1 Coagulation Laboratory, Division of Haematology, University Hospital of Zürich, Sternwartstrasse 14, CH-8091 Zürich, Switzerland. 2 Department of Anaesthesiology, University Hospital of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
* Corresponding author. E-mail: donat.spahn{at}chuv.hospvd.ch
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Abstract |
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Keywords: blood, coagulation ; complications, haemorrhage ; complications, thromboembolism
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The coagulation system: new aspects |
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Despite this significant diversification, the coagulation proteins are the core components of the haemostatic system, forming a complex interplay that is still not entirely understood. Whereas the classic separation of the coagulation pathway into the extrinsic pathway (initiated by tissue factor) and intrinsic pathway (initiated by contact activation) still has certain validity, the newer time-based structuring provides a much more authentic description of the coagulation process.25 This involves the following steps (Fig. 1).
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Perioperative thromboembolism |
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Antithrombotic regimens
Low-molecular weight heparin (LMWH) is the gold standard in surgical thromboprophylaxis. As has been shown in a direct comparison of several studies using different prophylaxis regimens in hip replacement patients, LMWH, hirudin and adjusted-dose unfractionated heparin (UFH) led to the highest risk reduction.20 Whereas hirudin is associated with an unacceptably high rate of bleeding complications and adjusted-dose UFH is laborious and requires more than one injection per day (or an infusion), LMWH has no such disadvantage and is easy to use as a once-per-day injection without the necessity of monitoring. It is notable that the greatest reduction in the risk of thrombosis has been found in patients with high-risk operations and/or important personal risk factors.60 61 Although the currently available LMWHs, including certoparin, dalteparin, enoxaparin, nadroparin, tinzaparin and reviparin, differ in their pharmacokinetic properties, there is no evidence so far that any one of these products offers more or less protection from thromboembolism. In addition, none of the different LMWHs has been found to be especially useful or disadvantageous for specific patient groups (e.g. renal or liver insufficiency, heparin-induced thrombocytopenia) despite the different pharmacology of the various LMWHs.
There are at least three prophylactic LMWH regimens in use in patients undergoing high-risk operations (Table 3).33 In Europe, prophylaxis is traditionally started 12 h before surgery, whereas in North America it is initiated 1248 h after surgery. The third regimen starts prophylaxis either more than 12 h before or 12 h after surgery. LMWH prophylaxis is started before surgery on the basis of previous observations that surgical interventions led to activation of coagulation, probably promoting the generation of thrombi.21 Unfortunately, the optimal regimen is uncertain because direct comparisons between these regimens with sufficiently large sample sizes are not available. A recent analysis of pooled data from several studies using either pre- or postoperative prophylaxis, however, has shown that there is no convincing evidence that starting prophylaxis before surgery is associated with a lower incidence of venous thromboembolism than starting after surgery.100
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New antithrombotic drugs
There are many new anticoagulant drugs under investigation that target novel sites in the coagulation pathway, including tissue-factor/FVIIa, FVa and FVIIIa, FIXa, FXa, FXIIIa, PAI-1 and thrombin.108 Only a few of them, however, have recently entered or will soon enter the market. One such new anticoagulant is fondaparinux (Arixtra®), a synthetic molecule that is structurally and functionally like heparin, consisting of five saccharide units (pentasaccharide). Like heparin, it binds and activates antithrombin but inhibits only FXa and not thrombin.19 Fondaparinux is being tested extensively in large phase 3 trials in patients undergoing major orthopaedic surgery. These trials have revealed that fondaparinux 2.5 mg once daily, starting 6 h after surgery, gives a clear benefit compared with enoxaparin.103 In particular, the overall incidence of venous thromboembolism up to day 11 was reduced from 13.7% (371 of 2703 patients) in the enoxaparin group to 6.8% (182 of 2682 patients) in the fondaparinux group, with a common odds reduction of 55.2% in favour of fondaparinux. It should be noted that in some studies the postoperative interval before starting with the first dose was considerably different between the enoxaparin and fondaparinux groups (1224 vs 6 h). In addition, although the endpoints of these studies were venographic thromboses, there was no benefit of fondaparinux over enoxaparin with regard to the frequency of symptomatic DVT. It will be interesting to see the results of studies using fondaparinux for other prophylactic indications.
Another new anticoagulant agent is melagatran (Exanta®), a non-covalent, synthetic, direct thrombin inhibitor. Interestingly, it is also available in an oral preparation (ximelagatran) with very predictable and reproducible pharmacokinetic and pharmacodynamic profiles.53 Besides oral administration, melagatran has a number of benefits, including rapid onset of action, lack of drugfood interactions, and no requirement for routine blood coagulation monitoring. Both drug forms have been tested in two large trials as prophylactic treatment in major orthopaedic surgery.27 29 In one study, melagatran was tested against dalteparin (both drugs given before surgery followed by ximelagatran), while in the other study ximelagatran was tested against warfarin (both started after surgery). The studies concluded that both regimens (subcutaneous melagatran followed by oral ximelagatran and oral ximelagatran alone) were safe, well tolerated and as effective as the other regimen tested. Although registration of (xi)melagatran has already been filed in several countries, some open questions need to be clarified. For instance, there is at present no drug available to antagonize the effect of melagatran. Furthermore, the prothrombin time (PT) does not seem to be an adequate test to measure melagatran activity (if necessary), as the same melagatran concentration has been found to be associated with widely varying PT/international normalized ratio (INR) results depending on the specific assay used.68
Thromboprophylaxis in patients undergoing regional anaesthesia
Neuraxial anaesthesia and analgesia provide excellent postoperative analgesia and allow early mobility after major surgery.9 44 76 84 In addition, there is a considerable group of patients who wish to stay awake during surgery. Epidural anaesthesia and analgesia are therefore used frequently in many centres, although a true outcome benefit in terms of mortality or major organ dysfunction could not be confirmed in two recent large-scale prospective randomized studies, with the exception of reduced pulmonary complications.76 84
The most feared complication of neuraxial anaesthesia is epidural haematoma, which has potentially devastating neurological complications. As more and more patients are treated with drugs interfering with blood coagulation or platelet function, the anaesthetist is frequently faced with the problem of whether neuraxial anaesthesia is still an option or whether such co-medication means it is contraindicated (Table 4). Several US and European societies have issued guidelines on locoregional anaesthesia in patients treated with heparin, oral anticoagulation, drugs interfering with platelet function, and other drugs used for thromboprophylaxis.35 44 89
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Reproducing and commenting on these guidelines is beyond the scope of this review, but the essential aspects are summarized in Table 5. Many centres have established local guidelines pending evidence-based national guidelines (particularly regarding issues not fully covered, such as drug combinations, including the addition of heparin to antiplatelet drug therapy).
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Perioperative haemorrhage |
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Nevertheless, preoperative laboratory testing, including PT, aPTT, platelet count and even larger batteries of tests, have become routine in most institutions. The physician's sense of security and the perceived protection from legal liability may be the driving forces. As a substantial percentage of all unexpected abnormalities detected by preoperative laboratory tests are ignored, liability would be even greater in such cases.37 92 Thus, despite the importance of a bleeding history, the ideal strategy in predicting perioperative haemorrhage using coagulation tests remains unknown.
Assessment of the bleeding patient
Surgery or major trauma is the ultimate test of the haemostatic system. Patients who have never bled to any significant degree can bleed excessively during surgery. Rapid and appropriate diagnostics to detect a possible underlying haemostatic defect, either inherited or acquired, are of pre-eminent importance. A haemostatic defect should always be considered if bleeding occurs simultaneously at multiple sites, presents as slow oozing from a non-identifiable source, or is delayed after initially adequate haemostasis. Bleeding from a single site or sudden onset of massive bleeding is probably due to a local structural defect. Assessment of a patient with a suspected coagulation defect should always include a thorough re-evaluation of his or her history, determination of any drugs given before surgery, including crystalloids, colloids and blood products, and a physical examination to determine the type and location of the bleeding. Initial laboratory evaluation should cover the entire range of possible coagulation defects, including clotting factor deficiencies, thrombocytopenia (and if possible thrombocytopathia), hyperfibrinolysis, and disseminated intravascular coagulation (DIC). Figure 2 gives a brief overview of how to proceed if prolongation of either the PT or aPTT occurs.
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FFP and platelet transfusions are relatively frequently associated with side-effects such as febrile, non-haemolytic and allergic transfusion reactions, bacterial contamination, and transfusion-related acute lung injury.6 39 69 75 94 Such products should be restricted to situations in which their efficacy has been documented. However, there is amazingly little scientific information available concerning the clinical efficacy of FFP and platelet transfusions.1 93 The few existing guidelines consist more of expert opinion than of scientific evidence.
Anaesthetists1 and oncologists93 have issued guidelines for platelet transfusion. According to these guidelines, prophylactic platelet transfusions are indicated in leukaemia patients at platelet counts <10 000 µl1 in the absence of fever, heparin treatment or active minor bleeding (although lower, safe thresholds have been described by Gmür and colleagues)34 87 and with platelet counts <20 000 µl1 in the presence of such risk factors.93 For major surgery, platelet transfusions are recommended to maintain platelet counts above 50 000 µl1, particularly if microvascular bleeding occurs.1 93 Minor surgery, however, can be performed without platelet transfusion in patients with a platelet count <50 000 µl1.58 In certain situations in which platelet dysfunction may be present, such as after cardiopulmonary bypass, and when the consequences of bleeding might be devastating, such as in neurosurgery, maintaining platelet counts between 50 000 and 100 000 µl1 may be necessary. Only with severe platelet dysfunction will platelet counts >100 000 µl1 require transfusion.
Transfusion of FFP is considered to be indicated in the following situations: urgent reversal of anticoagulation induced by vitamin K antagonists (besides the use of prothrombin complex concentrates), microvascular bleeding in the presence of an elevated PT (INR >1.6) or aPTT (>1.5 times normal) and microvascular bleeding in patients transfused with >1 blood volume when PT and aPTT are unavailable.1 81 In contrast, FFP transfusions are contraindicated as volume replacement.1 81 Hopefully, the strict use of such guidelines will decrease the number of inappropriate FFP transfusions.65
Red blood cell transfusions have also been advocated to improve blood coagulation.82 104 105 It is unlikely, however, that reduction of the haematocrit alone compromises blood coagulation significantly. We have shown that decreasing the haematocrit gradually from 40% to 10%, thereby maintaining platelet count and coagulation factors at normal levels, does not compromise blood coagulation in any way, as assessed by thrombelastography.47
Haemostatic drug therapy
Besides transfusion therapy, treatment of bleeding is often supplemented with one or more haemostatic drugs. However, most of these drugs are substitutes for single or combined clotting factors, which do not induce coagulation but only replenish absent or diminished coagulation factors. This is important, as coagulation factor concentrates such as fibrinogen, prothrombin complex concentrate and vWF concentrate are too often administered in an attempt to improve coagulation, even though there is no deficiency of the relevant clotting factor. Although it has long been known that further elevation of above-normal levels of a single coagulation factor, e.g. FVIII or FIX, leads to more effective in vitro coagulation, as evidenced by a shortened coagulation time,32 58 there is no evidence that this occurs in vivo or stops bleeding. Apart from the vast experience and evidence of the efficacy of coagulation factor concentrates in the treatment of hereditary coagulation factor deficiencies such as haemophilia, afibrinogenaemia and vWF disease, there is only sparse evidence of the efficacy of these concentrates in patients with surgical bleeding.10 11 13 64 On the basis of these considerations and the fact that the minimal concentration of a specific coagulation factor required for normal haemostasis is known from in vitro experiments, it seems reasonable to administer coagulation factor concentrates only in cases in which a deficiency of the corresponding factor has been demonstrated. To clarify the appropriate use of coagulation factor concentrates in surgery, however, randomized trials are needed.
Other widely used haemostatic drugs are antifibrinolytic agents, including tranexamic acid, aminocaproic acid and aprotinin, which inhibit the activation of plasminogen and the activity of plasmin, respectively.107 As shown in several randomized, placebo-controlled studies, both aprotinin and tranexamic acid can significantly reduce blood loss in cardiac surgery when used prophylactically.17 62 71 78 Whether these results translate into a better overall outcome and justify routine use in all patients with cardiac surgery, however, is still debated.
Prophylactic use of antifibrinolytics, mainly aprotinin, in liver transplantation has also revealed encouraging results.80 83 The blood-sparing effect of aprotinin was found to be significant during the post-reperfusion period, suggesting that inhibition of reperfusion-associated hyperfibrinolysis is related to its efficacy. With the currently available knowledge, aprotinin seems to effectively reduce blood loss during orthotopic liver transplantation regardless of the indication.79 In major orthopaedic surgery, mainly joint replacement surgery, the use of antifibrinolytics has revealed conflicting results, making their widespread use as routine medication to reduce blood loss unlikely.3 38 50 106
Apart from their positive effects in prophylaxis, antifibrinolytics have shown limited benefits so far in stopping bleeding episodes. Significant efficacy has been found only in primary menorrhagia and in gastrointestinal and urogenital bleeding.67 This may be explained by the fact that mucous membranes are rich in fibrinolytic substances. In old uncontrolled studies, aprotinin was been associated with an increased rate of thrombotic complications, including myocardial infarction and pulmonary embolism, in patients undergoing cardiac surgery. Although such adverse effects have also been reported more recently,36 randomized, controlled studies have so far failed to demonstrate a significant increase in thrombotic complications in patients treated with aprotinin.17 50
Desmopressin is an analogue of arginine vasopressin and induces release of vWF from the vascular endothelium, thereby elevating both vWF and FVIII in the circulation. Desmopressin has been shown to be effective in treating bleeding in patients with congenital, mild haemophilia A and vWF disease type 1.67 To reduce blood loss during surgery in patients with otherwise normal haemostasis, desmopressin proved to be less effective. In a meta-analysis of 17 trials in 1171 patients, investigating desmopressin as prophylactic treatment in cardiac surgery, desmopressin reduced blood loss by only 9%, which was considered not to be clinically relevant.18 Newer studies have confirmed these observations, stating that, despite improvement in platelet function, desmopressin does not seem to have obvious beneficial effects on postoperative haemostasis in patients without any bleeding disorder who are undergoing elective cardiac surgery.74 Whether a subgroup of patients on preoperative aspirin benefit from desmopressin needs to be investigated further. Moreover, in a comprehensive review analysing 14 randomized trials of 1034 adult patients scheduled for varying non-urgent surgery, the authors found that there is no convincing evidence that desmopressin minimizes perioperative the allogeneic red blood cell transfusion requirement in patients who do not have congenital bleeding disorders. This suggests that there is no benefit in using desmopressin as a means of minimizing perioperative allogeneic red blood cell transfusion.41 All in all, it seems evident that desmopressin primarily provides benefits in patients with mild congenital haemophilia A or vWF disease.
rFV11a
Although not yet approved for indications other than bleeding in haemophiliacs with antibodies, rFVIIa (NovoSeven®) may be the ultimate haemostatic drug. rFVIIa is so far the only haemostatic drug that not only replaces a missing factor but actively initiates and promotes the coagulation process. This is a novel and very promising strategy to treat haemorrhagic diseases. The haemostatic effect of rFVIIa depends on its property of binding to TF and activated platelets, thereby rapidly activating FII to thrombin and FX to FXa respectively.31 70 86 The result is a local thrombin burst that enables feedback activation of intrinsic coagulation factors, the activation of more platelets, and finally the generation of fibrin. A major advantage of rFVIIa is that this procoagulant effect does not occur systemically in the circulation but is limited to the site where the vessel injury occurred. In about 300 case reports and small series of patients with severe, life-threatening bleeding, rFVIIa has proved to be a very potent haemostatic drug, whatever the cause of the bleeding.2 42 For instance, rFVIIa has been used successfully in patients with coumarin-induced bleeding, upper gastrointestinal bleeding, severe thrombocytopenia and thrombocytopathia and in patients with severe haemorrhage from trauma, neurosurgery, cardiac surgery and obstetric surgery. So far, there is only one randomized, controlled study of rFVIIa evaluating its prophylactic effect in patients undergoing retropubic prostatectomy.30 The study showed that, with one dose of rFVIIa 40 µg kg1 given during surgery, transfusion frequency could be reduced from 58% in the placebo group to 0% in the rFVIIa group. Preliminary results from new studies evaluating the efficacy of rFVIIa in patients undergoing hepatectomy and patients suffering from severe upper gastrointestinal bleeding have similarly shown that blood loss can be reduced remarkably with rFVIIa.63 However, detailed data have not yet been published. In addition, large, randomized studies in patients with severe trauma, liver transplantation and intracerebral haemorrhage are continuing. They will provide more information to clarify the uncertainties regarding its indications, optimal dose regimen, the optimal timing, the influence of the platelet count, and its cost-effectiveness.
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Emerging challenges |
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Summary |
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Indications and thromboprophylaxis regimens are reviewed (Tables 1 3), including the use of recently introduced drugs such as fondaparinux and (xi)melagatran. The impact of such treatment on patients undergoing regional anaesthesia (Tables 4 and 5) are outlined. Diagnostic procedures (Fig. 2, Table 6) and treatment regimens for patients with pre-existing or intraoperative coagulation defects are increasingly challenging and these are discussed in detail.
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Addendum |
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References |
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