Coagulation Factor Deficiencies Research Articles

Successful management of a pregnancy complicated by ollier disease and coagulation factors deficiency – A rare case report

Successful management of a pregnancy complicated by ollier disease and coagulation factors deficiency – A rare case report

Evaluation of the Effect of Regular Administration of Coagulant Factors on the Joint Pain Level and Dimensions of the Quality of Life of the Patients Suffering from Some Bleeding Disorders (BDs)

Background: Blood coagulation is a process that prevents blood loss. Lack of coagulation factors (inherited or acquired) disrupts this path. The prevalence of coagulant deficiency including VIII and XIII factors in Sistan and Baluchistan province is higher than in other parts of Iran. This study aimed to investigate the condition of patients suffering from some bleeding disorders (BDs) in terms of regular coagulant takes and their effects on quality of life.
 Methods: Our cross-sectional study was descriptive-analytical. Thirty-five BD patients suffering the blood coagulant deficiency enrolled, and were sorted into 5 groups.
 Results: The mean (±SD) age in the hemophilia A and B groups were (16.25 ± 8.15), and (8.14 ± 3.9), and other coagulation factor deficiencies including VWF, XIII, and IX were (15.1 ± 7.8), (15.5 ± 2.4), and IX (19.0 ± 11.5) respectively. The quality of life in group A (81.3 ± 14.9) compared to groups B (50 ± 0.25) and IX (47.5 ± 24.1) had a significant difference (p value < 0.05). In addition, there was a significant difference in group XIII (79.2 ± 29.2) compared to groups B (50 ± 0.25) and IX (47.5 ± 24.1) (p value < 0.05). Generally, the quality of life was higher in women (10 people) (72.5 ± 26.2) than in men (26 people) (61.1 ± 24.5). Furthermore, the Visual analog scale for pain in group A (1.3 ± 0.4) had a significant difference compared to group B (3.5 ± 0.43), IX (7.8 ± 0.9), XIII (0.4 ± 4.3) and VWF (3.2 ± 0.38) (p value < 0.05).
 Conclusion: In sum, patients with hemophilia A and coagulation factor XIII deficiency had low levels of joint pain and a high level of quality of life dimensions.

Late-onset vitamin K deficiency bleeding: a preventable yet prevailing cause of intracranial hemorrhage in young infants—an ambispective descriptive study

BackgroundVitamin K deficiency bleeding (VKDB) may present as intracranial hemorrhage (ICH) in young infants, which results in severe morbidity and mortality. This study aims to determine the clinical presentation, risk factors, and outcome of children with VKDB.MethodsThis was an ambispective descriptive study conducted from January 2015 to August 2023 in southern India. Infants from 8 days to 6 months of age, diagnosed as VKDB based on bleeding with elevated PIVKA (protein induced by vitamin K absence) and prolonged prothrombin time, which is rapidly corrected 24 h after administration of vitamin K, were included. Infants with bleeding due to other causes, such as inherited clotting factor deficiency, cholestasis, and sepsis, were excluded. A structured data collection proforma was used to collect data.ResultsOut of 62 cases, 28 were excluded due to various causes, and 34 were analyzed. The median age at symptom onset was 54 days, and males were 22 (64.7%). Term gestation was 25 (73.5%), and low birth weight was 13 (38.2%), and 8 (23.5%) required NICU admission. All received vitamin K prophylaxis at birth. Thirty-three (97%) were exclusively breastfed. The most common presenting complaints were poor activity and convulsion. A total of 97% of children had ICH, and 5 (14.7%) had skin bleed. Twenty-three (67.6%) infants had complete recovery, 6 (17.6%) had sequelae (2 had hemiparesis, 2 monoparesis, and 2 quadriplegia), and 5 (14.7%) children expired.ConclusionVitamin K deficiency commonly presents as intracranial hemorrhage in infants. Exclusive breastfeeding is a significant risk factor for vitamin K deficiency, followed by low birth weight and prematurity.

Assessment of oral health awareness and hygiene practice in hemophilic patients in Indore: A cross-sectional study

: Haemophilia is a genetic X linked recessive bleeding disorder characterized by a deficiency or absence of certain clotting factors in the blood, primarily factors VIII (haemophilia A) or factor IX (haemophilia B). Dental caries and periodontal diseases are two main oral diseases affecting majority of population, but their effects are enhanced in hemophiliacs and medically compromised patients. There is a lack of epidemiological studies regarding oral health and oral hygiene of hemophilic patient especially in central India. This study therefore, aimed to evaluate the oral hygiene awareness and hygiene practices of patients with hemophilia in Indore district. This cross-sectional study was conducted on 30 hemophilic patients who were selected via snow ball sampling technique. The patients who were ready to participate voluntarily in the study were included. A study questionnaire in Hindi and English was given to the patients to obtain their knowledge about oral hygiene and dental health awareness.: Thirty hemophilic patients participated in the study with a mean age of 20 ±15 years. All the participants were male. Although hemophilic patients were conscious of oral hygiene, the study found most of them had poor dental practices. The majority of participants (56.67%) reported of using soft-bristled brushes. Only 56.67% of the participants reported cleaning their mouths after meals and having seen gum bleeding. The majority of hemophilia patients (46.15%) reported using Factor VIII, while some also used Tranexamic acid (15.39%).: Oral hygiene is crucial for everyone, but it holds particular importance for individuals with hemophilia. Good oral hygiene reduces the need for invasive dental treatments, minimizing potential complications.

Rates of venous thromboembolism and use of thromboprophylaxis after major orthopedic surgery in patients with congenital hemophilia A or B: a systematic review

BackgroundVenous thromboembolism (VTE) is a well-recognized complication after total joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies, and administering pharmacologic thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk. ObjectivesTo analyze best available evidences of VTE rates in persons with hemophilia A or B undergoing lower limb TJR and the use of postoperative pharmacologic thromboprophylaxis. MethodsWe systematically screened 4 online biomedical databases to identify studies reporting VTE rates in patients with hemophilia after TJR. Case reports and case series with less than 10 patients were excluded. ResultsTwenty-six observational studies were included in this systematic review, reporting 1181 TJRs in patients with hemophilia A or B. Eight studies had VTE rates as the primary outcome. Five studies reported screen-detected VTE, while 21 reported symptomatic VTE events. Overall, 17 VTE events were reported (1.4%; 95% CI, 0.9%-2.3%), including 10 (6.6%) after 151 surgeries with postoperative VTE screening and 7 (0.7%) after 1080 surgeries without postoperative screening. Thromboprophylaxis protocols were specified in 21 studies; postoperative thromboprophylaxis was used in 15 (1.3%) surgeries. This information was not available for 29.0% of the analyzed population. ConclusionDespite the low thromboprophylaxis use in patients with hemophilia, rates of symptomatic VTE after TJR appeared to be low. We also highlighted the need to better report the thrombotic outcome in persons with hemophilia to face the ongoing changes in the hemophilia landscape.

Study on Red Cell Indices in Chronic Liver Disease in Tertiary Level Hospital

Background: Chronic liver disease (CLD) in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. Liver diseases are frequently associated with hematological abnormalities. Bleeding and defective blood coagulation contributes to the anemia in CLD patients. Other mechanisms of anemia include aplastic anemia secondary to previous hepatitis, or side effects of treatment of hepatitis with chemotherapeutic agent. Other different factors, such as malabsorption, malnutrition or direct toxic effect also contribute to hematological abnormalities. The examination of complete blood count is common, economically cheap and readily available laboratory procedure. Red cell indices are valuable in the evaluation of morphologic characteristic of anaemias or hematological abnormalities in CLD patients. Objectives: To assess the red cell indices in chronic liver disease patients. Materials & method: This descriptive type of cross-sectional study was conducted in Department of Medicine, Dhaka Medical College Hospital, Dhaka, among 75 cases of Chronic liver disease patients. Samples were selected by purposive sampling technique. Detail demographic data were collected from the patients and recorded in structured case report form. Clinical examination and relevant investigation were done meticulously. Data was processed and analysed with the help of computer program SPSS and Microsoft excel. Quantitative data expressed as mean and standard deviation and qualitative data as frequency and percentage. Results was presented by tabulation and graphical presentation in the form of tables, pie chart, graphs, bar diagrams, histogram & charts etc. Result: Maximum number of patients, 37(49.3%) were between 31-40 years of age with mean age of the patient was 37.58 ± 8.23 years. Out of 75 cases 58(77.0%) patients were male and 17(23.0%) were female. Male-female ratio was 3.34:1. Majority of patients belonged to Child Pugh score B. Prevalence of anaemia was 54(72%) in CLD patients. Microcytic anaemia was predominant and Normocytic anaemia was second most common. Hb concentration & MCV decreases with the severity of Child Pugh score. Abnormalities of red cell indices were positively associated with severity of CLD. Conclusion: Present study concluded that chronic liver diseases are associated with hematological abnormalities. Patients with severe hepatocellular disease develop defects of blood coagulation as a consequence of endothelial dysfunction, thrombocytopenia, deficiencies of coagulation factors and various associated disorders. In overall patients, Child Pugh class C cases had significant low hemoglobin in comparison to rest of group. Assessing the severity and type of anaemia by red cell indices is a useful tool for proper treatment, prognosis in patients of CLD for reducing the mortality and morbidity. J MEDICINE 2024; 25: 41-45

Safety of Tonsillectomy and/or Adenoidectomy in Pediatric Patients with Prolonged Activated Partial Thromboplastin Time and Factor XII Deficiency.

To evaluate the safety and feasibility of tonsillectomy and/or adenoidectomy (T&A) in pediatric patients with prolonged activated partial thromboplastin time (APTT) and coagulation factor deficiency. A prospective study was admitted to the children undergoing T&A at our institution between October 2019 and January 2020, specifically focusing on preoperative coagulation function. Within this group, we identified 5 patients exhibiting prolonged APTT and coagulation factor deficiencies, constituting the experimental group, and 10 patients matched by gender and age with normal blood coagulation function were selected as the control group. Comparative analyses between the two groups were conducted, focusing on surgical duration, intraoperative bleeding volume, duration of hospital stay, and postoperative complications such as active bleeding across the groups. At the six-month postoperative mark, a reassessment of coagulation functions and factor assays was conducted within the experimental group. No statistically significant differences were discovered in terms of surgical duration or bleeding volume when comparing the experimental subgroups with their respective control counterparts. Furthermore, there were no incidences of postoperative active bleeding observed in any of the groups. Notably, postoperative APTT values (32.7 ± 1.7s) exhibited a significant disparity compared to preoperative levels (43.7 ± 1.8s, p < 0.01). Coagulation factors demonstrated normalization, evidenced by a significant difference in postoperative Factor XII levels (40.2 ± 5.4%) compared to preoperative levels (63.1 ± 5.9%, p < 0.01). Prolonged APTT with FXII factor deficiency does not show a significant bleeding tendency and is not a contraindication for T&A surgery. Post T&A surgery, children with abnormal coagulation function and deficient clotting factors show significant improvement compared to pre-surgery. It is important to consider that chronic inflammation in adenoids and tonsils may contribute to the prolongation of APTT and the manifestation of Factor XII deficiency.

A Study to Assess Knowledge Regarding Hemophilia among Parents of Hemohilic Children in New Civil Hospital, Surat

Hemophilia was thought to be a uniform entity for several centuries. The discovery that the coagulation defect in the blood of one hemophilic could be normalized by infusion of blood from another hemophilic in 1940 led to finding that there were two types of hemophilia: hemophilia A, due to deficiency of coagulation factor Ⅷ and Hemophilia B, caused by the reduction of coagulation factor Ⅸ. Hemophilia was divided into three different degrees of severity: severe, moderate and mild. In severe hemophilia, the plasma content of coagulation factor activity is less than 1% of normal, compared with 1 to 4% in moderate hemophilia and 5 to 40% in mild cases.

Multiple Coagulation Factor Deficiency: A Series of Eight Cases

Multiple Coagulation Factor Deficiency: A Series of Eight Cases

ACQUIRED HAEMOPHILIA A

Acquired haemophilia A (AHA) is a rare disease believed to be caused by spontaneous inhibition of clotting Factor VIII by autoantibodies. This is in contrast to the more common congenital haemophilias which are largely due to an absolute deficiency in coagulation factors. It has a prevalence of approximately one per million per year. However, this figure may be underestimated because there are many undocumented cases due to a lack of recognition. Patients who develop this disease may present with catastrophic bleeding despite having no previous bleeding history. In this study, we report a case of acquired Haemophilia A presenting with spontaneous unprovoked bruising and discuss the approach to diagnosis and how to alert the clinician to suspect this potentially rare but devastating disease.

Advances and challenges with gene therapy for haemophilia

Summary:&#x0D; Haemophilia rare inherited bleeding disorder caused by deficiency in clotting factor that affects around 6,000 people in the UK. Patients with haemophilia require regular prophylactic infusions of the deficient clotting factor intravenously, which causes a large burden on patients and their families. Gene therapy holds promise as a potential cure for Haemophilia. This article critically evaluates the existing evidence for gene therapy in Haemophilia.&#x0D; Relevance:&#x0D; There are several gene therapies in development for inherited conditions such as Haemophilia. Valoctocogene Roxaparvovec, a gene therapy for Haemophilia, is currently being assessed by regulatory authorities worldwide. Medical students and practicing physicians must be aware of the current evidence base for gene therapy for Haemophilia as well as the limitations thereof to help patients make informed decisions on whether gene therapy is a suitable treatment option for them. &#x0D; Take Home Messages:&#x0D; The current evidence shows that gene therapy is likely to be effective in increasing clotting factor levels and reducing bleeds for at least 3 years. However, long-term data is limited, and therefore, the durability of the treatment is unknown. Additionally, there is limited evidence on the safety and efficacy of gene therapy in patients with pre-existing antibodies to the viral vector, patients with inhibitors to the clotting factor, and children.

THE STATE OF THE HEMOCOAGULATION LINK IN THE HEMOSTASIS SYSTEM OF MICE AFTER PARTIAL LIVER RESECTION UNDER ADMINISTRATION OF PLATELET AUTOMESOCONCENTRATE

The purpose of the study is to evaluate the indicators of the hemocoagulation link in the hemostasis system of mice after partial resection of the liver under the platelet automesoconcentrate administration.&#x0D; Materials and methods. 2/3 of the liver was resected in wild-type mice. The animals were divided into three groups: I - control; II – mice that underwent partial hepatectomy; ІІІ – mice that were injected with automesoconcentrate of platelets in a dose of 1 ml/kg during surgery into the liver remnant.&#x0D; Results and discussion. The study has shown that during the first day following the liver resection, hemocoagulation processes decrease that was indicated by a reduction in the content of platelets and fibrinogen in the blood and a simultaneous increase in the parameters of thrombin time, prothrombin time, and International Normalized Ratio. In the period from the 4th to the 7th day of the study, an increase in the levels of platelets and fibrinogen and a decrease in the indicators of thrombin time, prothrombin time, and Activated Partial Thromboplastin Timer were revealed, however, the studied indicators did not acquire the values ​​of the control group of animals. Administration of automesoconcentrate is a dose of 1 ml/kg directly into the liver remnant during the hepatectomy procedure helps to normalize the hemocoagulation system on the seventh day after the procedure.&#x0D; Administration of automesoconcentrate also prevents the development of hypocoagulation, vascular wall defects (vasculitis, reduction in the thickness of the walls of microvessels), deficiency of blood coagulation factors. The high concentration of platelets in the automesoconcentrate enables to effectively avoid the loss of platelets and fibrinogen, coagulation factor V, coagulation factor VIII and other coagulation components. Along with this, the automesoconcentrate helps to restore the functional capacity of the liver after resection of a significant part of it, since hepatectomy damages the liver function of patients.&#x0D; Conclusions. Administering platelet automesoconcentrate effectively prevents the loss of platelets, fibrinogen, coagulation factor V, coagulation factor VIII, and other crucial coagulation components.

Management of pregnant women who have bleeding disorders.

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant.

IBC-Oxford University2023_BJSPoster_1Laparoscopic Sleeve Gastrectomy in a Patient with Severe Haemophilia A

Abstract Introduction Haemophilia A is an X linked inherited bleeding disorder caused by deficiency in coagulation factor VIII (FV III). To prevent spontaneous bleeding in muscles and joints, patients with severe Haemophilia A should receive prophylactic replacement therapy with dosing adjusted according to body weight. Case presentation A 19-year-old male patient who is well known to have Haemophilia A, that has been diagnosed shortly after birth during routine circumcision. The patient had presented to our clinic with BMI of 53.9 kg/m2. He was counselled for laparoscopic sleeve gastrectomy after failure of many trials to lose weight. He and his father were counselled for procedure pros and cons. Routine preoperative work up had been performed (Full labs, Abdomen Ultrasound, Dietician consultation, Anaesthesia consultation, Cardiology consultation). Haematological consultation had been done and consultant opinion was to give prophylactic factor VIII 7500 IU: 2 hours prior to surgery, 24 hours after surgery, 72 hours after surgery Extra precaution had been taken in the perioperative period in the form of careful cannulation, IM injections had been avoided completely, no anticoagulants, 1:1 Nursing care, careful patient handling and positioning, continuous monitoring (planned ICU admission for first 24 hours then HDU admission for 48 hours), senior Anaesthetist and senior Anaesthesia technician, on-table gastroscopy, smooth bougie tube placement (size 36F), careful haemostasis by way of slow Harmonic sealing, clipping of short gastrics, 1 minute stapler compression (All green reloads), full stapler line plication and omental patching, maintenance of stable blood pressure during surgery. Patient had an uneventful postoperative recovery, apart from mild bilateral subconjunctival haemorrhages that had subsided spontaneously. Conclusion Laparoscopic sleeve gastrectomy can be performed smoothly in patients with Haemophilia A with proper perioperative multidisciplinary care management.

Performance of a direct oral anticoagulant removal reagent, DOAC-StopTM, for lupus anticoagulant testing

Abstract Objective Routine use of direct factor Xa inhibitor (direct oral anticoagulant; DOAC) therapy necessitates a modified lupus anticoagulant (LAC) testing method for this population. To remove interfering DOACs in specimens, DOAC-StopTM treatment was used on LAC specimens to assess for antiphospholipid syndrome (APS) without altering patient’s anticoagulation treatment. Methods DOAC-StopTM was evaluated with our LAC testing panel with dilute Russell viper venom time (dRVVT), and Silica Clotting Time (SCT) assays, both of which activate coagulation. DOAC-StopTM beads were used for pretreatment by addition and rocking for 5 minutes, followed by 5000 rpm centrifugation for 5-minutes. Treated plasma supernatant was used for a screen, confirm (addition of phospholipid), 50:50 mix (addition of reagent plasma with coagulation factors), and confirm 50:50 mix phases of testing. The Total Ratio (TR; ratio between screen and confirm ratios relative to mean of normal ranges) was calculated and used per the package insert for interpretation. Implementation data was assessed for interpretation differences between groups with and without DOAC-StopTM treatment. Results Patients being tested for APS by LAC assay with and without DOAC therapy were included. DOACs included apixaban or rivaroxaban. Primary interpretations included no evidence of a LAC (NELAC), evidence of LAC, and results more consistent with coagulation factor deficiency. The effectiveness of DOAC removal was established by spiking NELAC samples with apixaban and treating with DOAC-StopTM, resulting in removal of anti-factor Xa activity. An apixaban spiking study with NELAC and LAC patient specimens with LAC testing before and after DOAC-StopTM treatment demonstrated unchanged interpretations. In a test modification study, Rivaroxaban resulted in positive dRVVT interpretations in nine of ten patients. All but one became negative after DOAC-StopTM treatment. Two SCT interpretations became positive after treatment. Apixaban resulted in two positive dRVVT interpretation in nine patients, one of which became negative after DOAC-StopTM treatment. SCT interpretations remained unchanged. Review of implementation data (n=78) with nine patients on DOACs having DOAC-StopTM treatment demonstrated similar patterns of test interpretation. Interpretations included: “no evidence of a LAC” in 53% (n=41) without and 55% (n=5) with DOAC-StopTM, “Does not meet criteria” in 17% (n=13) without and 11% (n=1) with DOAC-StopTM, “Evidence of a LAC” in 21% (n=16) without and 33% (n=3) with DOAC-StopTM. The remaining eight patients without DOAC-StopTM treatment had interpretations including factor deficiency, warfarin effect, equivocal, or concerning for interference. Conclusion Patients on DOACs benefit from DOAC-StopTM –enable LAC testing for APS assessment. Data analysis demonstrates that DOAC-StopTM effectively removes DOAC interference in the majority of tests with similar rates of major interpretation categories. LAC testing and interpretation for patients on DOAC therapy shows promise with novel approaches and reagents such as DOAC-StopTM, though interpretative challenges with false-positives and false-negatives continue.

Impact of Blood Group O and Von Willebrand Factor on Bleeding Severity in Patients with Von Willebrand Disease and Bleeding Disorder of Unknown Cause

Background: In patients with bleeding, von Willebrand disease (VWD) is diagnosed at von Willebrand factor (VWF) levels of ≤50 IU/dL ( James et al. Blood Adv. 1:280-300. 2021). Nevertheless, the majority of patients with a mild to moderate bleeding disorder (MBD) is diagnosed with bleeding disorder of unknown cause (BDUC), upon exclusion of VWD, platelet function defects (PFD), and coagulation factor deficiencies (CFD). Bleeding severity in patients with VWD does not correlate well with VWF levels in type 1 VWD, suggesting other modifiers of the bleeding tendency, when patients with severe VWD are excluded. Blood group O (BG O) is associated with lower VWF levels and has been found to be overrepresented in VWD. In BDUC patients, BGO is also overrepresented and recognized as an independent risk factor for bleeding severity and recurrent bleeding ( Mehic et al. Blood Adv.20: 5157-5164. 2020; Mehic et al. JTH. 7: 1757-1768. 2023). Aim: This study aimed to comprehensively investigate the clinical phenotype of patients with VWD or BDUC from the Vienna Bleeding Biobank (VIBB) and evaluate the direct effect of ABO BG on bleeding severity beyond its effect on VWF levels. Methods: Patients with VWD or BDUC from the VIBB, a single-center cohort study (EC 603/2009), were categorized by lowest VWF, as measured by VWF:antigen (VWF:Ag) or VWF ristocetin co-factor activity (VWF:RCo), into four groups: &amp;lt;30 IU/dL (very low VWF), 30-50 IU/dL (low VWF), 51-80 IU/dL, and &amp;gt;80 IU/dL. Patients diagnosed with PFD (n=221), CFD (n=28), or other diagnoses (n=4) were excluded. To study the association of BG O with bleeding severity irrespective of VWF levels, we fitted linear regression models adjusting for age, sex, and lowest VWF. We allowed for non-linearity by modelling age and sex with restricted cubic splines. Results: A total of 637 patients, 18 (2.8%) with very low VWF, 55 (8.6%) with low VWF, 237 (37.2%) with VWF levels ranging from 51 to 80 IU/dL and 327 (51.3%) with VWF levels &amp;gt;80 IU/dl, were included in this analysis, as summarized in Table 1. BG O was more prevalent in patients with very low VWF levels (61%), low VWF levels (71%), and VWF levels 51-80 IU/dL (66%) than in patients with VWF levels &amp;gt;80 IU/dL (30%). Patients with low VWF were youngest, followed by very low VWF and those with VWF 51-80 IU/dL. Age was highest in the patient group with VWF levels &amp;gt;80 IU/dL at clinical presentation and might influence VWF levels and bleeding scores. With regard to bleeding severity, patients with very low VWF levels had highest median bleeding scores or number of bleeding manifestations, while the bleeding severity was similar amongst the other three categories (Table 1). VWF levels did not correlate with bleeding severity scores (Vicenza score: Spearman rho=-0.03, p=0.53; ISTH BAT: rho=-0.02, p=0.75; number of bleeding manifestations: rho=-0.02, p=0.66). In linear regression, holding age, sex, and lowest VWF levels constant, predicted mean bleeding scores and number of bleeding manifestations were higher with BG O (Vicenza score mean difference [MD], 0.64; 95% confidence interval [95%CI], 0.12 to 1.25; p=0.015; ISTH BAT MD 0.52; 95%CI, -0.25 to 1.28; p=0.18; number of bleeding manifestations MD, 0.24; 95%CI, -0.06 to 0.54; p=0.12) (Figure 1). Conclusion: Our findings demonstrate an overlap between VWD and BDUC with a similar clinical phenotype and bleeding phenotype, but increased severity in patients with VWF levels &amp;lt;30 IU/dL. Patients with BG O had increased bleeding scores compared to those with BG non-O. BG O appears to be an independent factor in modifying bleeding severity in both patients with VWD or BDUC across all VWF ranges.

Liver Sinusoidal Endothelial Cells but Not Hepatocytes Express a Fluorescent Reporter Under the Endogenous F8 Promoter in a New Hemophilia a Mouse Model

Hemophilia A (HA) is an inherited bleeding disorder caused by mutations in the F8 gene leading to a deficiency in coagulation factor VIII (FVIII). Treatment of patients with HA has centered around replacement of FVIII protein. Gene therapy provides the possibility of permanently altering the HA phenotype. Gene therapy for HA induces FVIII expression in hepatocytes, despite the well supported belief that FVIII is not made within hepatocytes but rather in liver sinusoidal endothelial cells (LSECs). Ectopic expression of FVIII in hepatocytes has been implicated in mild toxicities and FVIII decline observed in adeno-associated viral (AAV) vector-based gene therapy, the causes of which remain unknown. Extrahepatic production of FVIII, e.g. in lymphoid tissues, has been controversial. A better understanding of where FVIII is produced is needed to improve gene therapy for HA and inform development of other therapeutic interventions. We developed in collaboration with Jackson Laboratory a new strain of hemophilic mice on the C57BL/6J background expressing the fluorescent protein mScarlet under the endogenous F8 promoter. Using the CRISPR/Cas9 gene editing system, we inserted a transgene encoding mScarlet into exon 1 of the mouse F8 gene through homology-directed repair. We selected mScarlet for its relative brightness and stability, to maximize the chances of detecting its expression despite weak F8 promoter activity. The donor DNA consisted of two homology arms flanking the mScarlet-encoding transgene followed by the bovine growth hormone polyadenylation [poly(A)] signal. Insertion of the transgene at the first F8 codon in exon 1 and inclusion of poly(A) ensured knock-out of F8. Male animals showed a bleeding phenotype consistent with other HA mouse strains, such as C57BL/6J HA and B6/129 HA. We performed retro-orbital bleeding and tested mouse plasma samples using the activated partial thromboplastin time (aPTT) assay. Animals expressing mScarlet (n=4) and C57BL/6J HA mice (n=3) had similarly prolonged aPTT (mean 57 seconds) compared to non-hemophilic C57BL/6J mice (n=5, 41 seconds). Production of mScarlet was first evaluated in the hepatocytes and LSECs of mScarlet mice (n=3) using flow cytometry. The livers were perfused in situ via the portal vein with a perfusion and collagenase medium. The livers were then processed into single cell suspensions, and hepatocytes and LSECs were separated by centrifugation. An anti-CD31 antibody was used to identify LSECs. Hepatocytes were identified by exclusion of CD45.2 + cells. CD31 +cells from mScarlet mice but not from control C57BL/6J mice expressed mScarlet. Neither mouse strain had detectable mScarlet in hepatocytes. Flow cytometry was then used to evaluate mScarlet in the splenic endothelial cells (ECs) and leukocytes. Using in situtranscardiac perfusion, mScarlet or control C57BL/6J mice received a perfusion and collagenase medium. Following processing into single cell suspensions, ECs were isolated from other splenic cells by magnetic separation using CD31 microbeads. Anti-CD31 and anti-CD45.2 antibodies were used to identify ECs and splenic leukocytes, respectively. Neither cell type from mScarlet or control mice had detectable mScarlet. We next evaluated mScarlet expression via fluorescent microscopy of liver and spleen sections. Before sectioning, tissues were fixed using in situ transcardiac perfusion fixation. Since mScarlet fluorescence was not detectable in tissue sections, we employed an anti-mScarlet antibody. Anti-mScarlet binding was detectable in liver sections from mScarlet but not control C57BL/6J mice. The staining pattern was consistent with the sinusoidal arrangement of hepatic capillaries running between rows of hepatocytes toward central venules. We found the same staining pattern using an anti-CD31 antibody, supporting that the mScarlet-expressing cells were LSECs but not hepatocytes. No anti-mScarlet binding was detected in the spleens from either mScarlet or C57BL/6J mice. We propose that FVIII is produced in LSECs but not in hepatocytes, splenic endothelial cells, splenic or hepatic leukocytes. Our novel mouse model expressing a well-defined and readily detectable reporter protein overcomes the limitations of immunohistochemistry using anti-FVIII antibodies, which complicated previous studies on the cellular origins of FVIII. Further investigation of extrahepatic FVIII production is ongoing.

Advancing Hemophilia Prophylaxis: Personalized Low-Dose CFC and Emicizumab in Resource-Limited Settings

Introduction: Hemophilia, a congenital bleeding disorder resulting from clotting factor deficiency, significantly impacts the lives of persons due to recurrent bleeding. Prophylaxis, involving clotting factor replacement, has been recognized as a vital approach to reduce complications and to improve the quality of life in people with hemophilia. However, access to this remains limited, in low-income countries like India. This study examines the effectiveness of personalized low-dose clotting factor concentrates (CFC) prophylaxis and Emicizumab in children with hemophilia, aiming to achieve zero annual bleed rates (ABR), thereby enhancing their well-being and reducing healthcare burden. Patients and Methods: This retrospective observational study was conducted at the Hemophilia Treatment Centre (HTC) in Aluva, Kerala, India, spanning from May 31, 2022, to June 1, 2023. Study included children under 18 years with hemophilia A/B, with or without inhibitors, who had commenced prophylaxis with personalized low-dose CFC since 2015 and completed one year of prophylaxis. The total sample size was 31. Data on ABR, Annual Joint Bleed Rate (AJBR), Hemophilia Joint Health Status (HJHS) score, and Functional Independence Score Hemophilia (FISH) were extracted from the HTC registry.Standard half-life CFCs were used for prophylaxis, with a starting frequency of twice a week for Factor VIII and once a week for Factor IX. Patients were regularly followed up in the Hemophilia Clinic, and the frequency/doses of prophylaxis were increased in case of breakthrough bleeds. Additionally, children were advised to organize peak activities to coincide with the days of CFC injections. Personalization of doses was not based on pharmacokinetic software but was determined through close monitoring and individual adjustments.Health education on identifying and managing bleeding episodes followed ISTH guidelines. Prophylaxis outcomes were assessed with changes in ABR and AJBR during the last year of prophylaxis and compared to the bleed rates in the one year prior to prophylaxis. Changes in HJHS and FISH were documented for older children. All analysis were done using SPSS version24. For quantitative variables results were presented as mean with standard deviation and for qualitative variables, results were presented in percentages. Comparison achieved with standard paired t-test, and p value &amp;lt; 0.05 considered as significant. Results: Out of 36 children receiving prophylaxis, 31 met the inclusion criteria. Among them,10 (32%) received Emicizumab prophylaxis, while 21 (68%) were managed with personalized low-dose CFC prophylaxis. Hemophilia A constituted 24(77%) of cases, mostly classified as severe disease-29 (94%). Table :1 summarises the patient characteristics, prophylaxis dose, cost and outcome measures of the study population.The personalized low-dose CFC prophylaxis had significant measurable improvements, reducing the ABR from 14.90 to 2.90( p 0.000) and the AJBR from 4.95 to 1.43( p 0.004). Additionally, HJHS improved from 3.30 to 0.95( p 0.102), and FISH increased from 29.90 to 32.00( p 0.020).Children on Emicizumab achieved exceptional results, with all reporting zero ABR ( p 0.027), and AJBR ( p 0.131) even with lower than recommended doses(1.02mg/kg/week). In contrast, personalized low-dose CFC prophylaxis (Factor VIII: 36.35/kg/week, Factor IX:32/kg/week) showed varied outcomes, with only 4(19%) achieving zero ABR. HJHS and FISH were not evaluated in Emicizumab group as 7(70%) were belonging to the age group of less than 5 years. Conclusion: This study highlights the effectiveness of personalized low-dose CFC prophylaxis and Emicizumab in reducing bleeding rates and improving musculoskeletal health and functional independence in children with hemophilia. Emicizumab prophylaxis demonstrated remarkable outcomes, achieving zero bleeds even with lower doses. However, personalized low-dose CFC prophylaxis struggled to achieve zero bleed rates for most of them. The findings underscore the need for alternative strategies and increased accessibility to Emicizumab and other newer drugs to achieve the goal of zero bleed rates for children with hemophilia in resource-limited settings. The study's results provide hope for achieving zero bleed rates, ultimately enhancing the well-being of children with hemophilia in resource-limited regions.

Randomized, Active-Control Phase 3 Study of Four-Factor Prothrombin Complex Concentrate Versus Frozen Plasma in Bleeding Adult Cardiac Surgery Patients

Background and Significance: Patients following cardiac surgery often develop coagulopathic bleeding and associated poor outcomes. The development of coagulopathy is multifactorial, including anticoagulation, hemorrhage, hemodilution and consumptive losses after tissue injury and during cardiopulmonary bypass (CPB). Reduced thrombin generation due to coagulation factor deficiency is an important contributor to post-CPB bleeding. Prothrombin complex concentrate (PCC; off-label) and frozen plasma (FP) are administered for coagulation factor replacement during surgery. The LEX-211 (FARES-II) study will determine if four-factor PCC (4F-PCC, Octaplex, Octapharma) is clinically non-inferior to FP regarding hemostatic effectiveness in cardiac surgery patients requiring coagulation factor replacement. Study Design and Methods: LEX-211 (FARES-II; NCT05523297) is a multicenter, randomized, active-control, prospective, Phase 3 trial that is being conducted at 13 hospitals in Canada and the United States. The study is being conducted in accordance with the Declaration of Helsinki. The study includes patients ≥18 years old undergoing cardiac surgery with CPB who require coagulation factor replacement due to bleeding and known (e.g., as indicated by international normalized ratio) or suspected coagulation factor deficiency. Exclusion criteria include heart transplant, insertion/removal of ventricular assist devices, high probability of death within 24 hours, severe right heart failure, heparin contraindications, thromboembolic events within the prior 3 months, and IgA deficiency. Patients will be randomized to 4F-PCC or FP when the blood bank receives the first order for coagulation factor replacement (Figure 1). For 4F-PCC dosing, patients weighing ≤60 kg will receive 1,500 international units (IU), and those &amp;gt;60 kg will receive 2000 IU. For FP, patients weighing ≤60 kg will receive 3 U and patients weighing &amp;gt;60 kg will receive 4 U. Patients are treated according to their assigned group until a maximum of 2 doses of 4F-PCC/FP have been administered during the treatment period (24 hours after initiation). If additional treatment is required, patients in both groups receive FP. The primary endpoint is the hemostatic response to 4F-PCC vs. FP, rated ‘effective’ if no further hemostatic intervention (systemic hemostatic agents, i.e., platelets, cryoprecipitate, other coagulation factor products, or a second dose of study drug, or surgical re-opening for bleeding) is required within 60 minutes to 24 hours after initiation of the first dose. Secondary and safety endpoints, with their timings, are described in Table 1. An unblinded interim analysis (100 evaluable patients/group) will test sample size assumptions and enable re-estimation if necessary. Depending upon the interim results, and accounting for dropouts (20% anticipated), the total sample size will range between 513-1,250 patients. The non-inferiority of the primary endpoint of ‘haemostatic response’ will be tested for 4F-PCC vs. FP using a Farrington-Manning score test with a non-inferiority margin of 0.10 at a one-sided significance level alpha of 2.5%. If non-inferiority is demonstrated, the superiority of 4F-PCC with regard to the primary endpoint will be investigated. LEX-211 (FARES-II) is in progress, with the first study site initiated in Q4 2022. Currently, &amp;gt;150 patients have been included in the study. Completion is expected in Q4 2024. The results of this study will inform clinical practice for bleeding cardiac surgery patients requiring coagulation factor replacement, potentially reducing allogeneic blood product usage and improving patient outcomes.

Health Care Resource Use, Comorbidities, and Costs of Hemophilia A Patients in France: A Nationwide Claims Database Analysis

Background and objectives Hemophilia A is an inherited bleeding disorder characterized by a deficiency in blood clotting factor VIII (FVIII). Its severity varies based on the degree of FVIII deficiency, with the most severe cases experiencing frequent spontaneous hemorrhages (FVIII levels &amp;lt; 1 IU/dL). Treatment options include on-demand administration following a hemorrhage or prophylaxis to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the coagulation factors, leading to more aggressive and expensive treatments. The aim of this study was to describe Hemophilia A patients according to severity in France in 2021, including sociodemographic characteristics and comorbidities, current treatments, healthcare resource use and related costs. Methods This study used the French health-insurance claims database (SNDS) containing pseudonymized individual data for over 66 million people. Hemophilia A patients are fully covered in France and might be identified by the ICD-10 code D66. Patients alive on January 1st, 2021, were selected after exclusion of those presenting with Willebrand disease and other rare bleeding disorders. Comorbidities were identified through validated algorithms. An age and gender matched control group without Hemophilia A was randomly selected in the general population: for each HA patient a subject of the same age, gender and region of residence was randomly selected among the overall population of French citizens (excluding HA patients). Sub-group analyses were performed according to the treatment pattern (on demand / in prophylaxis) and the presence of inhibitors (defined with the treatment: emicizumab before October 2019, high dose of factor VIII or bypassing agents). Direct costs were estimated in a societal perspective. Results 5,507 patients with Hemophilia A were identified. Mean age was 36 years and 97.3% were males. Compared to controls, hemophilia patients had significantly (p&amp;lt;0.05) more frequently an HIV infection, hepatitis B or C, and a hepatic disease (Figure 1). There were no significant differences for chronic cardiopathy, coronary artery disease, chronic heart failure and arrhythmia. Respectively 4,056 (73.7%), 36 (0.7%), 1,243 (22.6%) and 172 (3.1%) patients were treated on demand without and with inhibitors and in prophylaxis without and with inhibitors. Compared to controls, patients with hemophilia A had more frequent consultations with general practitioners and hospital specialists, visits to emergency unit, with nurses and physiotherapists (Table 1). They also were more frequently treated with analgesics and corticosteroids but less frequently with non-steroid anti-inflammatory drugs. The proportion of hemophilia A patients hospitalized was higher than controls, overall and also for bleeding episodes and for orthopedic surgery. The mean annual direct medical costs (drugs, consultations, hospitalizations, ...) varied strongly according to treatment modalities and presence of inhibitors: €11,471 for patients treated on demand without inhibitors (versus €1,806 for their matched controls)€76,332 for patients treated on demand with inhibitors (versus €2,288 for their matched controls)€247,937 for patients treated in prophylaxis without inhibitors (versus €1,159 for their matched controls)€349,616 for patients treated in prophylaxis with inhibitors (versus €1,342 for their matched controls). The majority of the costs was related to antihemophilic drugs: 64%, 60%, 94% and 93% respectively in the 4 treatment groups. Conclusion: These results highlight the burden of hemophilia A in terms of comorbidities, healthcare consumptions and cost. The cost of Hemophilia A varied greatly with disease severity and presence of inhibitors and was mostly due to the antihemophilic drugs.