The transfusion of blood components is part of the everyday clinical routine in the operating room. Many operations are rendered possible through the availability of blood components. However, surgeons and anaesthetists are well aware of the potential side-effects of blood transfusions, such as transfusion-related lung injury, bacterial contamination with subsequent septic deterioration, viral infections or potential immunomodulatory effects [1-3]. Further, patients nowadays are also aware of these risks and may ask for bloodless operative strategies. Surgeons have adapted their techniques such that surgical blood loss is minimized. Anaesthetists have also developed techniques to reduce perioperative blood loss, such as deliberate hypotension, autotransfusion and haemodilution [4-7]. Despite these efforts, some patients suffer from substantial blood loss, the reason being a diffuse bleeding. Once initiated by surgical procedures, a vicious circle may be entered which cannot be treated or stopped by the surgeon, since it is not a single vessel contributing to this blood loss, but a diffuse bleeding from numerous tiny capillaries. In the following, this type of blood loss will be referred to as 'non-surgical blood loss'. Since it cannot be treated mechanically by clipping or ligation, it is mostly the anaesthetist who is challenged by this type of bleeding. An imbalance between coagulation and fibrinolysis, and a lack or malfunction of platelets are possible reasons for such non-surgical bleeding. Any such specific disturbances should be treated immediately. However, in some cases the reason for non-surgical blood loss remains obscure, and no causative treatment seems available.
In this review, we establish a step-by-step approach to the treatment of such non-surgical blood loss. However, it is important to notice that after each step the situation should be re-evaluated, in particular, to determine whether the blood loss really is of a non-surgical nature. Methods described in the following may be ineffective in case of surgical blood loss.
Figure 1 schematically shows an escalating approach to non-surgical bleeding.
The first step is the administration of desmopressin. Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. DDAVP causes a release of von Willebrand's factor from endothelial storage sites and, thus, improves primary haemostasis. Platelets are more likely to bind with their glycoprotein receptors to the damaged endothelium due to the increase in the concentration of von Willebrand's factor on the surface of damaged endothelium, and because DDAVP increases the density of glycoprotein receptors on the platelet surface [8,9]. DDAVP is of use in healthy subjects [10-12] and will also shorten the prolonged bleeding time in patients with platelet dysfunction related to uraemia, liver cirrhosis or treatment with non-steroidal anti-inflammatory drugs [13,14]. The maximum effect of DDAVP can be obtained at a dose of 0.3 μg kg−1body weight .
However, DDAVP should not be administered routinely due to a number of side-effects; the most important of which is vasodilatation with subsequent fall in blood pressure. DDAVP is also ineffective in blood loss reduction in patients with undisturbed haemostasis . In routine coronary artery bypass grafting (CABG), e.g. DDAVP administration had no beneficial effect on perioperative blood loss . However, in more complicated cardiac surgery, such as repeat surgery or valve replacements or in patients preoperatively treated with aspirin, the administration of DDAVP caused a significant reduction in blood loss [18,19]. Thus, DDAVP should only be given to patients who have been intraoperatively diagnosed with diffuse bleeding. When substantial blood loss is anticipated, prophylactic administration seems reasonable. Once bleeding is established there is evidence that DDAVP administration can improve haemostasis [20,21]. It should be given as an intravenous (i.v.) infusion of 0.3 μg kg−1 over 30 min to prevent hypotension. Since the endothelial storage sites need some time to be refilled, a repeat dose of DDAVP should not be given earlier than 6 h after the first dose. Simultaneously with the DDAVP administration, blood should be taken to monitor prothrombin time using the international normalized ratio and to measure platelet count. If the platelet count is low (<80 × 109L−1) or there is a prolonged international normalized ratio (>1.5) and the administration of DDAVP has proved ineffective, blood components should be transfused (Fig. 1, Step 2).
A search of the MEDLINE database for evidence-based studies on transfusion practice for fresh frozen plasma (FFP) and platelets revealed little information. In 1994, the ASA established a Task Force on Blood Component Therapy to develop evidence-based indications for transfusing red blood cells, platelets and FFP in perioperative settings . The ASA Guidelines recommend platelet transfusion in cases where the platelet count is below 50 × 109L−1. With intermediate platelet counts (50-100 × 109L−1), the indication should be based on the patient's risk for significant bleeding. It is well established that platelet transfusion increases platelet count and they are often used to improve primary haemostasis. The magnitude of effect is variable and is influenced by the release of stored platelets from the spleen and peripheral platelet destruction. Platelet concentrates derived from a single donor and collected by apheresis are preferable when compared to pooled platelets . Four to six units of pooled platelets are equivalent to one single donor platelet apheresis concentrate . Transfusion of one apheresis platelet concentrate will increase the platelet count by approximately 25 × 109L−1 in the average non-immunized adult. There is indirect evidence from non-surgical settings regarding the effectiveness of platelets in controlling bleeding. Studies of leukaemic patients with platelet counts of 30 × 109L−1 or less suggest that the incidence of spontaneous bleeding can be decreased by platelet transfusions. However, similar studies in surgical patients are lacking. Stephan and colleagues have looked at the efficacy of prophylactic platelet transfusion in critically ill thrombocytopaenic patients . Thrombocytopaenia in itself was associated with a significantly higher mortality rate. Further, transfusion of platelets with subsequent correction of platelet counts led to a significant reduction in mortality. Stephan and colleagues concluded that thrombocytopaenia is linked to mortality because it reflects the severity of the underlying illness, and that the transfusion of platelets in such critically ill patients serves to improve outcome .
FFP is administered to improve international normalized ratio and for preoperative correction of known coagulation factor deficiencies for which specific concentrates are unavailable. In case of perioperative non-surgical bleeding, FFP is used to treat microvascular bleeding when prothrombin and partial thromboplastin times are >1.5 times normal. Evidence for depletion of coagulation factors to an extent sufficient to produce perioperative bleeding due to dilutional coagulopathy is limited. Blood coagulation usually is undisturbed as long as all coagulation factor concentrations are at least 20-30% of normal and when fibrinogen concentrations are >75 mg dL−1[25,26]. However, in patients undergoing massive transfusion, a dilutional coagulopathy is a relevant clinical problem. Particularly, when autotransfusion devices are used to minimize the loss of red blood cells, a dilutional coagulopathy must be considered. The process of washing the salvaged red blood cells to eliminate cellular debris, fragments and added heparin washes out the plasma, including all coagulation factors. The dose of FFP needed to treat a coagulopathy is quite substantial: 1 mL kg−1 body weight leads to only a 1% increase in coagulation factors. This implies that for an average adult (80 kg body weight), 4 units FFP (≈800 mL) produces a 10% increase in coagulation factors. Anything less cannot cause any significant improvement in coagulation. Unfortunately, clinicians often under-treat coagulopathies and order 1-2 units of FFP, a dose that neither improves coagulation nor is cost-effective  and potentially puts the patient at risk of transfusion-related diseases.
If bleeding continues despite the previous measures (DDAVP, FFP and platelets), and if a surgical cause for the blood loss has been excluded, then antifibrinolytic agents are the next option in the anaesthetists arsenal to fight blood loss (Fig. 1, Step 3). Physiologically, coagulation and fibrinolysis are normally balanced, leading to sufficient clotting to arrest any type of bleeding, while at the same time preventing clots developing spontaneously without underlying tissue damage. Both coagulation and fibrinolysis are essential for life.
Surgical procedures, like any other wounds, trigger an activation of the coagulation pathway, thus guaranteeing that we do not bleed to death . However, in order to prevent general clotting with subsequent embolization, the fibrinolytic system is also activated. Although coagulation and fibrinolysis normally are balanced, this may no longer hold true in the perioperative setting. The fibrinolytic system may dominate, as seen in patients undergoing cardiopulmonary bypass (CPB), or patients undergoing surgery on extremities with the use of a tourniquet to provide a bloodless field. The administration of an antifibrinolytic agent may then serve to bring coagulation and fibrinolysis back into balance. A recent meta-analysis showed that aprotinin, as well as certain lysine analogues (tranexamic acid and epsilon-aminocaproic acid), significantly reduced blood loss, and this translated into a significantly reduced exposure to homologous blood components .
While aprotinin is preferred by many centres in cardiac surgery for reasons other than reduction in blood loss (it has an anti-inflammatory action), other antifibrinolytics (such as tranexamic acid or epsilon-aminocaproic acid) have the same effect on blood loss, but are much cheaper. Further, aprotinin has the potential to possibly cause an anaphylactic reaction following previous exposure to aprotinin.
While antifibrinolytics normally cause a reduction in blood loss, this certainly does not hold true for every patient. Thromboelastography may help to differentiate between hyperfibrinolysis and hypocoagulation in the bleeding patient . However, this technique is neither widely accepted nor readily available in most hospitals. The same limitations hold true for the in vitro bleeding time , a standardized in vitro test to simulate the rather non-specific in vivo bleeding time. Thus, the administration of antifibrinolytic agents tends to be empirical rather than being based upon specific tests indicating the efficacy of this therapeutic approach. However, in cases of non-surgical bleeding refractory to DDAVP, FFP and platelets, the administration of antifibrinolytics is a reasonable and often effective approach.
Antithrombin III and prothrombin complex concentrates
In cases where the international normalized ratio remains inadequate, FFP has already been transfused and blood loss has not stopped, consideration should be given to transfusing prothrombin complex concentrates (PCC) and antithrombin III (AT III) (Fig. 1, Step 4). AT III, the main physiological serine protease inhibitor, plays an important role in the regulation of haemostasis. This glycoprotein is synthesized in the liver and appears to be the most active serine protease inhibitor generated during blood coagulation . Its activity is increased 1000-fold by heparin and heparan sulphate. The concentration of AT III in plasma is decreased in the conditions associated with disseminated intravascular coagulation, particularly in sepsis and shock. AT III should be administered, if it is thought that the non-surgical bleeding is related to disseminated intravascular coagulation. In clinical practice, this disorder can be diagnosed on the basis of the following findings:
• an initial platelet count of <100 × 109L−1 or a rapid decline in the platelet count;
• prolongation of clotting times, such as prothrombin time and activated partial thromboplastin time;
• the presence of fibrin-degradation products in plasma;
• low plasma concentrations of coagulation inhibitors, such as AT III .
Uncontrolled clinical studies have reported that AT III substitution might prevent disseminated intravascular coagulation and death in septic shock [34,35]. Fourrier and colleagues conducted a randomized double-blind placebo-controlled trial in 35 patients with documented septic shock and disseminated intravascular coagulation . The duration of disseminated intravascular coagulation was significantly reduced in the AT III group. Mortality was reduced, but the difference did not reach statistical significance . Imperfect design and small size of most trials of AT III in human beings may explain this lack of significance, but a large multicentre trial of AT III in sepsis is in progress and may help to settle the issue of its efficacy .
PCC seems to offer a fast and easy method to improve coagulation compared with the transfusion of FFP. PCC contains factors V, VII, IX and X. One should keep in mind that only FFP contains all coagulation factors and fibrinolytics, which are important in treating patients suffering from ongoing blood loss. The dosage of PCC can be calculated in the following way:
It is noteworthy that over the last two decades the thrombogenicity of PCC has generated controversy . Staudinger and colleagues conducted a prospective clinical study on 16 intensive care patients suffering from acquired coagulation deficiencies and haemorrhage . Patients received 2000 factor IX units of a commercially available PCC (i.v.). The authors could not demonstrate any evidence for induction of disseminated intravascular coagulation. Staudinger and colleagues concluded that the use of PCC seems reasonable, if rapid correction of acquired coagulation factor disturbances is needed, keeping the possible risk of thrombogenicity in mind . Prophylactic administration of AT III first, before PCC is given, has been proposed as a method to avoid thromboembolic complications after PCC therapy . Staudinger and colleagues do not recommend this strategy of prophylactic AT III administration, because substantial prospective data supporting any possible beneficial effects of this regimen are absent .
Administration of factor XIII is the penultimate step for treating non-surgical blood loss (Fig. 1, Step 5). The functional A-chain of coagulation factor XIII is a transglutaminase that catalyses the formation of cross-linking epsilon-lysine bonds between fibrin molecules resulting in significant increases in mechanical clot strength and resistance to proteolytic processes caused by plasmin . Individuals suffering from congenital factor XIIIa deficiency have a severe bleeding disorder that can be treated prophylactically with infusions of human recombinant coagulation factor XIIIa concentrates. When treating patients with ongoing blood loss, it should always be kept in mind that platelet count and factor XIIIa levels are closely related. Platelets play a critical role in maintaining clot strength and serve as an alternate source of factor XIIIa [43,44]. In turn, coagulation factor XIIIa stabilizes the clot and links platelets to it. A combination of adequate platelet counts and factor XIIIa concentrates might provide sufficient haemostasis and stop bleeding in critically ill patients [45,46]. In severe bleeding, 2500 IU of coagulation factor XIIIa should be administered i.v. for adult patients. A commercial package of 1250 IU contains 120-320 mg total protein corresponding to 500 units factor XIIIa, 120-150 mg human albumin, 80-120 mg glucose and 140-220 mg sodium chloride.
Administration of factor VIIa is the last step in the management of non-surgical blood loss (Fig. 1, Step 6). As a 'rescue'-approach to improve coagulation in these critically ill patients the use of recombinant factor VIIa in a concentration of 50-100 μg kg−1 is recommended  (Fig. 1, Step 5).
Coagulation factor VII initiates haemostasis by binding to membrane-bound glycoprotein tissue factor at the site of injury, forming a tissue factor-factor VIIa complex . The complex activates thrombin generation and platelets. Activated platelets are essential for the development of a full thrombin burst, which is necessary for the development of a solid fibrin plug. Initially, recombinant factor VIIa was developed for the prevention of spontaneous bleeding episodes and for diminution of intraoperative blood loss for patients suffering from haemophilia. The development of antibodies against clotting factors VIII or IX can occur as a consequence of therapy with replacement coagulation factors, or in patients with acquired coagulation disorders, e.g. critically ill patients with ongoing haemorrhage. For these indications, recombinant factor VIIa has been shown to be efficacious and safe  and is now an accepted treatment . In animal experiments no potential for thrombogenicity of recombinant factor VIIa could be found . Recombinant factor VIIa increases thrombin generation in patients suffering from thrombocytopaenia , even in patients refractory to platelet transfusion due to platelet-specific antibodies . Despite these advantages one should keep in mind that each dose of the protein is currently very expensive. The clearance of recombinant factor VIIa is approximately 30-35 mL kg−1 h−1 in adults and even greater in children, requiring repeated dosing approximately every 2 h for maintenance of efficacy [51,54]. Although factor VII is a component of FFP and PCC, the isolated administration of this coagulation factor as a last resort for treatment of ongoing bleeding is reasonable [55,56]: recombinant factor VIIa exerts its maximum effect in a 10-fold higher concentration than the physiological level of factor VIIa. In contrast to FFP and PCC, recombinant factor VIIa is given in supra-physiological doses, which means that its administration is a pharmacological therapy and not just a substitution of a single coagulation factor. A supraphysiological dose can compensate for a lack of coagulation factors VIII or IX, the so-called 'bypass' effect , and in this case the development of a thrombin burst is not influenced by any coagulation defect. Currently, a multicentre, randomized controlled clinical trial looking at the efficacy of factor VIIa in bleeding trauma patients is in progress.
The treatment of critically ill patients has substantially improved over the last few decades but non-surgical bleeding remains a problem. Optimization of the coagulation system is easy to demand but is a major challenge to produce. This review describes a step-by-step approach for the management of non-surgical bleeding. While most non-surgical bleeding can be managed using this approach a small number of patients still continue to bleed. In these cases, the surgeon should re-evaluate the bleeding in terms of its surgical origin. If this can positively be excluded, and if all the above-mentioned measures fail to reduce, or preferably stop the bleeding, the further treatment of such uncontrolled bleeding remains symptomatic (e.g. transfusion of packed red blood cells). The patient's risk of perioperative morbidity (such as renal failure, transfusion-related acute lung injury, sepsis or systemic inflammatory response syndrome) and even mortality is extremely high. In this context, it should be remembered that even now the entire pathophysiological background of coagulation disorders often remains obscure: the impact of the various pro- and anti-inflammatory mediators including the complement system is not fully elucidated. Until these issues are resolved, treatment of bleeding patients in some cases remains symptomatic rather than causative.
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