of coagulation tests.
  • Samples should preferably be taken either immediately after the diagnosis of thrombosis has been confirmed (before medication) or 1-3 months after withdrawing anticoagulants, if they are not to be taken permanently.
  • However, anticoagulant treatment planned to be used for a longer time must not be withdrawn for the sake of taking laboratory samples.
    • For example, severe thrombosis, family history or a permanent risk factor, such as obesity
  • The most common causes of thrombophilia can be found by genetic (FV-Leiden, prothrombin mutation) and antibody tests (anticardiolipin and anti-beta-2-glycoprotein antibody tests) not affected by the condition for which the samples are taken or by medication.
  • Anticoagulant therapy affects lupus anticoagulant, antithrombin and protein C and S levels.
    • Negative lupus anticoagulant results are reliable.
  • Functional coagulation tests (plasma antithrombin 3, protein C, free protein S antigen, factor FVIII, lupus anticoagulant) reflect the patient's normal situation after at least 3 months have elapsed from thrombosis and its treatment.
  • In patients with antiphospholipid antibody syndrome Systemic Lupus Erythematosus (Sle), the examination should be repeated after 12 weeks.
    • Antibody levels may vary because of consumption due to the thrombosis.
    • The onset of both venous and arterial thromboses and their tendency to recur are typical and require permanent antithrombotic treatment.
  • Thrombophilia tests may need to be repeated for acquired thrombophilias (functional coagulation tests and antiphospholipid antibodies) in association with conditions such as antiphospholipid antibody syndrome and recurring thrombosis or after pregnancy.

Treatment and prevention of thrombosis

Prevention of thrombosis

  • Patients who have had thrombosis but are not permanently on anticoagulants normally require long-term prophylactic treatment in situations involving an increased risk of thrombosis. See also local recommendations.
    • Major procedures (duration > 2 h), such as joint replacement surgery, surgical treatment of fractures or multiple injuries, cancer surgery, pelvic or abdominal surgery and invasive bone surgery
    • Indications associated with internal diseases, bed rest exceeding 4 days, severe infection, lung disease or heart failure
    • Duration of prophylactic treatment 1 month, for instance; see table T1.
    • See also article on Prevention of venous thromboembolism Prevention of Venous Thromboembolism.
  • If there is a high risk of recurring thrombosis (deep vein thrombosis, pulmonary embolism), long-term anticoagulant therapy can be used to prevent recurrence. In such cases, after therapeutic doses, antithrombotic doses can be used, depending on the choice of medication; see table T1.

Patients with an increased risk of bleeding

  • When starting or monitoring anticoagulant therapy, the following need to be considered:
    • anaemia
    • drug interactions (check locally available drug database)
    • thrombocytopenia
    • liver and kidney function
    • good control of hypertension
    • any history of bleeding diathesis or severe bleeding.
  • Anticoagulant therapy should be given with care to patients with an increased risk of bleeding.
  • For aspects related to bleeding diathesis and surgery see local recommendations.
  • In special cases, low molecular weight heparin at prophylactic doses may need to be accepted as sufficient for the treatment of thrombosis.
  • The platelet limit for anticoagulant treatment is approximately 30 × 109 /l in the absence of other severe risks of bleeding.
  • If drug therapy is out of the question due to a bleeding diathesis, mechanical pump treatment (calf, foot) of lower limbs or, rarely, temporary vena cava filter

Drug options for the prevention of thrombosis in hospitalized patients or after surgery if there is an increased risk of recurring deep vein thrombosis or recurring pulmonary embolism or of stroke and systemic embolization after atrial fibrillation of non-valvular origin

Venous thrombosis prophylaxis
DrugMost common daily doseSpecial daily dose1 (/vrk)
Dalteparin (Fragmin® )5 000 IU s.c. once daily2 500 IU s.c. once daily
Enoxaparin (Enoxaparin® , Ghemaxan® , Inhixa® )40 mg (4 000 IU) s.c. once daily20 mg (2 000 IU) s.c. once daily
Fondaparinux (Arixtra® )2.5 mg s.c. once daily1.25 mg s.c. once daily
Tinzaparin (Innohep® )3 500-4 500 IU s.c. once daily
  • Not recommended for patients with liver failure
2 500 IU s.c. once daily
  • Not recommended for patients with liver failure
Unfractionated heparin5 000 IU s.c. 3 times daily5 000 IU s.c. twice daily
Dabigatran (Pradaxa® )2,3 220 mg p.o. once daily150 mg p.o. once daily
Rivaroxaban (Xarelto® )2 10 mg p.o. once daily
Apixaban (Eliquis® )2 2.5 mg p.o. twice daily (24 h after surgery)
Prevention of recurring deep vein thrombosis and recurring pulmonary embolism or of stroke and systemic embolization after atrial fibrillation of non-valvular origin
DrugMost common daily doseSpecial daily dose1
Warfarin (Marevan® )P.o., INR target 2-3 (2.5-3.5)
Dabigatran (Pradaxa® )3 150 mg p.o. twice daily110 mg p.o. twice daily
Rivaroxaban (Xarelto® )4 20 mg p.o. once daily15 mg p.o. once daily
Apixaban (Eliquis® )4 5 mg p.o. twice daily2.5 mg p.o. twice daily
Edoxaban (Lixiana® )5 60 mg p.o. once daily30 mg p.o. once daily
1 Patient with low weight and advanced age, kidney failure, risk of bleeding
2 Only for elective knee or hip replacement surgery (10-35 days depending on the surgical procedure and individual risk of thrombosis)
3 Interactions require a reduced dose (verapamil, amiodarone or quinidine).
4 The dose for long-term prevention of deep vein thrombosis or pulmonary embolism (more than 6 months from thrombosis) is lower than the therapeutic dose (rivaroxaban 10 mg once daily, apixaban 2.5 mg twice daily).
5 Interactions require a reduced dose (concomitant use of P-glycoprotein inhibitors: ciclosporin, dronedarone, erythromycin, ketoconazole).

    References

    • [Deep vein thrombosis and pulmonary embolism]. A Current Care Guideline. Working group appointed by the Finnish Medical Society Duodecim, the Finnish Society of Angiology, and the Finnish Cardiac Society. Helsinki: Finnish Medical Society Duodecim, 2023 (accessed 17.4.2024). Available in Finnish at http://www.kaypahoito.fi/hoi50022.
    • Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv 2023;7(22):7101-7138 [PubMed]
    • National Institute for Health and Care Excellence (NICE) guideline on diagnosis, management, and thrombophilia testing of venous thromboembolic diseases. NICE 2020:NG158, last updated 2023 Aug 2 http://www.nice.org.uk/guidance/ng158
    • Arachchillage DJ, Mackillop L, Chandratheva A, et al. Thrombophilia testing: A British Society for Haematology guideline. Br J Haematol 2022;198(3):443-458 [PubMed]