Department of Haematology, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK
Accepted for publication: December 12, 1999
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Abstract |
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Keywords: blood, coagulation; complications, haemostasis; complications, thrombosis; surgery
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Introduction |
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Inherited disorders of haemostasis |
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Haemophilia A and haemophilia B
Haemophilia A, the most common of the haemophilias, is associated with deficiency of factor VIII coagulant protein. Haemophilia B (Christmas disease) is caused by deficiency of factor IX coagulant protein. Both these conditions have sex-linked recessive inheritance, affected males being born to carrier females, although up to 50% of cases appear de novo as a result of new mutations. The clinical severity of bleeding relates directly to the degree of deficiency. Spontaneous bleeding, classically haemarthroses, occur in severe cases (<2% coagulant factor VIII) while the moderately deficient (210% coagulant factor VIII) and those mildly affected (>10% coagulant factor VIII) may be expected to bleed excessively only after trauma or surgery. Some of the carrier females have significantly reduced coagulation factors and may behave clinically as mild cases themselves. This is particularly important in obstetric practice and in the peri-operative period, when specific replacement therapy may be required.
Over the last 50 yr, there has been progressive refinement in the provision of specific coagulant factor replacement therapy from fresh whole blood to the plasma-free recombinant products which have become available in the last 10 yr. In the intervening period, coagulation factor concentrates were obtained by fractionation from human plasma pooled from several thousand donations. Before the introduction of viral inactivation in 1985, the vast majority of patients treated with concentrate, which was thus derived from pooled plasma, contracted transfusion-transmitted hepatitis C (HCV) and half of those in the UK with severe haemophilia also acquired the human immunodeficiency virus (HIV).
In view of this history, therapeutic strategies to replace coagulation factors are also designed to minimize exposure to plasma components wherever possible.47 Recommended therapeutic products are described in Table 2. For major surgery, a target concentration of 100% factor VIII is set to be maintained for the first 57 postoperative days, whereas minor procedures may be adequately covered by concentrations of 50% after the first day. Doses of factor VIII required to meet these targets are listed in Table 3. Many patients with moderate or mild haemophilia A produce a 2- to 4-fold increase in factor VIII in response to 1-deamino-8-D-arginine vasopressin (DDAVP), which will be adequate to cover minor surgery. Where higher concentrations are required, recombinant coagulant factor concentrate is the recommended replacement for all new patients and for children under 16 yr with haemophilia A and haemophilia B. For those over 16 yr, already established on treatment, high-purity coagulant factor replacement may be used. Since 1985, all such plasma products have been subjected to viral inactivation by heat treatment or a solvent detergent method to kill viruses with a lipid envelope (e.g. hepatitis B virus, HCV and HIV). More recently, an additional terminal filtration step has been introduced by some manufacturers to prevent the transmission of viruses which lack a lipid envelope, such as human parvovirus B19 and hepatitis A, by their products.
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Von Willebrands disease
The basic defect in this condition is abnormal production of von Willebrand factor (vWF), a long protein monomer produced from the Weible Palade bodies of endothelial cells and from the alpha granules of platelets. vWF functions primarily in platelet adhesion to the subendothelial layers at high shear rates and, in addition, acts as a carrier molecule for factor VIII coagulant protein in the circulation. Hence, the clinical presentation is characterized by mucosal bleeding and easy bruising in association with a prolonged bleeding time in the majority of kindreds, where inheritance is autosomal dominant. It is the commonest of the inherited bleeding disorders, and it has been suggested that it might be present in as many as 20% of women with menorrhagia. Very rarely, the condition occurs in a severe form with autosomal recessive inheritance, very low concentrations of vWF and clinical features more like classical haemophilia, spontaneous haemarthroses occurring as well as mucosal bleeding.
Von Willebrands disease is diagnosed48 by measuring factor VIII coagulant protein (VIIIc), vWF antigen (vWFAg) and platelet activity as an estimate of binding to platelet glycoprotein with ristocetin as cofactor (vWRiCof), all of which will be reduced to 40% or less, giving rise to a prolonged bleeding time in the presence of a normal platelet count. These assays are, however, measuring labile factors which are influenced by stress and the results may therefore be variable and require repetition to confirm the diagnosis.
It is usually possible to avoid the use of blood components to control haemorrhage in the majority of cases of von Willebrands disease. The antifibrinolytic agent tranexamic acid reduces minor bleeding, e.g. menorrhagia or epistaxis, and is prescribed in the postoperative period. DDAVP administered 90 min before operation at a dose of 0.3 µg kg1 may be expected to increase concentrations of vWFAg and factor VIII coagulant protein to normal (>100 IU ml1) in the majority who have a quantitative defect of vWFAg. Although further doses may be given postoperatively, the effect is maximal on first administration of DDAVP in any treatment episode as tachyphylaxis is well recognized. In a small proportion of cases, namely those with a qualitative defect of vWFAg or with the more severe autosomal recessive type, a plasma product will be required to supplement vWFAg and VIIIc together. Haemate P (Centeon) and 8Y (BPL) are two intermediate-purity factor VIII concentrates which fulfil these criteria and are licensed for use in the UK.
Inherited platelet disorders
These are uncommon conditions. Inherited thrombocytopenia of clinical significance will usually be diagnosed in childhood and platelet concentrates are required to support surgery. The better-defined thrombocytopathias (platelet function defects) are also very rare.
Glanzmanns disease
Glanzmanns thrombaesthenia is characterized by the absence of platelet glycoprotein IIb/IIIa, which binds fibrinogen and is the site of the platelet-specific HPA 1a antigen. Platelet transfusion35 in patients with Glanzmanns thrombaesthenia is therefore associated with the development of anti-HPA 1a antibodies, necessitating the selection of donors lacking this antigen. Sometimes, HLA selection may be required in addition.
BernardSoulier disease
This is associated with a defect of platelet binding to collagen, demonstrated by absent aggregation on exposure to ristocetin. Glycoprotein Ib/IX, which is the platelet-binding site for collagen, is not, however, associated with a platelet-specific antigen site, and patients may usually, therefore, be repeatedly transfused with platelet concentrate35 without acquiring specific antibodies.
Platelet storage pool defects
Far more common, but with less well-defined causes, are the platelet storage pool defects, many of which are reversed by administration of DDAVP. Where this agent fails to correct a prolonged bleeding time, transfusion with platelet concentrate will be required to cover surgery. Since the introduction of universal leukodepletion of platelet concentrate in the UK in 1998, the incidence of febrile transfusion reactions and development of HLA antibodies has been significantly reduced.8 34
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Acquired disorders of haemostasis |
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Disseminated intravascular coagulation (DIC)
DIC is the most common consumptive coagulopathy, often with a prodromal thrombocytopenia giving way to hypofibrinogenaemia as a result of excessive fibrinolysis, the latter demonstrated by increased fibrin(ogen) degradation products and D-dimers. In the absence of sepsis or obstetric causes, extensive endothelial damage with collagen exposure may initiate the process. The main causes of DIC are listed in Table 4.
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The prescription of heparin is controversial,13 with reports of benefit in amniotic fluid embolism,23 but is a brave course to take in the haemorrhagic patient. In acute promyelocytic leukaemia, however, where disseminated intravascular coagulation is a frequent association, heparin and platelet support may be used to advantage to cover remission induction1 22 and sometimes an antifibrinolytic agent may be helpful, depending on the coagulation profile.
Microangiopathic haemolytic anaemias
Less common are the microangiopathies, which are thought to be immune in origin and in which platelet transfusion is contraindicated.
Thrombotic thrombocytopenic purpura (TTP). In TTP, there is a predominantly neurological deficit caused by thrombosis in small cerebral vessels in association with fever and thrombocytopenia, and there is often evidence of an underlying immune disorder. Recently, it has been shown that there is an increase in very large molecular weight multimers of vWF as a result of the formation of an antibody to their cleaving metalloprotease.
Haemolytic uraemic syndrome (HUS). By contrast, HUS features renal dysfunction with thrombocytopenia, often after an infection, particularly with enteric pathogens which produce a verotoxin in children.
In both HUS and TTP, thrombocytopenia is the predominant haematological feature, in association with microangiopathic haemolysis. The treatment for both conditions is total plasma exchange (1 volumes), replacing with cryoprecipitate supernatant2 39 plasma, which is deficient in high molecular weight von Willebrand multimers. Platelet transfusion must be avoided.
The immune thrombocytopenias
The main causes of autoimmune thrombocytopenias are described in Table 5. Their prognosis and management varies according to their causative antibody and presentation.15 16 25 An acute thrombocytopenia caused by IgM antibodies is the commonest form in childhood, commonly following a viral illness and usually recovering spontaneously with no need for therapeutic intervention.
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The permanent risk of overwhelming postsplenectomy infection remains. Vaccination against pneumococcal pneumonia should be administered before operation in the form of Pneumovax and pneumococcal antibodies quantitated every 510 yr, with booster immunization as necessary. To obtain an optimal response, immunization should start 23 months before surgery. In addition, vaccination against Haemophilus influenzae B and the meningococcal strains A and C should be provided, with a recommendation for lifelong oral prophylaxis against encapsulated organisms with daily penicillin V or erythromycin.33 In view of the rebound thrombocytosis which usually occurs immediately after operation, such individuals are at increased risk of venous thromboembolism in the peri-operative period and require adequate anticoagulant prophylaxis until they are fully mobile.
Unfortunately, about one-quarter of cases of chronic thrombocytopenia fail to respond to these measures and must then be managed on the basis of their haemorrhagic risk. Other treatment strategies include alternative immunosuppressants, e.g. azathioprine, cyclosporin, vincristine and synthetic hormones, e.g. danazol.
Thrombocytopenia in pregnancy
Special consideration must be given to the management of thrombocytopenia in pregnancy.32 Maternal thrombocytopenia is a frequent occurrence in pregnancy, the causes of which are set out in Table 6. The platelet count tends to fall in a normal pregnancy. Although mild thrombocytopenia (120150 x 109 litre1) is not uncommon, it is important that more serious underlying disease is excluded.
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When autoimmune thrombocytopenia is present in pregnancy, management is directed at maintaining a maternal platelet count above 50 x 109 litre1 to minimize peripartum haemorrhage and prevent spontaneous fetal haemorrhage. Evidence of associated autoimmune disorders, such as the antiphospholipid syndrome, should be sought. In many cases, no intervention is necessary and vaginal delivery proceeds uneventfully, although epidural anaesthesia is contraindicated if the platelet count falls below 80 x 109 litre1. If the platelet count falls below 50 x 109 litre1, specific measures are required to prevent bleeding at delivery. Treatment options are corticosteroids and high-dose i.v. immunoglobulin (0.4 g kg1 daily for 5 days) Where these modalities fail, consideration should be given to high-dose methylprednisolone and other immunosuppressants, such as azathioprine. Splenectomy should be a last resort in the presence of a gravid uterus, but is best performed before 28 weeks with the support of platelet transfusion.
The neonates of such severely affected mothers require careful surveillance for the first few days after delivery, as the nadir in the platelet count occurs from the second to the fifth day of postnatal life as the splenic circulation is established.
The thrombocytopenia and disseminated intravascular coagulation of obstetric complications such as pre-eclampsia will require specific transfusion support in line with the results of serial monitoring of the coagulation profile, with urgent delivery of the fetus to secure early resolution. More rarely, recovery may be delayed until a few days after the baby is delivered in the presence of maternal haemolysis with elevated liver enzymes and low platelets (HELLP) syndrome.
Thrombocytopenia as a feature of thrombotic thrombocytopenic purpura and the haemolytic uraemic syndrome is a rare event in pregnancy and the post-partum period. Additional features include microangiopathic haemolytic anaemia with fluctuating neurological signs and deteriorating renal function. Evidence of DIC is absent and prompt delivery does not expedite clinical resolution. Furthermore, platelet transfusion is contraindicated and urgent plasma exchange is required, replacing with fresh frozen plasma.
Massive transfusion
Massive transfusion involves the replacement of circulating blood volume within 24 h and often much more quickly. Stored red cells are deficient in functional platelets and plasma reduction effectively removes coagulation factors. Transfused red cells serve to dilute out the patients native coagulation reserves.7 These effects are exacerbated by the infusion of dextrans and/or starch. Specific transfusion of coagulation factors in the form of fresh frozen plasma52 and platelet concentrate35 should be guided by the results of the coagulation profile, which must be repeated until haemostasis is achieved.
Each unit of blood is collected from the donor in 63 ml of anticoagulant (citrate phosphate dextrose with adenine), and higher volumes transfused lead to citrate toxicity with associated hypocalcaemia. In emergency situations, when blood is transfused rapidly, cooled red cells may also contribute to the patients falling pH. Care must be exercised in the use of blood-warmers and pumps to ensure their proper function, in order to avoid haemolysis of red cells for transfusion. Potassium toxicity rarely presents problems in this situation except in neonates.
Extracorporeal circuits
Widely used for many years in cardiopulmonary bypass procedures, other extracorporeal techniques, such as intraoperative cell salvage, may now contribute to the support of various operative procedures. When platelets are exposed to large areas of inert material, some are retained there, rendering the patient thrombocytopenic. Reduced temperatures inhibit the production of thromboxane A2 in some platelets, while others aggregate spontaneously and prematurely. Those platelets which do return to the patients circulation may thus have been injured on their journey, for early sequestration in the spleen. For these reasons, the bleeding patient may benefit from platelet transfusion, irrespective of the postoperative platelet count after bypass procedures.
Anticoagulation administered to facilitate cardiopulmonary bypass procedures may also be associated with postoperative bleeding. Heparin is reversed by protamine sulphate,9 which, in excess, gives rise to a consumptive coagulopathy. If neutralization is incomplete, active heparin may reappear in the circulation 26 h after operation as it is released from heparinprotamine complexes in the extravascular compartment.
Acquired inhibitors of coagulant factors
Whilst inhibitors occur quite frequently as IgG antibodies directed against transfused factor VIII concentrate, the occurrence of antibodies to coagulation factors de novo is a much rarer event.20 These are diagnosed in the presence of a prolonged time in a coagulation screen which fails to be corrected on addition of normal plasma. Commonly associated with autoimmune disorders, drug reactions or the post-partum period, patients with inhibitors usually present with severe mucosal bleeding, whereas spontaneous haemarthrosis is uncommon. In the postoperative period, this may lead to wound haematoma and/or secondary haemorrhage. The principles of management are threefold: to treat any underlying cause; to restore the deficient coagulation factor; and to block the formation of its inhibitor. In acquired haemophilia, agents prescribed to achieve haemostasis include large doses of factor VIII concentrate of human origin and porcine factor VIII. When the titre of factor VIII inhibitor exceeds 100 units per millilitre, specific factor VIII concentrate is no longer effective. Attempts may then be made to secure haemostasis by bypassing factor VIII, using partly activated mixtures of vitamin K-dependent clotting factors (II, VII, 1X and X), although there is an associated thrombotic risk.
Such products include intermediate purity factor IX (9A, BPL), FEIBA (factor eight bypassing activity) (Immuno) and Autoplex (Baxter). Recombinant activated factor VII (rVIIa) may be effective when these plasma-derived products fail. Immunosuppression should be prescribed simultaneously, as high-dose steroids, i.v. immunoglobulin or alkylating agents. Where inhibitors arise in response to transfusion of factor concentrate, the relative risks and benefits must be considered carefully before any operative procedure is planned. Every effort must be made to suppress inhibitor formation before elective surgery is contemplated.
More recently, factor V inhibitors have been described following the application of topical fibrin glue and thrombin.
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Intermediate coagulation disorders |
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Renal disease
In renal failure, a decrease in erythropoietin production gives rise to anaemia with a falling haematocrit. Together with acquired disorders of platelet adhesion and a platelet storage pool defect,30 this leads to an increased bleeding time, which may sometimes be corrected by DDAVP.31 The anaemia may be improved preoperatively using erythropoietin, with iron supplements as appropriate.50
By contrast, secondary polycythaemia as a result of renal disease is associated with a raised haematocrit and increased risk of thrombosis.
Liver disease
The liver is the production site of the majority of coagulation factors, hence disturbance of liver function may lead to a tendency to bleeding. Where cirrhosis ensues, disturbance of liver architecture predisposes5 to a chronic consumptive coagulopathy.10 If this is then complicated by portal hypertension, splenic sequestration contributes to the thrombocytopenia as another source of bleeding. Ascitic fluid produced in cirrhosis has been shown to contain procoagulants, including tissue factor, factor X activator, collagen and endotoxin, which predispose to thrombosis after shunting.
Systemic lupus erythematosus
Two major coagulation problems occur within the clinical spectrum of systemic lupus erythematosus. A common association is immune thrombocytopenia; the bleeding diathesis associated with this problem is discussed above. Systemic lupus erythematosus in some individuals is also associated with the production of an antibody to glycoprotein Ib, found on the platelet membrane. This may give rise to an antiphospholipid syndrome (APS), an acquired procoagulant state characterized by recurrent venous and arterial thromboembolism.18 Cerebral episodes present a particular problem in APS, and recurrent miscarriage is a common presentation in young women with this condition. The antibody, which is known as the lupus anticoagulant, is associated with a prolonged activated partial thromboplastin time which fails to correct with normal plasma, indicating the presence of an inhibitor. Anticardiolipin antibodies are also increased. Long-term oral anticoagulant therapy is prescribed to control symptoms. Successful outcome of pregnancy has been achieved with the prescription of aspirin and low molecular weight heparin prophylaxis. Clearly, these patients present a very high risk of thrombosis in the peri-operative period and are best managed with therapeutic doses of i.v. unfractionated heparin.
Haematological malignancy
Disseminated intravascular coagulation in acute promyelocytic leukaemia has been discussed already. Far more common are the myeloproliferative disorders, which are caused by excessive activity of the pluripotential stem cell or lack of negative feedback in its production and differentiation. Diseases in this group include polycythaemia vera, chronic granulocytic leukaemia, essential thrombocytosis and myelofibrosis. Their course is chronic and often associated with a thrombocytosis. Although this creates an increased risk of thrombosis in the peri-operative period, necessitating anticoagulant prophylaxis, the abnormal platelets produced by the defective stem cells may not function normally in response to the blood loss of surgery. Every effort should be made to restore the blood count parameters to normal before elective procedures, but abnormal bleeding, even in the presence of a normal or raised platelet count, may be controlled by transfusion of platelet concentrate35 in such patients.
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (type 2) is a disorder in which a falling platelet count occurs in association with a progressive thrombotic tendency, which affects large vessels, both arterial and venous.11 24 More than half of those affected sustain limb amputation and the mortality is high. The thrombocytopenia is caused by a specific antibody to platelet factor 4 which promotes platelet aggregation to initiate thrombosis. It usually occurs as an acquired primary immune state between 5 and 10 days after heparin therapy is initiated, more commonly after therapeutic doses of the unfractionated drug than low molecular weight heparin.49 It may occur before 5 days as a secondary response on inadvertent re-exposure to heparin. Although a number of antibody detection tests have been set up, the diagnosis is essentially clinical and must be followed by immediate withdrawal of heparin and anticoagulation with a heparinoid such as danaparoid or lepirudin, as parenteral therapy, to cover the introduction of oral coumarins. Should the same patient require surgery in the future, heparin must be avoided in favour of the heparinoids described above.17
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The hypercoagulable state: hereditary thrombophilia |
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More recently, a clear relationship has been established between arterial thrombosis and hyperhomocysteinaemia,43 the latter being common in individuals with a variant of the enzyme methylene tetrahydrofolate reductase, particularly in the homozygous state, the prevalence being approximately 12%.14
The discrepancy between recorded thrombosis and the prevalence of these genetic variants in the general population indicates that, in most cases, other factors play a part in their causation. In terms of management, therefore, treatment is directed at the history of clinical events rather than the identification of isolated risk factors. Although the presence of additional prothrombotic markers may be considered in the risk assessment used to plan anticoagulant prophylaxis in the peri-operative period, this rarely influences decisions about the prescription of long-term oral anticoagulant therapy. A first episode of venous thromboembolism is treated with a discrete course of anticoagulant therapy followed by thrombophilia screening a few weeks after the end of treatment. Only after a second spontaneous event is it usual to recommend life-long therapy.51
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Anticoagulant management in the peri-operative period |
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There remain two major risk groups who will require conversion to i.v. unfractionated heparin in the peri-operative period to maintain therapeutic anticoagulation in the absence of postoperative bleeding.21 26 These are patients with mechanical cardiac valve prostheses45 and those with a history of acute venous thromboembolism within the previous 4 weeks or during a current pregnancy. The heparin must be stopped 6 h before the operation and restart 12 h after operation, and oral coumarin should be reintroduced as soon as possible thereafter.26 Epidural anaesthesia is best avoided for those on therapeutic heparin.6
Even in the absence of any known thrombophilia markers, surgical patients are at increased risk of venous thromboembolism as a result of their immobility and the postoperative inflammatory response.40 44 All should be assessed for their individual risk in relation to the procedure planned, and advised about the importance of leg exercise and early mobilization. Appropriate antiembolism hosiery should be fitted. Anticoagulant prophylaxis with subcutaneous unfractionated heparin will cover moderate- and high-risk surgery, including operations on pelvic sites and arthroplasty, but very high-risk patients may benefit from a prophylactic dose of a low molecular weight heparin. Such prophylaxis is not usually associated with increased bleeding in the peri-operative period, but should not be prescribed for neurosurgical procedures.
In recent years, a number of low molecular weight heparins (LMWH) have been produced with specific anti-Xa activity.19 Administered by the subcutaneous route, they are as effective as i.v. unfractionated heparin (UFH) in treating acute venous thromboembolism.28 The comparative properties of LMWH and UFH are described in Table 8. Although all are licensed in the UK for deep venous thrombosis, only one LMWH (tinzaparin) has a licence recommendation for the treatment of pulmonary embolism.41 In most cases, their use requires only monitoring of the platelet count to exclude heparin-induced thrombocytopenia, although anti-Xa concentrations require checking in patients with renal failure and in the critically ill. It has been suggested that haemorrhagic complications are less frequent with LMWH than UFH because of their specificity of action.23
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