Haematology
A 54 year old man is brought to the Emergency Department by his workmates. He was cutting wood in a factory when his hand slipped and he sustained a laceration to his left palm. His workmates describe minor bleeding at the scene that was easily controlled with direct pressure. He has a past medical history of pulmonary embolism for which he is prescribed warfarin. His INR is 6.5. On examination you note bleeding continues when direct pressure is removed. How should his anticoagulation be reversed?
Answer:
| Scenario | Management |
|---|---|
| INR 5.0 - 8.0, no bleeding |
|
| INR 5.0 - 8.0, minor bleeding |
|
| INR > 8.0, no bleeding |
|
| INR > 8.0, minor bleeding |
|
| Major bleeding |
|
Anticoagulants
Haematology
Last Updated: 17th March 2023
Warfarin
Mechanism of action:
Warfarin is a vitamin K antagonist that acts by inhibiting vitamin K dependent clotting factors (II, VII, IX, X) in addition to the anticoagulant proteins C and S.
Indications:
Warfarin is licensed for:
- Prophylaxis of systemic embolism in people with rheumatic heart disease and atrial fibrillation
- Prophylaxis after insertion of prosthetic heart valves
- Prophylaxis and treatment of venous thrombosis and pulmonary embolism
- Transient ischaemic attacks
Warfarin takes at least 48 to 72 hours for the anticoagulant effect to develop and if an immediate effect is required, heparin must be given concomitantly and continued for at least 5 days and until the INR is greater or equal to 2.0 for more than 24 hours.
Contraindications:
Warfarin is contraindicated:
- In people with:
- Haemorrhagic stroke
- Clinically significant bleeding
- Severe hepatic impairment
- Within 72 hours of major surgery with risk of severe bleeding
- Within 48 hours postpartum
- In pregnant women — due to the risk of teratogenicity
- In people taking drugs where interactions lead to a significantly increased risk of bleeding
Cautions:
Warfarin should be used with caution in the following groups:
- Elderly people.
- People with increased risk of bleeding — warfarin should be used with extreme caution if the benefit of anticoagulation outweighs the risk. Risk factors for bleeding include:
- History of gastrointestinal bleeding
- History of peptic ulceration
- Recent ischaemic stroke
- Uncontrolled hypertension
- Concurrent nonsteroidal anti-inflammatory (NSAID) use
- Recent surgery
- The postpartum period — should be delayed until risk of bleeding is low, usually 5–7 days after delivery
- People with:
- Thrombophilia — warfarin should be introduced slowly due to the risk of skin necrosis
- Thyroid disorders — the rate of warfarin metabolism depends on thyroid status
- Risk factors for overcoagulation, such as severe hypertension, or severe renal or hepatic impairment — international normalized ratio (INR) should be monitored more frequently
- Mild to moderate hepatic or renal impairment
Adverse effects:
- Bleeding is a common adverse effect of all anticoagulants, including warfarin, and it can occur in any part of the body.
- Rare or very rare — alopecia, nausea, and vomiting
- Frequency unknown — blue toe syndrome, diarrhoea, fever, haemothorax, jaundice, pancreatitis, skin reactions, and abnormal hepatic function
- Skin necrosis and calciphylaxis are rare but serious adverse effects of warfarin:
- Warfarin-related skin necrosis presents as painful, localised skin lesions (due to thrombosis of venules and capillaries) within subcutaneous fat.
- Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality
- Advise people taking warfarin to seek urgent medical advice if they develop a painful skin rash
Interactions:
If prescribing a drug that may interact, check the person’s international normalized ratio (INR) 3–5 days after starting treatment with the new drug.
| Increased anticoagulant effect | Decreased anticoagulant effect |
|---|---|
| Alcohol (can increase or decrease) | Tricyclic antidepressants (can increase or decrease) |
| Amiodarone | St John's wort |
| Antibiotics (co-trimoxazole, metronidazole, quinolones, macrolides) | Vitamin K-containing vitamin complexes, some enteral feeds, mineral supplements, and green vegetables |
| Antidepressants (SSRIs, SNRIs, TCAs) | Rifampicin |
| Azoles | Carbamazepine |
| Cranberry juice | Phenobarbital |
| Corticosteroids | Primidone |
| Fibrates | Azathioprine |
| NSAIDs | Phenytoin |
| Thyroxine | Griseofulvin |
Monitoring and reversal:
The anticoagulant effect of warfarin is measured as the international normalized ratio (INR). A target INR of 2.5 is recommended for most indications.
| Scenario | Management |
|---|---|
| INR 5.0 - 8.0, no bleeding |
|
| INR 5.0 - 8.0, minor bleeding |
|
| INR > 8.0, no bleeding |
|
| INR > 8.0, minor bleeding |
|
| Major bleeding |
|
Direct oral anticoagulants (DOACs)
Mechanism of action:
DOACS (apixaban, dabigatran, edoxaban, and rivaroxaban) are anticoagulants with a novel mode of action.
- Apixaban, edoxaban, and rivaroxaban are direct and reversible inhibitors of factor Xa (inhibition of factor Xa prevents thrombin generation and thrombus development).
- Dabigatran is a reversible inhibitor of free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.
Indications:
- All the DOACs are licensed for:
- Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with certain risk factors
- Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
- Prevention of recurrent DVT and PE in adults
- Prevention of venous thromboembolic events in adults who have undergone elective hip or knee replacement surgery
- In addition, rivaroxaban is licensed for:
- Prevention of atherothrombotic events following an acute coronary syndrome with elevated cardiac biomarkers (in combination with aspirin alone or aspirin and clopidogrel)
- Prevention of atherothrombotic events in people with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events (in combination with aspirin)
Monitoring and reversal:
- Unlike warfarin, apixaban, dabigatran, edoxaban and rivaroxaban do not require regular international normalised ratio (INR) monitoring.
- The most common adverse effect of anticoagulants is bleeding; however, while there is an antidote for warfarin, of the new anticoagulants, there is currently only an antidote for dabigatran.
- Idarucizumab (Praxbind®) is the first agent to be licensed in the UK that reverses the anticoagulant effect of a DOAC. Its action is specific against dabigatran. It is licensed for use in adults treated with dabigatran when rapid reversal of its anticoagulant effects is required for emergency surgery or urgent procedures, or in life-threatening or uncontrolled bleeding.
- Andexanet alfa is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding, only if the bleed is in the gastrointestinal tract.
- Management of a bleeding complication in secondary care consists of stopping treatment and general haemostatic measures, such as mechanical compression and surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy), or platelets.
Heparin
Mechanism of action:
- Unfractionated heparin potentiates the activity of antithrombin III, causing inactivation of thrombin. The heparin-antithrombin III complex also inhibits factor Xa and some other factors.
- Low molecular weight heparin (LMWH) preparations inhibit only factor Xa.
Contraindications:
Heparins are contraindicated:
- In people with current (or history of) heparin-induced thrombocytopenia
- In people with acute bacterial endocarditis
- In people with active major bleeding, and conditions with a high risk of uncontrolled bleeding, including recent haemorrhagic stroke, major trauma, recent brain, spinal cord or eye surgery, haemophilia and thrombocytopenia
- In people with active gastric or duodenal ulceration
Adverse effects:
- Bleeding
- Heparin-induced thrombocytopenia (immune-mediated effect that usually develops after 5 - 10 days, signs may include a 30% reduction of platelet count, thrombosis, or skin allergy; if HIT is suspected or confirmed, heparin should be discontinued and an alternative anticoagulant given)
- Hyperkalaemia (due to inhibition of aldosterone secretion; patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible)
- Osteoporosis (risk lower with LMWH)
- Alopecia
- Hypersensitivity reactions
- Injection site reactions
Low molecular weight heparin vs unfractionated heparin:
Low molecular weight heparin (LMWH) preparations have largely replaced unfractionated heparin. Unfractionated heparin (UFH) is usually given by continuous intravenous infusion for the smoothest control and is the treatment of choice where rapid reversal of anticoagulation may be required (e.g. in surgical patients or late pregnancy). Therapy is monitored by maintaining the APTT at 1.5 - 2.5 times the upper limit of normal. Important advantages of UFH compared to LMWHs are that its renal excretion is minimal, it has a relatively short half-life and its effects can be easily monitored by aPTT and rapidly reversed by protamine. The use of UFH may be preferred over LMWHs for treatment indications in patients with severe renal impairment.
| Advantages of LMWH |
|---|
| Greater ability to inhibit factor Xa directly, interacting less with platelets and so may have a lesser tendency to cause bleeding |
| Greater bioavailability and longer half-life in plasma making once daily subcutaneous administration possible |
| More predictable dose response avoiding the need for routine anticoagulant monitoring |
| Lower associated risk of heparin-induced thrombocytopenia or of osteoporosis |
Reversal:
Because it has a short duration of action, if haemorrhage occurs it is usually sufficient to withdraw unfractionated or low molecular weight heparin, but if rapid reversal of the effects of the heparin is required, protamine sulfate is a specific antidote (but only partially reverses the effects of low molecular weight heparins).
Report A Problem
Is there something wrong with this question? Let us know and we’ll fix it as soon as possible.
Loading Form...
- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
