Factor VIII Research Articles

The Role of the Hemostasis and Thrombosis Unit in the Management of the Patients with Acquired Hemophilia.

Acquired hemophilia A (AHA) is a rare autoimmune disease characterised by the presence of autoantibodies against coagulation factor VIII (FVIII), leading to spontaneous haemorrhage in patients without a prior family or personal history of bleeding. This study describes the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcomes of 41 AHA patients, along with specific case reports. Diagnosis and treatment occurred between 2005 and 2023. The median age at diagnosis was 67.8 years (range 15-93). Among the 41 patients, 10 (24%) were idiopathic, 4 (10%) were postpartum, 18 (44%) had autoimmune diseases, and 9 were diagnosed with cancer. Diagnostic delay exceeded 30 days in 15 out of the 41 cases (36.5%). A total of 38 out of the 41 (93%) patients presented with spontaneous bleeding, with mucocutaneous bleeding being the most common presentation (23/41, 56%). Four patients experienced postpartum bleeding. Clinical remission was achieved in 100% of patients, and no patient died. Haemostatic and Immunosuppressive therapy is essential in AHA, and it should be started as soon as possible in patients with bleeding. However, a significant delay in diagnosis was observed. The absence of mortality is likely attributable to the management of the disease within a specialised Haemostasis and Thrombosis Unit, which offers a clinical ward, a specialised laboratory, and a dedicated ambulatory service. The Italian Society for the Study of Haemostasis and Thrombosis (SISET) is working to secure recognition for this essential role in every hospital.

Effects of coagulation factors on bone cells and consequences of their absence in haemophilia a patients

Haemophilia is associated with reduced bone mass and mineral density. Due to the rarity of the disease and the heterogeneity among the studies, the pathogenesis of bone loss is still under investigation. We studied the effects of coagulation factors on bone cells and characterized in a pilot study the osteoclastogenic potential of patients’ osteoclast precursors. To evaluate the effect of coagulation factors on osteoclasts, we treated Healthy Donor-Peripheral Blood Mononuclear Cells (HD-PBMC) with Factor VIII (FVIII), von Willebrand Factor (VWF), FVIII/VWF complex, activated Factor IX (FIXa), activated Factor X (FXa) and Thrombin (THB). FVIII, VWF, FVIII/VWF, FXa and THB treatments reduced osteoclast differentiation of HD-PBMC and VWF affected also bone resorption. Interestingly, PBMC isolated from patients with moderate/severe haemophilia showed an increased osteoclastogenic potential due to the alteration of osteoclast precursors. Moreover, increased expression of genes involved in osteoclast differentiation/activity was revealed in osteoclasts of an adult patient with moderate haemophilia. Control osteoblasts treated with the coagulation factors showed that FVIII and VWF reduced ALP positivity; the opposite effect was observed following THB treatment. Moreover, FVIII, VWF and FVIII/VWF reduced mineralization ability. These results could be important to understand how coagulation factors deficiency influences bone remodeling activity in haemophilia.

Saliva from persons with hemophilia A triggers coagulation via extrinsic tenase complexes

Human saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, i.e. persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not perform prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva from persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva from persons with severe FVII deficiency is unable to restore blood coagulation, which is due to the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva from FVII deficient persons. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.

Superior Prophylactic Effectiveness of a Recombinant FVIIIFc Over Standard Half-Life FVIII in Hemophilia A: A-SURE Study.

The 24-month, prospective, non-interventional, European multicenter A-SURE study evaluated the real-world effectiveness of prophylaxis using an extended half-life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half-life (SHL) FVIII products in patients with hemophilia A. Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses. Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of -0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of -54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development. rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption.

Real-world experience of emicizumab prophylaxis in Korean children with severe hemophilia A without inhibitors

PurposeHemophilia A is a genetic disorder characterized by a lack of factor VIII (FVIII). Emicizumab, a recombinant humanized bispecific monoclonal antibody, mimics the function of FVIII. In this article, we present data on an initial real-world evaluation of emicizumab use in Korean children with severe hemophilia A without inhibitors.MethodsThis study was conducted from June 2020 to March 2024 at 4 centers in Korea. The participants were pediatric patients with severe hemophilia A without inhibitors who had received emicizumab treatment for over 6 months. The mean and median annualized bleeding rates (ABRs) and mean and median annual joint bleeding rates (AJBRs) were compared.ResultsEach of the 21 patients in the study received an emicizumab loading regimen of 3 mg/kg weekly for 4 weeks, followed by a modified maintenance regimen of which 2 patients (9.5%) received a 1.5 mg/kg weekly dose, 3 patients (14.3%) received a 6 mg/kg dose every 4 weeks, and the remaining 16 patients (76.2%) received a 3 mg/kg dose every 2 weeks. Before emicizumab prophylaxis initiation, the mean and median ABRs for all patients were 7.04 (SD ± 5.83) and 6.52 (range 0–21.74), respectively. After receiving emicizumab treatment, the mean and mediam ABRs decreased to 0.41 and zero, respectively. Additionally, 85.7% of the patients achieved no bleeding events within 6 months of starting the treatment.ConclusionThese first real-world data in Korea indicate that emicizumab is effective and safe for pediatric patients with severe hemophilia A without inhibitors.

Activity Assessment of Factor Replacement Therapies to Guide Infusion Rate Protocols in Patients with Bleeding Disorders

Abstract Introduction The development of institutional protocols guiding administration of clotting factor replacements in patients with bleeding disorders requires an understanding of product stability over infusion duration. Inclusion of new factor products on formulary at our institution raised consideration for optimal administration routes, including whether a bolus intravenous push versus infusion over 4-12h provided acceptable factor activities. Here we assessed the activity of two clotting factor replacement therapies over a 24h period to guide clinical care protocols. Method This study was performed in the Special Coagulation Lab as a collaboration between pharmacy, hematology, and laboratory medicine. Two vials each of Novoeight, a recombinant antihemophilic factor used in patients with factor VIII deficiency, and Vonvendi, a recombinant von Willebrand Factor (VWF) replacement approved for prophylaxis in adults with Type 3 von Willebrand Disease, were reconstituted to clinically relevant potencies (13 IU/ml, Novoeight; 27 IU/ml, Vonvendi). Products were spiked separately into factor VIII-deficient plasma (Novoeight) or assay diluent (Vonvendi), given inability to obtain VWF-deficient plasma, and tested for activity at various timepoints. Novoeight samples were assessed by traditional one-stage FVIII assays, while Vonvendi samples were assessed for VWF antigen, ristocetin cofactor activity (RCA), and glycoprotein Ib binding activity (GP1bM). Results Novoeight samples maintained similar FVIII activities at all timepoints tested, with differences falling within the coefficient of variation of the assay. Specifically, the two samples had FVIII levels of 108% and 95% at baseline and levels of 98% and 91%, respectively, at 12h, which was the timepoint of greatest interest given plans to allow 12h infusion rates. For Vonvendi samples, measurement of VWF antigen remained fairly stable throughout the 24h period. However, VWF activity decreased in both RCA and GP1bM assays over time, including by 4h. RCA values were 193% and 190% at baseline, 113% and 95% at 4h, and 63% and 63% at 12h. GP1bM was 140% and 133% at baseline, 92% and 91% at 4h, and 56% and 70% at 12h. Together, these results supported implementation of protocols allowing for extended (up to 12h) infusion of Novoeight and short (3-5min) bolus infusion of Vonvendi. Conclusion Our study demonstrated maintained Novoeight activity over the study period, confirming infusion rates of 12h should be efficacious. Conversely, Vonvendi yielded significantly decreased activity levels in as little as 4h, indicating the need for faster infusion rates. Based on our results, current practices at our institution were adapted to include extended infusion for Novoeight only. Drug activity studies may not directly reflect patient outcomes, and additional studies of factor activities following product infusion into patients and clinical hemostasis correlates are necessary. Nevertheless, the clinical lab should continue to play a primary role in testing, monitoring, and developing patient care protocols for therapeutic drugs through multidisciplinary collaboration.

Factor Replacement Treatment for Hemophilia A: Achievements and Perspectives.

The mainstay of treatment for persons with hemophilia A (PwHA) with severe bleeding phenotype is prophylaxis. The pharmacokinetic (PK) profile of native factor VIII (FVIII) imposes the need for rather frequent intravenous injections to ensure effective prophylaxis, but this represents a relevant treatment burden and is associated with suboptimal adherence to treatment. In this light, the advent of extended half-life (EHL) FVIII molecules has improved prophylaxis feasibility and outcomes by favoring treatment individualization and tailoring protection according to specific clinical and nonclinical needs. Different technologies have been used to enhance FVIII PK properties including Fc-fusion and conjugation with polyethylene glycol. Data from clinical development programs for such molecules, together with growing real-world experience, have shown numerous benefits related to the use of EHL FVIII in PwHA. Recently a new class of ultra-long-acting EHL FVIII has been developed to further improve protection against bleeding episodes and achieve the ambitious goal of providing PwHA with hemostatic protection in the nonhemophilia range over longer time periods, hence ensuring very low bleeding rates and improving joint health and quality of life. In this review, the achievements and perspectives of replacement therapies for PwHA are summarized and discussed.

Real-world insights into the management of hemophilia A in Italy: treatment patterns and healthcare resource utilization

PurposeThis real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.MethodsFrom Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021–2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021–2022 having at least 12-month follow-up were assessed.ResultsAmong included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.ConclusionThese findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

Acute abdomen: an atypical presentation of acquired hemophilia

Acquired hemophilia is a rare but potentially life-threatening disorder characterized by the development of acquired hemophilia A, leading to bleeding complications. Spontaneous, mild-to-life-threatening bleeding in typically elderly individuals without a personal or family history of bleeding is the hallmark of acquired hemophilia A (AHA), a rare autoimmune bleeding illness caused by the formation of auto-antibodies against endogenous factor VIII (FVIII). This hallmark represents our present case, with no obvious history related to the bleeding issue. Prompt detection and treatment of bleeding are essential for the best outcomes. We present a case of a 66-year-old male who had acute-onset severe abdominal pain and with constipation for five days, associated with nausea and loss of appetite. On physical examination, the patient appeared pale, and abdominal examination revealed diffuse tenderness with guarding. Initial evaluation revealed tachycardia and hypotension. Initial abdomen X-rays revealed features suggestive of small bowel obstruction. The patient was stabilized with intravenous fluids, referred to a surgical team, and admitted to the acute bed in the general ward for further management. Keywords: Acquired Hemophilia; Auto-Antibodies; Factor VIII; Intraabdominal Bleeding Citation: Hehsan MR. Acute abdomen: an atypical presentation of acquired hemophilia. Anaesth. pain intensive care 2024;28(5):974−976; DOI: 10.35975/apic.v28i5.2556 Received: March 19, 2024; Reviewed &amp; Accepted: September 08, 2024

From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms.

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.

CHIEF: A retrospective self-control study of children with severe hemophilia A without inhibitors comparing emicizumab to FVIII prophylaxis.

Hemophilia A (HA) is an X-linked bleeding disorder diagnosed by a deficiency in factor VIII (FVIII). For severe HA (SHA), prophylaxis clotting factor concentrates (CFC) has become the standard of care; however, it imparts a high treatment burden and typically results in an annualized bleeding rate (ABR) of 2-6. Emicizumab, a subcutaneously administered FVIII substitute, has become the de facto standard-of-care prophylaxis for children with SHA in many countries. Previous clinical trials of emicizumab have assessed ABR in patients greater than 12years without inhibitors, and in children less than 12years with inhibitors; however, there is little information published regarding the ABR of emicizumab compared to CFC in non-inhibitor SHA children. Using a retrospective electronic medical record chart review, we conducted a self-control analysis of 15 patients less than 12years of age during equivalent periods of CFC versus emicizumab prophylaxis. The mean ABR on CFC and emicizumab was 1.79 and 1.13 (p=.092), respectively, with a substantially decreased rate of joint bleeds (CFC 0.94; emicizumab 0.33; p=.001) and spontaneous bleeds (CFC 0.79; emicizumab 0.23; p=.008). No safety events were recorded for patients while administering emicizumab. The mean annual cost of CFC prophylaxis was $515,340 (SD $199,540), compared to $328,410 (SD $137,230) for emicizumab prophylaxis (p<.001). Emicizumab resulted in an improved ABR compared to CFC, especially for joint and spontaneous bleeds, had fewer administration complications, and was substantially less expensive compared to CFC prophylaxis; however, more research is necessary for a complete understanding of the effect of emicizumab on joint health and muscle bleeds.

Efficient generation of liver sinusoidal endothelial-like cells secreting coagulation factor VIII from human induced pluripotent stem cells

Liver sinusoidal endothelial cells (LSECs) and LSEC progenitor cells (LPCs) derived from human pluripotent stem cells (PSCs) are expected as valuable cell sources for the development of cell therapy for hemophilia A, a congenital deficiency of coagulation factor VIII (FVIII), as LSECs are responsible for FVIII production. However, there is room for improvement in the efficiency of LSECs and LPCs differentiation from PSCs. In this study, we sought to optimize the method of mesoderm differentiation induction, the initial step of LSEC differentiation from PSCs, to efficiently induce LSEC-like cells capable of secreting FVIII from human induced pluripotent stem cells (iPSCs). Following optimization of the concentration and stimulation period of CHIR99021 (glycogen synthase kinase 3β inhibitor), bone morphogenetic protein 4, fibroblast growth factor 2, and Activin A in the mesoderm induction step, approximately 65% and 54% of cells differentiated into LPCs and LSEC-like cells, respectively. Furthermore, we observed substantial FVIII protein secretion from LSEC-like cells in vitro. In conclusion, we established an efficient method for obtaining LPCs and functional LSEC-like cells from iPSCs in vitro.

Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model

BackgroundInhibitor eradication to restore factor VIII (FVIII) efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI. Estimating the individual chance of ITI success allows clinicians, patients, and their families to support shared decision-making. ObjectiveWe aimed to identify clinical predictors of ITI success and to develop a clinical prediction model to estimate the chance of successful ITI in persons with severe HA. MethodsThis multicenter study included persons with severe HA who received ITI. Clinical data were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. A multivariable logistic regression model was developed. Model performance and internal validation were performed. ResultsOf 206 participants with median age of 19.8 months (IQR 12.1-38.8) at ITI start, 148 (71.8%) achieved ITI success. Our clinical prediction model included four predictors of ITI success: cumulative number of FVIII exposure days at inhibitor development, peak inhibitor titer, ethnicity, and F8 mutation type. The C-statistic was 0.801 (95% CI, 0.70-0.87). ConclusionIn our study including 206 people with severe HA and inhibitors, we developed a clinical prediction model to estimate the chance of successful ITI. After future external validation, this clinical prediction model may be useful for informing clinicians and families.

Evaluating the Role of Silymarin in Coordinating the Relationship between Inflammation and Thrombosis by Affecting Endothelial Cells

Background: A widespread crosstalk between inflammation and coagulation has been shown in numerous studies. This suggests that coagulation can trigger an inflammatory response which ultimately leads to coagulation activation. Previous research has shown that polyphenols can affect blood pressure and endothelial dysfunction, resulting in reduced risk of cardiovascular diseases. This study aimed to investigate whether Silymarin, a flavonolignans, could play a role in the interaction between inflammation and coagulation by influencing endothelial cells. Materials and Methods: In this experimental study, human umbilical vein endothelial cells (HUVECs) were seeded with and without various concentrations of silymarin. In vivo, treatment with silymarin was also carried out. Coagulative and fibrinolytic factors, including Von Willebrand factor (VWF) and Factor VIII (FVIII), tissue plasminogen activator-1 (TPA-1), and inflammatory factors, including interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-α), were evaluated by flow cytometry, Real-Time Polymerase Chain Reaction (qPCR), Enzyme-Linked Immunosorbent Assay (ELISA) and Immunocytochemistry (ICC). Results: Silymarin increased the gene expression, release, and storage of VWF while diminishing the gene expression, release, and storage of TPA-1 (P ˂ 0.05). The activity of FVIII was dramatically increased, and IL-8 and TNF-α levels were augmented. The in vivo study also indicated an elevated plasma level of VWF and IL-8 by silymarin administration. Conclusion: The results showed that, although silymarin reduces inflammatory factors, it can affect coagulation factors by increasing the levels of VWF and FVIII activity and inhibiting TPA-1 production, thereby making thrombosis probable. Consequently, it is advisable to prescribe this medication with caution for individuals who are susceptible to thrombotic events.

Clinical and Humanistic Burden of Non-inhibitor HaemophiliaA in Five European Countries: Insights from the CHESSII Study.

HaemophiliaA (HA) is a congenital bleeding disorder caused by a deficiency/absence of factorVIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESSII) study. CHESSII was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18years) individuals with haemophiliaA or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Use of coagulation factor concentrates and blood transfusion in cardiac surgery: a retrospective cohort study of adults with hereditary and acquired bleeding disorders

BackgroundCardiac surgery poses a significant risk of perioperative bleeding and allogeneic blood transfusions, particularly in patients with bleeding disorders. Increasingly frequent use of coagulation factor concentrates could impact haemorrhagic risks, thromboembolic events, and costs. We describe the use of coagulation factor concentrates and allogeneic blood products in cardiac surgical patients with hereditary and acquired bleeding disorders to assess pertinent outcomes, including perioperative haemorrhage, thromboembolism, and hospital costs. MethodsWe conducted a retrospective cohort study using the Premier Health Database, including adult cardiac surgical patients diagnosed with hereditary or acquired bleeding disorders compared with those without bleeding disorders. ResultsPatients with acquired bleeding disorders required more extensive use of coagulation factor concentrates and blood products compared with those with hereditary bleeding disorders or without bleeding disorders. The highest exposures to coagulation factor concentrates were found in the acquired bleeding disorders group, with 24% receiving factor VIIa and 11.7% receiving prothrombin complex concentrate. This group also experienced significantly higher rates of complications, including a 15.8% rate of haemorrhage and a 19.2% rate of thromboembolic events. The acquired bleeding disorders group had longer intensive care and hospital stays, and the highest mortality rate (19.2%). The increased use of perioperative replacement of factor VIII and factor IX in the hereditary bleeding disorders group led to increased pharmacy costs but did not significantly impact blood bank charges. ConclusionsAcquired bleeding disorders in cardiac surgery patients are associated with increased use of haemostatic interventions, postoperative complications, and increased healthcare costs. Improved management of perioperative haemostasis and thromboprophylaxis strategies are essential for optimising patient outcomes and reducing expenses.

Investigations on the Hemostatic Potential of Physiological Body Fluids.

Current blood coagulation models consider the interactions between blood, the vessel wall, and other tissues that expose tissue factor (TF), the main initiator of coagulation. A potential role of body fluids other than blood is generally not considered. In this review, we summarize the evidence that body fluids such as mother's milk saliva, urine, semen, and amniotic fluid trigger coagulation. The ability of these body fluids to trigger coagulation is explained by the presence of extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes (i.e., complexes of TF and activated factor VII) that can trigger coagulation. Why these body fluids share this activity, however, is unknown. Possible explanations are that these body fluids contribute to hemostatic protection and/or to the regulation of the epithelial barrier function. Further investigations may help understand the underlying cellular and biochemical pathways regulating or contributing to coagulation and innate immunity, which may be directly relevant to medical conditions such as gastrointestinal bleeding and chronic inflammatory bowel disease.

Efficacy and safety of a recombinant von Willebrand factor treatment in acquired von Willebrand syndrome in case of bleeding and surgical procedures.

Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France. To describe the real-world experience of using rVWF in non-surgical bleeding and surgical procedures in patients with AVWS. Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres. During bleeding, the median number of infusions was only 1 (range 1-27) with a median loading dose of 58IU/kg (range 17-116) rVWF and a total median dose of 65IU/kg (range 35-1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1-8) with a preoperative loading dose of 60IU/kg (range 23-118) rVWF and a total median dose of 123IU/kg (range 31-542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported. This French 'real-world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern.

Correlating COVID-19 severity with biomarker profiles and patient prognosis

COVID-19's long-lasting and complex impacts have become a global concern, with diverse clinical outcomes. This study evaluated 226 participants to understand the clinical spectrum of COVID-19/Long COVID (LC), exploring how disease severity correlates with sociodemographic factors and biomarkers. Determinants related to COVID-19 severity included age (P < 0.001), lower education (P < 0.001), ethnicity (P = 0.003), overweight (P < 0.001), MTHFR gene rs1801133 (P = 0.035), cardiovascular diseases (P = 0.002), diabetes mellitus (DM) (P = 0.006), Factor VIII (FVIII) (P = 0.046), von Willebrand factor (VWF) (P = 0.002), and dimer D (DD) (P < 0.001). Six months later, in a portion of the monitored participants, a significant reduction in FVIII (P < 0.001), VWF (P = 0.002), and DD (P < 0.001) levels was observed, with only DD returning to normal values. Different systemic sequelae were identified, with higher incidences of joint pain and myalgia in participants with a clinical history of DM, chronic lung disease (CLD) and sustained high interleukin 6 values in the convalescent phase. CLD, COVID-19 severity and high DD levels increased the risk of developing dyspnea and palpitations. Women were more likely to develop lower limb phlebitis long-term, while sustained elevated FVIII in the convalescent phase was associated with an increased risk of swelling. Regular physical activity had a protective effect against swelling. This study highlights factors contributing to COVID-19 severity/LC, emphasizing endothelial cell activation as a potential mechanism.

Trial Of Pathogen-reduced Cryoprecipitate vs. Cryoprecipitated AHF to Lower Operative Transfusions (TOP-CLOT): study protocol for a single center, prospective, cluster randomized trial

BackgroundIntraoperative hemorrhage in cardiac surgery increases risk of morbidity and mortality. Low pre-operative and perioperative levels of fibrinogen, a key clotting factor, are associated with severity of hemorrhage and increased transfusion of blood components. The ability to supplement fibrinogen during hemorrhagic resuscitation is delayed 45–60 min because cryoprecipitated antihemophilic factor (cryo AHF) is stored frozen, due to a short post-thaw shelf life. Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex, IFC) can be kept thawed, at room temperature, for up to 5 days, making it possible to be immediately available for hemorrhaging patients. This trial will investigate if earlier correction of acquired hypofibrinogenemia with IFC in hemorrhaging cardiac surgery patients reduces the total number of perioperatively transfused allogeneic blood products (red blood cells, plasma, and platelets) as compared to cryo AHF.MethodsThis is a single center, prospective, cluster randomized trial with an adaptive design. Acquired hypofibrinogenemia will be assessed by rotational thromboelastometry (ROTEM) and the threshold for cryo AHF/IFC transfusion defined as FIBTEM A10 ≤ 10 mm in bleeding patients. IFC/cryo AHF will be randomized by 1-month blocks. Cardiac surgery patients will be enrolled in the study if they have an eligible procedure and at least one dose of a cryo AHF/IFC product (approximately 2 g fibrinogen) is transfused. Data from the electronic health record, including the blood bank and lab information systems, will be prospectively collected from the health system’s data warehouse.DiscussionThis trial aims to provide evidence of the clinical efficacy of utilizing readily available thawed IFC during acute bleeding in the cardiac surgery setting compared to traditional cryo AHF.Trial registrationClinicalTrials.gov NCT05711524. Feb 3, 2023.