Changes in coagulation factors in patients with burns during acute blood loss

A prospective study was undertaken to determine the change in coagulation factors in patients undergoing tangential excisions of burn wounds when red blood cells preserved with ADSOL (adenine, dextrose, saline, and mannitol) and crystalloid solution were used for volume replacement. Nine patients with burns were studied, three on two separate occasions. No patient had a history of a bleeding disorder or had taken aspirin within 10 days of surgery. Results of preoperative coagulation studies were all within normal limits. The initial levels of coagulation factor and rates of removal were compared with those of 12 patients without burns who were undergoing elective surgery and who also had massive intraoperative blood loss. Coagulation factor levels measured included the platelet count, fibrinogen, factors V, VIII, and IX. These were determined before blood loss and each time loss and replacement of one third of a patient's calculated blood volume occurred during a tangential excision of a burn wound. The data showed that patients with burns have significantly higher baseline levels of platelets, fibrinogen, and factor VIII than patients without burns do. The removal rates of platelet and factor IX are significantly lower among patients with burns than among patients without burns. No patient in the study group developed a coagulopathy or received fresh frozen plasma or platelet supplementation. These findings suggest that the intraoperative blood losses that occurred during tangential excisions of burn wounds were made safe by the higher than normal preoperative levels of platelets, fibrinogen, and factor VIII and by the slow wash-out curve for platelets and factor IX. Prophylactic use of either fresh frozen plasma or platelet concentrates is not indicated unless a specific deficit or coagulopathy has been identified.     

Treatment of congenital and acquired hemophilia patients by extracorporeal removal of antibodies to coagulation factors: a review of US clinical studies 1987-1990. Hemophilia Study Group

This paper reviews the use of extracorporeal immunoadsorption with immobilized Staphylococcal Protein A in attempts to lower the inhibitor titer in 22 patients with either congenital hemophilia or with acquired inhibitors. Eighty-five immunoadsorption procedures were performed at 13 locations in the United States between June, 1987 and February, 1990. In general, immunoadsorption was shown to efficiently remove IgG and, in eight congenital hemophilia patients, it also produced a clinically significant lowering of inhibitors allowing effective conventional factor replacement therapy. Three of thirteen congenital hemophilia patients treated received factor concentrate prior to immunoadsorption and were anamnestic at the time of treatment. Although they experienced substantial lowering of their inhibitor titers, it was not sufficient to allow effective factor replacement. The effectiveness of immunoadsorption therapy in the 9 patients with acquired inhibitors was more difficult to evaluate due to the wide variety of concomitant medications which were employed, although in several patients serious bleeding episodes were substantially improved (or halted) following immunoadsorption. Side effects associated with immunoadsorption were slight. These findings suggest that immunoadsorption can be a significant benefit to patients with inhibitors, particularly if it is instituted prior to factor administration.     

血友病患者全膝置换围手术期的凝血因子替代治疗

背景：世界血友病协会的治疗指南明确表示,关节置换应当在保证患者凝血因子活性的情况下进行。目的：观察血友病关节炎患者行人工膝关节置换围手术期凝血因子替代治疗的安全性和有效性。方法：1997/2006在血液内科的配合下,围手术期行凝血因子Ⅷ和Ⅸ活性水平监测,根据指南制定常规流程,进行因子Ⅷ（冻干人凝血因子Ⅷ）或因子Ⅸ（凝血酶原复合物）的替代治疗,对4例血友病关节炎患者共6个膝关节行人工膝关节置换治疗。结果与结论：围手术期应用凝血因子进行常规替代治疗,血友病患者围手术期出血量与类风湿关节炎和骨关节炎患者差异无显著性意义（P=0.885）。置换后早期3个膝关节出现关节内血肿或肌肉出血,其中1例患者因凝血因子抑制性抗体形成,导致1侧膝关节置换后伤口裂开,行扩创清理后,伤口愈合良好。4例患者6个膝关节置换后没有晚期感染、假体松动、移位和断裂等并发症发生。所有4例患者置换前膝关节KSS评分平均28.2分,功能评分平均35分。置换后KSS评分85.2分,功能评分87分,与普通类风湿关节炎和骨关节炎膝关节置换后评分相似,但平均住院天数延长约3倍,住院费用为普通膝关节置换的2.5~3倍。结果显示凝血因子的替代治疗和凝血因子水平监测是保证血友病关节炎行人工膝关节置换最后成功的关键。     

血友病患者全膝置换围手术期的凝血因子替代治疗

背景:世界血友病协会的治疗指南明确表示,关节置换应当在保证患者凝血因子活性的情况下进行。目的:观察血友病关节炎患者行人工膝关节置换围手术期凝血因子替代治疗的安全性和有效性。方法:1997/2006在血液内科的配合下,围手术期行凝血因子Ⅷ和Ⅸ活性水平监测,根据指南制定常规流程,进行因子Ⅷ(冻干人凝血因子Ⅷ)或因子Ⅸ(凝血酶原复合物)的替代治疗,对4例血友病关节炎患者共6个膝关节行人工膝关节置换治疗。结果与结论:围手术期应用凝血因子进行常规替代治疗,血友病患者围手术期出血量与类风湿关节炎和骨关节炎患者差异无显著性意义(P=0.885)。置换后早期3个膝关节出现关节内血肿或肌肉出血,其中1例患者因凝血因子抑制性抗体形成,导致1侧膝关节置换后伤口裂开,行扩创清理后,伤口愈合良好。4例患者6个膝关节置换后没有晚期感染、假体松动、移位和断裂等并发症发生。所有4例患者置换前膝关节KSS评分平均28.2分,功能评分平均35分。置换后KSS评分85.2分,功能评分87分,与普通类风湿关节炎和骨关节炎膝关节置换后评分相似,但平均住院天数延长约3倍,住院费用为普通膝关节置换的2.5~3倍。结果显示凝血因子的替代治疗和凝血因子水平监测是保证血友病关节炎行人工膝关节置换最后成功的关键。     

Comparison of fresh frozen plasma with a standardized serum protein solution following therapeutic plasma exchange in patients with autoimmune disease: a prospective controlled clinical trial.

The aim of the study was the comparison of the influence of fresh frozen plasma (FFP) (Freiburg, Germany) and Biseko, Biotest Pharma GmbH (Dreieich, Germany), as a plasma substitute (a standardized, virus inactivated human serum protein solution) on the coagulation factors, inhibitors, proteins, and complement factors in the plasma of autoimmune disease patients following membrane plasma separation. Patients (n = 24) with autoimmune disease were randomized to receive either FFP or Biseko for membrane plasma separation therapy. During each plasma exchange, 100% of the plasma volume was replaced by the respective substitute. Plasma exchange volume was performed once daily for 3 days. Target test parameters of the coagulation system were fibrinogen, fibrinopeptide A, factor VIII (FVIIIC), von Willebrand factor antigen (vWFAg), partial thromboplastin time (PTT), thromboplastin time (Quick value), and antithrombin (AT III). The immunoglobulins were IgG, IgA, and IgM and C-reactive protein (CRP). The thrombocytes were platelet factor 4 (PF4), and complement factors were C3 and C4. Biseko was well tolerated with 1 mild adverse drug reaction (ADR) (n = 1) while FFP gave rise to ADR on 7 occasions (n = 4). Statistically significant differences in the 2 groups were observed for fibrinogen, PTT, Quick value, and AT III. From the clinical point of view, all fluctuations and differences in parameter levels remained clinically silent. The differences had no clinical consequences. Reflecting on a potential decrease in the risk of infections in comparison to FFP therapy and the lower rate of adverse drug reactions, it is possible to postulate an advantage of Biseko for plasma exchange therapy.     

Acute coagulopathy in pregnancy

Pregnancy alters both the fibrinolytic system and coagulation cascade. In addition, pregnancy presents unique triggering mechanisms for DIC. Management of DIC in pregnancy should include removal of the triggering mechanism, blood, and factor replacement. Inherited coagulation defects, while rarely resulting in bleeding diathesis in the pregnant patient, do require monitoring of maternal factor levels. Genetic counseling should be offered to all patients with inheritable coagulation disorders.     

Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis

BACKGROUND: Anaphylactic or atypical reactions, characterized by flushing, hypotension, dyspnea, and bradycardia, have been reported in patients undergoing hemodialysis, low-density lipoprotein apheresis, IgG affinity column apheresis, therapeutic plasma exchange, and desensitization immunotherapy while receiving angiotensin-converting enzyme (ACE) inhibitor therapy. STUDY DESIGN AND METHODS: Records were reviewed of 299 consecutive patients undergoing therapeutic plasma exchange with colloid replacement at the University of North Carolina Hospitals from September 1981 through December 1993. Charts were selected for further analysis if atypical reactions (flushing or hypotension defined as a mean decrease in blood pressure of 20 torr or greater) occurred during apheresis or if there was concurrent administration of an ACE inhibitor. RESULTS: Fourteen (4.7%) of 299 patients were receiving ACE inhibitor therapy at the time of apheresis; all 14 experienced an atypical reaction. In contrast, 20 (7%) of 285 patients not receiving ACE inhibitors developed atypical reactions (p < 0.001). The 14 ACE inhibitor patients accounted for 41 percent (14/34) of all patients having atypical reactions during apheresis. CONCLUSION: Patients receiving ACE inhibitor therapy who are undergoing therapeutic plasma exchange with albumin replacement solutions are at high risk (100%) for atypical reactions. It is recommended that ACE inhibitors be withheld for at least 24 hours before that procedure.     

Immunoadsorption with single-use columns for the management of bleeding in acquired hemophilia A: a series of nine cases

BACKGROUND: Acquired hemophilia A in a setting of bleeding or required surgery frequently places patients into a state of critical illness with high mortality. In this context immunoadsorption (IA) can be used to eliminate coagulation inhibitors quickly to employ recombinant coagulation factors more effectively. However, since acquired hemophilia is a rare condition the therapy is little standardized. METHODS: We report on a retrospective analysis of nine cases of acquired hemophilia A treated with IA using disposable adsorber columns. Data collection was performed by retrospectively reviewing the patients' files regarding clinical course, mode of therapy, inhibitor titers, and coagulation status. RESULTS: Inhibitor titers were effectively reduced in all but one patient following the treatment with IA. In two out of seven patients surviving the acute bleeding an inhibitor relapse occurred. The overall remission rate was determined as 77.8% within a median follow-up of 613 days. In two of our nine patients fatal outcome resulted due to major bleeding complications. IA treatment showed good tolerability and no fatal complications were caused. CONCLUSION: The presented cases support our assumption that patients with acquired hemophilia A benefit from IA with disposable columns in a setting of acute bleeding. This modality of IA is able to eliminate inhibitors reliably and quickly. IA in general is substantially speeding up the progress of therapy preventing bleeding complications constantly threatening the patient and reducing the dosages of coagulation factor therapy. We encourage IA with disposable columns in all bleeding patients with acquired hemophilia to aggressively lower the inhibitors.     

Therapeutic modulation of coagulation in sepsis

Based on the increasing knowledge of defects in haemostasis in patients with sepsis as well as on the non-conclusive results of studies which tried to increase the prognosis by modulating cytokine response of the patients, in the last years the impact of therapeutic modulation of coagulation in sepsis has been investigated. In contrast to the results of phase III studies with the coagulation inhibitors antithrombin and tissue factor pathway inhibitor recombinant human activated protein C (rhAPC) resulted in a significant reduction in mortality for the whole study population. Data analyses showed, that treatment with rhAPC was clinically beneficial especially in patient groups who showed a high mortality in the placebo arm. Inhibition of thrombus formation due to the therapy with natural coagulation inhibitors resulted in an increase of sepsis-imminent haemorrhage, which became significant in some studies. Treatment with antithrombin and heparin resulted in a considerable increase in bleeding complications and on the other hand, may have antagonized the expected effect of antithrombin on the patient's prognosis. Some results suggesting beneficial effects of heparin on patient prognosis in the placebo arms and on the other hand negative effects of heparin in the verum arms -- especially with antithrombin or tissue factor pathway inhibitor -- let to a controversial discussion of the risk/benefit relation of heparin, given in prophylactic doses to patients with severe sepsis. Whereas the impact and optimal application of heparin to patients with severe sepsis needs to be clarified study results with rhAPC resulted in the approval of this therapy and the implementation in the guidelines of the treatment of patients with severe sepsis.     

Continuous venovenous haemofiltration using polyacrylonitrile filters does not activate contact system and intrinsic coagulation pathways

Objectives: To investigate whether continuous venovenous haemofiltration using polyacrylonitrile filters causes activation of the contact system and intrinsic coagulation pathways and if this, and/or low plasma levels of endogenous anticoagulants, influences filter lifespan. Design: Observational study. Setting: University Teaching Hospital Intensive Care Unit. Patients: Twelve critically ill patients with acute renal failure receiving continuous venovenous haemofiltration. Interventions: Blood samples were taken before starting haemofiltration, at 15 min, 1 h, 3–4 h, 8–12 h, 24 h and at 24-h intervals thereafter until filter blockage occurred. Measurement was made of the contact and intrinsic coagulation system proteins factor XII, activated factor XII and prekallikrein and the protease inhibitors antithrombin III, heparin co-factor II, alpha₂-macroglobulin and C1-esterase inhibitor. Thrombin-antithrombin complex levels were measured to provide evidence of thrombin generation. Results: (i) Factor XII, prekallikrein and contact system inhibitors were subnormal in 10/12 and activated factor XII raised in 11/12 patients at baseline, implying pre-existing contact pathway activation. (ii) No change occurred during haemofiltration in the intrinsic coagulation pathway factor or inhibitor levels. (iii) Clotting of the filter circuit within the first 24 h occurred in 5/12 and was associated with low baseline levels of antithrombin III and heparin co-factor II. Only in these patients did thrombin-antithrombin complex levels rise significantly. Conclusions: The contact system was not activated further by continuous venovenous haemofiltration using polyacrylonitrile filters in critically ill patients. Premature clotting of the haemofilter circuit was more common in patients with very low levels of antithrombin III and heparin co-factor II; although this was related to thrombin generation, the intrinsic coagulation pathway does not appear to be implicated. Received: 6 February 1995 Accepted: 4 October 1996     

Pharmacotherapy of haemophilia A

Introduction: Haemophilia A is due to factor VIII (FVIII) deficiency. The main treatment is replacement therapy with FVIII concentrates. However, these concentrates carried a high risk of blood-borne viral infections and still have a high risk of inducing anti-FVIII inhibitors.

Areas covered: An overview of products available and therapeutic options for haemophilia A management in order to help in decision making. A literature search using Medline with the keywords: ‘haemophilia’, ‘factor VIII’, ‘therapy’, ‘inhibitor’, ‘concentrate’, ‘bleeding’, ‘prophylaxis’, ‘on demand’, ‘plasma-derived’, ‘recombinant’, ‘coagulation factors’, ‘immunotolerance’ was performed. The years 1960 – 2010 are included.

Expert opinion: Progress in management of patients with haemophilia A has allowed increased life expectancy and quality of life. There is evidence that prophylaxis prevents or, at least, slows down arthropathy development when started early in childhood. FVIII concentrates have achieved high levels of blood-borne pathogen safety. However, treatment is frequently complicated by development of FVIII-neutralizing inhibitors, which prevent control of bleeding and predispose to a high morbidity and mortality risk. Bypassing agents are effective in bleeding treatment in a high percentage of cases. Prophylaxis with bypassing agents and their use in combination are offering opportunities in management of inhibitor patients. More evidence is necessary to understand how to prevent and manage this complication.     

Factor Xa-inhibition in interventional cardiology

The recently established correlation between bleeding events and clinical outcomes in patients with coronary artery disease undergoing either non-invasive or invasive treatment for acute coronary syndromes (ACS) highlights the unmet need for safer anticoagulants that can be used in conjunction with dual or triple antiplatelet therapy. The central position of the coagulation factors IIa and Xa within the coagulation system account for their prominent role as targets for anticoagulants. Unfractionated heparin (UFH) achieves a variable indirect inhibition of both factors. The low molecular weight heparins (LMWH) show favourable pharmacokinetics over UFH and have a more pronounced activity against factor Xa as opposed to thrombin which may partially account for the benefits observed with LMWH in clinical trials. New agents that have been developed allow for a selective inhibition of factor Xa. Recently, exciting results have been reported with an indirect selective inhibitor of factor Xa in patients with ST-elevation myocardial infarction (STEMI) -acute coronary syndromes (ACS) and non-STEMI-ACS. In this article the pharmacology of the indirect selective factor Xa inhibitors Fondaparinux and Idraparinux will be discussed along with the direct selective factor Xa inhibitors DX-9065a and Otamixaban in the setting of interventional cardiology.     

OBI-1, porcine recombinant Factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human Factor VIII

Hemophilia A is caused by a deficiency in blood coagulation Factor (F)VIII. Treatment for acute bleeding in patients comprises prophylactic infusion with human plasma-derived (pd) or recombinant (r)FVIII to increase circulating FVIII levels. However, alloantibodies (inhibitor) may arise in patients, limiting the efficacy of replacement therapy, especially in patients who develop high-titer inhibitors. For these patients, FVIII-bypassing agents are proposed, but there is a rare risk of thrombotic events. Porcine pdFVIII successfully achieves hemostatic FVIII levels in patients in whom human FVIII was ineffective, but possible residual viral contamination and immunogenicity prevents routine use. OBI-1, being developed by Ipsen and Inspiration Biopharmaceuticals Inc, is a bioengineered form of porcine rFVIII that is highly purified. OBI-1 has the procoagulant and biochemical properties of porcine pdFVIII, with improvements in risk of toxicity, infection and ease of manufacture. OBI-1 demonstrated significantly less immunogenicity than pdFVIII in a murine model of hemophilia A. Moreover, in cynomolgus monkeys, OBI-1 did not generate detectable inhibitors. OBI-1 was effective in a phase II, open-label clinical trial in patients with hemophilia A and inhibitor against porcine FVIII, who were experiencing a non-life or -limb threatening bleed. OBI-1 was well tolerated, without drug-related serious adverse events and is promising for further studies.     

B cell–activating factor modulates the factor VIII immune response in hemophilia A

Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell–activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody–mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.     

Treatment and prevention of bleeding in congenital hemophilia A patients with inhibitors

The treatment of bleeding in hemophilia A patients with persistent inhibitory antibodies to factor VIII is problematic. The current standard hemostatic agents for inhibitor patients are recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC). These “inhibitor bypassing agents” are less reliably effective than are replacement therapies for patients without inhibitors, and there are no validated laboratory assays to monitor their efficacy. Furthermore, only single rFVIIa and APCC products are available worldwide, and their use can be complicated, albeit rarely, by thrombotic events. For all these reasons, new approaches to treat bleeding in inhibitor patients are eagerly awaited. These new approaches include replacement therapy with porcine factor VIII concentrate (currently approved for use in acquired hemophilia patients), bispecific antibodies to simulate the biologic function of factor VIII (already in use in some jurisdictions), pegylated forms of activated factor VII, and strategies targeting the natural anticoagulants TFPI and antithrombin, which create a hypercoagulable phenotype to counterbalance the hypocoagulability imposed by hemophilia.     

Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices

Atrial fibrillation (AF) is said to be an epidemic, affecting 1%-1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke. New antithrombotic drugs include both parenteral agents (e.g. a long-acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe. Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin. A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation. Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF-related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with 'upstream' therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions.     

New anticoagulants

This review updates the latest developments concerning new anticoagulants. It describes potential targets in the coagulation pathway: inhibition of the initiation of coagulation, factor Xa and thrombin inhibitors. The focus is laid on substances in late development that already passed the phase II trial for venous thromboembolism (VTE)-prevention as "proof of concept". In the group of factor Xa inhibitors, the indirect inhibitor Fondaparinux has got approval for the indications prevention and therapy of VTE and acute coronary syndromes (OASIS 5 and 6). Rivaroxaban is the first direct factor Xa inhibitor that was admitted for approval in the indication VTE-prevention. The first trial of the program RECORD 1-4 was finished, trials for the indications therapy of VTE (EINSTEIN) and stroke prevention in atrial fibrillation (ROCKET AF) are in phase III. The use in acute coronary symptoms is - like apixaban - evaluated in phase II. The ADOPT trial with apixaban for VTE-prevention, as well as the BOTTICELLI trial for atrial fibrillation, have reached phase III. After the withdrawal of Ximelagatran, Dabigatran is the most developed direct thrombin inhibitor, being extensively studied in the comprehensive phase- III-program REVOLUTION and in approval for the indication VTE-prevention.     

Novel assays in the coagulation laboratory: a clinical and laboratory perspective

The ability to monitor Factor VIII (FVIII) and Factor IX (FIX) levels is integral to the clinical management of hemophilia A and B patients, respectively. Factor activity levels are checked during regular follow-up, post-infusion of factor concentrates, during pre- and post-operative assessments, and when the presence of an inhibitor is suspected. However, the ability to accurately and reproducibly measure factor activity levels with standard coagulation assays has been challenging due to the emergence of recombinant factor concentrates with extended half-lives. Similarly, special considerations must be given to the type of inhibitor assay used in patients with acquired hemophilia receiving recombinant porcine FVIII replacement. Alternative approaches to achieve hemostasis with clotting factor mimetics and interference of endogenous anticoagulants lack standardized assays for monitoring hemostatic efficacy. Laboratory assays measuring dynamic clotting parameters such as thrombin generation or whole blood viscoelasticity may provide a way forward, but have yet to enter routine clinical use. This review highlights the role of specialized coagulation assays in an era where multiple new hemostatic therapeutics for hemophilia are available, and underscores the need for clear communication between bedside and laboratory clinicians.     

Heparin, thrombin and Factor Xa inhibitors

Direct and indirect coagulation inhibitors are used to inhibit the activity of the serine proteases of the coagulation system. Indirect inhibitors act via antithrombin and heparin cofactor II. The main representatives are heparins, lowmolecular-weight heparins, fondaparinux, idraparinux and danaparoid. They bind to antithrombin and potentiate the inactivation of factor Xa and other serine proteases. Direct thrombin inhibitors bind reversibly to thrombin without cofactor. Anticoagulants are determined by global and specific anticoagulant methods. New anticoagulants are developed such as oral factor Xa inhibitors, oral thrombin inhibitors, antibody against activated factor VII, recombinant tissue pathway inhibitor to improve inhibition of blood coagulation or to induce nonanticoagulant effects (e. g. activated protein C in septicaemia). New anticoagulant methods are developed to improve and specify the anticoagulant effect of anticoagulants in thromboembolic diseases.     

New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology

A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may result in depletion of platelets and coagulation factors, which may cause bleeding. Recent understanding of important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of the fibrinolytic inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular fibrin deposition. Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C.