Perioperative transfusion strategy]

Tactics in blood transfusion have evolved considerably during the last ten years. Awareness of infectious risks and economic considerations have lead legislators to draw the guidelines for a safer transfusion. Their aim is to promote a better transfusion in smaller quantities at a lower risk. The goal of perioperative blood replacement is to maintain hemoglobin, blood volume and coagulation factors at an adequate level. This can be carried out by either homologous or autologous transfusion. Fresh frozen plasma transfusion is only required in severe bleeding where coagulation factors are depleted. The plasma substitutes must be used according to their intrinsic properties and their cost. The choice of an autologous technique depends on the type of surgical procedure, the expected blood loss and the economic resources available. Autologous blood transfusion may be optimized by the association of various techniques. This transfusion strategy must be elaborated by all the medical protagonists implicated in transfusion procedures.     

Gerinnungstherapie beim Polytrauma ohne Point-of-care-Testung

Analysis of blood coagulation with thrombelastometry (ROTEM?) and thrombelastography (TEG?) and analysis of thrombocyte function by a Multiplate? assay is possible in only a few hospitals in Germany. Recently, the grade of recommendation (GoR) for point-of-care (POC) testing in official guidelines was increased and is now classified as GoR 1C. If a POC-based option is not available alternatives must be used. Besides blood products (RBC, FFP, TC), coagulation factor concentrates are used to treat trauma-induced coagulopathy. The benefits of therapy with factor concentrates are fewer immunological and infection side effects as well as faster effects after administration of specific coagulation factors. A good outcome in patients with multiple trauma is only possible by an adequate transfusion regime and administration of coagulation factors.     

Dilutional coagulopathy, an underestimated problem?

When no fresh frozen plasma is available, acute major blood loss is compensated above all with crystalloids, colloids and erythrocyte concentrates, meaning that all plasma clotting factors are diluted. Consumption coagulopathy is almost always accompanied by dilutional coagulopathy. Formulas for calculating critical blood loss and standard coagulation tests are often not helpful in the case of massive transfusion. On the other hand, systems suitable for point of care, such as thrombelastography, have important advantages. In the case of consumption and dilutional coagulopathy plasma coagulation is disturbed and critical values are first seen for fibrinogen. Not only is fibrin polymerization impaired by the bleeding-induced loss and dilution of fibrinogen, but also by interaction with artificial colloids, particularly hydroxyethyl starch preparations. Therapy of consumption and dilutional coagulopathy calls for fresh frozen plasma. If this is not available in sufficient quantity or within a reasonable time, coagulation factor concentrates must be used. Neither fresh frozen plasma therapy nor treatment with coagulation factor concentrates has been the subject of detailed clinical study. Further studies are needed to work out guidelines for coagulation management in the case of massive blood loss.     

Neue (Querschnitt-)Leitlinien der Bundesärztekammer für die Hämotherapie mit gefrorenem Frischplasma

Some new blood products and plasma derivatives have extended the possibilities in hemotherapy to such an extent that the therapeutic and evidence-based therapy options can only really be managed with the aid of guidelines. Four approved plasma preparations are available in Germany: fresh frozen plasma, lyophilized plasma, solvent-detergent (SD) pool plasma and methylene blue-light-treated plasma. Evidence of the clinical efficacy of plasma is mainly based on uncontrolled observational studies, case reports or expert opinion. Plasma is indicated for complex coagulopathy associated with manifest or imminent bleeding, particularly with massive transfusion, disseminated intravascular coagulation and liver disease. With the exception of emergency situations when clotting assay results are not available in time, a clinically relevant coagulopathy must be verified before plasma is administered. The rapid infusion of at least 10 ml of plasma per kg body weight is required to significantly increase the respective clotting factor or inhibitor levels. Prothrombin complex concentrates (PPSB) should be preferred to plasma for the rapid reversal of oral anticoagulation. Side effects of plasma are rare but have to be considered.     

Haemostaseological aspects of perioperative blood management

Recent studies in humans have shown that tissue factor on the surface of endothelial cells, monocytes, or subendothelial structures sparks plasmatic coagulation. In vivo, there is no functional separation of an "endogenous" and "exogenous" pathway of the coagulation cascade. However, global laboratory tests run along such pathways due to preincubation with specific activators and, hence, allow localization of inherited coagulation defects. Coagulation inhibitors such as antithrombin or activated protein C are accelerated in their activity by cell surface glycoproteins and almost completely inactivate procoagulant activity in the microcirculation. Antithrombin binds to endothelial glycosaminoglycans and then significantly increases anticoagulant activity. Protein C is activated by the thrombin-thrombomodulin-complex and inactivates factors V a and VIII a, respectively. Additionally, activated protein C has a profibrinolytic effect. Both systems physiologically counteract the procoagulant transformation of endothelial and monocyte cell surfaces which occurs in critically ill patients due to induction of tissue factor, suppression of thrombomodulin, and removal of glycosaminoglycans from the cell surface. The distinction of static and dynamic coagulation disorders is useful since static disorders seldom require therapeutic interventions although global laboratory tests may continuously deteriorate. Dynamical disorders are symptoms of an underlying disease, and consumption coagulopathy with disseminated fibrin deposition and oozing occurs when coagulation turnover cannot be stopped. Antithrombin substitution is a well documented therapeutic option along with fresh frozen plasma and erythrocyte concentrate transfusion for blood substitution. Recent case reports in patients with irreversible bleeding complications favour the application of a recombinant factor VII concentrate. A rising perspective to decrease the use of heterologous blood and blood products may be intraoperative plasma retransfusion. The quality of such plasma undergoing consecutive filtration steps has to be clinically studied. The application of a synthetic platelet substitute, the "plateletsome", containing platelet glycoproteins led to significantly improved haemostasis without generating systemic procoagulant activity. In a far future, procoagulant cell surface transformation may be influenced by topic application of inhaled thrombomodulin loaded liposomes or by sense or antisense oligonucleotides inducing thrombomodulin expression or suppressing tissue factor expression, respectively.     

Management of massive operative blood loss

Coagulopathy associated with massive operative blood loss is an intricate, multicellular and multifactorial event. Massive bleeding can either be anticipated (during major surgery with high risk of bleeding) or unexpected. Management requires preoperative risk evaluation and preoperative optimization (discontinuation or modification of anticoagulant drugs, prophylactic coagulation therapy). Intraoperatively, the causal diagnosis of the complex pathophysiology of massive bleeding requiring rapid and specific coagulation management is critical for the patient's outcome. Treatment and transfusion algorithms, based on repeated and timely point-of-care coagulation testing and on the clinical judgment, are to be encouraged. The time lapse for reporting results and insufficient identification of the hemostatic defect are obstacles for conventional laboratory coagulation tests. The evidence is growing that rotational thrombelastometry or modified thrombelastography are superior to routine laboratory tests in guiding intraoperative coagulation management. Specific platelet function tests may be of value in platelet-dependent bleeding associated e.g. with extracorporeal circulation, antiplatelet therapy, inherited or acquired platelet defects. Therapeutic approaches include the use of blood products (red cell concentrates, platelets, plasma), coagulation factor concentrates (fibrinogen, prothrombin complex, von Willebrand factor), pharmacological agents (antifibrinolytic drugs, desmopressin), and local factors (fibrin glue). The importance of normothermia, normovolemia, and homeostasis for hemostasis must not be overlooked. The present article reviews pathomechanisms of coagulopathy in massive bleeding, as well as routine laboratory tests and viscoelastic point-of-care hemostasis monitoring as the diagnostic basis for therapeutic interventions.     

Vitamin K and its rôle in blood coagulation

Although the exact mechanism of blood coagulation is not fully understood, it is generally accepted that prothrombin, thromboplastin and calcium interact to form thrombin which combines with fibrinogen to form fibrin. The only physiological anticoagulant known is heparin, which is not found in circulating blood in any appreciable amount.Vitamin k apparently is a precursor or possibly an enzyme in the formation of prothrombin, which is a product of liver metabolism. Absorption of the natural fat-soluble vitamin k from the intestinal tract requires the presence of adequate bile salts and a normal intestinal mucosa. Its utilization after assimilation depends on the presence of healthy liver tissue for the formation of prothrombin.Synthetic vitamin k products, generally more potent than the natural vitamin, are naphthoquinone derivatives, most of which are water-soluble and can be administered parenterally.Vitamin k is of greatest value in correcting the abnormal blood coagulation due to hypoprothrombinemia as a result of obstructive jaundice or biliary fistulas. It is also useful in correcting hypoprothrombinemia of the newborn.All patients submitted to biliary tract surgery in the presence or absence of jaundice should have prothrombin determinations and vitamin k therapy preoperatively and postoperatively. The plasma prothrombin response to vitamin k therapy in the presence of a hypoprothrombinemia may be used as a sensitive liver function test.In the recommended therapeutic doses vitamin k and its related synthetic products are not toxic.     

New aspects of therapy with blood and blood components

For diminishing transfusion risks and for ethical and economical reasons a rational hemotherapy is indispensable. The "Berner model" referred to here contains an acceptable explanation. It is evident that the overwhelming part of surgical interventions is accomplished by using erythrocyte concentrates. Therefore, fresh whole blood and fresh frozen plasma are better available. Coagulational active plasma fractions have unchanged indications for a rational substitution of coagulation factors. New indications for some blood components are described.     

Frischplasma und Faktorenkonzentrate zur Therapie der perioperativen Koagulopathie

Acquired, perioperative coagulopathy often develops due to acute bleeding. In the case of primarily healthy patients with normal bone marrow and liver functions, a lack of coagulation factors initiates coagulopathy before secondary thrombopenia arises. Replacement of coagulation factors can be performed by infusion of fresh plasma (single donor or pooled plasma) or concentrates of clotting factors. Fresh plasma as well as concentrates of clotting factors available in German-speaking countries are of high quality and fulfil all safety standards. Undesirable side-effects due to transmission of infections and immunological reactions are – in all probability – more uncommon for virus-inactivated plasma and clotting factors than for single donor plasma. In contrast, thromboembolic complications are unlikely when using fresh frozen plasma, because it contains a balanced ratio of pro-coagulatory and anti-coagulatory factors. For virus-inactivated pooled plasma and concentrates of clotting factors, sporadic reports of thromboembolic events have been published. Concentrates of clotting factors can be stored easily and are rapidly prepared for use. In contrast, fresh frozen plasma has to be thawed before application leading to a significant delay in the schedule. During activated hemostasis, the half-life of clotting factors is significantly reduced in comparison to a stable physiological situation. In the case of perioperative coagulopathy higher dosages of fresh plasma and clotting factors than those recommended in published guidelines are often necessary for successful treatment. When using fresh plasma for coagulation therapy the resulting volume load must be considered. In conclusion, a modern concept of perioperative coagulation management should include fresh plasma as well as concentrates of clotting factors. The anesthetist should be familiar with the available components and be able to consider and adapt them to the individual situation.     

Fresh plasma and concentrates of clotting factors for therapy of perioperative coagulopathy: what is known?

Acquired, perioperative coagulopathy often develops due to acute bleeding. In the case of primarily healthy patients with normal bone marrow and liver functions, a lack of coagulation factors initiates coagulopathy before secondary thrombopenia arises. Replacement of coagulation factors can be performed by infusion of fresh plasma (single donor or pooled plasma) or concentrates of clotting factors. Fresh plasma as well as concentrates of clotting factors available in German-speaking countries are of high quality and fulfil all safety standards. Undesirable side-effects due to transmission of infections and immunological reactions are--in all probability--more uncommon for virus-inactivated plasma and clotting factors than for single donor plasma. In contrast, thromboembolic complications are unlikely when using fresh frozen plasma, because it contains a balanced ratio of pro-coagulatory and anti-coagulatory factors. For virus-inactivated pooled plasma and concentrates of clotting factors, sporadic reports of thromboembolic events have been published. Concentrates of clotting factors can be stored easily and are rapidly prepared for use. In contrast, fresh frozen plasma has to be thawed before application leading to a significant delay in the schedule. During activated hemostasis, the half-life of clotting factors is significantly reduced in comparison to a stable physiological situation. In the case of perioperative coagulopathy higher dosages of fresh plasma and clotting factors than those recommended in published guidelines are often necessary for successful treatment. When using fresh plasma for coagulation therapy the resulting volume load must be considered. In conclusion, a modern concept of perioperative coagulation management should include fresh plasma as well as concentrates of clotting factors. The anesthetist should be familiar with the available components and be able to consider and adapt them to the individual situation.     

Coagulation disorders following severe trauma: surgeon's role in prevention

INTRODUCTION: Severe trauma must be considered a "systemic disease" that could lead to severe systemic complications. PHYSIOPATHOLOGIC IMPLICATIONS: Coagulation disorders are present in most trauma patients as hemorrhagic disorder, thrombosis, or like in DIC, with both coexistent phenomenon. Trauma determine the activations of intrinsic and extrinsic coagulation pathways, and of platelets. Intrinsic pathway activation induce a pro-coagulant function and the activation of fibrinolytic system. Both system activation explain low incidence of deep venous thrombosis. Post-traumatic activation of extrinsic coagulation lead to thrombin and fibrin production. In trauma patients platelets activation is related to endothelial damage, exposition of collagen, interaction with PAF and presence of microorganisms. Post-traumatic DIC is characterized by procoagulant factors activation, with intravascular deposit of fibrin and thrombosis, and by hemorrhagic disorders due to consumption of platelet and procoagulant factors. Lower levels of antithrombin III, in trauma patients, are strictly related to severity of damage and shock. Coagulation disorders related to sepsis, that often complicate trauma, are added to those determined by trauma, with a negative synergic effect. Medical treatment with massive infusion of colloid and crystalloid solution, and fluid, and massive transfusion of plasma and red blood cells can determine dilutional thrombocytopenia, reduced activity of coagulation factors and reduced haemostatic activity of RBC due to excessive haemodilution--Hct <20%. PREVENTION STRATEGY: To avoid post-traumatic coagulation disorders is important to prevent sepsis, thrombocytopenia and reduced activity of coagulation factors and of RBC, as well as prevent and immediately treat shock. The early use of high dose antithrombin concentrate, is important to prevent DIC and MOFS, and administer subcutaneous or intravenous heparin, in absence of hemorrhagic disorders that contraindicate its use.     

A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage.

BACKGROUND: Randomized controlled trials of how best to administer fresh frozen plasma (FFP) in the presence of ongoing severe traumatic hemorrhage are difficult to execute and have not been published. Meanwhile, coagulopathy remains a common occurrence during major trauma resuscitation and hemorrhage remains a major cause of traumatic deaths, suggesting that current coagulation factor replacement practices may be inadequate. METHODS: We used a pharmacokinetic model to simulate the dilutional component of coagulopathy during hemorrhage and compared different FFP transfusion strategies for the prevention or correction, or both, of dilutional coagulopathy. Assuming the rates of volume replacement and loss are roughly equal, we derived the hematocrit and plasma coagulation factor concentration over time based on the rate of blood loss and replacement, the hematocrit and coagulation factor concentration of the transfusate, and the hematocrit and plasma factor concentration at the time when FFP transfusion begins. RESULTS: Once excessive deficiency of factors has developed and bleeding is unabated, 1-1.5 units of FFP must be given for every unit of packed red blood cells (PRBC) transfused. If FFP transfusion should start before plasma factor concentration drops below 50% of normal, an FFP:PRBC transfusion ratio of 1:1 would prevent further dilution. CONCLUSION: During resuscitation of a patient who has undergone major trauma, the equivalent of whole-blood transfusion is required to correct or prevent dilutional coagulopathy.     

Massive transfusion and coagulopathy: pathophysiology and implications for clinical management

PURPOSE: To review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both elective surgical and trauma settings, and to recommend the most appropriate treatment strategies. METHODS: Medline was searched for articles on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." A group of experts reviewed the findings. Principal findings: Coagulopathy will result from hemodilution, hypothermia, the use of fractionated blood products and disseminated intravascular coagulation. The clinical significance of the effects of hydroxyethyl starch solutions on hemostasis remains unclear. Maintaining a normal body temperature is a first-line, effective strategy to improve hemostasis during massive transfusion. Red cells play an important role in coagulation and hematocrits higher than 30% may be required to sustain hemostasis. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. In trauma patients, tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. The use of platelets and/or fresh frozen plasma should depend on clinical judgment as well as the results of coagulation testing and should be used mainly to treat a clinical coagulopathy. CONCLUSIONS: Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial and multicellular event. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding.     

Volume substitution in shock

Shock treatment seems optimal when a "balanced" fluid and volume regimen, including both crystalloid (Ringer's acetate) and about 3% colloid, is used. Dextran is the colloid of choice due to its beneficial effects on plasma volume, hemorrheology, and microvascular blood flow. Dextrans exert, in addition, inhibiting effects on the shock- and trauma-induced activation of the cascade system, whereby the risk of complications in the form of multiple organ failure is reduced. Infusion of red blood cells, plasma or thrombocytes should be based on a proper assessment of each individual patient's actual need of oxygen transporters and coagulation factors.     

Blood transfusion and reducing the need for blood in heart transplantation

Viral infections transmitted by the donor organ or by blood and blood products are severe complications in heart transplantation. The use of blood and blood saving management is evaluated in 57 consecutive orthotopic heart transplantations. Indication was cardiomyopathy in 63%, coronary artery disease in 30%, valve disease in 5%, congenital in 5%, arrhythmia in 5% and primary cardiac malignancy in 2%. Previous open heart surgery was performed in 32%, and 81% had anticoagulation, with a mean quick value of 0.28 +/- 0.13. The total use of blood and blood products was 1151 units and was distributed as follows: whole blood and packed cells 41%, platelets 17%, fresh frozen plasma (FFP) and coagulation factors 36%, albumine 7%. Anticoagulated recipients received more FFP and factors, 7.9 +/- 5.7 U vs. 4.4 +/- 4.8 U. In the reoperation group 78% vs. 22% (p less than 0.001) in the primary operation group received platelets. Hemodilution to hematocrit 0.24 instead of 0.30 lead to a decrease of red cell transfusions per patient from 12.3 +/- 6.7 U to 6.3 +/- 7.4 U (p less than 0.001) and the percentage of patients receiving red cells was reduced from 100% to 82%. Intraoperative hemofiltration was performed in 49% (mean filtration volume was 1652 +/- 910 ml). No differences in the amount of blood and blood products could be shown. Heart transplantation is an operation with a high need for blood and blood products. Reoperation and anticoagulation are predictors for a higher use of platelets, FFP and coagulation factors. Hemodilution reduces the use of red cells, whereas intraoperative hemofiltration has no influence on the use of blood.     

The concept of blood components in surgical hemotherapy

During the past 7 years, 85% of all red cell units have been transfused as concentrates (RCC) with a haematocrit of 70% at our University Hospital. The basic concept is to exploit the differing critical levels of various parameters in the circulation of the patient. In per cent of normal, we have: blood volume 100%, haematocrit 80%, total serum protein 60%, plasmatic coagulation factors 35%, and platelets 25%. This permits the stepwise use of a plasma substitute, RCC, 5% albumin, and fresh frozen plasma or whole blood. A retrospective, but carefully controlled study of 372 patients showed that this system has no negative effects on the postoperative course. Its logistic advantage is that the plasma from the blood donations used to treat about 80% of surgical patients can be diverted to fractionation into specific derivatives, whereas it does not increase the needs for albumin.     

Blood coagulation and autologous blood transfusion in cardiac surgery

Study Objective: To review the basic pathophysiology of altered coagulation associated with cardiopulmonary bypass and autologous blood transfusion in cardiac surgery.

Design: Review of rational use of heparin, mechanisms and treatment of coagulation disorders, and autologous blood transfusion.

Setting: Cardiac surgery in community and academic hospitals.

Patients: Adult cardiac surgical patients.

Main Results: Heparin is most commonly used for anticoagulation during cardiopulmonary bypass. Although activated clotting time is widely used to assess heparin-induced anticoagulation, the minimum time to prevent clotting during cardiopulmonary bypass remains unclear. Activated clotting time is affected by many factors other than heparin, such as antithrombin III, blood temperature, platelet count, and age. The rational use of activated clotting time still must be defined.

The frequency of abnormal bleeding after cardiopulmonary bypass is significant. Although inadequate surgical hemostasis is the most frequent cause of bleeding, altered coagulation often is present. A decreased number of functional platelets is one of the important causes of bleeding diathesis. Platelet dysfunction is induced by perioperative medication such as aspirin. Cardiopulmonary bypass decreases functional platelets by degranulation, fragmentation, and loss of fibrinogen receptors. Medications such as prostacyclin and iloprost may be useful to protect these platelets. Desmopressin increases factor VIII:C and von Willebrand's factor, leading to a decrease in bleeding time. Desmopressin may be useful to decrease blood loss in repeat cardiac operations, complex cardiac surgery, and abnormal postoperative bleeding.

Patients undergoing coronary artery bypass grafting immediately after streptokinase infusion also are at risk for abnormal bleeding. Transfusion of fresh frozen plasma and cryoprecipitate may be necessary.

Autologous blood transfusion is cost-effective and the safest way to avoid or decrease homologous blood transfusion. Predonation, intraoperative salvage, and postoperative salvage are encouraged. Erthroprotein may be useful in increasing the amount of predonation red cells.

Conclusions: Coagulation disorders in cardiac surgery are caused by many factors, such as heparin, platelet dysfunction, and fibronolysis. Rational use of blood component therapy and medications such as heparin, protamine, and desmorpessin are mandatory. Autologous blood transfusions is very useful in decreasing or obviating the use of homologous blood transfusion.     

Disseminated intravascular coagulation in a patient undergoing removal of humeral head for pain relief.

Disseminated intravascular coagulation (DIC) was recently observed intraoperatively in a patient who required removal of her right humeral head for pain relief. Despite normal preoperative coagulation parameters, the patient developed wound oozing soon after suturing the skin. Coagulation profile revealed decreased platelets, plasma coagulation factors and fibrinogen in association with elevated fibrin degradation products. To manage the DIC, urinastatin and gabexate mesilate, along with blood component replacement, proved effective.     

Treatment of fulminant falciparum malaria with erythrapheresis

Ten days after his return from Cameroon, a twenty-six year old Frenchman, serving on voluntary service overseas, presented with fulminant falciparum malaria: shock, altered consciousness, haemolytic anaemia, threatening disseminated coagulation (platelets less than 150 X 10(-6).l-1; prothrombin time and Stuart factor less than 50%; fibrinogen less than 1.5 g.l-1). In spite of quinine therapy, parasitaemia increased from 4 to 35% within 24 h. Using an Haemonetics V50, the exchange of one and a half red blood cell masses was carried out with 17 red blood cell packs. Calcium gluconate was used to prevent the hypocalcaemia induced by the anticoagulant solution. The patient's platelets and plasma were completely reinjected. The result was very satisfactory. This kind of exchange, well tolerated clinically and biologically, would seem better than the classical exchange transfusion. When 10% of the red blood cells are infected by Plasmodium falciparum, it is necessary to exchange from one and a half to two blood masses. Lesser exchanges are always associated with important relapses and quinine therapy must be carried on during and after the exchange. Restricting this exchange only to red blood cells enabled the patient to benefit from his own coagulation factors, antibodies and platelets, and consequently to reduce the number of blood donors involved. However, metabolites (especially bilirubin and circulating immune complexes) were not eliminated. Partial plasmapheresis may be associated with erythropheresis using human albumin as plasma substitute. This technique needs to be assessed, in order to optimize immediate efficiency and post-transfusion infectious risk.     

An evaluation of a polyethersulfone hollow fiber plasma separator by animal experiment

Membrane plasma separators are being used routinely for therapy in various diseases. In this study, a newly developed plasma separator made of polyethersulfone (PES) hollow fibers was evaluated for its plasma filtration efficiency and blood compatibility by animal experiment. Hemolysis did not occur under the usual conditions of plasma separation. The sieving coefficients of total protein and albumin were over 95%, and the total cholesterol was over 90% throughout the perfusions. Decreases in white blood cells, platelets, fibrinogen, and coagulation factors were observed during the early stage of plasma separation, but appear to be within acceptable ranges for clinical use.