10 Haematological disorders

Sickle cell disease 206

Porphyria 210

Rare blood disorders 214

Coagulation disorders 216

Haemophilia and related clotting disorders 218

Thrombocytopenia 220

Anticoagulants 222

Antiplatelet drugs 228

Fibrinolytics 230

Antifibrinolytics/haemostatic drug therapy 232

Haematological management of the bleeding patient 234

Hypercoagulability syndromes 236

Bone marrow failure: infiltration by tumour or suppression by drugs.

Megaloblastic anaemias: folate or vitamin B₁₂ deficiency.

Complex anaemias: effects on production and breakdown, e.g. renal failure, rheumatoid arthritis, and hypothyroidism.

Haemolytic anaemias: either inherited (thalassaemia, sickle cell disease, spherocytosis), acquired (autoimmune, drugs, infections), or physical (mechanical heart valves, DIC, jogging).

Symptoms of the commonest causes should be elicited, including relevant family history; always enquire about NSAIDs and alcohol.

Respiratory and cardiovascular history may be worsened by the anaemia or make its impact greater.

Much can be deduced from the Hb and mean corpuscular volume (MCV) alone, but in many instances a blood film gives additional useful information.

Confirmatory tests such as ferritin, B₁₂/folate levels, reticulocyte count, direct Coombs test, erythrocyte sedimentation rate, liver/renal function, and bone marrow should be requested as appropriate.

When delay to surgery is possible it is more appropriate and safer to treat the underlying cause and raise the Hb slowly with simple, effective measures, e.g. oral iron, B₁₂ injections. Transfusing a patient with pernicious anaemia may precipitate heart failure.

Red cell transfusion is indicated if the Hb level is <7g/dl.

Checking a HemoCue^® reading gives comparable results to a Coulter^® counter and can help to avoid a transfusion if >8g/dl.

Each case must be assessed with a view to coexistent disease, expected intraoperative blood loss, and whether acute or chronic.

For patients with ischaemic heart disease

For patients who may tolerate anaemia poorly, e.g. patients >65yr or those with significant respiratory disease, consider raising transfusion threshold to 9–10g/dl.

These patients have a positive sickle test but normal blood film and Hb level. This can be confirmed by Hb electrophoresis, but in an emergency a normal blood film should suffice.

These patients do not need special treatment, other than avoidance of hypoxia, dehydration, infection, acidosis, and hypothermia.

There is great variability, not only between patients but also within individual patients at different periods of life. Many remain well most of the time.

Vaso-occlusive crises are the most common cause of morbidity and mortality. The presentation may be dramatic with acute abdomen, ‘acute chest syndrome’ (acute pneumonia-like), stroke, priapism, and painful dactylitis. By the time patients reach adulthood most will have small, fibrotic spleens. A less acute complication is proliferative retinopathy due to retinal vessel occlusion and neovascularisation (more common in HbSC disease).

Aplastic crises are characterised by temporary shutdown of the marrow manifested by a precipitous fall in Hb and an absence of reticulocytes. Infection with parvovirus B19 and/or folate deficiency are often responsible.

Sequestration crises occur mainly in children. Sudden massive pooling of red cells in the spleen can cause hypotension and severe exacerbation of anaemia, with fatal consequences unless transfusion is given in time.

Haemolytic crises manifest by a fall in Hb and rise in reticulocytes/bilirubin, and usually accompany vaso-occlusive crises. Chronic haemolysis leads to gallstones in virtually all patients with SCD, though many remain asymptomatic.

Screening tests for sickling which rely on deoxygenation of HbS are positive in both HbSS and HbAS.

Hb electrophoresis distinguishes SS, AS, and other haemoglobinopathies. Measurement of the HbS level is important in certain clinical situations (e.g. crises) where a level of <30% is aimed for. It is not necessary to wait for the results of electrophoresis before embarking on emergency surgery; clinical history, Hb level, a positive sickle test, and the blood picture usually allow distinction between SCD and sickle cell trait. A mixed-race patient usually has sickle cell trait.

For crises—rest, rehydration with oral/IV fluids, antibiotics if infection is suspected, maintain PaO₂, keep warm, prompt and effective analgesia (traditionally diamorphine/morphine is used over pethidine; regional anaesthesia very effective).

Blood transfusions may be life saving, but the indications are limited. Exchange transfusions have a role in some vaso-occlusive crises (acute chest syndrome, stroke). Always discuss with a haematologist. For patients with high perioperative risk, transfusing to achieve an HbS level of <30% may decrease complications but is controversial.

Dehydration: allow oral fluids as late as possible and pre- and postoperative IV fluids.

Hypoxia: pulse oximetry and prophylactic oxygen.

Prophylactic antibiotic cover should always be considered because of increased susceptibility to infection.

Positive pressure ventilation may be required to achieve normocarbia and avoid acidosis.

Hypothermia should be avoided by warming the operating room, using a fluid warmer, and active warming such as a Bair Hugger^®. Core temperature should be monitored.

Regional anaesthesia is not contraindicated and tourniquets can be used if limbs are meticulously exsanguinated prior to inflation.

Affects 0.1% of African-Americans.

Intermediate in severity between sickle cell disease and trait.

Patients develop anaemia, splenomegaly, jaundice, aseptic necrosis of the femoral head, hepatic disease, retinal disease, and bone marrow and splenic infarcts.

Myocardial necrosis has been described after general anaesthesia.

Management principles are as for sickle cell disease.

Variegate porphyria (VP). Common in Afrikaners—increased copro- and protoporphyrin in the stool. Dermal photosensitivity.

Hereditary coproporphyria (HCP). Very rare—increased urinary porphyrins. Dermal photosensitivity.

Acute porphyric crises may be precipitated by drugs, stress, infection, alcohol, menstruation, pregnancy, starvation, and dehydration.

Symptoms include acute abdominal pain, vomiting, motor and sensory peripheral neuropathy, autonomic dysfunction, cranial nerve palsies, mental disturbances, coma, convulsions, and pyrexia.

Individuals may have normal biochemical tests between attacks.

Patients may present with unrelated pathology, e.g. appendicitis.

Symptoms may mimic surgical pathologies, e.g. acute abdominal pain, acute neurology.

Any patient giving a strong family history of porphyria must be treated as potentially at risk. Latent carriers may exhibit no signs, be potentially negative to biochemical screening, but still be at risk from acute attacks.

Minimise preoperative fasting. Use glucose/saline IV (avoid dextrose alone due to frequency of hyponatraemia).

Regional anaesthesia—bupivacaine is considered safe for epidural anaesthesia, but in the context of any peripheral neuropathy, detailed preoperative examination and documentation is essential. In acute porphyric crises, regional anaesthesia should be avoided as neuropathy may be rapid in onset and progressive.

General anaesthesia—propofol is the induction agent of choice. Maintenance with nitrous oxide and/or propofol infusion. There are numerous case reports of safe use of halothane and isoflurane.

Neuromuscular blockade—suxamethonium and vecuronium are considered safe (atracurium controversial). Fentanyl, morphine, and pethidine all considered safe.

Monitoring—invasive blood pressure during acute crisis as hypovolaemia is common and autonomic neuropathy may cause labile blood pressure. Perform central venous pressure monitoring if clinically indicated.

Convulsions—treat with diazepam, propofol, or magnesium sulphate (avoid barbiturates and phenytoin).

Remember that the onset of a porphyric crisis may be delayed for up to 5d.

Reverse factors that increase ALA synthetase (the initial enzyme responsible for haem production). Give haem arginate 3mg/kg IV once daily for 4d (leads to negative feedback to ALA synthetase). Treat infection, dehydration, electrolyte imbalance, and give glucose (20g/hr).

Treat symptoms with ‘safe’ drugs.

Monitor the patient appropriately.¹

The inflexible red cells are phagocytosed in the spleen, resulting in a microspherocytic anaemia with marked reticulocytosis. The cells’ increased osmotic fragility is diagnostic.

Splenomegaly is common. Splenectomy leads to a 50–70% increase in red cell survival.

Splenectomy should not be performed in children <6 yr of age, and should ideally be preceeded by pneumococcal, meningococcal, and HIB vaccines and lifelong oral penicillin, to help avoid infection.

There are no particular anaesthetic considerations.

The disease may afford some protection against malaria and is prevalent in endemic areas.

The G6PD enzyme is responsible for the production of NADPH, which is involved in the cell's defence against oxidative stresses such as infections (usually viral, but also septicaemia, malaria, and pneumonia) or oxidative drugs (aspirin, quinolones, chloramphenicol, isoniazid, probenecid, primaquine, quinine, sulphonamides, naphthalene, and vitamin K).

Additionally, drugs producing methaemoglobinaemia, such as nitroprusside and prilocaine, are contraindicated as patients are unable to reduce methaemoglobin, thereby diminishing oxygen-carrying capacity.

Classically, ingestion of broad (fava) beans results in haemolysis (favism).

Usually the haemolysis of red cells occurs 2–5d after exposure, causing anaemia, haemoglobinaemia, abdominal pain, haemoglobinuria, and jaundice.

Diagnosis is made by demonstration of Heinz bodies and red cell G6PD assay. (G6PD levels may be falsely raised/normal in acute haemolysis.)

Treatment includes discontinuation of the offending agent and transfusion may be required.

Diagnosis is confirmed by haemoglobin electrophoresis and/or globin chain analysis.

The disease is prevalent in people of Mediterranean (mainly B), African (A and B) and Asian (mainly A) extraction.

Patients with A-thalassaemia have mild or moderate anaemia.

Those with severe B-thalassaemia, also called thalassaemia major, are transfusion dependent.

Since there is no iron-excreting mechanism, iron from transfused blood builds up in the reticuloendothelial system, until it is saturated, when iron is deposited in parenchymal tissues, principally the liver, pancreas, and heart.

Preoperative preparation should include assessment of the degree of major organ impairment (heart, liver, pancreas) secondary to iron overload.

High-output congestive cardiac failure with intravascular volume overload is common in severe anaemia and should be treated preoperatively by transfusion.

Previous transfusion exposure may cause antibody production and therefore crossmatching may be delayed.

The exceedingly hyperplastic bone marrow of the major thalassaemias may cause overgrowth and deformity of the facial bones, leading to airway problems and making intubation difficult.

Acquired disorders are due to lack of synthesis of coagulation factors, increased loss due to consumption (e.g. disseminated intravascular coagulation), massive blood loss, and the production of substances that interfere with their function.

A family history may be elicited (haemophilia A and B—sex-linked recessive; von Willebrand's disease—autosomal dominant with variable penetrance) but cannot be relied upon (absent in 30% of haemophiliacs).

Response to previous haemostatic challenges (tonsillectomy, dental extractions) may indicate the severity of the coagulopathy, e.g. in severe haemophilia A (factor VIII <2%) bleeding occurs spontaneously; in mild haemophilia A (factor VIII 5–30%) bleeding occurs only after trauma.

Concurrent and past medical problems such as liver disease, malabsorption (vitamin K deficiency), infection, malignancy (DIC), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis) as well as medications (anticoagulants, aspirin, and NSAIDs) may be relevant.

Abnormalities due to liver disease and vitamin K deficiency—give daily vitamin K (phytomenadione) 10mg slowly IV. FFP (15ml/kg) may be needed in addition if the presenting symptom is bleeding.

Previously untreated mild haemophilia requires strenuous efforts at avoiding blood products. Desmopressin infusion of 0.3µg/kg in 50–100ml 0.9% sodium chloride over 30min, with the use of tranexamic acid, can be used for mild disease or where there is low risk of bleeding.

In elective cases factor levels should be obtained prior to surgery. Depending on the type of surgery, the factor level should be 50–100% of normal and maintained for 2–7d post procedure. If factors are necessary, the treatment of choice is now recombinant material in accordance with established guidelines. Always involve a haemophilia specialist.

Cryoprecipitate (contains factor VIII) and fresh frozen plasma (contains factor IX) should be used to correct these clotting factors only in an emergency, when concentrate is unavailable, due to their chance of transmitting infection.

NSAIDs, other anticoagulants, antiplatelet drugs, and IM injections should be avoided.

von Willebrand's disease is divided into three subtypes. After subtyping (type 2B is non-responsive) a therapeutic trial of desmopressin (dose as in haemophilia) with before-and-after levels of von Willebrand factor is performed. Responders should have desmopressin for bleeding or prophylactically prior to surgery. Non-responders can have intermediate purity factor VIII concentrate (which includes von Willebrand factor) or cryoprecipitate.

Increased platelet consumption, with an immune basis (ITP, drugs, viral infections, systemic lupus erythematosus, lymphoproliferative disorders) or without an immune basis (DIC, TTP, cardiopulmonary bypass).

Dilution, following massive transfusion of stored blood.

Splenic pooling (hypersplenism).

Unexpected thrombocytopenia should always be confirmed with a second sample and a blood film.

Minor procedures such as bone marrow biopsy may be performed without platelet support provided adequate pressure is applied to the wound.

For procedures such as insertion of central lines, transbronchial biopsy, liver biopsy, or laparotomy, the platelet count should be raised to at least 50 × 10⁹/l.

For lumbar puncture, epidural anaesthesia, and operations in critical sites such as the brain or eyes, the platelet count should be raised to 100 × 10⁹/l (see also p. 784 and p. 1174).

In ITP, platelet transfusions should be reserved for major haemorrhage. Preparation for surgery entails the use of steroids or high-dose immunoglobulins initially.

IM injections and analgesics containing aspirin or NSAIDs should be avoided.

Desmopressin 0.3µg/kg in 50–100ml saline over 30min may improve platelet function in renal failure, haemophilia, and von Willebrand's disease.

Recommended targets:

Reversal of a high INR can be achieved in several ways depending on the circumstances. In the absence of bleeding, with an INR <5, reducing or omitting a dose is usually sufficient; if INR is 5–9 give vitamin K 1–2mg orally in addition. If there is minor bleeding or a grossly raised INR >9, give a small oral or IV dose of vitamin K (2–5mg). Life-threatening bleeding requires slow IV vitamin K (10mg) and either prothrombin complex concentrate or FFP. The last two cases must be discussed with a haematologist.

Warfarin pharmacokinetics and dynamics can be affected by a multitude of other drugs (see BNF¹ for a fuller discussion). The important anaesthetic interactions include:

Potentiation (by inhibition of metabolism): alcohol, amiodarone, cimetidine, ciprofloxacin, co-trimoxazole, erythromycin, indometacin, metronidazole, omeprazole, paracetamol.

Inhibition (by induction of metabolism): barbiturates, carbamazepine.

In addition drugs that affect platelet function can increase the risk of warfarin-associated bleeding, e.g. aspirin and NSAIDs.

Limited evidence suggests that patients having surgery without discontinuation of oral anticoagulation have a perioperative major bleeding risk of 10% (one third needing transfusion).

The risk of thromboembolism from a mechanical heart valve in the mitral or aortic region without oral anticoagulation has an estimated annual incidence of 17% or approximately 0.4% for an 8d perioperative period.

The perioperative risk of arterial thromboembolism in patients who have atrial fibrillation and no anticoagulation is approximately 1%.

The risk stratification for patients with prior venous thromboembolism (VTE) is different to the arterial thromboembolism of mechanical heart valves and atrial fibrillation. Embolic stroke is fatal or associated with significant neurological deficit in 70% of cases. Recurrent VTE is fatal in 4–9% with less morbidity. In addition, low dose anticoagulation has been shown to be effective in ‘bridging therapy’ for recurrent VTE but not for arterial embolism.

Warfarin should be stopped at least 5d prior to elective surgery to allow the INR to decrease below 1.5—the level usually considered to be safe for surgery (may need to be <1.2 for high-risk surgery).

Once the INR is <2 alternative pre- and postoperative prophylaxis should be considered.

In patients at high risk of thromboembolism a continuous IV infusion of unfractionated heparin should be started at 1000U/hr and adjusted to keep the APTR between 1.5 and 2.5. This should be stopped 6hr prior to surgery and restarted 12hr afterwards This should be continued until INR >2.0.

Warfarin therapy should be restarted within 12–24hr and may take up to 48hr to become therapeutic.

Except in cases of high-risk bleeding, IV heparin can usually be replaced by the use of SC LMWH (prophylactic or treatment dose). Again this should be continued until warfarin is restarted and the INR >2.0.

In patients who are receiving bridging anticoagulation with therapeutic-dose LMWH, there is no established role for routine perioperative monitoring of antifactor Xa levels, as in certain non-operative settings.

Alternative methods of embolism prophylaxis should be considered such as compression stockings, and compression pumps should be considered in all cases (see p. 12).

If the risk of venous thromboembolism is very high (e.g. very recent thromboembolism) and effective anticoagulation cannot be undertaken, the insertion of a caval filter should be considered.

In emergency surgery there is too little time to withdraw warfarin and specialist haematological advice should be sought. Prothrombin complex concentrates (such as Octaplex or Beriplex) have replaced FFP as first-line treatment. The dose varies depending on the initial INR. Vitamin K 5–10mg slowly IV should also be given, Fresh frozen plasma (10–15ml/kg) is a cheaper and viable alternative, but is not as effective.

Hypertension

Age 75yr or older

Diabetes mellitus

Unfractionated heparin is given by IV bolus or infusion. It is monitored by prolongation of the APTT (maintain at 1.5–2.5 times normal laboratory value).

A validated regime is to give a bolus of 80U/kg followed by an infusion of 18U/kg/hr and check first APTT after 6hr.

It has a narrow therapeutic window with complex pharmacokinetics and great inter-patient variation in dose requirements.

Half-life is 1–2hr so stopping it is usually enough to reverse excessive anticoagulation or bleeding. If bleeding is severe protamine can be used.

Protamine sulphate counteracts heparin. If given within 15min of heparin, 1mg protamine IV neutralises 100U of heparin. After this less protamine is required as heparin is rapidly excreted. It should be given slowly to avoid hypotension to a maximum of 50mg—a higher dose is itself anticoagulant.

Complications of heparin include heparin-induced thrombocytopenia (HIT), which can cause serious venous and arterial thrombosis. Patients on heparin for 5d or more should have their platelet counts checked. This is less of a problem with LMWH heparin.

Low-molecular-weight heparin (LMWH) is replacing unfractionated heparin for both prophylaxis and treatment of thromboembolism and unstable coronary artery disease. Administered once daily by SC injection, it needs no monitoring (although antifactor Xa levels can be measured in renal failure). Many patients with deep vein thrombosis are now managed as outpatients.

LMWH is renally excreted so should be used with caution in renal failure.

The reversal of LMWH is more difficult, although protamine up to 50mg seems to be clinically effective.

Dose is monitored according to APTT and reduced in renal failure.

Given by continuous IV infusion as half-life is ∼3min.

Recently licensed for prophylaxis of venous thromboembolism in major orthopaedic surgery of the lower limbs.

A recent study has suggested it may be more effective than LMWH.

The initial dose should not be given until 6hr after surgical closure.

It must be started within 24–48hr of the onset of sepsis—evidence suggests the earlier the better. It is given as a continuous infusion for 96hr.

As a natural anticoagulant it inhibits the coagulation pathway at several points.

It should be stopped at least 2hr prior to invasive procedures or surgery and cannot be started for at least 12hr after surgery.

Contraindications include any major bleeding risk, other anticoagulants, platelet count <30 × 10⁹/l, severe hepatic disease, intracranial pathology, and epidural catheters.

If serious bleeding occurs, discontinue therapy. There is no specific antidote and supportive therapy with blood and blood products may be required.

Should be given immediately in acute myocardial infarction.

Low-dose aspirin is a mainstay for secondary prevention of thrombotic vascular events in vascular and cardiac disease.

May also be used in angina, post coronary bypass surgery, intermittent claudication, atrial fibrillation, and primary prevention of ischaemic cardiac disease.

If aspirin is to be stopped it takes 7–9d for platelet function to return to normal.

There are few published trials looking at perioperative bleeding.

In coronary artery bypass grafting aspirin increases perioperative bleeding but increases graft patency.

In transurethral prostatectomy aspirin considerably increases perioperative bleeding.

Minor surgery to skin or cataract surgery does not require aspirin to be stopped.

On balance aspirin should be stopped for at least 7d prior to surgery when the risks of perioperative bleeding are high (major surgery) or where the risks of even minor bleeding are significant (retinal and intracranial surgery). This risk of bleeding must be balanced against the possibility of precipitating a thromboembolic event, particularly in patients with unstable angina.

Also used for secondary prevention of stroke and transient ischaemic attacks.

Dipyridamole needs to be stopped at least 7d prior to surgery, but probably has less effect than aspirin.

Used with aspirin in acute coronary syndrome and for prevention of ischaemic events in symptomatic patients. Also commonly used after coronary stents to maintain patency.

Can be used in peripheral arterial disease or post ischaemic stroke.

Needs to be stopped 7d prior to surgery to avoid antiplatelet effect.

If rapid reversal is necessary for bleeding or emergency surgery, platelet transfusions have been used with some success. However, as it is a prodrug and undergoes biotransfomation these may be ineffective if given just after a dose—therefore try to delay surgery by 24hr. If impossible, case reports have suggested that aprotinin may be useful.

Abciximab (ReoPro^®) is licensed as an adjunct to aspirin and heparin in percutaneous transluminal coronary intervention.

Eptifibatide (Integrilin^®) and tirofiban (Aggrastat^®) are used to prevent early myocardial infarction in unstable angina and non-ST-segment-elevation myocardial infarction.

These drugs are potent inhibitors of platelet function. Abciximab binds strongly to platelets and has a half-life of several days. Platelet transfusions will be needed to control profound bleeding.

Eptifibatide and tirofiban are significantly renally eliminated. Therefore if renal function is normal, full reversal will occur within 4–8hr from discontinuation of therapy. For more rapid reversal, platelet transfusions are less helpful as free drug is circulating (but the addition of FFP may be beneficial).

For elective surgery, as the half-life of abciximab is several days, it should be discontinued a week prior to surgery. Eptifibatide and tirofiban need only 8hr if renal function is normal.

Evidence is also increasing that the risks of stopping antiplatelet therapy during the perioperative period are far higher than the risks of bleeding.

The American Heart Association and European Society of Cardiology have recommended that all elective surgery is postponed until after the 12 month period of dual therapy.

If surgery cannot be postponed then ideally it would proceed with the continuation of dual (or at the very least) single therapy.

Early discontinuation of antiplatelet therapy is the most significant determinant of stent thrombosis which can have a mortality of up to 50%.

Any acute bleeding can be reversed with platelet transfusion.

All cases must be discussed on a case by case basis between cardiologist, surgeon, and anaesthetist.

The risk of stent thrombosis associated with stopping antiplatelet agents is also influenced by factors such as the nature of the lesion and timing of the procedure. It is likely to be highest when multiple recently implanted stents are present, particularly involving arterial bifurcations, and in patients with renal impairment, diabetes, and dehydration.

Alteplase (rt-PA, tissue plasminogen activator) and streptokinase by continuous infusion.

Reteplase and tenecteplase by bolus injection (making them ideal for early community injection).

Used for acute myocardial infarction where benefits outweigh risks.

Benefit greatest with early injection, ECG changes with ST elevation or new bundle branch block, and anterior infarction.

Alteplase, reteplase, and streptokinase need to be given within 12hr of symptom onset, ideally within 1hr; use after 12hr requires specialist advice. Tenecteplase should be given as early as possible and usually within 6hr of symptom onset.

Should be used in combination with antithrombin (LMWH) and antiplatelet (aspirin) therapy to reduce early reinfarction.

Alteplase, streptokinase, and urokinase can be used for other thromboembolic disorders such as deep-vein thrombosis and pulmonary embolism. Alteplase is also used for acute ischaemic stroke. Treatment must be started promptly.

Contraindications include any risk of bleeding, especially trauma (including prolonged CPR), recent surgery, GI tract, and intracerebral pathology.

Streptokinase can cause allergic reactions and should be used only once due to the production of antibodies.

Serious bleeding calls for the discontinuation of therapy and may require coagulation factors. Cryoprecipitate (high levels of factor VIII and fibrinogen) and FFP (factors V and VIII) as well as platelets may all be required. Antifibrinolytics such as aminocaproic acid, tranexamic acid, and aprotinin may also be useful.

Bleeding times are prolonged for up to 24hr after these drugs. In emergency surgery reversal will be required.

Urokinase is also licensed to restore the patency of occluded intravenous catheters and cannulas blocked with fibrin clots. Inject directly into catheter or cannula 5000–25 000 units dissolved in suitable volume of sodium chloride 0.9% to fill the catheter or cannula lumen; leave for 20–60min, then aspirate the lysate; repeat if necessary.

Tranexamic acid is 10 times more potent than aminocaproic acid.

Useful in postoperative bleeding predominantly in prostatectomy and dental extractions (particularly in haemophiliacs).

Also useful in reversal of thrombolytics.

Contraindicated in DIC.

Usual dose of tranexamic acid is 1g tds orally.

The drug is still available though not actively marketed by Bayer.

It is contraindicated for repeated use within a year due to anaphylaxis.

It can cause renal failure and is contraindicated in renal insufficiency.

The drug is useful during the anhepatic phase of liver transplantation where its use is guided by thromboelastography.

Can be used (0.3µg/kg given in 50–100ml saline over 30min) for haemophilia A and von Willebrand's disease to double or quadruple levels of vWF or factor VIII.

Platelet function may also be improved in patients in renal failure and aspirin-induced platelet dysfunction.

This effect appears localised to the area where the vessel is damaged, leading to few systemic side effects.

Numerous case reports have shown rVIIa to have potent haemostatic effects even when other treatments have failed and whatever the cause of bleeding. These must be balanced against potential thrombogenic risk (highlighted by recent reissue of a warning by the manufacturer) and a Cochrane review (updated February 2009) that concluded the data supporting the off-licence use of rFVII are weak.

Dosing and mode of delivery (IV bolus or continuous infusion) have still not been established (20–40µg/kg has been used).

Indications are treatment and prophylaxis of congenital or acquired deficiency of factors II, VII, IX, and X (such as during warfarin treatment).

Contraindications are angina, recent MI, and history of heparin-induced thrombocytopenia.

Side effects include thrombosis and hypersensitivity/anaphylaxis.

A coagulopathy is more likely if bleeding is simultaneous from several sites or is slow in onset.

A single site or sudden massive bleeding suggests a surgical source.

Coagulation tests may help but often take some time to be obtained.

Remember blood products also take time to arrive.

Treatment should be aimed primarily at removal or control of the underlying cause while support is given to maintain tissue perfusion and oxygenation.

Abnormal coagulation parameters in the presence of bleeding or the need for an invasive procedure are indications for haemostatic support. Further useful information can often be gained from a thromboelastograph where available (see p. 1060). Transfusion of platelets and FFP (15ml/kg initially or 4U in an average adult) should help restore platelets, coagulation factors, and the natural anticoagulants antithrombin-III and protein C. Cryoprecipitate (2 pools or 10U initially) may also be necessary if the fibrinogen level cannot be raised above 1g/l by FFP alone.

Indications for heparin, concentrates of antithrombin, and protein C are not established. Antifibrinolytics such as tranexamic acid are generally contraindicated in DIC.

Massive transfusion of stored blood perioperatively may cause significant coagulation disorders due to the lack of factors V, VIII, and XI. DIC and thrombocytopenia may also be present. Therapy consists of replacement FFP, cryoprecipitate, and platelets as guided by coagulation tests and thromboelastography. A haematologist should be consulted.

Several case reports have shown good results from giving factor VIIa in cases of uncontrollable haemorrhage.

It is associated with infections (especially gram-negative bacteraemia), placental abruption, amniotic fluid embolism, major trauma, burns, hypoxia, hypovolaemia, and severe liver disease.

Haemorrhage, thrombosis, or both may occur.

Chronic DIC is associated with aneurysms, haemangiomas, and carcinomatosis.

Laboratory abnormalities are variable, depending on the severity of DIC, and reflect both consumption of platelets and coagulation factors as well as hyperplasminaemia and fibrinolysis.

Discuss treatment options with a haematologist.

Secondary: due to compensatory erythropoietin increase (high altitude, cardiorespiratory diseases—especially cyanotic, heavy smoking, methaemoglobinaemia), or inappropriate erythropoietin increase (renal diseases—hydronephrosis, cysts, carcinoma, massive uterine fibromyomata, hepatocellular carcinoma, cerebellar haemangioblastoma).

Relative: ‘stress’ or ‘spurious’ polycythaemia. Dehydration or vomiting.

Plasma loss: burns, enteropathy.

Splenomegaly.

Thrombocythaemia in 50% of cases.

Differential diagnosis is with other causes of polycythaemia. These can be excluded by history, examination, and blood tests including bone marrow aspiration, arterial blood gases, and erythropoetin levels.

Genetic testing can reveal the JAK 2 mutation in 90–95% of patients with PV and 50% of patients with myelofibrosis.

Therapy is aimed at maintaining a normal blood count by venesection and myelosuppression with drugs.

Thrombosis is a frequent cause of death and 30% of cases develop myelofibrosis and 15% acute leukaemia.

Closely related to polycythaemia vera with recurrent haemorrhage and thrombosis.

Recurrent haemorrhage and thrombosis are the principal clinical features.

Abnormal large platelets or megakaryocyte fragments may be seen on a blood film.

Differential diagnosis is from other causes of a raised platelet count: e.g. haemorrhage, chronic infection, malignancy, polycythaemia vera, myelosclerosis, and chronic granulocytic leukaemia.

Platelet function tests are consistently abnormal.

Radioactive phosphate or alkylating agents are used to keep platelet counts down.

Antithrombotic stockings and intermittent compression devices should be used with SC heparin.

Haematological advice may be required.