Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Thrombin generation in plasma of patients with haemophilia A and B with inhibitors: Effects of bypassing agents and antithrombin reduction.

Antithrombin (AT) reduction has been shown to improve thrombin generation (TG) in haemophilia with or without inhibitors. As treatment with bypassing agents (BPAs) may be required in patients with breakthrough bleeding while receiving AT-lowering therapy, we assessed TG in platelet-poor plasma samples from haemophilia patients in the presence of BPA (recombinant activated factor VII [rFVIIa; 1.25 or 2.5 µg mL-1] or activated prothrombin complex concentrate [aPCC; 0.5 or 1 U mL-1]) and AT reduction (anti-AT antibody). Mean ± SEM baseline peak thrombin height was 19.9 ± 4.3 nM in plasma from haemophilia patients (n = 12) and 230.5 ± 9.8 nM in healthy males (n = 24). Reduced AT improved mean peak thrombin height in haemophilia patient plasma to 75.4 ± 17.4 nM. Spiking of 90% AT-reduced haemophilia patient plasma with 2.5 µg mL-1 rFVIIa or 1 U mL-1 aPCC increased the mean peak thrombin height to 82.5 ± 12 nM and 134.8 ± 18.7 nM, respectively. Peak thrombin levels did not exceed the range for healthy volunteers when plasma samples from haemophilia patients with in vitro AT reduction were treated with BPAs, suggesting the potential use of BPAs in conjunction with AT reduction. Further clinical investigations are needed to confirm the safety of this approach.

Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives.

Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient's clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described.

Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome--a case control study.

Bernard-Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi-quantitative questionnaire, platelet parameters, PFA-100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61-platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P = 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF.

Solulin increases clot stability in whole blood from humans and dogs with hemophilia.

Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)-deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor-initiated fibrin formation and tissue-plasminogen activator-induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/µM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses.

An in-vitro assessment of tranexamic acid as an adjunct to rFVIII or rFVIIa treatment in haemophilia A.

Haemophilia is characterised by defective thrombin generation, reduced clot stability and spontaneous bleeding. Treatment with factor VIII (FVIII) concentrate or bypassing agents (e.g. recombinant factor VIIa (rFVIIa)) is generally effective. Occasionally, haemostasis is not achieved, which may reflect a failure of factor concentrate to normalise clot stability. Tranexamic acid (TXA) is often used to aid haemostasis in surgery (e.g. joint replacements and dental procedures). Used routinely as an adjunct, it may enhance clot stability and allow effective, reliable, and cost-effective treatment at lower doses of factor concentrate. This study hypothesised that clot stabilising adjunct TXA is required in addition to factor substitution to normalise clot stability in whole blood from patients with severe haemophilia A. The in vitro effect of varying concentrations of recombinant FVIII or recombinant FVIIa and adjunct TXA on whole blood clot stability was measured by thromboelastometry. Coagulation was triggered by tissue factor and clots were challenged with tissue plasminogen activator. The area under the elasticity curve was the primary endpoint. High concentrations of FVIII and rFVIIa increased clot stability to levels that were not significantly different from controls (Mean ± SD: control 112,694 ± 84,115; FVIII 78,662 ± 74,126; rFVIIa 95,918 ± 88,492). However, the response was highly variable between individuals and demonstrates why some patients show clinical resistance to treatment. Addition of TXA resulted in normalised clot stability in all individuals, even when combined with the lowest doses of factor concentrate. The results support the concept that a more efficient, reliable and cost effective treatment may be obtained if TXA is combined with factor concentrates to treat individuals with haemophilia.

Complementary effect of fibrinogen and rFVIIa on clotting ex vivo in Bernard-Soulier syndrome and combined use during three deliveries.

Women with Bernard-Soulier syndrome (BSS) are considered to be at high risk of serious bleeding during childbirth. Due to the frequently occurring platelet transfusion refractoriness, alternative prophylactic therapy is required. Using rotational thromboelastometry, we evaluated the whole blood coagulation profile of a pregnant woman with BSS before and after spiking ex vivo with different concentrations of recombinant activated factor VII (rFVIIa) and fibrinogen. As experiments suggested improved clotting with clinically applicable concentrations of both agents in a complementary manner, the findings were confirmed on blood from a non-pregnant woman and three men suffering from BSS. During delivery, bleeding refractory to platelets occurred and immediately following delivery she received both rFVIIa and fibrinogen intravenously. Immediate cessation of bleeding occurred, and no postpartum hemorrhage was seen. Another woman with BSS later also received the same rFVIIa and fibrinogen treatment prophylactically after delivery without any postpartum bleeding. Eventually, the first woman during her second delivery received the same treatment again prophylactically without any bleeding. No side effects were observed during these three deliveries. Our observations suggest that rFVIIa combined with fibrinogen may provide a beneficial clinical hemostatic effect partly by separate but complementary mechanisms.

Combination of recombinant factor VIIa and fibrinogen corrects clot formation in primary immune thrombocytopenia at very low platelet counts.

Haemostatic treatment modalities alternative to platelet transfusion are desirable to control serious acute bleeds in primary immune thrombocytopenia (ITP). This study challenged the hypothesis that recombinant activated factor VII (rFVIIa) combined with fibrinogen concentrate may correct whole blood (WB) clot formation in ITP. Blood from ITP patients (n = 12) was drawn into tubes containing 3·2% citrate and corn trypsin inhibitor 18·3 µg/ml. WB [mean platelet count 22 × 10(9) /l (range 0-42)] was spiked in vitro with buffer, donor platelets (+40 × 10(9) /l), rFVIIa (1 or 4 µg/ml), fibrinogen (1 or 3 mg/ml), or combinations of rFVIIa and fibrinogen. Coagulation profiles were recorded by tissue factor (0·03 pmol/l) activated thromboelastometry. Coagulation in ITP was characterized by a prolonged clotting time (CT, 1490 s (mean)) and a low maximum velocity (MaxVel, 3·4 mm × 100/s) and maximum clot firmness (MCF, 38·2 mm). Fibrinogen showed no haemostatic effect, whereas rFVIIa reduced the CT and increased the MaxVel. The combination of fibrinogen and rFVIIa revealed a significant synergistic effect, improving all parameters (CT 794 s, MaxVel 7·9 mm × 100/s, MCF 50·7 mm) even at very low platelet counts. These data suggest that rFVIIa combined with fibrinogen corrects the coagulopathy of ITP even at very low platelet counts, and may represent an alternative to platelet transfusion.

Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial.

BACKGROUND: Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. METHODS: In this single-center, prospective, placebo-controlled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. RESULTS: Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery. CONCLUSIONS: Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders.

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life. RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities. RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection. CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

Living with an ultra-rare inherited bleeding disorder is challenging. Patients can feel alone and unsure of where to find support because their disorder is so rare. In this paper, a group of ultra-rare bleeding disorder experts, including doctors, researchers, regulators, patient advocates, and patients, identify the research that could best improve the lives of people with these disorders. They propose a national network of specialists who can help doctors, who may never have seen these disorders before, to find the right diagnosis faster. A centralized laboratory specialized in ultra-rare bleeding disorders could also improve diagnosis and do research studies. This would help us learn, for example, how symptoms change throughout a patient's life, how effective different treatments are, and what it is like for patients to live with these disorders. A second research priority is to better understand each individual disorder so that the best treatments can be chosen or developed. A pathway showing doctors which treatment options to try, in which order, would help them help their patients. The third research priority is to make it easier to study new treatments for ultra-rare bleeding disorders. This requires designing studies with very small numbers of participants, identifying meaningful outcomes to measure, and convincing pharmaceutical companies to invest in these studies. International agreement on these requirements would allow more patients to participate and benefit from the research. These top-priority research goals should greatly improve knowledge about, and diagnosis and treatment of, ultra-rare inherited bleeding disorders.

Fibrinogen as a hemostatic agent.

Coagulation factor I (fibrinogen) plays an essential role in the hemostatic system by bridging activated platelets and being the key substrate for thrombin in establishing a consolidating fibrin network. Fibrinogen is synthesized in the liver and the plasma concentration is 1 to 5-4.0 g/L. During recent 10 years, fibrinogen has been recognized to play an important role in controlling hemorrhage. Dilutional coagulopathy induced by colloid plasma expanders is characterized by fibrinogen deficiency and dysfunctional fibrin polymerization. Trauma and use of extracorporeal circulation is also known to reduce levels of fibrinogen. A series of laboratory experiments and experimental animal studies have suggested fibrinogen as a potent hemostatic agent. These data are supported by retrospective surveys as well as a series of prospective proof of principal clinical trials. This article provides a description of the biochemistry and mechanisms of fibrinogen as well as the etiology for developing fibrinogen deficiency. Furthermore, it summarizes laboratory and experimental data on the role of fibrinogen in dilutional coagulopathy and addresses laboratory monitoring issues. Finally, it lists retrospective and prospective studies, which have been designed to assess the clinical efficacy and safety of hemostatic intervention with fibrinogen concentrate.

Comparison of whole blood fibrin-based clot tests in thrombelastography and thromboelastometry.

BACKGROUND: Fibrin-based clot firmness is measured as maximum amplitude (MA) in the functional fibrinogen (FF) thrombelastographic assay and maximum clot firmness (MCF) in the FIBTEM thromboelastometric assay. Differences between the assays/devices may be clinically significant. Our objective was to compare clot firmness parameters through standard (FF on a thrombelastography device [TEG®]; FIBTEM on a thromboelastometry device [ROTEM®]) and crossover (FF on ROTEM®; FIBTEM on TEG®) analyses. METHODS: Whole-blood samples from healthy volunteers were subjected to thrombelastography and thromboelastometry analyses. Samples were investigated native and following stepwise dilution with sodium chloride solution (20%, 40%, and 60% dilution). Samples were also assessed after in vitro addition of medications (heparin, protamine, tranexamic acid) and 50% dilution with hydroxyethyl starch, gelatin, sodium chloride, and albumin. RESULTS: FF produced higher values than FIBTEM, regardless of the device, and TEG® produced higher values than ROTEM®, regardless of the assay. With all added medications except heparin 400 U/kg bodyweight, FF MA remained significantly higher (P < 0.05) than FIBTEM MCF, which was largely unchanged. FF MA was significantly reduced (P = 0.04) by high-dose heparin and partially restored with protamine. Fifty percent dilution with hydroxyethyl starch, albumin, and gelatin decreased FIBTEM MCF and FF MA by >50%. CONCLUSIONS: These results demonstrate differences when measuring fibrin-based clotting via the FF and FIBTEM assays on the TEG® and ROTEM® devices. Point-of-care targeted correction of fibrin-based clotting may be influenced by the assay and device used. For the FF assay, data are lacking.

Parallel use of by-passing agents in haemophilia with inhibitors: a critical review.

In the absence of new outbreaks of transfusion-related infections, the occurrence of neutralizing antibodies currently remains the most prominent complication in haemophilia. Coagulation factor products that may circumvent the inadequate activation of factor X in classical haemophilia, often referred to as bypassing agents, have demonstrated a high degree of efficacy. A smaller number of patients have been described in whom either bypassing agent, or both, demonstrate diminished efficacy. In those cases, the use of both bypassing agents in parallel was attempted, either using simultaneous (combined) or alternating (sequential) infusion of the two drugs, reportedly with successful haemostasis. We speculated whether such treatment might cause thromboembolism. A thorough literature search disclosed 17 reports regarding the parallel use of bypassing agents in the same bleeding episode in 49 patients; reporting nine patients with acquired haemophilia and forty patients with congenital haemophilia with inhibitors. Notable incidences of thromboembolic manifestations were observed: in nine patients with acquired haemophilia, five and in 40 patients with congenital haemophilia five suffered from significant thrombotic complications, and overall four cases were fatal. Although efficacy of parallel treatment was reported excellent in most cases, thromboembolism is rare in haemophilia and parallel treatment with activated prothrombin complex concentrate and activated recombinant human factor VII appears to increase the risk of thrombosis in these patients.

A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients.

BACKGROUND: Fibrinogen concentrate administration can be guided by measuring fibrinogen concentration or quality of the fibrin-based clot. This study compared different fibrinogen concentration measurement methods with maximum clot firmness (MCF) of the fibrin clot, assessed by thromboelastometry (FIBTEM), in 33 cardiovascular surgery patients receiving fibrinogen concentrate for hemostatic therapy. STUDY DESIGN AND METHODS: Blood samples were collected after cardiopulmonary bypass (CPB) and after fibrinogen concentrate administration. FIBTEM MCF was measured using a rotational thromboelastometry device (ROTEM, Tem International). Fibrinogen concentration was measured using photo-optical (CA-7000, Siemens Healthcare Diagnostics), mechanical (KC-10 steel ball, Schnitger and Gross hook, Amelung GmbH), and electromechanical (STA-R, Diagnostica Stago) coagulometers. Assessments included agreement between fibrinogen concentration measurements and correlations between fibrinogen concentration and FIBTEM MCF. RESULTS: After CPB, correlations were significant (p < 0.001) between FIBTEM MCF and fibrinogen concentration determined by steel ball (r = 0.71), hook (r = 0.73), STA-R (r = 0.81), and CA-7000 (r = 0.82) coagulometers. After fibrinogen concentrate administration, agreement between fibrinogen measurement methods was severely impaired, and correlations with FIBTEM MCF were 0.39 (steel ball), 0.33 (hook), 0.59 (STA-R), and 0.33 (CA-7000). CONCLUSION: Agreement between fibrinogen concentration measurement methods decreased considerably after fibrinogen concentrate administration. All methods correlated acceptably with FIBTEM MCF at the end of CPB, but not after hemostatic therapy. Further investigation is needed to explain these findings.

Diagnostic performance and therapeutic consequence of thromboelastometry activated by kaolin versus a panel of specific reagents.

BACKGROUND: Thromboelastography/metry (TEG®; Haemoscope, Niles, IL/ROTEM®; Tem International GmbH, Munich, Germany) is increasingly used to guide transfusion therapy. This study investigated the diagnostic performance and therapeutic consequence of using kaolin-activated whole blood compared with a panel of specific TEM®-reagents to distinguish: dilutional coagulopathy, thrombocytopenia, hyperfibrinolysis, and heparinization. METHODS: Blood was drawn from 11 healthy volunteers. Dilutional coagulopathy was generated by 50% dilution with hydroxyethyl starch 130/0.4 whereas thrombocytopenia (mean platelet count 20 ×109/l) was induced using a validated model. Hyperfibrinolysis and heparin contamination were generated by tissue plasminogen activator 2 nM and unfractionated heparin 0.1U/ml, respectively. Coagulation tests were run on ROTEM® delta. RESULTS: Kaolin-activated whole blood showed no differences between dilutional coagulopathy and thrombocytopenia (mean clotting time 450 s vs. 516 s, α-angle 47.1° vs. 41.5°, maximum clot firmness 35.0 mm vs. 34.2 mm, all P values ≥0.14). Hyperfibrinolysis specifically disclosed an increased maximum lysis (median: 100%, all P values less than 0.001), and heparin induced a distinctly prolonged clotting time (2283 s, all P values less than 0.02). The coagulopathies were readily distinguishable using a panel of TEM-reagents. In particular, dilutional coagulopathy was separated from thrombocytopenia using FIBTEM (maximum clot firmness 1.9 mm vs. 11.2 mm, P < 0.001). The run time of analysis to achieve diagnostic data was shorter applying a panel of TEM-reagents. A transfusion algorithm based on kaolin suggested platelets in case of dilutional coagulopathy, whereas an algorithm applying TEM-reagents suggested fibrinogen. CONCLUSION: Monoanalysis with kaolin was unable to distinguish coagulopathies caused by dilution from that of thrombocytopenia. Algorithms based on the use of kaolin may lead to unnecessary transfusion with platelets, whereas the application of TEM-reagents may result in goal-directed fibrinogen substitution.

Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity.

Prothrombin complex concentrates (PCCs) are used mainly for emergency reversal of vitamin K antagonist therapy. Historically, the major drawback with PCCs has been the risk of thrombotic complications. The aims of the present review are to examine thrombotic complications reported with PCCs, and to compare the safety of PCCs with human fresh frozen plasma. The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents. The causes of PCC thrombogenicity remain uncertain but accumulating evidence indicates the importance of factor II (prothrombin). With the inclusion of coagulation inhibitors and other manufacturing improvements, today's PCCs may be considered safer than earlier products. PCCs may be considered preferable to fresh frozen plasma for emergency anticoagulant reversal, and this is reflected in the latest British and American guidelines. Care should be taken to avoid excessive substitution with prothrombin, however, and accurate monitoring of patients' coagulation status may allow thrombotic risk to be reduced. The risk of a thrombotic complication due to treatment with PCCs should be weighed against the need for rapid and effective correction of coagulopathy.

Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review.

INTRODUCTION: Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of fresh frozen plasma (FFP). Purified human fibrinogen concentrate may offer an alternative to FFP in some instances. In this systematic review, we investigated the current evidence for the use of FFP and fibrinogen concentrate in the perioperative or massive trauma setting. METHODS: Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasma fibrinogen level) of FFP or fibrinogen concentrate administration to patients in a perioperative or massive trauma setting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patient age, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies or other haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted and tabulated. RESULTS: Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessed outcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes. There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality (typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgical and/or nonmassive bleeding). Five studies reported the outcome of fibrinogen concentrate versus a comparator. The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay and increasing plasma fibrinogen levels. We found no fibrinogen concentrate comparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessed outcomes was reported in a number of noncomparator trauma studies. CONCLUSIONS: The weight of evidence does not appear to support the clinical effectiveness of FFP for surgical and/or massive trauma patients and suggests it can be detrimental. Perioperatively, fibrinogen concentrate was generally associated with improved outcome measures, although more high-quality, prospective studies are required before any definitive conclusions can be drawn.

No excess surgical blood loss in patients with acquired type 2A von Willebrand disease.

OBJECTIVES: Acquired type 2A von Willebrand disease may develop as a consequence of aortic valve stenosis and is associated with varying degrees of bleeding tendency. It remains unknown, whether it portends excess blood loss during aortic valve replacement. DESIGN: We consecutively enrolled 45 patients with severe aortic valve stenosis undergoing aortic valve replacement. Patients with acquired type 2A von Willebrand disease were identified measuring the von Willebrand factor high molecular weight multimer. Data on the intraoperative, early postoperative, and the total blood loss within 24 hours of surgery was obtained and compared between groups. RESULTS: Acquired type 2A von Willebrand disease was found in 33% (n = 15/45) of the patients. Baseline characteristics were similar between groups. Patients with acquired type 2A von Willebrand disease neither had excess median intraoperative blood loss (375 ml (interquartile range 100-450 ml) vs. 350 ml (interquartile range 250-500 ml), p = 0.59) nor increased median total blood loss (695 ml (interquartile range 450-850 ml) vs. 752 ml (interquartile range 575-1035 ml), p = 0.41) as compared to patients without acquired type 2A von Willebrand disease. CONCLUSION: Acquired type 2A von Willebrand disease was not associated with increased blood loss during aortic valve replacement in patients with severe aortic valve stenosis.

A critical evaluation of cryoprecipitate for replacement of fibrinogen.

Maintaining the plasma fibrinogen concentration is important to limit excessive perioperative blood loss. This article considers the evidence for this statement, and questions the justification for using cryoprecipitate rather than virus-inactivated fibrinogen concentrate to support plasma fibrinogen levels. Haemophilia was historically treated with cryoprecipitate, but specific coagulation factor concentrates are now preferred. In contrast, primary fractions of allogeneic donor blood, including cryoprecipitate, are still commonly used to treat perioperative bleeding. When compared with cryoprecipitate and fresh-frozen plasma (FFP), freeze-dried fibrinogen concentrate offers standardized fibrinogen content, faster reconstitution and improved efficacy. Pasteurization and purification processes employed in the preparation of fibrinogen concentrate reduce the risk of pathogen transmission and immune-mediated complications, in comparison with cryoprecipitate and FFP. When all costs associated with administration are taken into consideration, the cost of fibrinogen concentrate is not substantially different to that of cryoprecipitate. In conclusion, wider availability and use of fibrinogen concentrate may improve the management of perioperative bleeding. Further benefits may accrue from more rapid and accurate techniques for monitoring fibrinogen levels. Clinical studies are needed to evaluate methods of measuring fibrinogen and assessing fibrin polymerization, and to define critical haemostatic plasma fibrinogen concentrations in different perioperative situations.