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.     

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.     

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.     

Use of rotation thromboelastometry (ROTEM®) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate

Goal‐directed coagulation therapy is essential in the management of trauma patients with severe bleeding. Due to the complex nature of coagulation disorders in trauma, a quick and reliable diagnostic tool is essential. We report a severely injured multiple trauma patient who received haemostatic therapy with coagulation factor concentrates, guided by rotational thromboelastometry (ROTEM^®). Initial therapy consisted of fibrinogen concentrate (Haemocomplettan^® P), as maximum clot firmness in the ROTEM analyses was low, whereas clotting time was normal. Later on, prothrombin complex concentrate was given to optimise thrombin generation. This approach enabled extended emergency hemihepatectomy to be performed without using fresh frozen plasma. As the EXTEM maximum clot firmness showed good clot quality, no platelets were transfused despite low platelet counts. This case shows the potential success of treatment using both fibrinogen concentrate and prothrombin complex concentrate, not only in restoring haemostasis but also in minimising requirement for transfusion of allogeneic blood products.     

Inherited Bleeding Disorders in Dermatologic Surgery

BACKGROUND: A patient referred for Mohs micrographic surgery of a basal cell carcinoma had a history of a congenital clotting factor IX deficiency requiring recombinant factor IX replacement. OBJECTIVE: To examine the management and problems associated with cutaneous surgery in patients with inherited clotting factor deficiencies. METHODS: Case report and review of the medical literature. RESULTS: Reconstructive options must be carefully chosen to minimize bleeding in patients with clotting factor deficiencies. Preoperative consultation with a hematologist and coagulation factor replacement both before and after cutaneous surgery prevent excessive hemorrhage. CONCLUSION: Meticulous attention to hemostasis, careful preoperative assessment, and postoperative follow-up minimize complications in patients with known coagulation deficiencies who require cutaneous surgery.     

Drugs affecting coagulation

The clotting cascade is a complex process and is an important survival mechanism. Major haemorrhage and thromboembolic events remain major causes of increased morbidity and mortality. Drugs affecting coagulation have primarily been utilized to treat or reduce the risk of thromboembolic events. However, the recent progress in the management of major trauma and treating coagulopathy has resulted in further research and development of drugs that improve clotting function. Knowledge of drugs used for both clinical circumstances is now required when working in anaesthesia or intensive care.     

Activation of human coagulation system by liver-derived clotting factors of Banna minipig inbred line

The liver synthesizes most of the coagulation factors that play a major role in arresting hemorrhage. Matching hepatic coagulation factors is an important premise in successful xenotransplantation. As a unique inbred pig, the Banna minipig inbred (BMI) animals have a huge potential value for pig-to-human xenotransplantation, due to its clear genetic background and tiny interindividual differences. Whether the coagulation factors synthesized by porcine liver can trigger human clotting pathways has not been reported. This study focused on the activities of BMI coagulant factors synthesized exclusively by the liver to activate human clotting pathways. In these experiments we prepared coagulant factors II, V, VII, X, and XII synthesized exclusively by liver from BMI and humans. The factors were used in common correction tests, added to the corresponding factor-deficient human plasma to determine prothrombin times or activated partial thromboplastin time, thereby calculating BMI and human coagulant factor activities. BMI clotting factors XII, VII, and X triggered human intrinsic, extrinsic, and common pathways, respectively. BMI clotting factors II, V, VII, X, and XII activities were 3.2-, 3.7-, 4.7-, 2.9-, and 4.5-fold as potent as those from humans.     

The role of monitoring platelet function perioperatively and platelet transfusion for operated spontaneous intracerebral hemorrhage patients with long-term oral antiplatelet therapy: A case report

Introduction and importanceSpontaneous intracerebral hemorrhage (SICH) with long-term oral antiplatelet therapy (LOAPT) is known as a dilemma in balancing the risk of postoperative rebleeding and ischemic events because of confused coagulation function. We herein describe a report of perioperative management of spontaneous intracerebral hemorrhage patient on long-term oral antiplatelet therapy.Case presentationA 42-year-old male patient on long-term oral antiplatelet therapy presented with coma, and he was diagnosed with spontaneous intracerebral hemorrhage. Considering the patient's clinical condition, despite the thromboelastography suggested that the inhibition of platelet function was high preoperatively, an emergency craniectomy were underwent. After platelet transfusion during surgery and taking control of the clotting and platelet function postoperatively, the patient was stable without rebleeding and new ischemic events in perioperative period and recovered satisfactorily.Clinical discussionRare studies have provided evidence for managing operated spontaneous intracerebral hemorrhage patients on long-term oral antiplatelet therapy, and whether platelet transfusion is recommended was controversial. In this case, we presented monitoring and taking control of clotting and platelet function postoperatively would help in preventing rebleeding and ischemic events in such patients; moreover, platelet transfusion may quickly and safely reverse platelet dysfunction for emergency surgery. This case was the first to report platelet function and coagulation function management in spontaneous intracerebral hemorrhage patients with long-term oral antiplatelet therapy.ConclusionMonitoring and maintaining coagulation and platelet function perioperatively are essential to balance the risk of postoperative rebleeding and ischemic events.     

Monitoring heparin therapy with thromboelastography and activated partial thromboplastin time

Blood coagulability in patients undergoing anticoagulant therapy has been studied using the Thromboelastograph® and activated partial thromboplastin time. Currently used tests, such as activated partial thromboplastin time (APTT) and whole blood clotting time, lack sensitivity and do not correlate well with clinically significant bleeding and clotting events. The Thromboelastograph® is an instrument that allows continuous measurement of overall coagulation and fibrinolysis. Sixty patients on heparin therapy were monitored with thromboelastography and activated partial thromboplastin time. Continuous heparin infusion or intermittent administration was used. The Thromboelastograph® was found to be a more sensitive device for detection of response to heparin than APTT. Early response to heparin was reflected in the reaction time, k time, and maximum amplitude of the thromboelastogram. A more precise administration of heparin was made possible, resulting in use of less heparin and a more stable patient response. A more individualized approach to the patient's therapy was achieved by monitoring with the Thromboelastograph, and the best results were obtained with continuous infusion rather than intermittent administration of heparin.     

Gerinnungsmanagement beim Polytrauma

Hemorrhage after traumatic injury results in coagulopathy which only worsens the situation. This coagulopathy is caused by depletion and dilution of clotting factors and platelets, increased fibrinolytic activity, hypothermia, metabolic changes and anemia. The effect of synthetic colloids used for compensating the blood loss, further aggravates the situation through their specific action on the hemostatic system. Bedside coagulation monitoring permits relevant impairment of the coagulation system to be detected very early and the efficacy of the hemostatic therapy to be controlled directly. Administration of fresh frozen plasma (FFP), platelet concentrates and antifibrinolytic agents is essential for restoring the impaired coagulation system in trauma patients. Clotting factor concentrates should be administered if coagulopathy is based on diagnosed depletion of clotting factors, if FFP is not available and if transfusion of FFP is insufficient to treat the coagulopathy. Recombined FVIIa is frequently employed during severe bleeding which could not be treated by conventional methods but the results of on-going clinical trials are not yet available.     

Flap reconstruction in two patients with rare blood coagulation disorders

Coagulation disorders can be classified into two types: excessive bleeding and excessive clotting. Furthermore, the severity of the coagulation disorders can vary significantly among patients. We evaluated two relatively rare cases involving factor XIII subunit deficiency and antiphospholipid syndrome (APS) with concomitant systemic lupus erythematosus (SLE) in two patients undergoing flap reconstructions after tumor excision. In the patient with excessive bleeding as a result of a factor XIII subunit deficiency, flap necrosis occurred from a large subcutaneous hematoma that pressed on the perforator pedicle. Normal clotting function was restored during the surgery by administering a factor XIII preparation (Fibrogammin® P). The patient with excessive clotting as a result of APS and SLE suffered necrosis of the flaps after undergoing radial forearm free flap (RFFF) and pedicled pectoralis major musculocutaneous (PMMC) flap operations. With clotting factor deficiencies, there are patients in whom no evidence of a coagulation disorder exists preoperatively. It is important for surgeons to pay close attention to the potential for coagulation disorders patients and to consult with specialists promptly when indicated. Level of Evidence: Level V, risk/prognostic study.     

粘弹性凝血功能监测技术的应用及进展

外科手术围术期凝血功能的监测对出血原因的判断、指导止血措施的实施以及术后失血风险的预测极其重要。床边体外诊断实验（point—of—care,POC）凝血功能监测装置能对全血的粘弹特性进行评估,从而克服了常规凝血检测的一些局限性。POC凝血功能监测装置可对全血的粘弹特性进行实时监测,记录包括纤维蛋白形成、血凝块收缩、直至纤维溶解的整个凝血级联反应,全血测定的特点还决定了POC凝血功能监测装置可反映血小板的功能状态。目前,POC凝血功能监测装置已应用于临床实践,如心血管外科、肝脏外科、患者低凝或高凝状态的评估、抗凝治疗、抗血小板治疗以及凝血因子治疗的监测等。标准化的血样采集处理、严格的质量控制,有助于POC凝血功能监测装置检测结果的精确性。     

Factor XII Deficiency Acquired by Orthotopic Liver Transplantation: Case Report and Review of the Literature

Transmission of congenital clotting factor deficiencies after orthotopic liver transplantation is rare. There are published reports of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia, protein S, factor VII and factor XI deficiencies. We report a case of transmission of factor XII deficiency with liver transplantation in a patient with Budd-Chiari syndrome. There was a persistent elevation of the activated partial thromboplastin time (aPTT), but no evidence of bleeding while the patient was maintained on warfarin. The presence of a persistently abnormal aPTT may raise suspicion for the presence of a clotting factor deficiency; however, deficiencies of other clotting factors may not be readily apparent on routine blood tests performed in a donor. Being aware of the possibilities of transmission of these inherited deficiencies of coagulation factors will aid in their early detection and management in the transplant donor and recipient.     

Palliative open heart surgery in an infant with factor VII deficiency

An infant with factor VII deficiency underwent palliative open heart surgery for pulmonary atresia with an intact ventricular septum. No references had been found on the management of this rare coagulation disorder in infantile cardiac surgery. We describe the peri- and postoperative management with a replacement therapy including a recombinant factor VIIa concentrate. We conclude that an appropriate replacement therapy is needed to control bleeding during open heart surgery with factor VII deficiency.     

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损伤后进行性凝血功能障碍是损伤控制性外科的基本问题之一,但其具体发生的机制尚未完全明确。近年来提出的基于"细胞凝血模型"的理论对传统的内外源性凝血途径作出了有益的修正,也为临床损伤后凝血功能障碍的检测及治疗带来改变。具体表现为:首先,在凝血功能的检测上,血栓弹力图相对于传统的基于内外源性凝血途径的PT、APTT等检测手段,更能全面反映凝血全貌,同时也更为精确、快速;其次,在血栓弹力图指导下的目标导向性复苏策略,相对于按比例成分输血等损伤控制性复苏策略,能更为及时有效地纠正凝血功能障碍,减少输血量,改善病人预后;此外,合理、有效、及时地补充重组活化因子Ⅶ,对控制急性威胁生命的损伤出血病人有益。     

Compound 48/80 suppresses monocytic tissue factor-initiated extrinsic blood coagulation induced by bacterial endotoxin

BACKGROUND: Hypercoagulability is one of the commonly exhibited endotoxemia septic symptoms; it could contribute to the manifestation of disseminated intravascular coagulation presenting threats to cardiovascular functions. The underlying mechanism, however, remains largely complex and unknown. OBJECTIVES: We herein determine whether bacterial endotoxin (LPS) upregulates the activities of clotting factors in plasma, contributing to extrinsic hypercoagulation. Compound 48/80 (48/80) is also tested for its ability to suppress hypercoagulation. METHODS: In an in vitro infection model, we exposed whole blood to LPS (Escherichia coli 0111:B04; 100 ng/ml) for 2 h. Thrombin time (TT), prothrombin time (PT), and the activities of clotting factors ( FVII, FIX, FX ) in plasma contributing to the extrinsic coagulation were determined. Peripheral blood monocytes were isolated from Histoplaque 1077 gradient centrifugation, and the procoagulant activity was determined by a single-stage clotting assay on a Fibrometer. RESULTS: LPS drastically activated monocytic procoagulant activity which was defined as tissue factor (TF) activity, whereas LPS had no effect on TT, PT, and the activities of clotting factors in plasma. 48/80 not only instantaneously offset LPS-induced monocytic TF activation, but also significantly inhibited PT including the activities of clotting factors (FVII, FIX, and FX) in plasma, whereas TT remained unaffected. CONCLUSIONS: Monocytic TF activation was solely responsible for the extrinsic hypercoagulation in response to LPS. 48/80 effectively suppressed LPS-induced monocyticTF-initiated extrinsic coagulation at multiple sites, possibly presenting a new therapy for an instantaneous relief of hypercoagulation under septic conditions.     

Perioperative management of three patients with streptococcal toxic shock syndrome

We report the perioperative management of three patients with streptococcal toxic shock syndrome (STSS) caused by group A streptococcal infection. Three of two patients survived but one patient died from multiple organ dysfunction in spite of vigorous treatments. These patients required the treatments including administration of antibiotics, circulatory and respiratory care, surgical debridement, anticoagulant therapy for disseminated intravascular coagulation and hemofiltration. The early diagnosis and surgical intervention play a key role in the successful management of this syndrome because it has a rapid course and frequent fatal outcome. The anesthetic management of these patients should be targeted to maintain perfusion of the vital organs and to control the blood clotting disorders.     

抗凝药物发展的历史及最新进展

抗凝药物是通过影响凝血过程中的某些凝血因子阻止凝血过程的药物,可用于防止血管内栓塞或血栓形成的疾病,预防中风或其他血栓性疾病.对于血管外科医师来说,在新药层出不穷的今天,回顾抗凝药的发展历程、分类、抗凝机制以及了解其最新进展,无疑是十分重要的.本文就抗凝药的历史及应用进展作一综述.     

Prothrombin complex concentrates: a brief review

Prothrombin complex concentrates are haemostatic blood products containing four vitamin K-dependent clotting factors (II, VII, IX and X). They are a useful, reliable and fast alternative to fresh frozen plasma for the reversal of the effects of oral anticoagulant treatments (vitamin K antagonists). They are sometimes used for factor II or factor X replacement in patients with congenital or acquired deficiencies. They are widely prescribed in Europe. Several retrospective and prospective studies have demonstrated their efficacy in normalizing coagulation and in helping to control life-threatening bleeding. Few side-effects, mainly thromboembolic events, have been reported. The link between these events and prothrombin complex concentrate infusion has, however, often been brought into question. The use of prothrombin complex concentrates in new promising indications such as the management of massive bleeding requires prospective studies providing a high level of evidence in a high-risk setting.