Congenital Factor Deficiencies Research Articles

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.

Prothrombin deficiency with recurrent subretinal hemorrhage.

Ocular hemorrhage has been recorded in congenital factor deficiencies like hemophilia A, but it has never been documented in prothrombin deficiency. Here, we describe an unusual case of sudden vision loss in the right eye caused by subretinal hemorrhage following a coughing episode in a 67-year-old woman. Notably, the patient underwent left eye enucleation 12 years previously under similar circumstances due to subretinal hemorrhage. During the interview, it was discovered that the patient had a history of prothrombin deficiency, which was subsequently confirmed through laboratory testing. Aside from recurrent ocular bleeding and 1 instance of bleeding following dental extraction in childhood, there is no other history of bleeding. Subsequent molecular studies revealed a homozygous missense mutation at G1499A (Arg500Gln), a variant previously identified as R457Q. Although the likelihood of prothrombin deficiency initiating subretinal hemorrhage is low, it is likely to worsen retinal hemorrhage and contribute to difficulty in controlling bleeding. A comprehensive coagulation workup is essential in patients with ocular hemorrhage. Determining factor II activity should be included in individuals exhibiting variably prolonged prothrombin time and activated partial thromboplastin time with correction in mixing studies. Additional investigations, such as genetic sequencing and family studies, are advised for those with isolated low prothrombin levels.

Safety and efficacy of an anti–human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models

AbstractRebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

Von Willebrand Disease, Hemophilia, and Other Inherited Bleeding Disorders in Pregnancy.

Inherited bleeding disorders, which comprise von Willebrand disease (VWD), hemophilia, other congenital clotting factor deficiencies, inherited platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Although mild platelet defects may actually be more prevalent, the most common diagnosed bleeding disorder among women is VWD. Other bleeding disorders, including hemophilia carriership, are much less common, but hemophilia carriers are unique in that they are at risk of giving birth to a severely affected male neonate. General guidance for maternal management of inherited bleeding disorders includes obtaining clotting factor levels in the third trimester, planning for delivery at a center with hemostasis expertise if factor levels do not meet the minimum threshold (eg, less than 0.50 international units/1 mL [50%] for von Willebrand factor, factor VIII, or factor IX), and using hemostatic agents such as factor concentrates, desmopressin, or tranexamic acid. General guidance for fetal management includes prepregnancy counseling, the option of preimplantation genetic testing for hemophilia, and consideration of delivery of potentially affected male neonates with hemophilia by cesarean delivery to reduce the risk of neonatal intracranial hemorrhage. In addition, delivery of possibly affected neonates should occur in a facility where there is newborn intensive care and pediatric hemostasis expertise. For patients with other inherited bleeding disorders, unless a severely affected neonate is anticipated, mode of delivery should be dictated by obstetric indications. Nonetheless, invasive procedures such as fetal scalp clip or operative vaginal delivery should be avoided, if possible, in any fetus potentially affected with a bleeding disorder.

A Case of Congenital Mild Hemophilia Diagnosed After Wisdom Teeth Extraction.

Hemophilia A is a recessive congenital deficiency of factor VIII that is characterized by normal bleeding time, normal prothrombin time, and prolonged activated partial thromboplastin time. In moderate and severe cases, abnormal bleeding is observed even after minor trauma, and the diagnosis is usually made by the age of 5-6 years, whereas in mild cases, abnormal bleeding is detected after major trauma or surgery. Herein, we present a case of hemophilia A that was discovered due to difficulties with hemostasis after tooth extraction.

Perioperative Management of Patients with Rare Congenital Factor Deficiency

Perioperative Management of Patients with Rare Congenital Factor Deficiency

Planning Pregnancy and Birth in Women with Inherited Bleeding Disorders.

Inherited bleeding disorders are characterized by a diverse clinical phenotype within and across specific diagnoses. von Willebrand disease (VWD), hemophilia A, and hemophilia B comprise 95 to 97% of inherited bleeding disorders, with the remaining 3 to 5% attributed to rare bleeding disorders, including congenital fibrinogen disorders, factor deficiencies (affecting FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII), and platelet function defects. The pregnancy, birth, and the puerperium may be adversely influenced in the setting of an inherited bleeding disorder depending on its type and clinical phenotype. Obstetric hemostatic challenges may sometimes also unmask the presence of a previously unknown inherited bleeding disorder. This review aims to address the approach to pregnancy and birth in the context of an inherited bleeding disorder and highlights the significance of multidisciplinary input into the care of these women.

Recommendations for transfusion of blood products in neonatology

The scant evidence on the use of transfusions in neonatal care explains the limitations of current clinical guidelines. Despite this, in this document we explore the most recent evidence to make recommendations for the clinical practice. The prevention of anaemia of prematurity, the use of protocols and restrictive transfusion strategies constitute the best approach for clinicians in this field. In the case of platelet transfusions, the risk of bleeding must be assessed, combining clinical and laboratory features. Lastly, fresh frozen plasma is recommended in neonates with coagulopathy and active bleeding, with congenital factor deficiencies for which there is no specific treatment or with disseminated intravascular coagulation. All blood products have adverse effects that warrant a personalised and thorough assessment of the need for transfusion.

Spectrum of Inherited Bleeding Disorder with Special Reference to von Willebrand Disease in Eastern India.

Background The objective of this study is to study the prevalence, clinical spectrum, and hematological profile of inherited bleeding disorder with special reference to von Willebrand disease in eastern India. Materials and Methods This prospective study was done in a tertiary care center in the eastern part of India over 2 years. Detailed history and clinical findings were noted in a proforma. Laboratory analysis included prothrombin time, activated partial thromboplastin time, bleeding time, and fibrinogen assay along with tests related to specific factor assay. Results One hundred and five patients were diagnosed as suffering with the inherited bleeding disorder out of a total of 1,204 patients. The age of patients ranged from 13 days to 35 years. The most common presenting clinical feature was prolonged bleeding after cut (76.19%). Out of 105 patients, 97 patients (92.38%) had coagulation defect, 5 patients (4.76%) had von Willebrand disease (vWD), and 3 patients (2.85%) had platelet defect. Most common coagulation defect was hemophilia A (84 cases), followed by hemophilia B (8 cases). Other rare congenital factor deficiencies were seen in five cases (5.15%). Only platelet defect was Glanzmann's thrombasthenia (GT). The age of vWD patients ranged from 4.5 years to 24 years. Forty percent patients with vWD disease were type 1 followed by 40% of type 2N and 20% of type 3 vWD. Conclusion vWD was not so common in eastern India. vWD was present only in 4.76% cases in this study. The most common coagulation defect was hemophilia A (86.59%) in our study. GT was present in only 2.85% cases.

Recomendaciones para la transfusión de hemoderivados en neonatología

The scant evidence on the use of transfusions in neonatal care explains the limitations of current clinical guidelines. Despite this, in this document we explore the most recent evidence to make recommendations for the clinical practice. The prevention of anaemia of prematurity, the use of protocols and restrictive transfusion strategies constitute the best approach for clinicians in this field. In the case of platelet transfusions, the risk of bleeding must be assessed, combining clinical and laboratory features. Lastly, fresh frozen plasma is recommended in neonates with coagulopathy and active bleeding, with congenital factor deficiencies for which there is no specific treatment or with disseminated intravascular coagulation. All blood products have adverse effects that warrant a personalised and thorough assessment of the need for transfusion.

RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A

Hemophilia A is a hemorrhagic disease due to congenital deficiencies of coagulation factor VIII (FVIII). Studies show that hemophilia patients with anticoagulant deficiency present less severe hemorrhagic phenotypes. We aimed to find a new therapeutic option for hemophilia patients by RNA interference (RNAi) targeting heparin cofactor II (HCII), a critical anticoagulant protein inactivating the thrombin. The optimal small interfering RNA (siRNA) was conjugated to an asialoglycoprotein receptor ligand (N-acetylgalactosamine [GalNAc]-HCII), promoting targeted delivery to the liver. After administration, GalNAc-HCII demonstrated effective, dose-dependent, and persistent HCII inhibition. After 7 days, in normal mice, GalNAc-HCII reduced HCII levels to 25.04% ± 2.56%, 11.65% ± 2.41%, and 6.50% ± 1.73% with 2, 5, and 10 mg/kg GalNAc-HCII, respectively. The hemostatic ability of hemophilia mice in the GalNAc-HCII-treated group significantly improved, with low thrombus formation time in the carotid artery thrombosis models and short bleeding time in the tail-clipping assays. After repeated administration, the prolonged activated partial thromboplastin time (APTT) was reduced. A 30 mg/kg dose did not cause pathological thrombosis. Our study confirmed that GalNAc-HCII therapy is effective for treating hemophilia mice and can be considered a new option for treating hemophilia patients.

Development and application of global assays of hyper‐ and hypofibrinolysis

Numerous methods for evaluation of global fibrinolytic activity in whole blood or plasma have been proposed, with the majority based on tissue‐type plasminogen activator (t‐PA) addition to initiate fibrinolysis. We propose that such an approach is useful to reveal hypofibrinolysis, but t‐PA concentrations should be kept to a minimum. In this paper, we describe a low‐concentration t‐PA plasma turbidity assay to evaluate several congenital factor deficiencies, including plasminogen activator inhibitor‐1 (PAI‐1) and plasminogen deficiency, as well as hemophilia A and B. In addition, we demonstrate a threshold dependency on endogenous PAI‐1 levels. To assess endogenous hyperfibrinolysis, we suggest that assays that avoid t‐PA addition are preferable, with assays based on euglobulin fractionation remaining a viable choice. We describe a euglobulin fraction clot lysis time (ECLT) assay with spectrophotometric readout and other modifications, and evaluate it as a tool to measure hyperfibrinolysis in inherited clotting factor deficiency states. We demonstrate that the ECLT is predominantly driven by residual amounts of PAI‐1, t‐PA, and α2‐antiplasmin. These assays should be further evaluated for the detection of hypo‐ or hyperfibrinolysis in acquired thrombotic or hemorrhagic disorders.

Congenital Factor Deficiencies in Children: A Report of a Single-Center Experience.

Congenital factor deficiencies (CFDs) refer to inherited deficiency of coagulation factors in the blood. A total of 481 patients with CFDs, who were diagnosed and followed at our Pediatric Hematology and Oncology Clinic between 1990 and 2015, were retrospectively evaluated. Of the 481 cases, 134 (27.8%) were hemophilia A, 38 (7.9%) were hemophilia B, 57 (11.8%) were von Willebrand disease (vWD), and 252 (52.3%) were rare bleeding disorders (RBDs). The median age of the patients at the time of diagnosis and at the time of the study was 4.1 years (range: 2 months to 20.4 years) and 13.4 years (range: 7 months to 31.3 years), respectively. The median duration of the follow-up time was 6.8 years (range: 2.5 months to 24.8 years). One hundred nineteen (47.2%) of 252 patients with RBDs were asymptomatic, 49 (41.1%) of whom diagnosed by family histories, 65 (54.6%) through preoperative laboratory studies, and 5 (4.2%) after prolonged bleeding during surgeries. Consanguinity rate for the RBDs was 47.2%. Prophylactic treatment was initiated in 80 patients, 58 of whom were hemophilia A, 7 were hemophilia B, 13 were RBDs, and 2 were vWD. Significant advances have been achieved during the past 2 decades in the treatment of patients with CFDs, particularly in patients with hemophilias. The rarity and clinical heterogeneity of RBDs lead to significant diagnostic challenges and improper management. In this regard, multinational collaborative efforts are needed with the hope that can improve the management of patients with RBDs.

Methylmalonic Acidemia and Megaloblastic Anemia due to Congenital Intrinsic Factor Deficiency

Methylmalonic Acidemia and Megaloblastic Anemia due to Congenital Intrinsic Factor Deficiency

Severe Congenital Deficiency of Factor XIII: A Brief Report of Morbidity and Mortality Rates of Severe Congenital Deficiency of Factor 13 in Iran

Severe Congenital Deficiency of Factor XIII: A Brief Report of Morbidity and Mortality Rates of Severe Congenital Deficiency of Factor 13 in Iran

A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation

Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and α-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and α-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and α-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK-deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the α-kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti-thrombotic effects than inhibitors of α-kallikrein.

Clotting factor product administration and same‐day occurrence of thrombotic events, as recorded in a large healthcare database during 2008–2013

Thrombotic events (TEs) are serious adverse events that can occur following administration of clotting factors (CFs). To evaluate occurrence of same-day TEs for different CF products and potential risk factors. A retrospective cohort study of individuals exposed to CF products during 2008-2013 was conducted using a large commercial insurance database. CF products were identified by procedure codes, and TEs were ascertained via diagnosis codes. Crude same-day TE rates (per 1000 persons exposed) were estimated overall and by congenital factor deficiency (CFD) status, CF products, age and gender. Multivariable logistic regression analyses were used to control for confounding. Laboratory analysis was used to compare the procoagulant activities of FIX products. Of 3801 individuals exposed to CFs, 117 (30.8 per 1000) had same-day TEs recorded. The crude same-day TE rate was higher for CF users without CFD, 70.2 (102 of 1452), as compared with those with CFD, 6.4 (15 of 2349) (RR,11.0; 95% CI, 6.4-18.9). For individuals without CFD, a significantly increased same-day TE risk was identified for factor IX complex (OR,6.92; 95% CI,3.11-15.40), factor VIIa (OR,9.42; 95% CI,4.99-17.78) and other products when compared with fibrin sealant. An increased risk of a TE was found with older age (≥45years), history of TEs and underlying health conditions. The laboratory identified elevated procoagulant activity in Profilnine(®) and Benefix(®) . The study shows an increased same-day TE risk for CF users without CFD and suggests substantial off-label CF use. The study findings also show elevated same-day TE rates for different CF products and suggest the importance of product properties and patient factors.

Metabolic and hemodynamic effects of the growth hormone system - insulin-like growth factor

Significant congenital deficiency of growth factor (GF) results in pituitary nanism (dwarfism) and its substantial excess is accompanied by the development of gigantism or acromegaly. Its impact on the growth of the whole body or its individual parts is impossible without affecting metabolic processes and hemodynamic parameters. A number of investigations have proven that GF has a direct lipolytic effect: adequate replacement therapy for pituitary nanism gives rise to a reduction in fat depots. Since the concentration of GF is lower in obesity, Whether it may be used to treat this abnormality is considered.

Management of Pregnancy in a Chilean Patient with Congenital Deficiency of Factor VII and Glanzmann's Thrombasthenia Variant.

Patients with inherited bleeding disorders are rare in obstetric practice but present with prolonged bleeding even after minor invasive procedures. They require a combined approach with obstetric and hematological management of each case, including the neonatal management of a possibly affected fetus. We present the case of a pregnancy in a patient with combined Factor VII deficiency and Glanzmann's thrombasthenia, the successful obstetric and hematological management of the case, and a review of the literature.

Congenital thrombotic thrombocytopenic purpura caused by new compound heterozygous mutations of the ADAMTS13 gene

Upshaw-Schulman syndrome (USS) is due to severe congenital deficiency of von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 domains, nr 13) activity resulting in the presence of unusually large forms of VWF in the circulation, causing intravascular platelet clumping and thrombotic microangiopathy. Our patient, a 26-year-old man, had attacks of thrombotic thrombocytopenic purpura (TTP) with thrombocytopenia and a urine dipstick positive for hemoglobin (4+), often as the only sign of hemolytic activity. He had ADAMTS13 activity of <1% of normal plasma without the presence of inhibitors of ADAMTS13. ADAMTS13 deficiency was caused by two new mutations of the ADAMTS13 gene: a deletion of a single nucleotide in exon17 (c. 2042 delA) leading to a frameshift (K681C fs X16), and a missense mutation in exon 25 (c.3368G>A) leading to p.R1123H. This case report confirms the importance of the analysis of the ADAMTS13 activity and its inhibitor in patients who have episodes of TTP, with a very low platelet count and sometimes without the classic biochemical signs of hemolysis.