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Disorders of Thrombosis and Haemostasis
HAEMOLYMPHOID SYSTEM
Clinical anatomy
Disorders of Thrombosis and Haemostasis
Drawing from an intravenous pyelogram to show the relationship of the ureters to the bony landmarks
M J Nash Hannah Cohen
The surgical patient with a bleeding or thrombotic disorder presents a clinical challenge. The key to optimal management is early recognition of patients at risk coupled with close and effective liaison between the surgeon and haematologist. This article provides an overview of bleeding and thrombotic disorders with particular reference to surgical patients. Normal haemostasis Three physiological components act in concert to achieve haemostasis in vivo, namely the coagulation mechanism, platelets and the blood vessel wall. A physiological balance exists between pro- and anticoagulant mechanisms. Natural anticoagulants include heparan sulphate on endothelial cells, antithrombin and protein C and protein S. The process is completed by the dissolution of thrombi via the process of fibrinolysis, which enables repair of the damaged vascular endothelium.
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To identify the ureter at laparotomy, it is conveniently discovered at the bifurcation of the common iliac artery. Its thick muscular wall, which vermiculates when gently squeezed with non-toothed forceps, and the fact that it adheres to the overlying peritoneum like a fly stuck on fly-paper, are diagnostic.
Coagulation mechanism (Figure 1) The coagulation system is a finely balanced network of interacting procoagulant and anticoagulant factors. The modern view of the events involved in this process differs from the ‘extrinsic’ and ‘intrinsic’ pathways, which were traditionally discussed. The first event in the coagulation mechanism is the binding of circulating factor VII to tissue factor (TF) exposed at a site of vascular injury. The VIIa.TF complex activates factors X and IX. Factor IXa activates factor X in the presence of factor VIIIa and calcium. Factor Xa then converts prothrombin to thrombin in the presence of factor Va and calcium. Thrombin then converts fibrinogen to fibrin, which is then stabilized by cross-linking catalyzed by factor XIII.
Blood supply The ureter receives a rich segmental and anastomosing blood supply from all the available vessels along its course, i.e. the renal, gonadal, internal iliac and vesical vessels. Only extensive stripping will devascularise it. In searching for a radio-opaque ureteric stone on a radiograph, imagine the course of the ureter in relation to the bony skeleton; along the tips of the transverse processes, crosses the front of the sacro-iliac joint, swings out laterally to the ischial spine, then passes medially to the bladder (Figure 4). u
M J Nash is a Specialist Registrar on the North Thames Haematology rotation, London, UK, and is currently undertaking research into the modulation of cellular fibrinolysis by antiphospholipid antibodies. He qualified in 1995 from St Mary's Hospital Medical School, London, UK. Hannah Cohen is Consultant Haematologist at University College London Hospitals NHS Trust, London, UK. She qualified from the University of Manchester Medical School, UK, and trained in haematology at University College London Hospitals. Her research interests include the pathophysiology and management of antiphospholipid syndrome and the role of thrombophilias in pregnancy loss.
FURTHER READING Cross J, Dixon A K. The renal tract and retroperitoneum. In: Butler P, Mitchell A, Ellis H, Eds. Applied Radiological Anatomy. Cambridge: Cambridge University Press, 1999.
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Aspirin exerts its antiplatelet effect by irreversible acetylation of platelet cyclo-oxygenase, leading to reduced platelet TxA2 production. Thus, it takes 8–12 days (the platelet life span) for the effects of aspirin to ‘wash out’ of an individual’s platelets. This is in contrast to the reversible cyclo-oxygenase inhibition seen with other non-steroidal anti-inflammatory drugs. The ADP and TxA2 thus released activate more platelets, which in turn activate more platelets via their released products. A ‘platelet plug’ forms, which is reinforced by fibrin crosslinkage. The surface of platelets also serves an important procoagulant role. Negatively charged phospholipids (e.g. phosphatidylserine) are exposed on the platelet surface on activation. These phospholipids have an important role as a surface upon which the clotting factors meet.
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Fibrinolysis The fibrinolytic system is key to the resolution of blood clots. The essential reaction in fibrinolysis is the conversion of the proenzyme plasminogen to the active plasmin by tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator. Fibrinolysis activation pathways can be divided into extrinsic (t-PA mediated) and intrinsic (contact factor mediated), which interact. The major physiological activator of fibrinolysis is believed to be t-PA. Plasmin binds to, and cleaves, polymerized fibrin.
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Approach to the patient with bleeding In the surgical setting, careful assessment in the pre-admission clinic should enable identification of the patient with a preexisting bleeding disorder. In general, acquired disorders of haemostasis are much more common than inherited ones. The patient with severe bleeding peri- or postoperatively requires a local, pre-planned collaborative approach.
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Soon after the initiation of these events, circulating tissue factor pathway inhibitor (TFPI) inhibits the VIIa.TF complex. It is likely that continued fibrin generation is achieved by the back-activation of factor XI by thrombin itself. Thrombin also amplifies the system by activating the co-factors V and VIII. This view of coagulation explains why deficiency of factors VIII or IX (haemophilia A and B) may lead to severe bleeding problems and why factor XII deficiency does not. The coagulation mechanism is summarized in Figure 1, which also illustrates the position in the coagulation system of the natural anticoagulants, antithrombin, protein C and protein S.
History and examination The history is of paramount importance to identify patients at risk of bleeding. A history of bleeding following previous haemostatic challenges, including dental extractions, suggests there is a clinical problem even if the patient has a normal coagulation screen and platelet count. The pattern of bleeding is important: easy or spontaneous bruising, bleeding from mucous membranes, epistaxis or menorrhagia, and prolonged bleeding following minor trauma can be particularly indicative of a platelet defect (thrombocytopenia or platelet dysfunction) or vWD. Systematic enquiry and clinical examination may identify evidence of renal and hepatic pathology or malignancy, which can result in haemostatic disturbance. One must look for a history of ingestion of drugs (e.g. aspirin, warfarin) and also consider drugs which may result in thrombocytopenia. Some surgical procedures are more likely than others to result in haemostatic disturbance. Of particular note is cardiac surgery, where the large incision, the activation of platelets and clotting factors in the bypass circuit and hyperfibrinolysis are all contributory.
Platelets A critical initial step in primary haemostasis is the adhesion of platelets to the subendothelial connective tissue, exposed following vessel damage. von Willebrand factor (vWF) serves as a bridge between platelet receptors and the subendothelium. Following platelet adhesion, a series of metabolic pathways are initiated which result in platelet shape change, release of granule contents and aggregation. Released platelet granule contents include adenosine diphosphate (ADP), 5-hydroxytryptamine (5-HT) and platelet factor IV. Platelet production of thromboxane A2 (TxA2) also increases via platelet arachidonic acid metabolism. TxA2 exerts its action on platelets by reducing their intracellular cyclic adenosine monophosphate (cAMP) levels: this stimulates granule content release. TxA2 is also a potent vasoconstrictor: its actions antagonize those of prostacyclin produced by the vascular endothelium.
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Investigation Baseline tests in a patient suffering from, or at suspected risk of, a bleeding disorder include a blood count and film, renal and liver function tests, and a coagulation screen: prothrombin time
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(PT), activated partial thromboplastin time (APTT), thrombin time (TT) and functional fibrinogen quantitation. These tests form a crucial part of the first-line assessment of patients bleeding post-operatively. The causes of prolongation of the routine screening tests of coagulation are shown in Figure 2. The PT tests what was traditionally called the extrinsic pathway, while the APTT tests the intrinsic pathway. Distal to factor X, both the intrinsic and extrinsic systems converge on a final common pathway, leading to the formation of fibrin. The TT is prolonged by quantitative or qualitative reduction in fibrinogen activity and by inhibition of thrombin (for example by heparin, to which the test is particularly sensitive).
A prolonged bleeding time occurs when the platelet count falls below 100 x 109/L and there is a progressive increase as the platelet count falls below this level. Platelet disorders may be quantitative or qualitative. Platelet numbers may be reduced (thrombocytopenia) or increased (thrombocytosis). In certain situations, several platelet defects may coexist. For example, the thrombocytosis of myeloproliferative disorders may be associated with platelet dysfunction predisposing to both haemorrhage and thrombotic manifestations. Previously, a skin bleeding time was not infrequently performed to assess primary haemostatic function. This test is now seldom used and recently ‘in vitro’ bleeding time assays have become available, such as the Platelet Function Analyzer (PFA-100), which measures the time for a thrombus to form across a membrane coated with collagen and a platelet agonist. This gives an in vitro measurement of primary haemostasis.
Causes of abnormalities in first-line tests of haemostasis a) Thrombocytopenia • Increased destruction, consumption • Sequestration • Dilution
Management The treatment of clotting abnormalities and peri- or postoperative bleeding depends on the underlying cause and severity. The management of inherited factor deficiency, disseminated intravascular coagulation and massive blood loss is discussed later in this article. In general, when plasma replacement is indicated, fresh frozen plasma at a dose of 12–15 ml/kg will correct a prolonged PT or APTT not due to fibrinogen deficiency. A prolonged TT and/or quantitative or qualitative fibrinogen problem should be corrected by the administration of cryoprecipitate. Platelets may be administered to correct significant thrombocytopenia (see section on massive blood transfusion).
Non-immune (DIC, cardiopulmonary bypass, TTP) Immune (ITP, drugs, PTP) Hypersplenism Massive fluid replacement/ transfusion
• Inherited (e.g. Bernard– Soulier syndrome) • Bone marrow failure b) Coagulation screening tests • The APTT (normal 30–40 seconds) assays factors XII, XI, IX, VIII, X, V, II and fibrinogen • The PT (normal 11–16 seconds) assays factors VII, X, V, II and fibrinogen • The TT (normal 15–19 seconds) assays fibrinogen • Prolonged PT, APTT, TT and low platelets DIC, acute hepatic failure • Prolonged PT, APTT, and TT Heparin, hepatic failure, fibrinogen deficiency • Prolonged PT and APTT (TT normal) Vitamin K deficiency, warfarin. V, X and prothrombin deficiency • Prolonged APTT (PT and TT normal) Haemophilia A and B, vWD. XI, XII deficiency • Prolonged PT (APTT and TT normal) Early in warfarinization, VII deficiency
Pharmacological agents with haemostatic function Non-blood-derived agents which augment haemostatic function have the advantage of no infectious agent transmission risk and are also useful in the management of patients who find the use of blood products unacceptable. Aprotinin and tranexamic acid both inhibit the action of plasmin and therefore possess antifibrinolytic activity. In addition, aprotinin inhibits the contact activation of the coagulation mechanism. Aprotinin has been shown to reduce blood loss in cardiac surgery. Tranexamic acid is particularly useful given as a mouthwash and orally in reducing blood loss following dental extraction in patients with vWD or mild haemophilia A. Fibrin sealant may also reduce blood loss during surgery. Desmopressin exerts its action by raising plasma vWF and VIII levels. It is particularly useful in the operative management of patients with vWD or mild haemophilia A. Recombinant activated factor VII has been used in the management of patients with inhibitors to VIII and IX. However, the role of this compound in the management of bleeding in a variety of clinical settings is currently being explored and indications for its use are likely to expand.
DIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; ITP, immune thrombocytopenic purpura; PTP, post-transfusion purpura NB normal ranges for clotting assays will vary from centre to centre. With regard to prolonged clotting times, one will often see the laboratory perform a 50:50 mix. This process involves mixing the patient’s plasma with normal plasma. In general, if the prolongation of the clotting time is due to a factor deficiency, the time will correct. If the prolongation is due to an inhibitor (such as an antibody directed against a clotting factor or a lupus anticoagulant) the test will remain prolonged even in the presence of normal plasma.
Patients receiving oral anticoagulation The surgical patient on coumarin oral anticoagulation requires forward planning, except in the emergency situation where this is impossible. This enables reduction of warfarin’s effect by withholding warfarin rather than unnecessary reversal of
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warfarin’s effect by administration of vitamin K or fresh frozen plasma (FFP). Warfarin exerts its pharmacological action on vitamin K epoxide reductase. This enzyme is essential in the pathway for the addition of a carboxyl (COO–) group to glutamic acid residues on factors II, VII, IX, X and on protein C and protein S. Post-translational gamma carboxylation is essential for the function of these factors (pathway illustrated in Figure 3). The half-life of warfarin is approximately 48 hours and it should thus be stopped (or the dose reduced) in sufficient time to achieve the desired reduction in International Normalized Ratio (INR). The management of patients on oral anticoagulants perioperatively, addressed in national guidelines, should be individualized, with careful analysis of the risk to the patient of bleeding in the presence of anticoagulation against the risk of thrombosis in its absence. For minor procedures, the dose of warfarin can be adjusted to aim for an INR of 2.0–2.5 on the day of surgery. For major surgery, the choice is between stopping anticoagulation for a period around the operation and stopping warfarin but instituting perioperative anticoagulation with heparin. The former approach may be used for patients at low risk of thrombosis, such as those with atrial fibrillation and no previous thrombotic events. The latter approach may be employed for patients at perceived high risk of thrombosis, this group will include patients with a history of recurrent thrombotic events. Management should be according to local guidelines, specifying whether unfractionated or low-molecularweight heparin is used. It is usual to start heparin when the INR falls to 3.0. Surgery is usually undertaken when the INR is ≤1.5. Heparin should be discontinued pre-surgery to ensure that the APTT has fallen to ≤1.5. Of particular importance is the management of the patient with a mechanical heart valve. Meta-analysis has shown that the short-term risk of a period without anticoagulation in these patients is low, therefore in many cases such patients may be managed simply with a period of no anticoagulant. Some patients however, particularly those
with a caged-ball mitral valve prosthesis, may be at high risk of thrombosis, and should receive perioperative unfractionated heparin. Monitoring of heparin therapy depends on the form used. For unfractionated heparin given by continuous infusion, the APTT is monitored and the dose adjusted to give an APTT ratio 1.5–2.5 times normal. In the majority of cases, monitoring of low-molecular-weight heparin is unnecessary, as the dose is based on the patient’s weight. However, in some patients, such as those with renal impairment or who are pregnant, bioavailability of low-molecular-weight heparin can be unpredictable. Such patients should have their dose monitored by assay of anti-Xa activity levels in their plasma. Patients receiving antiplatelet therapy with aspirin or clopidogrel are frequently encountered in the pre-admission setting. In general, it is prudent to withhold administration of such drugs for at least ten days prior to surgery. In high-risk cardiac patients, however, the risk of thrombotic events may outweigh the risk of peri-operative bleeding. Acquired haemostatic failure Disseminated intravascular coagulation (DIC): DIC exists when excessive and inappropriate activation of the haemostatic system occurs within the circulation. In surgical patients, this phenomenon may be associated with prolonged operation time, extracorporeal circulation and massive blood transfusion. Other causes of DIC are listed in Figure 4. Typically, DIC presents with bleeding, including oozing from cannulation sites. Some patients present with manifestations of thrombosis: typically microthrombotic, leading to, for example, digital gangrene. Diagnosis of uncompensated DIC rests on demonstrating excessive consumption of coagulation factors and platelets with increased fibrinolytic activity. A prolonged APTT, PT and TT with a low fibrinogen (below 1.0 g/dl) with raised plasma fibrin degradation products (including D-dimer) is characteristic. DIC will not resolve until the underlying cause is diagnosed and treated. Supportive treatment with FFP, cryoprecipitate, red cell and platelet concentrates may be required. The aims of blood component support are similar to those in the massively transfused patient (see below).
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The patient receiving a massive blood transfusion: guidelines on the management of acute massive blood loss have recently been published. Some individuals require massive transfusion following, for example, trauma or emergency repair of an
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• Infection • Malignancy • Obstetric
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Septicaemia Metastatic carcinoma Septic abortion, abruption, eclampsia, amniotic fluid embolism Shock Extensive trauma, massive burns Hepatic Cirrhosis, acute necrosis Cardiac bypass surgery ABO-incompatible transfusion
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abdominal aortic aneurysm. The definition of massive transfusion is usually taken to represent transfusion of more than the patient’s blood volume in less than 24 hours. This situation can bring with it a worsening of the patient’s haemostatic function, which can be corrected by administration of FFP (to correct prolongation of the PT and APTT), cryoprecipitate (to correct hypofibrinogenaemia) and platelet concentrate. In patients bleeding heavily, a bleeding diathesis may be due more to secondary DIC than excessive transfusion and ‘dilution’ of clotting factors. Clotting factor depletion can, however, occur once approximately 80% of the patient’s circulating volume has been replaced. Formula replacement protocols for administering FFP or platelets in this situation should be avoided, since they may lead to inappropriate and/or inadequate red cell, platelet or plasma replacement. The patient’s clotting and blood count needs to be regularly monitored. An element of ‘planning ahead’ component ordering may be required in acute bleeds and it is understood that components may need to be ordered ahead of test results. Aims in a patient needing massive blood transfusion should be to maintain a haematocrit of >33%, a platelet count of >50 x 109/l, PT and APTT under 1.5 times normal and a fibrinogen of greater than 1.0 g/l. It is important to note that to treat a low fibrinogen, the product to give is cryoprecipitate. Some colloids may produce reduced haemostatic function. Dextran-based compounds may reduce plasma vWF levels and platelet adhesion.
half-life (and therefore the bioavailability) of VIII is significantly reduced. On routine tests, vWD will present with an isolated prolongation of the APTT due to reduced factor VIII. More specialized tests are needed to determine the subtype of vWD and the correct management. The bleeding diathesis in vWD can be very mild and consequently, patients often present only when provoked by trauma or surgery. The perioperative management of inherited bleeding disorders is the domain of close liaison between a specialist haematologist and a consultant surgeon. Patients with a bleeding disorder should undergo surgery in a haemophilia centre. In such patients, careful attention needs to be given to the strict avoidance of compounds (including some health shop preparations) prior to surgery, which can reduce haemostatic function. Attention must also be given to meticulous surgical haemostasis in the operating theatre. Therapeutic options to improve haemostatic function depend on the exact disorder. In general, therapy is aimed at avoidance of excessive bleeding by appropriate preoperative therapy. Specific factor replacement (e.g. VIII in haemophilia A or IX in haemophilia B) with monitoring of factor levels may be required. Recombinant factor VIIa may be indicated in haemophiliacs with acquired antibodies to factor VIII/IX. Studies are ongoing into the role of this agent in other inherited bleeding disorders. Wherever possible, blood product is avoided by the use of pharmacological agents such as desmopressin (which can raise factor VIII and vWF levels) and antifibrinolytic compounds such as tranexamic acid. Careful consideration needs to be given to whether or not these patients also receive thromboprophylaxis: non-pharmacological methods (calf pumps) may be particularly useful.
Systemic disease causing coagulation disturbance: the liver synthesizes all the procoagulant factors and the ‘natural’ anticoagulants (protein C, protein S and antithrombin). In addition, the absorption of vitamin K is dependent on bile reaching the duodenum and is therefore reduced in cholestasis. In general, the degree of prolongation of the PT and APTT reflect the degree of hepatic biosynthetic failure. Late in liver disease one may observe a prolongation of the TT due to dys- and/or hypo-fibrinogenaemia. Patients with liver disease may therefore require surgical procedures to be covered with intravenous vitamin K 1 prophylaxis and/or FFP and cryoprecipitate. Gastrointestinal malabsorption resulting in reduced bioavailability of vitamin K may also result in disturbance of coagulation. Patients with renal failure may manifest a bleeding diathesis. The pathogenesis of this appears to be a reduction in platelet function and platelet–vessel wall interactions. Moreover, the anaemia associated with renal disease may exacerbate the prolonged bleeding time. The bleeding time may be reduced in renal failure by the administration of desmopressin. The correction of the haematocrit to >30% by red cell transfusion or administration of erythropoietin may also improve haemostatic performance.
Thrombophilia (Figure 5): considerable attention has recently been paid in both the clinical and lay press to individuals with an inherited or acquired tendency to thrombosis, particularly with regard to venous thromboembolism. Postoperative lower limb deep venous thrombosis resulting in pulmonary embolism is still an important, and possibly under-diagnosed, problem. While much attention has focused on ‘thrombophilia screening’, it is important to remember that surgery and trauma are themselves able to increase an individual’s thrombotic risk. Stasis in the venous system due to postoperative immobility, coupled with an increase in circulating activated clotting factors, is also contributory. Moreover, plasma concentrations of fibrinogen, vWF and factor VIII all rise following trauma. The overall risk of an individual sustaining a thromboembolic event will also relate to other factors such as age, obesity, varicose veins, the presence of malignancy and the patient’s past thrombotic history. Other important prothrombotic factors include polycythaemia (primary or secondary) and thrombocytosis. Figure 5 illustrates the most common thrombophilia screening tests. A decision to test for thrombophilia and the interpretation of screening results needs to be made by an experienced haematologist in this field. It is also very important to note that the current thrombophilia screen probably picks up only about 50% of individuals with a predisposition to thrombosis. Consequently, patients with a past history of recurrent or serious thrombotic events should be treated as high risk with regard to thromboprophylaxis even if their screen is ‘negative’.
Inherited bleeding disorders: the most common disorder of this type facing the clinician in the UK is vWD. Understanding the diathesis in vWD can be confusing. To understand vWD one must remember that the vWF protein molecule, synthesized and released by the vascular endothelium, has many domains with different functions (platelet binding, collagen binding, factor VIII binding and vWF binding) and that vWF functions properly only when in multimeric form. Moreover, vWF acts as a carrier molecule for factor VIII, and without vWF the
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Investigations to detect a predisposition to thrombosis
Surgery in Carriers of Bloodborne Infections
General Blood Count (polycythaemia, thrombocytosis) Coagulation screen (lupus anticoagulant prolongs APTT) (prolonged TT with dysfibrinogenaemia)
Lynn A Riddell Kelly Morris
Detection of reduced ‘natural’ anticoagulants Antithrombin Protein C Protein S
Surgical personnel in contact with patients or clinical material are at continuous risk of acquiring blood-borne infections (BBIs), in particular hepatitis B virus (HBV), hepatitis C virus (HCV), and the human immunodeficiency virus (HIV). Recent concerns have highlighted the potential risk of prion transmission during surgery. It is impossible to prevent all exposures to potentially infected materials. Strategies to combat occupational infection include the universal use of precautions to avoid exposure, immunization, and post-exposure management. Relevant procedures also should include steps to minimize any threat to patients.
Detection of abnormal coagulation protein Activated protein C resistance and genotyping of factor V to detect the factor V Leiden mutation Prothrombin genotyping to detect the prothrombin G20210A mutation Tests for antiphospholipid syndrome IgG and IgM anticardiolipin antibodies Specific tests for lupus anticoagulant (Dilute Russell’s Viper Venom Time test with a platelet neutralisation procedure) Anti beta-2-glycoprotein I antibodies
Transmission during surgery The lifetime risk of surgical personnel acquiring a BBI is substantial. The greatest threats are HBV, HCV, and HIV, since the clinical and occupational consequences of chronic infection may be substantial. Individual risk varies depending on the pathogen involved, the likelihood that the source patient is infectious, and the nature of the exposure. Hepatitis viruses represent a greater risk to the surgeon than HIV. The risk of acquiring HBV from one percutaneous exposure is up to ten times higher than that for HCV, and up to 100 times greater than that for HIV. Exposure is defined as percutaneous (including via broken skin) or mucocutaneous contact with potentially infectious clinical material. Inoculation via ‘sharps’ injuries carries the highest risk of transmission. Likelihood of exposure is greatly related to adherence to universal precautions; non-compliance is associated with a considerably increased risk. The risk of an infectious exposure also depends on: • prevalence of the pathogen in the care setting • nature of the work of the health care provider • type of injury • host and viral factors.
Other tests Factor VIII assay (for elevated levels) Detection of the C677T methylene tetrahydrofolate reductase thermolabile variant Homocysteine levels 5
Local protocols defining patients at a high thrombotic risk and their optimal peri-operative management should be in place. Close attention should be paid to avoiding prolonged immobility and the careful use of heparin prophylaxis. Some patients will need management, as for the high-risk patients discussed in the section on anticoagulation. The period of postoperative increased thrombotic risk may extend for several weeks following surgery. u
FURTHER READING Bajaj S P, Joist J H. New insights into how blood clots: implications for the use of APTT and PT as coagulation screening tests and in the monitoring of anticoagulant therapy. Semin Thromb Haemostasis 1999; 25(4): 407–18. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101(2): 374–87. Hoffbrand A V, Pettit J. Essential Haematology, 3rd edition. Oxford: Blackwell Science, 1993. Hoffbrand A V, Lewis S M, Tuddenham E G D, Eds. Postgraduate Haematology, 4th edition. Oxford: Butterworth Heinemann, 1999. Stainsby D, MacLennan S, Hamilton P J. Management of massive blood loss: a template guideline. Br J Anaesth; 85(3): 487–91.
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Lynn A Riddell is a Consultant Physician in HIV and Genitourinary Medicine in Northampton, UK, and holds an Honorary Consultant position in HIV at St Bartholomew's Hospital, UK. She graduated from the University of Cape Town, South Africa, and completed postgraduate and specialist training at St Bartholomew's Hospital and the Radcliffe Infirmary, Oxford, UK. Kelly Morris is a clinician and freelance health writer and editor. She has worked in several clinical fields and as a senior editor at The Lancet. Her current clinical work is as clinical assistant/locum consultant in sexual health and HIV medicine at Northampton General Hospital, UK.
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Clinical anatomy
Disorders of Thrombosis and Haemostasis
Drawing from an intravenous pyelogram to show the relationship of the ureters to the bony landmarks
M J Nash Hannah Cohen
The surgical patient with a bleeding or thrombotic disorder presents a clinical challenge. The key to optimal management is early recognition of patients at risk coupled with close and effective liaison between the surgeon and haematologist. This article provides an overview of bleeding and thrombotic disorders with particular reference to surgical patients. Normal haemostasis Three physiological components act in concert to achieve haemostasis in vivo, namely the coagulation mechanism, platelets and the blood vessel wall. A physiological balance exists between pro- and anticoagulant mechanisms. Natural anticoagulants include heparan sulphate on endothelial cells, antithrombin and protein C and protein S. The process is completed by the dissolution of thrombi via the process of fibrinolysis, which enables repair of the damaged vascular endothelium.
4
To identify the ureter at laparotomy, it is conveniently discovered at the bifurcation of the common iliac artery. Its thick muscular wall, which vermiculates when gently squeezed with non-toothed forceps, and the fact that it adheres to the overlying peritoneum like a fly stuck on fly-paper, are diagnostic.
Coagulation mechanism (Figure 1) The coagulation system is a finely balanced network of interacting procoagulant and anticoagulant factors. The modern view of the events involved in this process differs from the ‘extrinsic’ and ‘intrinsic’ pathways, which were traditionally discussed. The first event in the coagulation mechanism is the binding of circulating factor VII to tissue factor (TF) exposed at a site of vascular injury. The VIIa.TF complex activates factors X and IX. Factor IXa activates factor X in the presence of factor VIIIa and calcium. Factor Xa then converts prothrombin to thrombin in the presence of factor Va and calcium. Thrombin then converts fibrinogen to fibrin, which is then stabilized by cross-linking catalyzed by factor XIII.
Blood supply The ureter receives a rich segmental and anastomosing blood supply from all the available vessels along its course, i.e. the renal, gonadal, internal iliac and vesical vessels. Only extensive stripping will devascularise it. In searching for a radio-opaque ureteric stone on a radiograph, imagine the course of the ureter in relation to the bony skeleton; along the tips of the transverse processes, crosses the front of the sacro-iliac joint, swings out laterally to the ischial spine, then passes medially to the bladder (Figure 4). u
M J Nash is a Specialist Registrar on the North Thames Haematology rotation, London, UK, and is currently undertaking research into the modulation of cellular fibrinolysis by antiphospholipid antibodies. He qualified in 1995 from St Mary's Hospital Medical School, London, UK. Hannah Cohen is Consultant Haematologist at University College London Hospitals NHS Trust, London, UK. She qualified from the University of Manchester Medical School, UK, and trained in haematology at University College London Hospitals. Her research interests include the pathophysiology and management of antiphospholipid syndrome and the role of thrombophilias in pregnancy loss.
FURTHER READING Cross J, Dixon A K. The renal tract and retroperitoneum. In: Butler P, Mitchell A, Ellis H, Eds. Applied Radiological Anatomy. Cambridge: Cambridge University Press, 1999.
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Aspirin exerts its antiplatelet effect by irreversible acetylation of platelet cyclo-oxygenase, leading to reduced platelet TxA2 production. Thus, it takes 8–12 days (the platelet life span) for the effects of aspirin to ‘wash out’ of an individual’s platelets. This is in contrast to the reversible cyclo-oxygenase inhibition seen with other non-steroidal anti-inflammatory drugs. The ADP and TxA2 thus released activate more platelets, which in turn activate more platelets via their released products. A ‘platelet plug’ forms, which is reinforced by fibrin crosslinkage. The surface of platelets also serves an important procoagulant role. Negatively charged phospholipids (e.g. phosphatidylserine) are exposed on the platelet surface on activation. These phospholipids have an important role as a surface upon which the clotting factors meet.
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Fibrinolysis The fibrinolytic system is key to the resolution of blood clots. The essential reaction in fibrinolysis is the conversion of the proenzyme plasminogen to the active plasmin by tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator. Fibrinolysis activation pathways can be divided into extrinsic (t-PA mediated) and intrinsic (contact factor mediated), which interact. The major physiological activator of fibrinolysis is believed to be t-PA. Plasmin binds to, and cleaves, polymerized fibrin.
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Approach to the patient with bleeding In the surgical setting, careful assessment in the pre-admission clinic should enable identification of the patient with a preexisting bleeding disorder. In general, acquired disorders of haemostasis are much more common than inherited ones. The patient with severe bleeding peri- or postoperatively requires a local, pre-planned collaborative approach.
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Soon after the initiation of these events, circulating tissue factor pathway inhibitor (TFPI) inhibits the VIIa.TF complex. It is likely that continued fibrin generation is achieved by the back-activation of factor XI by thrombin itself. Thrombin also amplifies the system by activating the co-factors V and VIII. This view of coagulation explains why deficiency of factors VIII or IX (haemophilia A and B) may lead to severe bleeding problems and why factor XII deficiency does not. The coagulation mechanism is summarized in Figure 1, which also illustrates the position in the coagulation system of the natural anticoagulants, antithrombin, protein C and protein S.
History and examination The history is of paramount importance to identify patients at risk of bleeding. A history of bleeding following previous haemostatic challenges, including dental extractions, suggests there is a clinical problem even if the patient has a normal coagulation screen and platelet count. The pattern of bleeding is important: easy or spontaneous bruising, bleeding from mucous membranes, epistaxis or menorrhagia, and prolonged bleeding following minor trauma can be particularly indicative of a platelet defect (thrombocytopenia or platelet dysfunction) or vWD. Systematic enquiry and clinical examination may identify evidence of renal and hepatic pathology or malignancy, which can result in haemostatic disturbance. One must look for a history of ingestion of drugs (e.g. aspirin, warfarin) and also consider drugs which may result in thrombocytopenia. Some surgical procedures are more likely than others to result in haemostatic disturbance. Of particular note is cardiac surgery, where the large incision, the activation of platelets and clotting factors in the bypass circuit and hyperfibrinolysis are all contributory.
Platelets A critical initial step in primary haemostasis is the adhesion of platelets to the subendothelial connective tissue, exposed following vessel damage. von Willebrand factor (vWF) serves as a bridge between platelet receptors and the subendothelium. Following platelet adhesion, a series of metabolic pathways are initiated which result in platelet shape change, release of granule contents and aggregation. Released platelet granule contents include adenosine diphosphate (ADP), 5-hydroxytryptamine (5-HT) and platelet factor IV. Platelet production of thromboxane A2 (TxA2) also increases via platelet arachidonic acid metabolism. TxA2 exerts its action on platelets by reducing their intracellular cyclic adenosine monophosphate (cAMP) levels: this stimulates granule content release. TxA2 is also a potent vasoconstrictor: its actions antagonize those of prostacyclin produced by the vascular endothelium.
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Investigation Baseline tests in a patient suffering from, or at suspected risk of, a bleeding disorder include a blood count and film, renal and liver function tests, and a coagulation screen: prothrombin time
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(PT), activated partial thromboplastin time (APTT), thrombin time (TT) and functional fibrinogen quantitation. These tests form a crucial part of the first-line assessment of patients bleeding post-operatively. The causes of prolongation of the routine screening tests of coagulation are shown in Figure 2. The PT tests what was traditionally called the extrinsic pathway, while the APTT tests the intrinsic pathway. Distal to factor X, both the intrinsic and extrinsic systems converge on a final common pathway, leading to the formation of fibrin. The TT is prolonged by quantitative or qualitative reduction in fibrinogen activity and by inhibition of thrombin (for example by heparin, to which the test is particularly sensitive).
A prolonged bleeding time occurs when the platelet count falls below 100 x 109/L and there is a progressive increase as the platelet count falls below this level. Platelet disorders may be quantitative or qualitative. Platelet numbers may be reduced (thrombocytopenia) or increased (thrombocytosis). In certain situations, several platelet defects may coexist. For example, the thrombocytosis of myeloproliferative disorders may be associated with platelet dysfunction predisposing to both haemorrhage and thrombotic manifestations. Previously, a skin bleeding time was not infrequently performed to assess primary haemostatic function. This test is now seldom used and recently ‘in vitro’ bleeding time assays have become available, such as the Platelet Function Analyzer (PFA-100), which measures the time for a thrombus to form across a membrane coated with collagen and a platelet agonist. This gives an in vitro measurement of primary haemostasis.
Causes of abnormalities in first-line tests of haemostasis a) Thrombocytopenia • Increased destruction, consumption • Sequestration • Dilution
Management The treatment of clotting abnormalities and peri- or postoperative bleeding depends on the underlying cause and severity. The management of inherited factor deficiency, disseminated intravascular coagulation and massive blood loss is discussed later in this article. In general, when plasma replacement is indicated, fresh frozen plasma at a dose of 12–15 ml/kg will correct a prolonged PT or APTT not due to fibrinogen deficiency. A prolonged TT and/or quantitative or qualitative fibrinogen problem should be corrected by the administration of cryoprecipitate. Platelets may be administered to correct significant thrombocytopenia (see section on massive blood transfusion).
Non-immune (DIC, cardiopulmonary bypass, TTP) Immune (ITP, drugs, PTP) Hypersplenism Massive fluid replacement/ transfusion
• Inherited (e.g. Bernard– Soulier syndrome) • Bone marrow failure b) Coagulation screening tests • The APTT (normal 30–40 seconds) assays factors XII, XI, IX, VIII, X, V, II and fibrinogen • The PT (normal 11–16 seconds) assays factors VII, X, V, II and fibrinogen • The TT (normal 15–19 seconds) assays fibrinogen • Prolonged PT, APTT, TT and low platelets DIC, acute hepatic failure • Prolonged PT, APTT, and TT Heparin, hepatic failure, fibrinogen deficiency • Prolonged PT and APTT (TT normal) Vitamin K deficiency, warfarin. V, X and prothrombin deficiency • Prolonged APTT (PT and TT normal) Haemophilia A and B, vWD. XI, XII deficiency • Prolonged PT (APTT and TT normal) Early in warfarinization, VII deficiency
Pharmacological agents with haemostatic function Non-blood-derived agents which augment haemostatic function have the advantage of no infectious agent transmission risk and are also useful in the management of patients who find the use of blood products unacceptable. Aprotinin and tranexamic acid both inhibit the action of plasmin and therefore possess antifibrinolytic activity. In addition, aprotinin inhibits the contact activation of the coagulation mechanism. Aprotinin has been shown to reduce blood loss in cardiac surgery. Tranexamic acid is particularly useful given as a mouthwash and orally in reducing blood loss following dental extraction in patients with vWD or mild haemophilia A. Fibrin sealant may also reduce blood loss during surgery. Desmopressin exerts its action by raising plasma vWF and VIII levels. It is particularly useful in the operative management of patients with vWD or mild haemophilia A. Recombinant activated factor VII has been used in the management of patients with inhibitors to VIII and IX. However, the role of this compound in the management of bleeding in a variety of clinical settings is currently being explored and indications for its use are likely to expand.
DIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; ITP, immune thrombocytopenic purpura; PTP, post-transfusion purpura NB normal ranges for clotting assays will vary from centre to centre. With regard to prolonged clotting times, one will often see the laboratory perform a 50:50 mix. This process involves mixing the patient’s plasma with normal plasma. In general, if the prolongation of the clotting time is due to a factor deficiency, the time will correct. If the prolongation is due to an inhibitor (such as an antibody directed against a clotting factor or a lupus anticoagulant) the test will remain prolonged even in the presence of normal plasma.
Patients receiving oral anticoagulation The surgical patient on coumarin oral anticoagulation requires forward planning, except in the emergency situation where this is impossible. This enables reduction of warfarin’s effect by withholding warfarin rather than unnecessary reversal of
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warfarin’s effect by administration of vitamin K or fresh frozen plasma (FFP). Warfarin exerts its pharmacological action on vitamin K epoxide reductase. This enzyme is essential in the pathway for the addition of a carboxyl (COO–) group to glutamic acid residues on factors II, VII, IX, X and on protein C and protein S. Post-translational gamma carboxylation is essential for the function of these factors (pathway illustrated in Figure 3). The half-life of warfarin is approximately 48 hours and it should thus be stopped (or the dose reduced) in sufficient time to achieve the desired reduction in International Normalized Ratio (INR). The management of patients on oral anticoagulants perioperatively, addressed in national guidelines, should be individualized, with careful analysis of the risk to the patient of bleeding in the presence of anticoagulation against the risk of thrombosis in its absence. For minor procedures, the dose of warfarin can be adjusted to aim for an INR of 2.0–2.5 on the day of surgery. For major surgery, the choice is between stopping anticoagulation for a period around the operation and stopping warfarin but instituting perioperative anticoagulation with heparin. The former approach may be used for patients at low risk of thrombosis, such as those with atrial fibrillation and no previous thrombotic events. The latter approach may be employed for patients at perceived high risk of thrombosis, this group will include patients with a history of recurrent thrombotic events. Management should be according to local guidelines, specifying whether unfractionated or low-molecularweight heparin is used. It is usual to start heparin when the INR falls to 3.0. Surgery is usually undertaken when the INR is ≤1.5. Heparin should be discontinued pre-surgery to ensure that the APTT has fallen to ≤1.5. Of particular importance is the management of the patient with a mechanical heart valve. Meta-analysis has shown that the short-term risk of a period without anticoagulation in these patients is low, therefore in many cases such patients may be managed simply with a period of no anticoagulant. Some patients however, particularly those
with a caged-ball mitral valve prosthesis, may be at high risk of thrombosis, and should receive perioperative unfractionated heparin. Monitoring of heparin therapy depends on the form used. For unfractionated heparin given by continuous infusion, the APTT is monitored and the dose adjusted to give an APTT ratio 1.5–2.5 times normal. In the majority of cases, monitoring of low-molecular-weight heparin is unnecessary, as the dose is based on the patient’s weight. However, in some patients, such as those with renal impairment or who are pregnant, bioavailability of low-molecular-weight heparin can be unpredictable. Such patients should have their dose monitored by assay of anti-Xa activity levels in their plasma. Patients receiving antiplatelet therapy with aspirin or clopidogrel are frequently encountered in the pre-admission setting. In general, it is prudent to withhold administration of such drugs for at least ten days prior to surgery. In high-risk cardiac patients, however, the risk of thrombotic events may outweigh the risk of peri-operative bleeding. Acquired haemostatic failure Disseminated intravascular coagulation (DIC): DIC exists when excessive and inappropriate activation of the haemostatic system occurs within the circulation. In surgical patients, this phenomenon may be associated with prolonged operation time, extracorporeal circulation and massive blood transfusion. Other causes of DIC are listed in Figure 4. Typically, DIC presents with bleeding, including oozing from cannulation sites. Some patients present with manifestations of thrombosis: typically microthrombotic, leading to, for example, digital gangrene. Diagnosis of uncompensated DIC rests on demonstrating excessive consumption of coagulation factors and platelets with increased fibrinolytic activity. A prolonged APTT, PT and TT with a low fibrinogen (below 1.0 g/dl) with raised plasma fibrin degradation products (including D-dimer) is characteristic. DIC will not resolve until the underlying cause is diagnosed and treated. Supportive treatment with FFP, cryoprecipitate, red cell and platelet concentrates may be required. The aims of blood component support are similar to those in the massively transfused patient (see below).
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The patient receiving a massive blood transfusion: guidelines on the management of acute massive blood loss have recently been published. Some individuals require massive transfusion following, for example, trauma or emergency repair of an
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Septicaemia Metastatic carcinoma Septic abortion, abruption, eclampsia, amniotic fluid embolism Shock Extensive trauma, massive burns Hepatic Cirrhosis, acute necrosis Cardiac bypass surgery ABO-incompatible transfusion
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abdominal aortic aneurysm. The definition of massive transfusion is usually taken to represent transfusion of more than the patient’s blood volume in less than 24 hours. This situation can bring with it a worsening of the patient’s haemostatic function, which can be corrected by administration of FFP (to correct prolongation of the PT and APTT), cryoprecipitate (to correct hypofibrinogenaemia) and platelet concentrate. In patients bleeding heavily, a bleeding diathesis may be due more to secondary DIC than excessive transfusion and ‘dilution’ of clotting factors. Clotting factor depletion can, however, occur once approximately 80% of the patient’s circulating volume has been replaced. Formula replacement protocols for administering FFP or platelets in this situation should be avoided, since they may lead to inappropriate and/or inadequate red cell, platelet or plasma replacement. The patient’s clotting and blood count needs to be regularly monitored. An element of ‘planning ahead’ component ordering may be required in acute bleeds and it is understood that components may need to be ordered ahead of test results. Aims in a patient needing massive blood transfusion should be to maintain a haematocrit of >33%, a platelet count of >50 x 109/l, PT and APTT under 1.5 times normal and a fibrinogen of greater than 1.0 g/l. It is important to note that to treat a low fibrinogen, the product to give is cryoprecipitate. Some colloids may produce reduced haemostatic function. Dextran-based compounds may reduce plasma vWF levels and platelet adhesion.
half-life (and therefore the bioavailability) of VIII is significantly reduced. On routine tests, vWD will present with an isolated prolongation of the APTT due to reduced factor VIII. More specialized tests are needed to determine the subtype of vWD and the correct management. The bleeding diathesis in vWD can be very mild and consequently, patients often present only when provoked by trauma or surgery. The perioperative management of inherited bleeding disorders is the domain of close liaison between a specialist haematologist and a consultant surgeon. Patients with a bleeding disorder should undergo surgery in a haemophilia centre. In such patients, careful attention needs to be given to the strict avoidance of compounds (including some health shop preparations) prior to surgery, which can reduce haemostatic function. Attention must also be given to meticulous surgical haemostasis in the operating theatre. Therapeutic options to improve haemostatic function depend on the exact disorder. In general, therapy is aimed at avoidance of excessive bleeding by appropriate preoperative therapy. Specific factor replacement (e.g. VIII in haemophilia A or IX in haemophilia B) with monitoring of factor levels may be required. Recombinant factor VIIa may be indicated in haemophiliacs with acquired antibodies to factor VIII/IX. Studies are ongoing into the role of this agent in other inherited bleeding disorders. Wherever possible, blood product is avoided by the use of pharmacological agents such as desmopressin (which can raise factor VIII and vWF levels) and antifibrinolytic compounds such as tranexamic acid. Careful consideration needs to be given to whether or not these patients also receive thromboprophylaxis: non-pharmacological methods (calf pumps) may be particularly useful.
Systemic disease causing coagulation disturbance: the liver synthesizes all the procoagulant factors and the ‘natural’ anticoagulants (protein C, protein S and antithrombin). In addition, the absorption of vitamin K is dependent on bile reaching the duodenum and is therefore reduced in cholestasis. In general, the degree of prolongation of the PT and APTT reflect the degree of hepatic biosynthetic failure. Late in liver disease one may observe a prolongation of the TT due to dys- and/or hypo-fibrinogenaemia. Patients with liver disease may therefore require surgical procedures to be covered with intravenous vitamin K 1 prophylaxis and/or FFP and cryoprecipitate. Gastrointestinal malabsorption resulting in reduced bioavailability of vitamin K may also result in disturbance of coagulation. Patients with renal failure may manifest a bleeding diathesis. The pathogenesis of this appears to be a reduction in platelet function and platelet–vessel wall interactions. Moreover, the anaemia associated with renal disease may exacerbate the prolonged bleeding time. The bleeding time may be reduced in renal failure by the administration of desmopressin. The correction of the haematocrit to >30% by red cell transfusion or administration of erythropoietin may also improve haemostatic performance.
Thrombophilia (Figure 5): considerable attention has recently been paid in both the clinical and lay press to individuals with an inherited or acquired tendency to thrombosis, particularly with regard to venous thromboembolism. Postoperative lower limb deep venous thrombosis resulting in pulmonary embolism is still an important, and possibly under-diagnosed, problem. While much attention has focused on ‘thrombophilia screening’, it is important to remember that surgery and trauma are themselves able to increase an individual’s thrombotic risk. Stasis in the venous system due to postoperative immobility, coupled with an increase in circulating activated clotting factors, is also contributory. Moreover, plasma concentrations of fibrinogen, vWF and factor VIII all rise following trauma. The overall risk of an individual sustaining a thromboembolic event will also relate to other factors such as age, obesity, varicose veins, the presence of malignancy and the patient’s past thrombotic history. Other important prothrombotic factors include polycythaemia (primary or secondary) and thrombocytosis. Figure 5 illustrates the most common thrombophilia screening tests. A decision to test for thrombophilia and the interpretation of screening results needs to be made by an experienced haematologist in this field. It is also very important to note that the current thrombophilia screen probably picks up only about 50% of individuals with a predisposition to thrombosis. Consequently, patients with a past history of recurrent or serious thrombotic events should be treated as high risk with regard to thromboprophylaxis even if their screen is ‘negative’.
Inherited bleeding disorders: the most common disorder of this type facing the clinician in the UK is vWD. Understanding the diathesis in vWD can be confusing. To understand vWD one must remember that the vWF protein molecule, synthesized and released by the vascular endothelium, has many domains with different functions (platelet binding, collagen binding, factor VIII binding and vWF binding) and that vWF functions properly only when in multimeric form. Moreover, vWF acts as a carrier molecule for factor VIII, and without vWF the
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Investigations to detect a predisposition to thrombosis
Surgery in Carriers of Bloodborne Infections
General Blood Count (polycythaemia, thrombocytosis) Coagulation screen (lupus anticoagulant prolongs APTT) (prolonged TT with dysfibrinogenaemia)
Lynn A Riddell Kelly Morris
Detection of reduced ‘natural’ anticoagulants Antithrombin Protein C Protein S
Surgical personnel in contact with patients or clinical material are at continuous risk of acquiring blood-borne infections (BBIs), in particular hepatitis B virus (HBV), hepatitis C virus (HCV), and the human immunodeficiency virus (HIV). Recent concerns have highlighted the potential risk of prion transmission during surgery. It is impossible to prevent all exposures to potentially infected materials. Strategies to combat occupational infection include the universal use of precautions to avoid exposure, immunization, and post-exposure management. Relevant procedures also should include steps to minimize any threat to patients.
Detection of abnormal coagulation protein Activated protein C resistance and genotyping of factor V to detect the factor V Leiden mutation Prothrombin genotyping to detect the prothrombin G20210A mutation Tests for antiphospholipid syndrome IgG and IgM anticardiolipin antibodies Specific tests for lupus anticoagulant (Dilute Russell’s Viper Venom Time test with a platelet neutralisation procedure) Anti beta-2-glycoprotein I antibodies
Transmission during surgery The lifetime risk of surgical personnel acquiring a BBI is substantial. The greatest threats are HBV, HCV, and HIV, since the clinical and occupational consequences of chronic infection may be substantial. Individual risk varies depending on the pathogen involved, the likelihood that the source patient is infectious, and the nature of the exposure. Hepatitis viruses represent a greater risk to the surgeon than HIV. The risk of acquiring HBV from one percutaneous exposure is up to ten times higher than that for HCV, and up to 100 times greater than that for HIV. Exposure is defined as percutaneous (including via broken skin) or mucocutaneous contact with potentially infectious clinical material. Inoculation via ‘sharps’ injuries carries the highest risk of transmission. Likelihood of exposure is greatly related to adherence to universal precautions; non-compliance is associated with a considerably increased risk. The risk of an infectious exposure also depends on: • prevalence of the pathogen in the care setting • nature of the work of the health care provider • type of injury • host and viral factors.
Other tests Factor VIII assay (for elevated levels) Detection of the C677T methylene tetrahydrofolate reductase thermolabile variant Homocysteine levels 5
Local protocols defining patients at a high thrombotic risk and their optimal peri-operative management should be in place. Close attention should be paid to avoiding prolonged immobility and the careful use of heparin prophylaxis. Some patients will need management, as for the high-risk patients discussed in the section on anticoagulation. The period of postoperative increased thrombotic risk may extend for several weeks following surgery. u
FURTHER READING Bajaj S P, Joist J H. New insights into how blood clots: implications for the use of APTT and PT as coagulation screening tests and in the monitoring of anticoagulant therapy. Semin Thromb Haemostasis 1999; 25(4): 407–18. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101(2): 374–87. Hoffbrand A V, Pettit J. Essential Haematology, 3rd edition. Oxford: Blackwell Science, 1993. Hoffbrand A V, Lewis S M, Tuddenham E G D, Eds. Postgraduate Haematology, 4th edition. Oxford: Butterworth Heinemann, 1999. Stainsby D, MacLennan S, Hamilton P J. Management of massive blood loss: a template guideline. Br J Anaesth; 85(3): 487–91.
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Lynn A Riddell is a Consultant Physician in HIV and Genitourinary Medicine in Northampton, UK, and holds an Honorary Consultant position in HIV at St Bartholomew's Hospital, UK. She graduated from the University of Cape Town, South Africa, and completed postgraduate and specialist training at St Bartholomew's Hospital and the Radcliffe Infirmary, Oxford, UK. Kelly Morris is a clinician and freelance health writer and editor. She has worked in several clinical fields and as a senior editor at The Lancet. Her current clinical work is as clinical assistant/locum consultant in sexual health and HIV medicine at Northampton General Hospital, UK.
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