Combined Deficiency Of Factor Research Articles

Hereditary combined deficiency of factors V and VIII: observations in the Russian population

Introduction. Combined deficiency of factors V and VIII is a rare hereditary bleeding disorder with a prevalence of 1:1,000,000 in the general population, but the disease is more common in regions where consanguineous marriages are acceptable. Data on this hereditary coagulopathy in the Russian Federation are limited.Aim: to analyze clinical and laboratory characteristics of the course of the disease in patients with hereditary combined deficiency of factors V and VIII in the Russian population.Materials and methods. The retrospective and prospective study involved 6 patients with hereditary combined deficiency of factors V and VIII in the Russian population.Results. The average age of patients was 50 years (32–72 years). The average age at the time of diagnosis was 40 years. Bleeding scores on the ISTH-BAT scale ranged from 17–29, with an average value of 23.5. The average value of activated partial thromboplastin time was 85 seconds, the prothrombin by Quick was 35 %, and the activity of FV and FVIII was 5.7 % and 9.0 %, respectively. The course of the disease was characterized more or less by cutaneous-mucous hemorrhagic syndrome, postoperative, obstetric-gynecological, and life-threatening bleeding.Conclusion. Clinical and laboratory characteristics of patients expand the understanding of hereditary combined deficiency of factors V and VIII and make it possible to accelerate diagnosis verification.

Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII.

Congenital combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D, OMIM 227300) is a rare hereditary coagulopathy and accounts for approximately 3% of cases of rare coagulation disorders. The prevalence of this disease in the general population is estimated to be 1:1,000,000 and is significantly higher in regions where consanguineous marriages are permitted, such as the Mideast and South Asia. The disease has an autosomal recessive mode of inheritance and therefore occurs with an equal incidence among males and females. Heterozygous mutation carriers usually do not have clinical manifestations. The molecular basis of this disease differs from that of stand-alone congenital deficiencies of FVIII and FV. F5F8D is caused by mutations in either LMAN1 or MCFD2, which encode components of a cargo receptor complex for endoplasmic reticulum to Golgi transport of FV and FVIII, leading to defects in an intracellular transport pathway shared by these two coagulation factors. Congenital combined deficiency of FV and FVIII is characterized by decreased activities of both FV and FVIII in plasma, usually to 5 to 30% of normal. Clinical manifestations in most cases are represented by mild or moderate hemorrhagic syndrome. The simultaneous decreases of two coagulation factors present complications in the diagnosis and management of the disease. In female patients, the disease requires a special approach for family planning, pregnancy management, and parturition. This review summarizes recent progress in clinical, laboratory, and molecular understanding of this disorder.

Gynecological bleeding in women with congenital bleeding disorders: A comprehensive cohort from Iran

BackgroundGynecological bleeding including menorrhagia and postpartum hemorrhage (PPH) face women's quality of life constantly with difficulties, especially those suffering from inherited bleeding disorders. In this study, we aim to evaluate gynecological bleeding particularly menorrhagia among Iranian women patients with inherited bleeding disorders admitted to the Iranian Comprehensive Hemophilia Care Center (ICHCC). MethodsThis study was conducted on 156 females aged ≥ 12 diagnosed with an inherited bleeding disorder in ICHCC. Demographic and laboratory data were documented for all patients. Bleeding questionnaires (the International Society on Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT), Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease (MCMDM-1), and Pictorial blood loss assessment chart (PBAC)) were filled out for all patients. For comparing metric and categorical parameters, Mann-Whitney was performed. Spearman's rho test was used for analyzing correlation. ResultsThe mean age of patients was 33. Von Willebrand disease (VWD), Factor (F) VII deficiency and combined factor deficiency were the most diagnosed disorders. The median of ISTH-BAT, MCMDM-1, and PBAC was 7,7, and 517, respectively. Menorrhagia was the most common reason for diagnosis. Menorrhagia and PPH domain scores ≥ 2 were recorded in 82 and 34 patients, respectively, and PBAC scores > 100 were seen in 118 patients. Significant positive correlations were observed between bleeding scores and menorrhagia and PPH scores. No significant correlations were recorded for VWF: Ag and VWF: RCo with menorrhagia and PPH scores; however, significant correlations were seen for VWF: Ag and VWF: RCo with bleeding score questionnaires. ConclusionMenorrhagia is the most common problem in females affected by different types of inherited bleeding disorders, particularly VWD. Increased awareness among gynecologists and hematologists about bleeding disorders in cases with unexplained menorrhagia is an essential step for optimal management.

Clinicopathological Features of Rare Bleeding Disorders in High Consanguinity Population; A Retrospective Analysis from Two Tertiary Hospitals in Saudi Arabia

BACKGROUND: Rare bleeding disorder (RBDs) encompasses a deficiency of one or more of FXIII, FXI, FX, FVII, FV, FII, and FI clotting factors, leading to bleeding disorders with variable presentations and outcomes ranging from none or minimal to life-threatening events. RBDs are still underdiagnosed and underreported, especially in Saudi population with a high prevalence of consanguinity. OBJECTIVES: The study aimed to determine the frequency of RBDs, grading of their bleeding severity, and assessment of clinical manifestations and management of RBDs in tertiary Saudi Arabian hospitals. DESIGN AND SETTINGS: This retrospective study of RBDs describes the clinicopathological features of refereed cases to both Prince Sultan Military Medical City and King Khaled University Hospital in Riyadh, Saudi Arabia, from September 2018 to September 2021. Any patient who had already been diagnosed or suspected to have RBDs was enrolled in the study. PATIENTS AND METHODS: Patient's medical records were reviewed for demographic data, clinical presentations, bleeding and family history, consanguinity, treatment outcomes, and molecular testing. Samples were run in specialized coagulation laboratories. Patients with liver dysfunction or acquired factor deficiency were excluded. Patients were categorized into four groups according to the severity of bleeding episodes: asymptomatic, Grade I, Grade II, and Grade III. RESULTS: A total of 26 cases with RBDs were identified during the study period. Most of the included patients are males and pediatrics (<14 years) representing 15 (57.7%) and 14 (53.8%), respectively. FVII was the most common factor deficiency encountered in 9 (35%) patients, followed by FXIII in 5 (19%), FXI in 4 (15%), FX in 3 (11.5%), FV in 3 (11.5%), and combined factor deficiency in 2 (8%) patients. 17 (65.4%) RBD patients presented with bleeding manifestation either with Grade I (9%), Grade II (39%), or Grade III (15%), whereas 47% were asymptomatic. CONCLUSION: The study emphasizes on importance of establishing a national registry of RBDs in Saudi Arabia and the need for further genetic studies to clarify the genotype/phenotype relationships.

Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII.

Mutations in lectin, mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency protein 2 (MCFD2) cause the combined deficiency of factor V (FV) and FVIII (F5F8D). LMAN1 and MCFD2 form a protein complex that transports FV and FVIII from the endoplasmic reticulum (ER) to the Golgi. Although both proteins are required for the cargo receptor function, little is known about the specific roles of LMAN1 and MCFD2 in transporting FV/FVIII. We used different LMAN1 and MCFD2 deficient cell lines to investigate the LMAN1/MCFD2-dependent FV/FVIII secretion pathway. LMAN1 deficiency led to more profound decreases in FV/FVIII secretion in HEK293T and HepG2 cells than in HCT116 cells, suggesting that regulation of cargo transport by the LMAN1/MCFD2 pathway varies in different cell types. Using these cell lines, we developed functional assays to accurately assess the pathogenicity of recently reported potential LMAN1 and MCFD2 missense mutations. LMAN1 with mutations abolishing carbohydrate binding can still partially rescue FV/FVIII secretion, suggesting that N-glycan binding is not essential for FV/FVIII transport. Surprisingly, overexpression of either wild-type or mutant MCFD2 is sufficient to rescue FV/FVIII secretion defects in LMAN1 deficient cells. These results suggest that cargo binding and transport are carried out by MCFD2 and that LMAN1 primarily serves as a shuttling carrier of MCFD2. Finally, overexpression of both LMAN1 and MCFD2 does not further increase FV/FVIII secretion, suggesting that the amount of the LMAN1-MCFD2 receptor complex is not a rate-limiting factor in ER-Golgi transport of FV/FVIII. This study provides new insight into the molecular mechanism of F5F8D and the intracellular trafficking of FV and FVIII.

The prevalence of rare bleeding disorders among children in the Russian Federation

Rare bleeding disorders account for about 3–5% of all inherited bleeding disorders. Due to the rarity and complexity of diagnosing these disorders, their prevalence estimates vary greatly. There is currently no national registry of rare inherited bleeding disorders and their prevalence across the country has not been studied yet. Aim: to estimate the prevalence of rare coagulation disorders among Russian children. For this multicenter study, we used retrospective anonymous patient data collected during clinical practice, so the approval of the ethics committee was not required. We analyzed completed questionnaires containing the number of patients with rare bleeding disorders aged from 0 to 18 years from 72 subjects of the Russian Federation. The survey had been conducted from April to June 2022. Our analysis included patients with deficiencies of factor I, II, V, VII, X, XI or XIII, as well as with combined factor deficiencies and unspecified hemorrhagic conditions. According to the reported data, the total number of children with rare bleeding disorders is 398. The most common disorder is deficiency of factor VII (52%, n = 210); it is followed by fibrinogen deficiency (16%, n = 63) and deficiency of factor X (12%, n = 48). Deficiencies of factors XI, V and XIII account for 9% (n = 35), 5% (n = 20), and 4.5% (n = 18) of all cases, respectively. Combined factor deficiency was diagnosed in 1.7% of patients (n = 7) and factor II deficiency was detected in only 1% of patients (n = 4). In order to determine the actual prevalence and incidence of rare coagulation disorders and their clinical manifestations and to identify the need for factor concentrates, it is necessary to establish a national registry of rare bleeding disorders, following the example of the national hemophilia registry.

Acquired Combined Factor Deficiency: Case Report

Acquired hemophilia is a rare bleeding disorder. Difenacoum (superwarfarin), an antivitamin K anticoagulant, has been commonly used as a rodenticide. Factors II, VII, IX, and X are reduced as a result of this inhibition. In this article, we have presented a case that had been exposed to superwarfarin according to our consideration, but for which factor XII, VIII, XI, V deficiency and presence of inhibitor could not be explained. Coagulation tests of the patient who applied for hematuria were prolonged. Factor II, V, VII, VIII, IX, X, XI, XII were low; antinuclear antibody, antiphospholipid antibody IgG, and anti-double stranded DNA antibodies were positive. When questioned, he admitted that they used rat poison in the bakery. In addition to fresh frozen plasma, vitamin K and plasma complex concentrate, factor VIII and factor IX were started. However, sufficient response could not be obtained since there were inhibitors against factor VIII and factor IX. Three sessions of plasmapheresis were performed to clear antibodies and immunosuppressive treatment was started. While coagulation tests were still long, there was no new bleeding and hematuria stopped. Immunosuppressive treatment and plasmapheresis may be tried if the replacement of deficient factors is not sufficient in acquired factor deficiency.

Low factor V level ameliorates bleeding diathesis in patients with combined deficiency of factor V and factor VIII

AbstractCombined factor V (FV) and FVIII deficiency (F5F8D) is a rare autosomal-recessive bleeding disorder caused by mutations in lectin mannose binding-1 (LMAN1) and multiple coagulation factor deficiency-2 (MCFD2). Six causative homozygous mutations (5 in LMAN1 and 1 in MCFD2) were identified in 6 patients with F5F8D. A thrombin-generation assay, triggered with tissue factor (1 pM) in F5F8D plasma, paradoxically exhibited enhanced thrombin generation compared with normal plasma. Significantly lower free tissue factor pathway inhibitor (fTFPI) was found in F5F8D patients compared with healthy controls (P < .01). Normalizing tissue factor pathway inhibitor α (TFPIα) in F5F8D plasma greatly delayed and reduced thrombin generation. Increasing FV concentrations by adding plasma FV to F5F8D plasma only caused a gradual decrease in thrombin generation, suggesting that low levels of TFPIα and FV cocontributed to the elevated thrombin generation by reducing anticoagulant effects. On the contrary, thrombin generation in F5F8D platelet-rich plasma (PRP) was significantly lower than in normal controls (P < .05); however, it was fully corrected by normalizing FVIII or after 1-deamino-8-d-arginine vasopressin (DDAVP) infusion, indicating that the hypocoagulable state of F5F8D patients is associated with low FVIII levels. In addition, plasma and platelet FV in F5F8D PRP were sufficient to support normal thrombin generation, and low TFPIα may have no effect on thrombin generation. DDAVP infusion induced a complete response in 5 F5F8D patients and a partial response in the remaining patient. Based on our findings, we suggest that DDAVP may be considered a potential substitute for FVIII concentrates, and fresh-frozen plasma (FFP) infusion may not be necessary for F5F8D patients with minor bleeding challenges.

Factor VII Deficiency in Systemic Primary Amyloidosis: A Rare Case

Introduction: Isolated and combined factor deficiencies are known to occur in systemic primary amyloidosis. The most common factor deficiency known in these cases is isolated factor X deficiency. Other factor deficiencies are relatively less frequent. Isolated factor VII deficiency occurs very rarely in cases of systemic primary amyloidosis.Case report: A 58-year-old male patient previously presenting to another health center with complaints of generalized edema, fatigue, and itching had proteinuria and then he was diagnosed with systemic primary amyloidosis after the renal biopsy for proteinuria etiology. The patient’s laboratory tests showed prolongation of prothrombin time and factor VII deficiency. The patient responded well to the treatment for primary amyloidosis and factor VII deficiency.Discussion: In cases of systemic primary amyloidosis, if the etiology of prolonged prothrombin time involves no liver disease, warfarin use, or malabsorption, physicians should always keep in mind rare factor deficiencies such as factor VII deficiency, along with common factor deficiencies.

Epidemiology of Hereditary Coagulation Bleeding Disorders: A 15-Year Experience From Southern Iran

Background: Data on the frequency of hereditary bleeding disorders (HBDs) and associated mortality and morbidities during a long-term follow-up from Iran are scarce. Objective: This study evaluated the epidemiologic features among patients with HBD in one of the largest referral centers in southern Iran. Methods: In this cross-sectional study, 619 patients with HBD were evaluated during the period 1996 to 2011. Aside from baseline characteristics and type of factor deficiency, associated morbidities including viral infections, neurological disorders, asthma, thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes, hypertension, cardiac and renal diseases were evaluated. Furthermore, among patients who died, the underlying disease and etiology of death were also evaluated. Results: Patients’ mean age was 24.4 ± 13.5 years. Factor VIII deficiency was the most prevalent type (50.4%) of HBD, and combined Von–Willebrand and factor XIII deficiency (2.3%) was the most prevalent type of combined factor deficiency. A total of 0.5% had hepatitis B and 11.5% had hepatitis C. Cardiac disease was seen in 1.5%, hypertension in 0.2%, renal disease in 0.2%, and diabetes in 1.3% of patients. Overall, 5.2% had intracranial hemorrhage, 2.1% had epilepsy, and 0.8% had mental retardation. During the 15-year follow-up, 22 patients died; car accident was the leading cause of death in this population. Conclusion: Associated morbidities were seen in 24.3% of patients with HBD. Most prevalent morbidities were HCV infections (11.5%) and neurological disease (7.3%). The mortality rate among patients with HBD was 3.4%, and the most common cause of death was accident, which is similar to that of normal Iranian populations.

Desmopressin acetate as a haemostatic elevator in individuals with combined deficiency of factors V and VIII: a clinical trial

ESSENTIALS: Combined factor V (FV) and factor VIII (FVIII) deficiency (CF5F8D) is an autosomal recessive coagulation disorder. Desmopressin acetate (DDAVP) was intravenously infused in 20 adult patients with CF5F8D. DDAVP can enhance FVIII levels but has no effect on FV levels in patients with CF5F8D. DDAVP can be substituted for FVIII concentrates in patients with CF5F8D. Combined factor V (FV) and FVIII deficiency (CF5F8D) is a rare inherited autosomal recessive double-gene disorder most frequently seen in the Middle East. Although affected individuals have deficiency of two coagulation factors (range 5-30%), their bleeding tendencies are similar to patients who have deficiency of a single coagulation factor at the same level. The mainstay of their treatment is infusion of FVIII concentrate and fresh frozen plasma. Here, the effect of intravenous infusion of desmopressin acetate (DDAVP) on elevation of coagulation FV and FVIII was investigated through a clinical trial in May 2015. In a registered controlled trial, DDAVP (dosage 0.3 μg kg(-1) ) was intravenously infused into 20 adult patients with CF5F8D over 20 min. After an hour, blood samples were collected and plasma levels of FV and FVIII were measured. This study revealed that DDAVP can enhance FVIII levels but has no effect on FV plasma concentration in patients with CF5F8D. Based on these findings, FVIII concentrates may be substituted for DDAVP in patients with CF5F8D.

Congenital combined deficiency of coagulation factors: a study of seven patients.

Combined deficiency of coagulation factors is considered as an extremely rare bleeding disorder (RBD) inherited in an autosomal recessive pattern. This disorder is more likely to occur in regions with a high rate of consanguineous marriages or in restricted communities. Sistan and Baluchistan, a province in southeast of Iran with a high rate of consanguinity, is a clear model of such regions with a very high prevalence of recessively inherited disorders. The aim of this study was to report the frequency of combined factor deficiency in this province. This descriptive study was conducted on 358 patients with RBD. Demographic information and medical history of each patient were recorded, and the patients were examined by a physician. Routine screening tests were carried out for all patients, and further coagulation tests including coagulation factor activity and antigen assays were subsequently performed for all suspected patients. Among 358 patients, four were found to be affected with combined factor (F)V and FVIII deficiency (F5F8D). In addition, one patient with combined deficiency of FVII-FXIII, one with combined FVII-FX and one with combined FVIII-FIX deficiency were identified. In Sistan and Baluchistan Province, coinheritance of recessively inherited disorders like combined coagulation factor deficiencies was surprisingly higher than expected.

Diagnosing von Willebrand Disease: A Short History of Laboratory Milestones and Innovations, Plus Current Status, Challenges, and Solutions

von Willebrand disease (VWD) is a disorder characterized by deficiency of, or defects in, von Willebrand factor (VWF). VWD was originally identified by Erik Adolf von Willebrand, who in early 1924 investigated a large family suffering from a bleeding disorder that seemed to differ from hemophilia. Erik von Willebrand undertook some initial laboratory investigations to conclude the involvement of a plasma factor, the lack of which prolonged the bleeding time, but failed to impair coagulation times and clot retraction. By the end of the 1960s, VWD was accepted as a combined deficiency of factor VIII (FVIII) and another plasma factor responsible for normal platelet adhesion. Just how these two functions were related to each other was less clear and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable; thus, VWD was poorly delineated from other coagulation and platelet disorders. The early 1970s saw a revolution in diagnostics when ristocetin was identified to induce platelet aggregation, and this formed the basis of the first consistent and reliable VWF "activity" test, permitting quantification of the platelet adhesive function missing in VWD. Concurrently, immunoprecipitating techniques specific for VWF were defined, and the application of such technologies permitted a clearer understanding of both VWF and VWD heterogeneity. Continued exploration of the structure and function of VWF contributed greatly to the understanding of platelet physiology, ligand receptor interaction and pathways of cellular interaction and activation. Recently, additional assays evaluating other functions of VWF, including collagen binding, platelet glycoprotein Ib binding, and FVIII binding, have improved the diagnosis of VWD. The purpose of this narrative review is to explore the history of phenotypic VWD diagnostics, with a focus on laboratory milestones from the past as well highlighting recent and ongoing innovations, and ongoing challenges and possible solutions.

Genotype and phenotype report on patients with combined deficiency of factor V and factor VIII in Iran

Combined factor V (FV) and factor VIII (FVIII) deficiency is a rare autosomal recessive bleeding disorder characterized by mild-to-moderate bleeding. Epistaxis, postsurgical bleeding and menorrhagia are the most common symptoms. The aim of this study is to report the phenotype-genotype characterization carried out in patients affected with combined FV and FVIII deficiency from Iran. A cross-sectional study was conducted in Shiraz Hemophilia Center, southern Iran. Twelve cases, seven men and five women coming from eight families were included in our study after taking consent form. Coagulation activity for all patients was measured. All exons and intron-exon junctions of lectin mannose binding protein 1 (LMAN1) gene and multiple coagulation factor deficiency 2 genes were amplified by PCR, and subsequently sequenced by the Sanger method. Patients[Combining Acute Accent] age ranged from 6 to 59 years mean ± SD: 23.8 ± 15.4 years and median: 22 years. No patient presented with severe bleeding symptom. Only one patient had severe FV and FVIII deficiency (both factor levels <1%). Four different type of mutations (duplication, insertion, splice site and nonsense), occurring in different locuses, were identified on LMAN1 gene in 12 Iranian patients. There was a significant correlation between FV and FVIII levels, which is indicative of association with loss of function of LMAN1 gene, and reduced plasma levels of both factors. Our study showed that all of our characterized patients with combined FV and FVIII deficiency present different homozygous mutations on LMAN1 gene introducing a premature stop codon. Larger studies are needed to calculate the correlation between factor levels, genetic and bleeding symptoms.

The Intracellular Cargo Receptor ERGIC-53 Is Required for the Production of Infectious Arenavirus, Coronavirus, and Filovirus Particles

SummaryArenaviruses and hantaviruses cause severe human disease. Little is known regarding host proteins required for their propagation. We identified human proteins that interact with the glycoproteins (GPs) of a prototypic arenavirus and hantavirus and show that the lectin endoplasmic reticulum (ER)-Golgi intermediate compartment 53 kDa protein (ERGIC-53), a cargo receptor required for glycoprotein trafficking within the early exocytic pathway, associates with arenavirus, hantavirus, coronavirus, orthomyxovirus, and filovirus GPs. ERGIC-53 binds to arenavirus GPs through a lectin-independent mechanism, traffics to arenavirus budding sites, and is incorporated into virions. ERGIC-53 is required for arenavirus, coronavirus, and filovirus propagation; in its absence, GP-containing virus particles form but are noninfectious, due in part to their inability to attach to host cells. Thus, we have identified a class of pathogen-derived ERGIC-53 ligands, a lectin-independent basis for their association with ERGIC-53, and a role for ERGIC-53 in the propagation of several highly pathogenic RNA virus families.

Rare Bleeding Disorders in Children: Identification and Primary Care Management

Bleeding symptoms are common in healthy children but occasionally may indicate an underlying congenital or acquired bleeding diathesis. The rare bleeding disorders (RBDs) comprise inherited deficiencies of coagulation factors I (congenital fibrinogen deficiencies), II, V, VII, X, XI, and XIII and combined factor deficiencies, most notably of factors V and VIII and of vitamin K-dependent factors. These disorders often manifest during childhood and may present with recurrent or even serious or life-threatening bleeding episodes, particularly during the neonatal period. Accordingly, primary care and other nonhematologist pediatric providers should be familiar with the clinical presentation and initial evaluation of these rare disorders. Bleeding manifestations generally vary within the same RBD and may be indistinguishable from 1 RBD to another or from other more common bleeding disorders. Serious bleeding events such as intracranial hemorrhage may be heralded by less serious bleeding symptoms. The results of initial coagulation studies, especially prothrombin time and activated partial thromboplastin time, are often helpful in narrowing down the potential factor deficiency, with factor XIII deficiency being an exception. Consultation with a hematologist is advised to facilitate accurate diagnosis and to ensure proper management and follow-up. The approach to bleeding episodes and invasive procedures is individualized and depends on the severity, frequency, and, in the case of procedures, likelihood of bleeding. Prophylaxis may be appropriate in children with recurrent serious bleeding and specifically after life-threatening bleeding episodes. When available, specific purified plasma-derived or recombinant factor concentrates, rather than fresh frozen plasma or cryoprecipitate, are the treatment of choice.

Fatal Bleeding Due to Acquired Factor IX and X Deficiency: A Rare Complication of Hepatic AL Amyloidosis

Purpose: Systemic AL amyloidosis is a disorder of progressive extracellular deposition of insoluble fibrils derived from λ/κ Ig light chains within various organs. Hepatic deposition (clinically silent) occurs in half of cases and liver is rarely the dominant organ. Often, bleeding in AL amyloidosis is multifactorial, including vessel fragility from amyloid infiltration, hyper fibrinolysis, platelet dysfunction and uremia. We report a case of amyloidosis with uncontrolled hemorrhage due to a severe acquired combined factors IX and X deficiency. Methods: A previously healthy 62-year-old man presented with acute abdominal pain with history of vague abdominal discomfort, fatigue, bruisability and microscopic hematuria for two months, but no findings to suggest nephrolithiasis or cancer were identified on imaging and cystoscopy. He was hemodynamically stable, exam was notable for some bruising, abdominal distention and tenderness, but no guarding or heptosplenomegaly. Results: Labs including CBC, electrolytes, LFTs, fibrinogen, thrombin time and D-dimer were normal. PT, INR, and PTT were elevated, but mixing studies were normal. Coagulation factor IX and X levels were noted to be deficient. Free λ light chain was elevated, corresponding to a monoclonal IgG λ band in the γ region, while free κ light chain and β2 microglobulin were normal. With the absence of personal and family history of liver disease, bleeding disorder and subsequent rise in alkaline phosphatase without biliary obstruction, it was concerning for an intrinsic liver disease. With acquired combined factor deficiency in the setting of MGUS, amyloidosis was considered. Liver biopsy was deferred given the concern for increased bleeding risk and hepatic rupture. He died of GI and intra-peritoneal bleeding, despite multiple transfusions including factors, FIEBA. Autopsy showed massive deposition of amyloid within liver and spleen, due to plasma cell dyscrasia with monotypic λ staining plasma cells in bone marrow accounting for 15% of nucleated cell forms. Conclusion: Delayed diagnosis is common in AL amyloidosis due to nonspecific clinical presentations, as in our case. Hepatic amyloidosis carries a poor prognosis, but has no specific effective treatment. Liver transplantation may be a life-saving procedure in selected cases of rapidly progressing hepatic amyloidosis.Figure: Liver section showing sinusoids distended by pink staining amyloid.

Rare case of combined factor V and factor X deficiency in pregnancy: presenting as secondary postpartum haemorrhage in first pregnancy and successful outcome in second pregnancy.

Isolated factor V and factor X deficiency is a very rare condition affecting 1 in 500,000-1,000,000 persons worldwide. We present a rare first reported case of combined deficiency of factor V and factor X where the patient developed secondary postpartum haemorrhage in first pregnancy, after which she was diagnosed to have this rare disorder and her subsequent pregnancy was then successfully managed.

Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1

Percutaneous coronary intervention (PCI) in patients with congenital coagulation factor deficiencies presents a unique challenge. They are not only at increased risk of perioperative bleeding but can also suffer thrombosis of the stent as preventive anticoagulation and antiplatelet therapy is difficult. Several cases of successful PCI have been described in patients with haemophilia A and B, but there are no reports in patients with combined coagulation factor deficiencies. We used PCI to treat the coronary artery disease in a patient with the combined deficiency of factor V and factor VIII (F5F8D) and analysed the molecular basis of the disorder for this patient. A 68-year-old patient was admitted for urgent PCI with bare metal stent placement after the diagnosis of the F5F8D. Peripheral blood DNA was extracted for the sequence analysis of LMAN1 and MCFD2 genes. Mutations in LMAN1 was confirmed by molecular cloning of the PCR product and resequencing of the resulting clones. The patient underwent successful PCI with good long-term outcome. Our patient tolerated anticoagulation therapy well, with unfractionated heparin, and double antiplatelet therapy while he was initially supported with fresh frozen plasma and recombinant FVIII. Molecular analysis revealed that the patient carries unusual compound heterozygous frameshift mutations on the same microsatellite repeat region in exon 8 of LMAN1, one of which is a novel mutation (c.912delA). Our results suggest that patients with F5F8D can safely undergo PCI for coronary artery disease, with the treatment individualized to the specific patient.

A 24-Year-Old Man with Previously Diagnosed Hemophilia

A 24-year-old Middle Eastern man diagnosed with hemophilia at the age of 4 or 5 years presented to the hematology clinic for follow-up after a recent hospitalization for excessive bleeding from an accidental knife cut. The patient reported a history of prolonged bleeding after teeth extractions, an upper gastrointestinal bleed 3 years previously, and excessive bruising since childhood. He denied hemarthroses but reported chronic pain in his ankles and joints. The patient reported having been treated for episodes of excessive bleeding with fresh frozen plasma (FFP)3 and factor VIII during past hospitalizations. Because of poor continuity of care, his disease had not been monitored or treated on an ongoing outpatient basis. The patient's family history is noteworthy for consanguineous parents (first cousins) and a sister who also experienced excessive bleeding, although her diagnosis was uncertain. Initial laboratory test results included a normal complete blood count, including platelets, a prolonged activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT) (Table 1). Fibrinogen activity was normal. A 1:1 mixture of the patient's plasma with pooled normal plasma demonstrated full correction of the PT and aPTT, a result consistent with factor deficiency. View this table: Table 1. Patient's laboratory results (citrated plasma). ### ADDITIONAL PATIENT DATA AND DIFFERENTIAL DIAGNOSIS Patients with isolated hemophilia A, B, or C (due to deficiencies in factors VIII, IX, and XI, respectively) or factor VIII deficiency due to von Willebrand disease typically have a prolonged aPTT but a normal PT. In the absence of anticoagulation therapy or suspected vitamin K deficiency, a prolonged PT in this patient's initial workup should raise clinical suspicion for a bleeding disorder of a different etiology. Given the patient's clinically notable bleeding symptoms since childhood, a genetic disorder should be considered. The differential diagnosis includes dysfibrinogenemia, prothrombin deficiency, factor V deficiency, combined deficiency of factors V and VIII (F5F8D), factor X deficiency, and hereditary combined deficiency of …