1st June 2023

Thrombosis

Venous thrombosis

Venous thrombosis includes both deep vein thrombosis (DVTs) and pulmonary emboli (PEs). Treatment of confirmed PEs/proximal DVTs is with anticoagulation; the first-line choice in these cases is either apixaban or rivaroxaban. If these medications are not suitable for any reason then low molecular weight heparin (LMWH) should be given for 5 days, then replaced by dabigatran or edoxaban. Alternatively, LMWH can be given alongside warfarin for >5 days (or until the INR is >2 on 2 consecutive readings) and then warfarin can be continued alone.

NICE guidelines for the investigation of unprovoked DVT advise a full medical history and physical examination, and full blood tests should be sent for FBC, U+E, LFTS, PT and APTT.  Patients should not be offered further investigations for cancer unless relevant symptoms or signs are apparent.

If a patient has an unprovoked PE/DVT, their ongoing risk of VTE versus their bleeding risk (e.g. using the HAS-BLED score) is assessed to decide whether anticoagulation should be continued for longer than 3 months (or 6 months for active cancer patients). If the DVT/PE was provoked, healthcare professionals can consider stopping anticoagulation once the patient has completed 3 months (for patients with active cancer, this decision should take place after 3-6 months). Again, the risk vs benefit of anticoagulation should be considered.

Risk factors

Strong risk factors include:

• Thrombophilia
• Trauma
• Following a period of immobility
• Malignancy
• Previous VTE
• Post-surgery

Weaker risk factors include:

• Myeloproliferative diseases, congestive heart failure, COPD, inflammatory bowel disease, some neurological diseases, obesity, increasing age, pregnancy/postnatal period, history of varicose veins, first degree relative with VTE, extended travel, HRT and oestrogen-containing contraceptive pills.

Thrombophilia 

Thrombophilia refers to both congenital and acquired conditions, which increase susceptibility to thrombosis.

Congenital causes

• Proteins C and S deficiency

Proteins C and S prevent coagulation, as these proteins mainly inactivate factors V and VIII. Deficiencies in these proteins, therefore, lead to hypercoagulable states. If there is suspicion of Protein C and Protein S deficiencies following thrombosis, testing should only be offered to patients who are stopping anticoagulation as results can be affected by anticoagulants.

• Factor V Leiden

The genetic mutation, Factor V Leiden causes a defect in factor V, meaning that protein C cannot inactivate it. Factor V is then working to continuously activate downstream clotting factors, causing a hypercoagulable state. Following acute thrombosis, if there is suspicion of Factor V Leiden, testing should only be offered to patients who are stopping anticoagulation as results can be affected by anticoagulants.

Acquired causes

• Antiphospholipid syndrome

Antiphospholipid syndrome can present with arterial or venous thrombosis and/or recurrent miscarriages. The patient must have one of the clinical features to make a diagnosis alongside one of the laboratory markers. Detection of anticardiolipin antibody, lupus anticoagulant or anti-b2-glycoprotein I antibody on >2 occasions at least 12 months apart is diagnostic. The lupus anticoagulant activity may prolong the APTT, therefore prolonged APTT alongside thrombosis or recurrent miscarriages should raise the question of antiphospholipid syndrome. It is important to consider prophylactic treatments (warfarin or anti-platelets) for antiphospholipid syndrome to reduce the risk of complications. As soon as a pregnancy is confirmed and throughout the pregnancy, LMWH alongside low-dose aspirin is recommended for patients with antiphospholipid syndrome and recurrent miscarriages. When there is no history of recurrent miscarriages but a history of intrauterine growth restriction or pre-eclampsia, monotherapy with low-dose aspirin should be considered.

• Paroxysmal nocturnal haemoglobinuria (PNH)

The incidence of arterial and venous thrombosis in patients with PNH is approximately 10%. PNH can cause hemolysis, thrombosis, and haemoglobinuria as a result of stem cell malfunction. CD55 and CD59 on the surface of the cell (GPI-anchored proteins) are deficient due to a mutation in the PIGA gene. The deficiency of these proteins results in complement activation, haemolysis and thrombosis. PNH is diagnosed by flow cytometric analysis looking at antibodies to GPI-anchored proteins. Treatment is with eculizumab or ravulizumab.

• Myeloproliferative neoplasms

Myeloproliferative neoplasms include polycythaemia vera, essential thrombocythemia and myelofibrosis. These conditions can cause venous and arterial thrombosis. Other signs of the underlying disorder would be present on the FBC, for instance thrombocytosis in essential thrombocythemia. On a peripheral blood sample, testing for JAK2, CALR and MPL can be sent. Myeloproliferative neoplasms are often associated with these mutations and identifying if a mutation is present can also guide treatment, for instance, by using a JAK2 inhibitor. A bone marrow biopsy may be required.

Anticoagulant therapy  

If a patient requires anticoagulation, consideration should be taken as to which anticoagulant to prescribe: warfarin, apixaban, dabigatran, rivaroxaban or edoxaban. Scores exist to help the prescriber decide whether anticoagulation is indicated, such as the CHA₂DS₂-VASc score for stroke risk in AF and the HAS-BLED score to assess the bleeding risk for patients with AF.

Warfarin

Warfarin inhibits clotting factors X, IX, VII, and II by inhibiting vitamin K  (this can be remembered by the mnemonic 1972). Patients who have been recently started on warfarin should have their INR levels checked regularly at first. The INR should be checked daily initially / alternate days until the INR is in the target therapeutic range on a minimum of 2 consecutive times, then twice weekly for 1-2 weeks, then at longer intervals thereafter (up to every 12 weeks).

Patients have different target INRs depending on the reason for anticoagulation. The images below, taken from NICE guidelines, suggest the recommended INR for different indications:

INR targets.

Image Source: National Institute for Health and Care Excellence (2022). Scenario: Warfarin. Available for free at: https://cks.nice.org.uk/topics/anticoagulation-oral/management/warfarin/ (Accessed on: 30 January 2023).

Warfarin can interact with many drugs which are cytochrome P450 inducers or inhibitors, as warfarin is metabolised via the cytochrome P450 system by CYP 2C9, 1A2, and 3A4.  After the initiation of one of the following drugs, the INR should be checked after 3-5 days. Drugs which are P450 inhibitors and may enhance the effect of warfarin include alcohol (acutely); amiodarone; certain antibiotics including sulfonamides, metronidazole, clarithromycin and ciprofloxacin; antifungal medications such as fluconazole and ketoconazole; antidepressants such as fluoxetine; aspirin; cranberry juice; clopidogrel; corticosteroids; protease inhibitors; fibrates; NSAIDS; tamoxifen; thyroxine. Drugs which are P450 inducers and therefore may reduce the effects of warfarin include St. John’s Wart, griseofulvin, rifampicin, carbamazepine, phenobarbital and phenytoin. There is a further list of drugs which require INR monitoring when used concurrently with warfarin on the NICE website.

A patient with an INR out of therapeutic range should be managed as per NICE guidelines:

Patients who take warfarin and require elective invasive procedures may need to temporarily stop warfarin. If there is a risk of severe bleeding with the procedure, patients will need to stop the warfarin 3 – 5 days before. If it is necessary to continue anticoagulation (i.e. high thrombotic risk), when the INR <2.5, heparin therapy should be started. In an emergency, warfarin can be reversed by vitamin K. For minor surgeries with a minimal bleeding risk, the surgery can be performed if the INR <2.5, but local guidelines should be viewed.

For dental procedures, the INR should be checked before the procedure (if the INR is usually stable, <72 hours before is sufficient). If the INR is <4, then the dental procedure can go ahead with no interruption to warfarin therapy. If the INR is >4, it should be delayed until it is <4.

Direct oral anticoagulants

Apixaban, rivaroxaban, edoxaban and dabigatran are all examples of direct oral anticoagulants (DOACs). The first three of these medications directly and reversibly inhibit factor Xa. Dabigatran works by reversibly inhibiting the thrombin molecule.

Unlike warfarin, DOACs do not need regular INR monitoring. However, contraindications to DOACs, such as severe hepatic disease, mechanical heart valve and severe renal disease. In these cases, warfarin is the only recommended anticoagulant.

Before commencing a DOAC, the below factors need to be considered:

• Body weight
• Renal function
• Interacting medications
• Different dosing regimens

Therapeutic fibrinolysis

Fibrinolytic therapies result in the breakdown of plasminogen into active plasmin. Fibrinolytic therapies are used to dissolve life-threatening thrombi to improve blood flow to vital organs. Examples include streptokinase, alteplase, etc. These agents can be used in many medical emergencies caused by the formation of clots listed below, but contraindications and risks must be considered prior to use:

• Acute ischaemic stroke

IV alteplase (a tissue plasminogen activator) is mostly used as a fibrinolytic therapy within 4.5 hours of stroke onset if no contraindications exist.

• Acute myocardial infarction

Fibrinolytic therapy is used to treat ST elevation myocardial infarctions if percutaneous coronary intervention (PCI) is unavailable or during transport to a hospital which provides PCI.

• Acute limb ischaemia

For non-life-threatening ischaemic limbs of <14-day duration, fibrinolysis can be used to achieve clot lysis. This can take up to 72 hours and therefore, it would not be appropriate for ischaemia which threatens a limb.

• DVT

DVTs are usually managed with anticoagulants. However, patients with a <14-day history of DVT symptoms, upper-extremity DVTs or proximal DVTs and good functional status can be considered for thrombolysis.

• PE

Fibrinolytic therapy can be used to treat acute massive PE, causing sustained hypotension and signs of haemodynamic compromise.