Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage

T. Bombeli1 and D. R. Spahn2,*

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


    Abstract
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
Understanding of blood coagulation has evolved significantly in recent years. Both new coagulation proteins and inhibitors have been found and new interactions among previously known components of the coagulation system have been discovered. This increased knowledge has led to the development of various new diagnostic coagulation tests and promising antithrombotic and haemostatic drugs. Several such agents are currently being introduced into clinical medicine for both the treatment or prophylaxis of thromboembolic disease and for the treatment of bleeding. This review aims to elucidate these new concepts and to outline some consequences for clinical anaesthesia and perioperative medicine.

Keywords: blood, coagulation ; complications, haemorrhage ; complications, thromboembolism


    The coagulation system: new aspects
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
The coagulation system is considered by many clinicians to consist just of platelets and clotting factors. For some time, however, it has been recognized that many more cellular and molecular components participate in the coagulation process, thereby forming a multifaceted, well-balanced system called haemostasis. Moreover, the coagulation system is not only made for forming clots but is also involved in a variety of defence systems, including tissue repair, defence against micro-organisms, autoimmune processes, arteriosclerosis, tumour growth and metastasis. The main cellular components of the coagulation systems are platelets, endothelial cells, monocytes and erythrocytes, and the main molecular components are the coagulation factors and inhibitors, fibrinolysis factors and inhibitors, adhesive proteins (e.g. von Willebrand factor, vWF), intercellular proteins, acute-phase proteins, immunoglobulins, calcium ions, phospholipids, prostaglandins and certain cytokines.

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).

  1. Initiation. Tissue factor (TF) expressed by the damaged vascular bed binds FVIIa (which circulates in small quantities), which then triggers coagulation by activating FIX to FIXa and FX to FXa. FXa then binds very rapidly to FII, producing small amounts of thrombin (FIIa). In a much slower reaction, FIXa binds to and activates FX to FXa (3 in Fig. 1). Most coagulation processes in vivo are considered to be initiated by tissue factor, whereas the clinical significance of the contact activation (activation of FXII) is still not yet entirely clear. A recent report, however, has shown that RNA from disrupted cells may be the long-sought FXII activator in vivo.72
  2. Amplification. Because the amount of thrombin generated at this stage is still too small to activate fibrinogen to fibrin, there are several feedback amplification mechanisms. First, generation of FVIIa is increased by activation of FVII bound to tissue factor by FVIIa, FIXa and FXa. Thrombin then activates the non-enzymatic cofactors FV and FVIII, which accelerate the activation of FII by FXa and of FXa by FIXa, respectively. In a further feedback loop (2 in Fig. 1), thrombin also activates FXI to FXIa, increasing the generation of FIXa.
  3. Propagation. To maintain continuous thrombin generation, ensuring the formation of a sufficiently large clot, large amounts of FXa are produced by the activation of FX by FIXa and FVIIIa (intrinsic tenase complex). FIXa stems primarily from the activation of FIX by the FVIIa/TF–complex.
  4. Stabilization. Maximum thrombin generation occurs after the formation of fibrin monomers. Only then is the amount of thrombin high enough to activate FXIII, a transglutaminase, which then cross-links the soluble fibrin monomers to a stable fibrin meshwork. In addition, thrombin then activates the thrombin-activatable-fibrinolysis-inhibitor (TAFI) that protects the clot from fibrinolytic attack.



View larger version (23K):
[in this window]
[in a new window]
 
Fig 1 Current model of coagulation and fibrinolysis. In vivo the coagulation process is initiated mainly by FVIIa bound to tissue factor (TF; large black arrow), which then activates both FX (1) and FIX (2) (=initiation phase). To increase thrombin generation further, thrombin activates FV, FVIII and FXI in a feedback-loop (3) (=amplification). Continuation of thrombin generation results mainly from the ongoing generation of FXa by FIXa and FVIIIa (=propagation). Maximum thrombin generation occurs only after the formation of fibrin, leading to the formation of FXIIIa, which then crosslinks the fibrin monomers (4) (=stabilization).

 
Surgical procedures often unbalance this elaborate system, leading to a tendency to either thrombosis or bleeding. Besides the operative intervention itself and many well-known clinical risk factors, including immobility, infections, cancer and drugs, there are various other perioperative factors that are increasingly being demonstrated to interfere with the coagulation system, such as hypothermia,56 metabolic acidosis,26 volume expanders49 and extracorporeal circulation.8 Such perturbation of coagulation can be assessed by various laboratory assays. For example, during the first several hours after surgery there are marked increases in tissue factor, tissue plasminogen activator, plasminogen activator inhibitor-1 (PAI-1) and vWF, leading to a hypercoagulable and hypofibrinolytic state, as evidenced by increased generation of coagulation activation markers, such as thrombin–antithrombin complexes, fibrinopeptide A and many others.52 57 The levels of these mediators are known to fluctuate rapidly and their degree of perturbation is dependent not only on the type, degree and duration of surgery, but also on the timing of blood collection.


    Perioperative thromboembolism
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
Who needs thromboprophylaxis?
Surgical patients are at risk of developing venous thromboembolism. It is, however, important to recognize that there exist both definable operative procedures and definable groups of patients with significantly higher than normal rates of postoperative thromboembolism. For instance, it has been shown that, without prophylaxis, the incidence of deep vein thrombosis (DVT) is about 14% in gynaecological surgery, 22% in neurosurgery, 26% in abdominal surgery and 45–60% in orthopaedic surgery. In patients with malignancy these rates are markedly higher.7 Furthermore, as shown in Table 1, there are numerous patient-specific risk factors that also influence the individual risk of thrombosis.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient-specific risk factors influencing the perioperative risk of thrombosis

 
Yet, despite this knowledge and the availability of effective prophylactic methods and consensus guidelines, thromboembolism remains an important problem in surgery. One reason is the low level of implementation of prophylaxis among many clinicians. In several surveys it has been demonstrated that there is still considerable under-use of thromboprophylaxis, because of lack of awareness of the problem of thromboembolism combined with fears of bleeding complications and scepticism about the cost-effectiveness of thromboprophylaxis.5 14 Decisions about the need for prophylaxis are, as indicated above, further complicated by the wide variation in the risk of thromboembolism according to the type of operation and patient-specific risk factors.51 To overcome this problem, a number of risk assessment models (RAMs) have been created to assist physicians in making decisions about whether prophylaxis is needed and which type is required.20 73 88 An example of an RAM, published by the American College of Chest Physicians,20 is given in Table 2. Although RAMs have their limitations, such as the lack of extensive validation in various surgical settings and the fact that patients sometimes cannot be categorized, there are many advantages that outweigh these limitations. The major advantages of RAMs are: (i) risk stratification is less likely to be forgotten in the daily routine if each patient has to be categorized before surgery; (ii) important risk factors are more often checked if the physician can follow a checklist; (iii) thromboprophylaxis is less physician-dependent within departments; and (iv) thromboprophylaxis is less under- or overused.


View this table:
[in this window]
[in a new window]
 
Table 2 Risk assessment model (RAM) from the American College of Chest Physicians. Adapted from Samama88

 
Based on our experience, RAMs can be easily implemented in daily routine and, in addition to the above-mentioned advantages, they produce greater awareness and more discussion about thromboprophylaxis and a greater sense of security among anaesthetists and surgeons.

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 12–48 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


View this table:
[in this window]
[in a new window]
 
Table 3 Current established LMWH regimens for perioperative thromboprophylaxis.

 
An increasing body of literature, generally examining hip replacement patients as a risk model, shows a significant incidence of DVT developing only weeks after hospital discharge.77 In particular, a recent epidemiological study of 19 586 patients with hip arthroplasty has shown that 76% of patients suffering from symptomatic thrombosis experienced these events only after hospital discharge (median time 17 days).110 Whereas the overall frequency of symptomatic thromboses was 2.8%, the rate of venographic thromboses found in intervention studies is as high as 20%. With regard to possible complications, such as pulmonary embolism and post-thrombotic syndrome, asymptomatic thrombosis can be considered to be clinically significant. However, whether extended thromboprophylaxis should be given to all patients routinely after high-risk surgery is still a matter of debate. Results of several studies using LMWH for 4–6 weeks after major orthopaedic surgery have shown that the rate of venographic thromboses can be reduced by more than 50%.77 110 Coumarins, though cheaper, do not seem to offer the same degree of protection.16 91 Results of a recent systematic review of all available studies supported the need for extended out-of-hospital prophylaxis in patients undergoing arthroplasty surgery.46 It should be noted, however, that the true benefit of treating asymptomatic, venographic thromboses is not yet clear and data about cost-effectiveness are still lacking.

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 (12–24 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 drug–food 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


View this table:
[in this window]
[in a new window]
 
Table 4 Contraindications to neuraxial anaesthesia and analgesia.

 
These guidelines are similar9 35 44 in the following respects:
Admitting that data are incomplete and, in the case of the newer antiplatelet and antithrombotic drugs, virtually non-existent. This applies equally to drug combinations.
Regarding the risk of epidural haematoma during placement and removal of an epidural catheter to be similar and therefore applying the same rules.
Considering the risk of peripheral nerve and plexus blocks to be smaller than the risk of epidural analgesia.
Suggesting the use of low concentrations of local anaesthetics in combination with opioids (and epinephrine).
Monitoring the patient after surgery to detect paralysis suggestive of an early epidural haematoma.
Not discussing whether stopping antiplatelet or antico agulation therapy is advisable just to allow neuraxial anaesthesia or analgesia to be instituted, given the fact that stopping such therapy per se may result in major com plications,22 48 89 possibly linked to postoperative hyperco agulability.43 90

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).


View this table:
[in this window]
[in a new window]
 
Table 5 Precautions for neuraxial anaesthesia or analgesia in patients taking anticoagulant drugs. Recommended minimum delay between last dose and placement or removal of epidural catheter and minimum delay after placement or removal of epidural catheter and subsequent dosing of the drug (modified according to references 33, 38, 105 and 106). The first number represents these authors' recommendations; recommendations also found in the literature are in parentheses.

 
Management of patients on oral anticoagulants
Perioperative management of patients on regular oral anticoagulants is guided by the risk of thromboembolism and the bleeding associated with different anticoagulant strategies. While the risk of haemorrhage depends mainly on the site and type of surgery, the risk of thromboembolism depends on the indication for regular oral anticoagulation (arterial or venous prophylaxis), how long ago the patient had a thrombosis, and on the type of surgery.55 Based on these variables, the physician needs to determine for each patient the length of the perioperative anticoagulant-free window and the indication, type and dose of an alternative anticoagulant given after discontinuing and before resuming oral anticoagulation. Principally, in patients at high risk of thromboembolism, the anticoagulant-free window should be as short as possible, and during the time from stopping them to resuming coumarins an alternative anticoagulant should be given at a therapeutic or high prophylactic dose. In this situation, intravenous UFH is most useful as it can be given up to 2–4 h before surgery, can be easily monitored, and can be restarted soon after surgery with slowly increasing doses. LMWHs are less useful because of their long half-life and the limited possibility of antagonizing their anticoagulant effect. In patients at low risk of thromboembolism, the oral anticoagulant-free window can be longer and an alternative anticoagulant, if necessary at all, can be given in prophylactic doses.54 In these cases, LMWHs may be preferred. Classification of patients into groups at high and low risk of thromboembolism, as shown in Table 6, is based mainly on the chronic, not necessarily perioperative, risk of recurrence, and is thus somewhat arbitrary.


View this table:
[in this window]
[in a new window]
 
Table 6 Recommended management of patients on regular oral anticoagulants

 
There is no strict rule as to when coumarins should be stopped before surgery, as this decision depends on several factors, including the degree of anticoagulation, the type of coumarin, the indication, the time between hospital admission and surgery, and whether UFH can be administered intravenously. Spontaneous normalization of the INR takes about 4 days before surgery in patients with an INR between 2 and 3 who are taking warfarin.109 Vitamin K takes at least 24 h to fully antagonize oral anticoagulation. If urgent reversal of oral anticoagulation is needed, treatment includes infusion of fresh frozen plasma (FFP) or prothrombin complex concentrate. With both FFP and prothrombin complex concentrate, elevated INR values can be lowered within minutes. Prothrombin complex concentrate, however, is increasingly being used because the effect is more reliable and less volume overload occurs than with FFP.66 A recent report has shown that recombinant, activated FVIIa (rFVIIa; NovoSeven®) can also lower INR values quickly and effectively.96 This treatment, however, should be considered only if severe bleeding occurs.


    Perioperative haemorrhage
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
Predictability of bleeding
Some bleeding is due to insufficient or ineffective local surgical haemostasis and a certain percentage of procedures are accompanied by a degree of haemorrhage that is deemed to be excessive. In a large meta-analysis of more than 50 studies of DVT prophylaxis with heparin, it was noted that among the 7486 controls given placebo, 3.3% were considered to have bled excessively and that 0.1% died as a result of haemorrhage.23 Is it possible to identify such patients before surgery? Even in the 1980s, several studies had clearly demonstrated that no coagulation test, including PT, aPTT and bleeding time, is capable of providing this information.85 102 Newer studies have substantiated these findings.92 New test systems, such as the platelet function analyser PFA-100, which tests the adhesion and aggregation capability of platelets in flowing whole blood, are of limited value in predicting bleeding. Two recent studies found no significant correlation between the calculated intra- and postoperative blood loss and PFA-100 values in patients undergoing cardiac surgery.28 59 Somewhat better performance was found for thrombelastography, with a negative predictive value for postoperative bleeding after cardiac surgery of >80%, particularly when it was combined with PFA-100 measurements.15 In particular, the angle alpha was the best predictor and, in combination with the adenosine diphosphate PFA test, the predictive accuracy was further increased, although the positive predictive value was small (41%). The best method to determine haemorrhagic risk with surgery is an adequate history and physical examination. This important message is based on several large trials showing that patients with a definite or suspicious history of bleeding are more likely to bleed during surgery than patients with a negative history.23 45 92 However, the bleeding history may be misleading in patients who have never been exposed to surgery or trauma, or if the interviewer fails to ask the appropriate questions.

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.



View larger version (18K):
[in this window]
[in a new window]
 
Fig 2 Laboratory evaluation of a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT). Antiphospholipid antibody (APA) tests, as mentioned in the aPTT tree, may include lupus anticoagulants, anticardiolipin antibodies and anti-ß2-GPI antibodies. Clotting mixing tests are performed to detect acquired neutralizing antibodies (inhibitors) to single coagulation factors. DD=D-dimers; DIC=disseminated intravascular coagulation; Fbg=fibrinogen; TT=thrombin time.

 
Transfusion therapy: evidence and guidelines
Transfusion of blood products is associated with various risks.1 39 97 Restricted use is therefore advisable39 but under-transfusion also needs to be avoided.105 Guidelines have been issued by a variety of societies and expert panels.1 4 24 95 99 This review focuses on FFP and platelet transfusions. Guidelines for red blood cell transfusions1 4 24 95 98 99 are beyond the scope of this article.

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 µl–1 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 µl–1 in the presence of such risk factors.93 For major surgery, platelet transfusions are recommended to maintain platelet counts above 50 000 µl–1, particularly if microvascular bleeding occurs.1 93 Minor surgery, however, can be performed without platelet transfusion in patients with a platelet count <50 000 µl–1.58 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 µl–1 may be necessary. Only with severe platelet dysfunction will platelet counts >100 000 µl–1 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 kg–1 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.


    Emerging challenges
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
A challenging and growing problem in surgery is the increased use of new, non-antagonizable anticoagulants such as fondaparinux (Arixtra®), (xi)melagatran (Exanta®) and recombinant nematode anticoagulant protein c2 (NAPc2), a FVIIa/TF inhibitor. Although in several non-clinical reports rFVIIa has been shown to partly reverse the anticoagulant effect of fondaparinux and NAPc2,12 63 it remains unclear whether rFVIIa is really effective in clinical situations and whether it can be used routinely in view of its high cost. Another non-antagonizable anticoagulant is recombinant activated protein C (drotrecogin alpha, Xigris®)which is currently approved only in patients with severe sepsis. Although situations where patients receiving this drug need surgery may occur only rarely, their management will be challenging. Bleeding is the most common adverse reaction associated with Xigris therapy. In the PROWESS sepsis trial, serious bleeding events were observed in 3.5% of Xigris-treated and 2.0% of placebo-treated patients during the 28-day study period.10 Because the risk of bleeding may be increased significantly in patients with risk factors for bleeding, the manufacturer recommends that Xigris should not be used with concurrent heparin therapy, platelet counts <30 000 µl–1 and INR>3.0. In cases of bleeding, the infusion should be stopped immediately. As there is no known antidote for Xigris and effective antihaemorrhagic strategies are not known, administration of rFVIIa could theoretically be considered. However, because Xigris is administered to patients with sepsis, the often concomitant DIC may limit the use of rFVIIa.


    Summary
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
Today's understanding of coagulation is time-based (Fig. 1). At the site of injury, tissue factor is expressed and binds to FVIIa, which circulates in minute quantities in its activated form, activating small quantities of FXa, which produces small amounts of thrombin (FIIa). By several positive feedback-loops, the generation of thrombin is amplified and propagated. When thrombin generation is maximal, fibrin monomers are formed.

Indications and thromboprophylaxis regimens are reviewed (Tables 1 Go3), 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.


    Addendum
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
A haemostatic (procoagulant) therapy using recombinant factor VIIa may be beneficial following major trauma. Preliminary results of a large pivotal phase II multi-centre study in 280 trauma patients have recently been reported (http://www.novonordisk.com/). Patients treated with recombinant factor VIIa received less red blood cell transfusions, had fewer complications and spent less time in intensive care units. Severe adverse events including thrombo-embolic complications were equal in both groups.


    References
 Top
 Abstract
 The coagulation system: new...
 Perioperative thromboembolism
 Perioperative haemorrhage
 Emerging challenges
 Summary
 Addendum
 References
 
1 American Society of Anesthesiologists. A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy: Practice guidelines for blood component therapy. Anesthesiology 1996; 84: 732–47[ISI][Medline]

2 Aledort LM. Recombinant factor VIIa is a pan-hemostatic agent? Thromb Haemost 2000; 83: 637–8[ISI][Medline]

3 Amar D, Grant FM, Zhang H, et al. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology 2003; 98: 337–42[CrossRef][ISI][Medline]

4 American College of Physicians. Practice strategies for elective red blood cell transfusion. Ann Intern Med 1992; 116: 403–6[ISI][Medline]

5 Anderson FA, Wheeler HB, Goldberg RJ et al. Physician practices in the prevention of venous thromboembolism. Ann Intern Med 1991; 115: 591–5[ISI][Medline]

6 Andreu G, Morel P, Forestier F, et al. Hemovigilance network in France: organization and analysis of immediate transfusion incident reports from 1994 to 1998. Transfusion 2002; 42: 1356–64[CrossRef][ISI][Medline]

7 Arcelus JI, Caprini JA, Motykie GD, et al. Matching risk with treatment strategies in deep vein thrombosis. Blood Coagulation Fibrinolysis 1999; 10 (Suppl): S37–43

8 Beihering RJ, ten Cate H, Hurmohamed MT et al. Anticoagulants and extracorporeal circuits. Semin Thromb Hemost 1997; 23: 225–33[Medline]

9 Bergqvist D, Wu CL, Neal JM. Anticoagulation and neuraxial regional anesthesia: perspectives. Reg Anesth Pain Med 2003; 28: 163–6[CrossRef][ISI][Medline]

10 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709[Abstract/Free Full Text]

11 Bick RL, Schmalhorst WR, Shanbrom E. Prothrombin complex concentrate: use in controlling the hemorrhagic diathesis of chronic liver disease. Am J Dig Dis 1975; 20: 741–9[ISI][Medline]

12 Bijsterveld N, Moons A, Boekholdt S, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550–6[Abstract/Free Full Text]

13 Bohrer H. Prothrombin complex concentrate substitution during liver transplantation. Thromb Res 1999; 95: S71–4[CrossRef][ISI][Medline]

14 Bratzler DW, Raskob GE, Murray CK, et al. Underuse of venous thromboembolism prophylaxis for general surgery patients. Arch Intern Med 1998; 154: 1909–12[CrossRef]

15 Cammerer U, Dietrich W, Rampf T, et al. The predictive value of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg 2003; 96: 51–7[Abstract/Free Full Text]

16 Caprini JA, Arcelus JI, Motykie G, et al. The influence of oral anticoagulation therapy on deep vein thrombosis rates four weeks after total hip replacement. J Vasc Surg 1999; 30: 813–20[ISI][Medline]

17 Casati V, Sandrelli L, Speziali G, et al. Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: a prospective, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 2002; 123: 1084–91[Abstract/Free Full Text]

18 Cattaneo M, Harris AS, Stromberg U, et al. The effect of desmopressin on reducing blood loss in cardiac surgery–a meta-analysis of double-blind, placebo-controlled trials. Thromb Haemost 1995; 74: 1064–70[ISI][Medline]

19 Cheng JWM. Fondaparinux: a new antithrombotic agent. Clin Ther 2002; 24: 1757–69[CrossRef][ISI][Medline]

20 Clagett GP, Anderson FA, Geerts WH, et al. Prevention of venous thromboembolism. Chest 1998; 114 (Suppl): 531S–60S[Free Full Text]

21 Cofrancesco E, Cortellaro M, Corradi A, et al. Coagulation activation markers in the prediction of venous thrombosis after elective hip surgery. Thromb Haemost 1997; 77: 267–9[ISI][Medline]

22 Collet JP, Himbet F, Steg PG. Myocardial infarction after aspirin cessation in stable coronary artery disease patients. Int J Cardiol 2000; 76: 257–8[CrossRef][ISI][Medline]

23 Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic and urologic surgery. N Engl J Med 1988; 318: 1162–73[ISI][Medline]

24 Consensus Conference: Perioperative red blood cell transfusion. JAMA 1988; 260: 2700–3[CrossRef][ISI][Medline]

25 Dahlbäck B. Blood coagulation. Lancet 2000; 355: 1627–32[CrossRef][ISI][Medline]

26 Davis JW, Parks SN, Kaups KL et al. Admission base deficit predicts transfusion requirements and risk of complications. J Trauma 1996; 4: 764–74

27 Eriksson BI, Bergqvist D, Kalebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441–5[CrossRef][ISI][Medline]

28 Forestier F, Coiffic A, Mouton C, et al. Platelet function point-of-care tests in post-bypass cardiac surgery: are they relevant? Br J Anaesth 2002; 89: 715–21[Abstract/Free Full Text]

29 Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Ann Intern Med 2002; 137: 648–55[Abstract/Free Full Text]

30 Friedrich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet 2003; 361: 201–5[CrossRef][ISI][Medline]

31 Friederich PW, Levi M, Bauer K, et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 2001; 103: 2555

32 Fritsma GA. Clot-based assays of coagulation. In: Corriveau DM, Fritsma GA, eds. Hemostasis and Thrombosis in the Clinical Laboratory. Philadelphia: Lippincott, 1988; 82–99

33 Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119: S132–750[Free Full Text]

34 Gmür J, Burger J, Schanz U, et al. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia. Lancet 1991; 338: 1223–6[CrossRef][ISI][Medline]

35 Gogarten W, Van Aken H, Brüttner J, Riess H, Wulf H. Rückenmarksnahe Regionalanästhesien und Thromboembolieprophylaxe/antithrombotische Medikation. Anästhesiol Intensivmed 2003; 44: 218–30

36 Golanski R, Golanski J, Chizynski K, et al. Low doses of aprotinin in aortocoronary bypass surgery—advantages and disadvantages. Med Sci Monit 2000; 6: 722–8[Medline]

37 Golub R, Cantu R, Sorrento JJ, et al. Efficacy of preadmission testing in ambulatory surgical patients. Am J Surg 1992; 163: 565–571[CrossRef][ISI][Medline]

38 Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anesth 2003; 90: 596–9[Abstract/Free Full Text]

39 Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts—blood transfusion. N Engl J Med 1999; 340: 438–47[Free Full Text]

40 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340: 409–17[Abstract/Free Full Text]

41 Henry DA, Moxey AJ, Carless PA, et al. Desmopressin for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001; 2: CD001884

42 Heuer L, Blumenberg D. Recombinant factor VIIa (NovoSeven®). Anaesthesist 2002; 51: 388–94[CrossRef][ISI][Medline]

43 Hobisch-Hagen P, Wirleittner B, Mair J, et al. Consequences of acute normovolaemic haemodilution on haemostasis during major orthopedic surgery. Br J Anaesth 1999; 82: 503–9[Abstract/Free Full Text]

44 Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28: 172–97[CrossRef][ISI][Medline]

45 Houry S, Georgeac C, Hay JM, Fingerhut A, Boudet MJ. A prospective multicenter evaluation of preoperative hemostatic screening tests. The French Associations for Surgical Research. Am J Surg 1995; 170: 19–23[CrossRef][ISI][Medline]

46 Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135: 858–69[Abstract/Free Full Text]

47 Iselin BM, Willimann PF, Seifert B, et al. Isolated reduction of haematocrit does not compromise in vitro blood coagulation. Br J Anaesth 2001; 87: 246–9[Abstract/Free Full Text]

48 Jackson MR, Clagett GP. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 2001; 119: 283S–299S[Free Full Text]

49 Jamnicki M, Bombeli T, Seifert B, et al. Low- and medium-molecular-weight hydroxyethyl starches: comparison of their effect on blood coagulation. Anesthesiology 2000; 93: 1231–7[CrossRef][ISI][Medline]

50 Jeserschek R, Clar H, Aigner C, et al. Reduction of blood loss using high-dose aprotinin in major orthopaedic surgery: a prospective, double-blind, randomized and placebo-controlled study. J Bone Joint Surg 2003; 85: 174–7[CrossRef]

51 Kakkar VV. Low molecular weight heparins: prophylaxis of venous thromboembolism in surgical patients. Semin Haematol 1997; 34: 9–19[ISI][Medline]

52 Kambayashi J, Sakon M, Yokota M, et al. Activation of coagulation and fibrinolysis during surgery, analyzed by molecular markers. Thromb Res 1990; 60: 157[CrossRef][ISI][Medline]

53 Kaplan KL, Francis CW. Direct thrombin inhibitors. Semin Hematol 2002; 39: 187–96[CrossRef][ISI][Medline]

54 Kearon C. Perioperative management of anticoagulants. In Ginsberg J, Kearon C, Hirsh J, eds. Critical Decisions in Thrombosis and Hemostasis. Hamilton, Ontario: B.C. Decker, 1998; 109–16

55 Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506–11[Free Full Text]

56 Kmiecik SA, Liu JL, Vaadia TS, et al. Quantitative evaluation of hypothermia, hyperthermia, and hemodilution on coagulation. J Extra Corpor Technol 2001; 33: 100–5[Medline]

57 Koh SC, Pua HL, Tay DH, et al. The effects of gynaecological surgery on coagulation activation, fibrinolysis and fibrinolytic inhibitor in patients with and without ketorolac infusion. Thromb Res 1995; 79: 501–14[CrossRef][ISI][Medline]

58 Lajmanovich A, Hudry-Clergeon G, Freyssinet JM, et al. Human factor VIII procoagulant activity and phospholipid interaction. Biochim Biophys Acta 1981; 678: 132–6[ISI][Medline]

59 Lasne D, Fiemeyer A, Chatellier G, et al. A study of platelet functions with a new analyzer using high shear stress (PFA-100) in patients undergoing coronary artery bypass graft. Thromb Haemost 2000; 84: 794–9[ISI][Medline]

60 Lassen MR, Borris LC, Christiansen HM, et al. Clinical trials with low-molecular weight heparins in the prevention of postoperative thromboembolic complications: a meta analysis. Semin Thromb Haemost 1991; 17: 284–90[ISI][Medline]

61 Leizorovicz A, Haugh MC, Chapuis FR, et al. Low molecular weight heparin in the prevention of perioperative thrombosis. BMJ 1992; 305: 913–20[ISI][Medline]

62 Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency: a multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994; 107: 543–51[Abstract/Free Full Text]

63 Lodge P, Jonas S, Jaeck D, et al. Recombinant factor VIIa (NovoSeven) in partial hepatectomy: a randomized, placebo-controlled, double-blind clinical trial. Accessed 4 November 2003. Available from: http://www.novonordisk.com/images/investors/conferences_abstracts/aasld_nov02_abstract_177.pdf

64 Lorenz R, Kienast J, Otto U, et al. Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol 2003; 15: 15–20[CrossRef][ISI][Medline]

65 Luk C, Eckert KM, Barr RM, et al. Prospective audit of the use of fresh-frozen plasma, based on Canadian Medical Association transfusion guidelines. Can Med Assoc J 2002; 166: 1539–40[Free Full Text]

66 Makris M, Greaves M, Phillips WS, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77: 477–80[ISI][Medline]

67 Mannucci PM. Hemostatic drugs. New Engl J Med 1998; 339: 245–53[Free Full Text]

68 Mattsson C, Menschiek-Lundin A, Wahlander K, et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thromb Haemost 2001; 86: 611–5[ISI][Medline]

69 Michlig C, Vu DH, Wasserfallen JB, et al. Three years of haemovigilance in a general university hospital. Transfus Med 2003; 13: 63–72[ISI][Medline]

70 Monroe DM, Hoffman M, Allan GA, et al. The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia. Semin Thromb Haemost 2000; 26: 373–7[CrossRef][ISI][Medline]

71 Mossinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation n pediatric surgery. Ann Thorac Surg 2003; 75: 430–7[Abstract/Free Full Text]

72 Nakazawa F, Kannemeier C, Trusheim H et al. A new factor triggering blood coagulation: The long sought natural ‘foreign’ surface. In: GTH Congress, Innsbruck, 2003: Abstract 19

73 Nicolaides AN, Bergqvist D, Hull R, et al. Consensus statement: prevention of venous thromboembolism. Int Angiol 1997; 16: 3–38[ISI][Medline]

74 Ozkisacik E, Islamoglu F, Posacioglu H, et al. Desmopressin usage in elective cardiac surgery. J Cardiovasc Surg (Torino) 2001; 42: 741–74[ISI][Medline]

75 Palfi M, Berg S, Ernerudh J, et al. A randomized controlled trial of transfusion-related acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion 2001; 41: 317–22[CrossRef][ISI][Medline]

76 Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann Surg 2001; 234: 560–9; discussion 569–71[CrossRef][ISI][Medline]

77 Planes A, Vochelle N, Darmon JY, et al. Risk of deep vein thrombosis after hospital discharge in patients having undergone total hip replacement; double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348: 224–8[CrossRef][ISI][Medline]

78 Pleym H, Stenseth R, Wahba A, et al. Single-dose tranexamic acid reduces postoperative bleeding after coronary surgery in patients treated with aspirin until surgery. Anesth Analg 2003; 96: 923–8[Abstract/Free Full Text]

79 Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000; 355: 1289–90[CrossRef][ISI][Medline]

80 Porte RJ, Slooff MJ. Aprotinin: safe and effective in all patients undergoing orthotopic liver transplantation? Liver Transpl 2001; 7: 808–10[CrossRef][ISI][Medline]

81 Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. Fresh-Frozen Plasma, Cryoprecipitate, and Platelets Administration Practice Guidelines Development Task Force of the College of American Pathologists. JAMA 1994; 271: 777–81[CrossRef][ISI][Medline]

82 Quaknine-Orlando B, Samama CM, Riou B, et al. Role of the hematocrit in a rabbit model of arterial thrombosis and bleeding. Anesthesiology 1999; 90: 1454–61[CrossRef][ISI][Medline]

83 Rentoul TM, Harrison VL, Shun A. The effect of aprotinin on transfusion requirements in pediatric orthotopic liver transplantation. Pediatr Transplant 2003; 7: 142–82[ISI][Medline]

84 Rigg JR, Jamrozik K, Myles PS, et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet 2002; 359: 1276–82[CrossRef][ISI][Medline]

85 Rohrer MJ, Michelotti MC, Nahrwold DL. A prospective evaluation of the efficacy of preoperative coagulation testing. Ann Surg 1988; 208: 554–7[ISI][Medline]

86 Ruf W. The interaction of activated factor VII with tissue factor: insight into the mechanism of cofactor-mediated activation of activated factor VII. Blood Coagul Fibrinolysis 1998; 9 (Suppl 1): S73–84[ISI][Medline]

87 Sagmeister M, Oec L, Gmur J. A restrictive platelet transfusion policy allowing long-term support of outpatients with severe aplastic anemia. Blood 1999; 93: 3124–6[Abstract/Free Full Text]

88 Samama CM. Applying risk assessment models in general surgery: effective risk stratification. Blood Coagul Fibrinolysis 1999; 10 (Suppl): S79–84[ISI][Medline]

89 Samama CM, Bastien O, Forestier F, et al. Antiplatelet agents in the perioperative period: expert recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) 2001—summary statement. Can J Anaesth 2002; 49: S26–35[ISI][Medline]

90 Samama CM, Thiry D, Elalamy I, et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001; 94: 74–8[CrossRef][ISI][Medline]

91 Samama CM, Vray M, Barre J, et al. Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecular-weight heparin with oral anticoagulant. Arch Intern Med 2002; 162: 2191–6[Abstract/Free Full Text]

92 Schein OD, Katz J, Bass EB, et al. The value of routine preoperative medical testing before cataract surgery. N Engl J Med 2000; 342: 168[Abstract/Free Full Text]

93 Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: 1519–38[Abstract/Free Full Text]

94 Silliman CC, Bjornsen AJ, Wyman TH, et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003; 43: 633–40[CrossRef][ISI][Medline]

95 Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions: developed by the Red Blood Cell Administration Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1998; 122: 130–8[ISI][Medline]

96 Soerensen B, Johansen P, Nielsen GL, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14: 469–77[CrossRef][ISI][Medline]

97 Spahn DR, Casutt M. Eliminating blood transfusions: new aspects and perspectives. Anesthesiology 2000; 93: 242–55[CrossRef][ISI][Medline]

98 Spahn DR, Schanz U, Pasch T. Perioperative Transfusionskriterien. Anaesthesist 1998; 47: 1011–20[CrossRef][ISI][Medline]

99 Stehling L, Luban NL, Anderson KC, et al. Guidelines for blood utilization review. Transfusion 1994; 34: 438–48[CrossRef][ISI][Medline]

100 Strebel N, Prins M, Agnelli G, et al. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2003; 163: 1451–6

101 Stuklis RG, O'Shaughnessy DF, Ohri SK. Novel approach to bleeding patients undergoing cardiac surgery with liver dysfunction. Eur J Cardiothorac Surg 2001; 19: 219–20[Abstract/Free Full Text]

102 Suchmann AL, Mushlin AL. How well does the activated partial thromboplastin time predict postoperative hemorrhage? JAMA 1986; 256: 750–3[Abstract]

103 Turpie AG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833–40[Abstract/Free Full Text]

104 Valeri CR, Cassidy G, Pivacek LE, et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion 2001; 41: 977–83[CrossRef][ISI][Medline]

105 Valeri CR, Crowley JP, Loscalzo J. The red cell transfusion trigger: has a sin of commission now become a sin of omission? Transfusion 1998; 38: 602–10[CrossRef][ISI][Medline]

106 Veien M, Sorensen JV, Madsen F, et al. Tranexamic acid given intraoperatively reduces blood loss after total knee replacement: a randomized, controlled study. Acta Anaesthesiol Scand 2002; 46: 1206–11[CrossRef][ISI][Medline]

107 Verstraete M. Clinical application of inhibitors of fibrinolytics. Drugs 1985; 29: 236–61[ISI][Medline]

108 Weitz JI, Hirsh J. New antithrombotic agents. Chest 2001; 119: 95S–107S[Free Full Text]

109 White RH, McKittrick T, Hutchinson R, et al. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122: 40–2[Abstract/Free Full Text]

110 White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158: 1525–31[Abstract/Free Full Text]