Clinical Analysis and Mental Health Survey of Hemophilia Carriers:a Cross-sectional Study

Objective:Hemophilia carriers(HCs),who are heterozygous for mutations in the clotting factor VIII/clotting factor IX gene(F8 or F9),may have a wide range of clotting factor levels,from very low,similar to afflicted males,to the upper limit of normal,and may experience mental health issues.The purpose of this study was to provide genetic information on mothers of hemophilia patients and to understand the clotting factor activity and phenotype of HCs.Additionally,we aimed to investigate the mental health status of HCs in China.Methods:A total of 127 hemophilia mothers,including 93 hemophilia A(HA)mothers and 34 hemophilia B(HB)mothers,were enrolled in this study.Long distance PCR,multiplex PCR,and Sanger sequencing were used to analyze mutations in F8 or F9.Coagulation factor activity was detected by a one-stage clotting assay.The Symptom Checklist 90(SCL-90,China/Mandarin version)was given to HCs at the same time to assess their mental health.Results:A total of 90.6%of hemophilia mothers were diagnosed genetically as carriers,with inversion in intron 22 and missense mutations being the most common mutation types in HA and HB carriers,respectively.The median clotting factor level in carriers was 0.74 IU/mL(ranging from 0.09 to 1.74 IU/mL)compared with 1.49 IU/mL(ranging from 0.93 to 1.89 IU/mL)in noncarriers,of which 14.3%of HCs had clotting factor levels of 0.40 IU/mL or below.A total of 53.8%(7/13)of HA carriers with low clotting factor levels(less than 0.50 IU/mL)had a history of bleeding,while none of the HB carriers displayed a bleeding phenotype.The total mean score and the global severity index of the SCL-90 for surveyed HCs were 171.00(±60.37)and 1.78(±0.59),respectively.A total of 67.7%of the respondents had psychological symptoms,with obsessive-compulsive disorder being the most prevalent and severe.The pooled estimates of all nine factors were significantly higher than those in the general population(P<0.05).Conclusions:The detection rate of gene mutations in hemophilia mothers was 90.6%,with a median clotting factor level of 0.74 IU/mL,and 14.3%of HCs had a clotting factor level of 0.40 IU/mL or below.A history of bleeding was present in 41.2%of HCs with low clotting factor levels(less than 0.50 IU/mL).Additionally,given the fragile mental health status of HCs in China,it is critical to develop efficient strategies to improve psychological well-being.

Bullous pemphigoid associated with acquired hemophilia A: A case report

BACKGROUND Acquired hemophilia A (AHA) is a rare and potentially severe bleeding disordercaused by circulating autoantibodies against factor Ⅷ (FⅧ). In approximately50% of the patients, the condition is associated with autoimmune diseases,cancers, medication use, pregnancy, and the post-partum period. Bullous pemphigoid(BP) is a chronic autoimmune subepidermal blistering disease associatedwith tissue-bound and circulating autoantibodies against BP antigens 180 (BP180)and 230 (BP230). AHA-associated BP has a high mortality rate;hence, the understandingof this disease must improve.CASE SUMMARY A 69-year-old man presented with erythema, blisters, blood blisters, and crustsaccompanied by severe pruritus for more than 20 days, and ecchymosis andswelling on his left upper arm for 3 days. Pathological examination revealed asubepidermal blister that contained eosinophils. Laboratory tests showed that theBP180 autoantibody levels had increased, isolated activated partial thromboplastintime was notably prolonged (115.6 s), and coagulation FⅧ activity wasextremely low (< 1.0%). Furthermore, the FⅧ inhibitor titer had greatlyincreased (59.2 Bethesda units). Therefore, the patient was diagnosed as having BP associated with AHA, prescribed 0.05% topical halometasone cream, and transferred to a higher-level hospitalfor effective treatment;however, he died after 2 days.CONCLUSION AHA associated BP is rare, dangerous, and has a high mortality rate. Therefore, its timely diagnosis and effectivetreatment are necessary.

Extra Dural Hematoma of the Dorso-Lumbar Region in a Hemophiliac: A Rare Entity

Introduction and objective: Hemophilia is a genetic bleeding disorder inherited as a recessive train linked to the male gender. Bleeding into the central nervous system in patients with hemophilia is an extremely dangerous condition that can be directly life-threatening, if left untreated. Extradural hematoma of the dorso-lumbar region is rare but potentially deadly disease in children. This condition can result in severe neurological deficits. We aim to discuss the clinical, radiological and progressive clinical aspects of this illness. Case report: We report the case of a 5-year-old child with severe hemophilia A treated for extradural hematoma of the dorso-lumbar region resulting from trauma. A spinal magnetic resonance imaging revealed an extradural hematoma. The patient was successfully treated with intensive replacement therapy and did not require surgical intervention. Conclusion: Extradural hematoma is a rare complication of hemophilia, that needs to be looked for in children who have bleeding disorders. For the best neurological outcome, early diagnosis is crucial.

血友病A患者会厌自发性出血1例

1临床资料患者,男,52岁,因“间断吐血2天”于2022-02-28夜间急诊收入我科。患者2d前晨起咳嗽后痰中带血,无法明确回答是否误卡异物,否认外伤史。既往患高血压15年,间断口服硝苯地平缓释片,血压控制在145/95 mm Hg;高血脂15年,间断口服辛伐他汀片,血脂控制正常。

Short-term outcome of total knee replacement in a patient with hemophilia:A case report and review of literature

BACKGROUND Hemophilia A is a rare inherited bleeding disorder caused by mutations in the factor Ⅷ gene. This clotting factor plays an intrinsic role in the blood coagulation pathway. Patients with hemophilia may develop orthopedic manifestations such as hemarthrosis, but multiple malunion of fractures over the knee is rare and difficult to treat.CASE SUMMARY We report a patient with hemophilia A who developed severe knee osteoarthritis along with fracture malunion and nonunion. Total knee replacement was performed using a custom-made modular hinged knee prosthesis(cemented) equipped with extended distal and proximal stems. At 3 years’ follow-up, the patient exhibited excellent clinical function and remained satisfied with the surgical outcome. Surgical intervention was accompanied by rigorous coagulation factor replacement.CONCLUSION This case highlights various unique scenarios specific to individuals with hemophilia and fracture deformity.

Successful reconstruction of an ankle defect with free tissue transfer in a hemophilia A patient with repetitive hemoarthrosis:A case report

BACKGROUND Hemophilia, an uncommon yet consequential hereditary bleeding disorder, manifests as two clinically indistinguishable forms that hinder the normal functioning of the coagulation cascade. This impairment renders individuals more susceptible to excessive bleeding during significant surgical interventions. Moreover, individuals with severe hemophilia frequently encounter recurring hemarthrosis, resulting in progressive joint destruction and, subsequently, the need for hip and knee replacement surgeries.CASE SUMMARY The patient was a 53-year-old man with hemophilia A as the underlying disease and had self-injected factor Ⅷ twice weekly for several decades. He had undergone ankle fusion surgery for recurrent hemarthrosis at the Department of Orthopedic Surgery 1 mo prior and was referred to our department because of skin necrosis after a hematoma at the surgical site. An anterolateral thigh perforator free flap was created after three cycles of factor Ⅷ administration in addition to the concomitant administration of tranexamic acid(TXA)(Transamin 250 mg cap, 1 cap tid, q8h). After the operation, from postoperative days(PODs) 1-5, the factor Ⅷ dose and interval were maintained, and q12h administration was tapered to q24h administration after POD 6. Because the patient’s flap was stable 12 d after the operation, factor Ⅷ administration was tapered to twice a week. At 6 mo follow-up, the patient recovered well without any complications.CONCLUSION To the best of our knowledge, there are very few reports of successful free flaps in patients with hemophilia, and none have been reported in patients with hemophilia A. Moreover, there are several reports on the efficacy of TXA in free flaps in general patients;however, there are no case reports of combining factor Ⅷ and TXA in patients with hemophilia. Therefore, we report this case to contribute to future academic research.

Characterization of Bleeding and Laboratory Phenotype in Hemophilia A Carriers: A Cross-Sectional Study in Benin

Background: In Africa, hemophilia is underdiagnosed and carriers have long been considered free from bleeding symptoms. However, recent research has begun to reveal hemostatic abnormalities and bleeding manifestations in carriers of hemophilia A, particularly due to excessive inactivation of normal X chromosomes. Objective: To describe the bleeding symptoms and hemostatic abnormalities in carriers of hemophilia A (HA) in Benin. Methods: This study was conducted as a prospective cross-sectional investigation between April 2021 to March 2022. The study population consisted of identified through pedigrees of persons with hemophilia A being treated in various hospitals in Benin. Data were collected through interviews conducted by trained physician and each carrier underwent a biological workup. Results: A total of 71 hemophilia A carriers were included and 38 of whom were obligatory carriers. Thirty-one carriers (43.7%) reported abnormal bleeding symptoms. Menorrhagia has (71%) being the most important manifestation, followed by bleeding during or after childbirth (45.2%). Among the 71 carriers, 45 were of reproductive age. Of whom 22 (48.8%) had a Higham score exceeding 100. Activated partial thromboplastin time was prolonged in 7 carriers (9.9%). The mean activity factor VIII:C (FVIII:C) levels were 68.8 ± 34.9 IU/dL. The average FVIII:C level in obligatory carriers was 56.9% and among potential carriers, the average FVIII:C level was higher at 80.4%. However twelve female carriers (16.9%) had FVIII:C levels < 40%. The FVIII:C/FvWAg ratio was below 0.7 in 73.2% of female drivers. Obligatory carriers (p = 0.00003) and FVIII;C/FvWAg ratio = 0.003) were statistically associated with abnormal bleeding symptoms, while blood group O (p = 0.0002) and FVIII/FvWAg ratio = 0.0016) were associated with a higher risk of menorrhagia. Conclusion: In Benin, carriers of haemophilia A present bleeding symptoms and haemostatic abnormalities. Further studies on a larger number of carriers are needed to better characterize and manage these patients.

Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells

Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells （iPSCs） derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX （F IX） gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA assay.Results The cell line bore a missense mutation in the 6th coding exon （c.676 C〉T） of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% （10/45） and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

Orthopedic disorders of the knee in hemophilia:A current concept review

The knee is frequently affected by severe orthopedic changes known as hemophilic arthropathy(HA) in patients with deficiency of coagulation factor Ⅷ or Ⅸ and thus this manuscript seeks to present a current perspective of the role of the orthopedic surgeon in the management of these problems.Lifelong factor replacement therapy(FRT) is optimal to prevent HA,however adherence to this regerous treatment is challenging leading to breakthrough bleeding.In patients with chronic hemophilic synovitis,the prelude to HA,radiosynovectomy(RS) is the optimal to ameliorate bleeding.Surgery in people with hemophilia(PWH) is associated with a high risk of bleeding and infection,and must be performed with FRT.A coordinated effort including orthopedic surgeons,hematologists,physical medicine and rehabilitation physicians,physiotherapists and other team members is key to optimal outcomes.Ideally,orthopedic procedures should be performed in specialized hospitals with experienced teams.Until we are able to prevent orthopedic problems of the knee in PWH will have to continue performing orthopedic procedures(arthrocentesis,RS,arthroscopic synovectomy,hamstring release,arthroscopic debridement,alignment osteotomy,and total knee arthroplasty).By using the aforementioned procedures,the quality of life of PWH will be improved.

Hemobilia as the initial manifestation of cholangiocarcinoma in a hemophilia B patient

Hemobilia is a rare manifestation of hemophilia and is usually iatrogenic following liver biopsy. There are only few reports of spontaneous hemobilia in hemophilia patients. Cholangiocarcinoma is a well-established cause of hemobilia. We describe a case of a 70-year-old male, with known haemophilia B and a past history of papillotomy, who presented with classical symptoms of hemobilia. The initial diagnostic work-up failed to demonstrate a potential cause of bleeding other than the coagulopathy. Three months later, he was readmitted to our hospital with a second episode of hemobilia. During the second work-up, a cholangiocarcinoma was diagnosed both by imaging studies and by a significant elevation of cancer antigen 19-9. Although hemobilia could be attributed to hemophilia, especially in a patient with previous papillotomy, an underlying malignancy of the biliary tree should be suspected.

A Retrospective Analysis of Intracranial Hemorrhage in Children with Hemophilia A

To investigate the incidence,risk factors,clinical manifestations and prognosis of intracranial hemorrhage (ICH)in children with hemophilia A in a center of China, we conducted a retrospective analysis of 126 children with hemophilia A at our hospital in recent 4 years.Thirty-six children with hemophilia A (including 19 severe cases,and 17 moderate cases complicated with joint diseases)received low dose factor Ⅷ (FⅧ) prophylaxis,and none of them had ICH.However,13 cases of hemophilia A not given prophylaxis were complicated with ICH (12 severe cases,and 1 moderate case)and demonstrated an incidence of 10.3%(13/126)in all patients,and 28.6%(12/42)in severe cases.Of the 13 cases,9 severe ICH cases had a definite history of head injury,accounting for 69.2%.Headache was common in children >3 years,but somnolence,irritability, gaze or convulsions in children <3 years.The most common findings of cranial CT scan included intracranial hematoma (9/13),and less commonly observed were subependymal hemorrhage and intraventricular hemorrhage.After administration of FⅧ,all patients survived.Hematoma of 6 cases was observed during CT reexamination after 1-3 months. During the follow-up period,only one case had slight activity limitation on one side of the limb,but steadily recovered.Besides the decreased concentration of FⅧ,trauma is the most common risk factor of ICH in children with hemophilia A.The active treatment can improve the prognosis of ICH in children with hemophilia A.

Genetic diversity of HCV among various high risk populations(IDAs,thalassemia,hemophilia,HD patients) in Iran

Objective:To determine the patterns of distribution of HCV genotypes among high risk population in north of Iran.Methods:A cross-sectional study was conducted on 135 HCV RNA-positive high risk individuals including thalassemia,hemophilia,patients under hemodialysis and intravenous drug addicts.HCV genotypes were determined based on amplification with type-specific primers methods.Results:Among the 187 anti-HCV positive samples,only 135 (72.2%)gave HCV-RNA positvity.Over all,the most identified HCV type was genotype 3a(51.1%) followed by 1a(27.4%),1b(8.2%).Sixteen(11.9%)out of 135 HCV RNA-positive participants have infected with more than one genotype or subtypes as follow:1a/1b in 11(8.2%),2/3a in 3 (2.2%),and 1a/1b/3a in 2(1.5%).Stratification of participants revealed that HCV subtype 3a was more prominent in thalassemia,hemophilia and HD patients but 1a and 1b were frequent in intravenous drug addicts.Conclusions:This study is the first report on HCV genotypes among Iranian subjects with different exposure categories resided in Mazandaran.where genotype 3a was found to be the most frequent genotype in thalassemia,hemophilia,and hemodialysis patients but not in IDAs.Since the addiction age is decreasing in Iran and a lot of addicts are IDAs.it might change the subtype pattern of HCV in general population.

Value of Contrast-enhanced Ultrasound in Evaluating Synovitis and Predicting Recurrent Joint Bleeding of Hemophilia

Objective Contrast-enhanced ultrasound(CEUS)is advantageous for evaluating microcirculation,and has been applied to assess arthritis in previous studies.However,CEUS examinations have not been studied for hemophilia arthritis.Hemophilia arthritis is different from other arthritis,because it is induced by spontaneous joint bleeding.Hence,CEUS may have special value in evaluating hemophilia arthritis.The present study assessed the value of CEUS in evaluating synovial hypertrophy and predicting recurrent joint bleeding in severe hemophilia A patients.Methods From August 2016 to January 2017,81 severe hemophilia A patients,who were referred to our hospital for ultrasound joint assessment with conventional ultrasound,were enrolled.Among these 81 patients,46 patients consented for CEUS examinations on the same day.Results Compared to color Doppler flow imaging(CDFI),four more joints presented with a blood flow signal under CEUS mode.In addition,the synovial hypertrophy measured by CEUS was thicker than that measured by conventional ultrasound.The ultrasound scores(including the total grey-scale ultrasound score,joint effusion/hemarthrosis,synovial hypertrophy,CDFI semi-quantitative score,and CEUS semi-quantitative score)were significantly higher in the joint bleeding group than in the no joint bleeding group(P<0.05).Furthermore,these ultrasound scores were positively correlated with the joint bleeding frequency,and had the highest correlation with the CEUS score(r=0.620,P<0.05).Conclusion CEUS can more accurately assess the degree of synovial hypertrophy and vascularization,and diagnose synovitis,when compared to conventional ultrasound.In addition,CEUS appears to be essential for evaluating the possibility of recurrent joint bleeding,and providing more reliable evidence for individualized treatment.

Successful emergency resection of a massive intra-abdominal hemophilic pseudotumor

An intra-abdominal pseudotumor is a rare complication of hemophilia. Surgical treatment is associated with high morbidity and mortality rates and reported cases are scarce. We present a 66-year-old Caucasian male suffering from severe hemophilia type A treated for 10 years with Factor Ⅷ. Major complications from the disease were chronic hepatitis B and C, cerebral hemorrhage and disabling arthropathy. Twenty-three years ago, retro-peritoneal bleeding led to the development of a large intra-abdominal pseudotumor, which was followed-up clinically due to the high surgical risk and the lack of clinical indication. The patient presented to the emergency department with severe sepsis and umbilical discharge that had appeared over the past two days. Abdominal computed tomography images were highly suggestive of a bowel fistula. The patient was taken to the operating room under continuous infusion of factor Ⅷ. Surgical exploration revealed a large infected pseudotumor with severe intra-abdominal adhesions and a left colonic fistula. The pseudotumor was partially resected en bloc with the left colon leaving the posterior wall intact. The postoperative period was complicated by septic shock and a small bowel fistula that required reoperation. He was discharged on the 73 rd hospital day and is well 8 mo after surgery. No bleeding complications were encountered and we consider surgery safe under factor Ⅷ replacement therapy.

Practical Guidance for Non-Specialist Physical Therapists Managing People with Hemophilia and Musculoskeletal Complications

People with hemophilia (PWH) have impaired blood coagulation and hemostasis. Bleeding into joints and muscles is the main manifestation of the disorder, causing severe joint damage and muscle complications. Lifelong, regular physical therapy is therefore important for PWH, in order to support recovery from bleeds and reduce recurrences. Ideally, these individuals should be in the care of a hemophilia treatment center (HTC), where a physical therapist (PT) should be a regular part of the comprehensive team. However, not all PWH have convenient access to an HTC, and they may be referred to local non-specialist PTs, who may have only limited experience with the condition, for day-to-day physical therapy treatment. This article, written by four experienced hemophilia PTs, introduces key aspects of the pathology of the hemophilic joint in adult PWH with musculoskeletal complications or established joint disease (or those with inhibitors) that are relevant to PTs. The characteristic differences between the joints of PWH and those of people with similar pathologies are clarified. Practical advice on how the physical therapy consultation can be adjusted for PWH is given, and the importance of communicating with the HTC emphasized. The aim of this narrative review is to raise awareness of hemophilia and joint disease for non-specialist PTs, and serve as helpful background information for PTs who encounter PWH with musculoskeletal complications or established joint disease in their clinics.

Hemophilic Pseudotumor: A Case Report and Review of Literature

A hemophilic pseudotumor is one of the rarer complications of hemophilia that results from repetitive bleeding resulting in an encapsulated mass of clotted blood and necrosed tissue. These have become rarer over the years with better treatment modalities for bleeding disorders like factor replacement. In this case report, we describe the natural history and clinical course of a patient with hemophilia who presented with a massive pseudotumor. A review of literature follows which explores all the relevant data to date on the presentation, complications, diagnostic modalities and therapies that have been implemented in the management of this rare complication of a common bleeding disorder.

Clinical, Therapeutic and Evolutive Aspects of Patients with Hemophilia in the Surgical Resuscitation Care Unit of Joseph Ravoahangy Andrianavalona JRA Hospital Antananarivo

Background: Hemophilia, a constitutional bleeding disease, has always been present in Madagascar considering children who died after bleeding circumcision, as reported in the family history of the diagnosed patients. Hemophilia is serious because of the potentially fatal risk of hemorrhage. The aim of this study was to evaluate the clinical, outcome and therapeutic aspects of inpatients with hemophilia in the Surgical Resuscitation Unit of JRA Hospital in Antananarivo. A descriptive and observational study was led about patients with hemophilia cared in the Surgical Resuscitation Unit from January 2011 to March 2018, studying age, type and severity of hemophilia, reason and duration of hospitalization, treatment instituted and outcome of patients. Results and comments: Thirty-six hemophiliacs (0.2%) were enrolled. The mean age was 9.52 years old;52.78% were with hemophilia B and 47.22% with hemophilia A, mainly severe. Clinical manifestations were muscle hematomas (25.71%), gum bleeding (14%), epistaxis (14.28%), gastrointestinal bleeding (11.42%), intracranial hemorrhage (11.42%), post circumcision bleeding (11.42%), hematuria, intraperitoneal hematomas and hemarthrosis. Treatment was based on factor concentrate substitution when available. The length of stay ranged from one to thirty days. The evolution was favorable except for two deaths related to delayed management of intracranial hemorrhage. Three patients with hemophilia A developed inhibitors. The results showed that throughout these years of study, a change in management was noted alongside. Conclusion: Hemophilia cases requiring hospitalization were managed in surgical resuscitation unit. The evolution was mainly related to the availability of clotting factor concentrates in coagulation factors, the delay in taking care of the patients and the presence of specialized staff.

Management of unstable angina in a patient with Haemophilia A

Hemophilia A is an X-linked recessive disorder characterized by a deficiency of coagulation factor Ⅷ(FⅧ) and therefore by a greater risk of bleeding during percutaneous interventional procedures and during the dual antiplatelet therapy(DAPT) in patients with ischemic heart disease. Information regarding safe percutaneous procedures in hemophiliacs is limited. Since the introduction of FVⅧ concentrates, the life expectancy of hemophiliac patients has improved and consequently, the rate of ischemic heart disease in this population is increased. Frequently the replacement therapy can trigger the onset of an acute coronary syndrome. We report a case of a patient with mild Hemophilia A, who presents with unstable angina, treated successfully with coronary angioplasty and drug eluting stent implantation without replacement of FVⅧ, treated with long term DAPT without major bleeding after six months of follow up.

Thromboelastography Use in the Perioperative Transfusion Management of a Patient with Hemophilia A Undergoing Liver Transplantation

The thrombelastogram is a method used to monitor clotting dynamics. Thrombelastography (TE) has been used to guide therapy of coagulation disorders mostly in cardiac surgery but also in liver surgery. TE is a useful tool for perioperative management of patients at risk for coagulopathy. There are several reports describing the use of the thrombelastogram in patients undergoing orthotopic liver transplantation (OLT), but only few cases include patients with both liver disease and inherited bleeding disorders. We describe the use of TE in a patient with hemophilia A and advanced cirrhosis undergoing OLT.