Compound Heterozygous Mutations in the F7 Gene in 2 Unrelated Families With Congenital Factor VII Deficiency.

Factor VII (FVII) deficiency is a rare bleeding disorder normally caused by homozygous and compound heterozygous mutations in the F7 gene. Whole-exome sequencing was performed to identify F7 mutations in 3 individuals from 2 unrelated families who were diagnosed with FVII deficiency. Four compound heterozygous mutations were identified and validated in these 3 probands with FVII deficiency. Among the 4 identified mutations, NM_000131.4:c.572-1_581del, NM_000131.4:c.1250A>G (p.Tyr417Cys), and NM_000131.4:c.647G>T (p.Gly216Val) were novel. All 3 novel mutations were predicted to be likely pathogenic by the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.

Inhibitor development in patients with congenital factor VII deficiency, a study on 50 Iranian patients.

: Congenital factor VII (FVII) deficiency is a rare bleeding disorder with an estimated prevalence of 1 per 500 000 in the general population. On-demand replacement therapy is the main therapeutic choice in patients with congenital FVII deficiency. Inhibitor formation against exogenous FVII is very rare and can cause challenges in the management of the disorder. The present study was conducted to assess the prevalence of FVII inhibitor in 50 patients with congenital FVII deficiency under on-demand or prophylaxis treatment by recombinant activated FVII. All patients with confirmed congenital FVII deficiency were assessed for inhibitor development in regular intervals. Inhibitor titer was determined by a modified Nijmegen-Bethesda assay. The study results were analyzed by SPSS software. Among all cases, two patients (4%) developed an FVII inhibitor. Case 1 was a 14-year-old boy with severe FVII deficiency (FVII activity <1%) with regular prophylaxis. The patient was a high-responder with high-titer FVII inhibitor (170 Bethesda Unit). This patient, who had a history of intracranial hemorrhage, had undergone brain surgery three times. The second patient was a 70-years old man with on-demand therapy that also developed a high-titer inhibitor (10 Bethesda Unit). This patient had experienced easy bruising and endured a few surgeries for his brain tumor and, finally, succumbed to the disease. Although the inhibitor formation is a rare phenomenon, it may result in a significant challenge to manage the affected patients.

Manejo de una paciente embarazada con déficit congénito de factor VII leve / Management of a pregnant patient with mild factor VII congenital deficiency

RESUMEN No hay guías específicas para el manejo de pacientes embarazadas con la deficiencia de Factor VII; no hay una correlación entre el nivel de FVII y el riesgo de hemorragia y el nivel del Factor VII aumento durante el embarazo. Presentamos un caso clínico, el manejo y las recomendaciones del consenso.

Hemophagocytic lymphohistiocytosis and congenital factor VII deficiency: a case report.

BACKGROUND: Hemophagocytic lymfohistiocytosis (HLH) is a rare, life-threatening hyperinflammation, characterized by immune system over-activation resulting in hemophagocytosis. HLH could appear as a primary disease caused by mutations of immune-regulatory genes, or develop as a result of viral or bacterial infections, or malignancy. Congenital factor VII (FVII) deficiency is a rare autosomal recessive disorder characterized by prolonged prothrombin time (PT) and low FVII, which may increase bleeding risk. CASE PRESENTATION: A 50-year-old woman was admitted for a fever persisted for 20 days, presenting with cytopenia, high hyperferritinemia, low activity of NK cells. Bone marrow aspiration showed hemophagocytosis. CT scanning found pulmonary infection. EBV and CMV were not detected. Genetic scanning did not find pathogenic mutation of a HLH NGS panel including 26 genes. This patient was treated as recommended by the HLH 2004 Guidelines. Coagulation tests identified FVII deficiency. Genetic analysis of F7 gene in the patient and her family members identified recurrent compound heterozygous F7 c.64 + 5G > A and c.1224 T > G (p.His408Gln) mutations in this patient and her brother who showed postoperative hemorrhage after surgical resection of renal cell carcinoma. Heterozygotes in this family were asymptomatic. CONCLUSIONS: To our knowledge, this is the first report of HLH in combination with congenital FVII deficiency in Chinese population.

[Congenital factor VII deficiency: about two family cases]. / Déficit congénital en facteur VII de coagulation: à propos de deux cas familiaux.

Factor VII deficiency is rare, with an estimated prevalence rate of 1/1,000,000. It is transmitted as an autosomal recessive trait. It can cause simple nosebleeds up to cerebral hemorrhage. Our study aims to focus on the clinical features and the importance of screening in patients with this rare deficit. We report the cases of two brothers with this deficit. Child aged 8 years, born to non-consanguineous marriage who was the youngest of two children. He had a history of post-circumcision bleeding and was admitted to our Department for the treatment of recurrent nosebleeds occurred over the last 4 years. Screening tests of hemostasis showed low Prothrombin (PT), normal Activated thromboplastin time (ATT), while factor assay revealed factor VII deficiency with a rate of 26%. The patient underwent spaced fresh frozen plasma (FFP) transfusions due to nosebleeds and wounds. Family screening was not performed. The eldest brother, aged 11 years, presented with very abundant nosebleeds. Somatic examination was unremarkable. Given his history, the patient underwent factor VII assay revealing a rate of 55% and parent screening was scheduled. The diagnosis of congenital factor VII deficiency in a patient motivates family screening in order to perform screening tests in other carriers of factor VII deficiency. This would avoid severe manifestations, even fatal, considering that studies have not shown a correlation between factor VII rate and the severity of patient's status.

Prophylaxis with recombinant-activated factor VII (rFVIIa) for minimally invasive surgery in a patient with congenital factor VII deficiency: a case report with a single-low dose of rFVIIa.

Congenital factor VII deficiency is a rare autosomal-recessive disorder and surgery in patients with factor VII deficiency has been reported to be endangered by intraoperative or postoperative bleeding, unless a replacement therapy is used. In this paper, we report a successful prophylaxis with single and low dose rFVIIa (12.5 microg kg(-1)) in a 22-year-old homozygote factor VII deficient patient who underwent laparoscopic gynecologic surgery. Minimally invasive surgeries, such as laparoscopic surgery, could be safely performed in patients with congenital factor VII using single and low dose rFVIIa combined with vigilant clinical observation and laboratory examination.

Congenital factor VII deficiency: therapy with recombinant activated factor VII -- a critical appraisal.

Congenital factor VII (FVII) deficiency is a rare bleeding disorder with high phenotypic variability, and optimal management has yet to be determined. Treatment has traditionally involved FVII replacement therapy using fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII concentrates. Recombinant activated FVII (rFVIIa, NovoSeven(R)), the first recombinant treatment option, has recently been approved in the European Union for use in congenital FVII deficiency, but has been available on an emergency and compassionate use basis since 1988. In FVII deficiency, rFVIIa serves as substitution therapy as it provides the physiological ligand (FVIIa) for tissue factor, its receptor exposed at the site of vascular injury. This paper provides an overview of published and unpublished experience with rFVIIa in patients with congenital FVII deficiency from the NovoSeven compassionate and emergency use programmes (1988-99) and of independent reports in the literature. Recombinant FVIIa has been reported to provide effective haemostasis in patients of all ages and in a range of bleeding situations, including acute central nervous system/life-threatening bleeding episodes (15 episodes in 12 patients), non-life-threatening bleeding episodes (>32 episodes in 17 patients), surgery (>40 interventions in 25 patients) and childbirth (three women). Preliminary reports suggest that it may also be effective prophylactically. The risk of thrombosis in FVII-deficient patients treated with rFVIIa is unknown, as is the occurrence of inhibiting antibodies. A postlicensure pharmacovigilance registry (Seven Treatment Evaluation Registry) has been set up to continue to monitor the efficacy and safety (including alloantibody development) of rFVIIa in patients with FVII deficiency.

[Factor VII deficiency and surgery]. / Déficit en facteur VII et chirurgie.

Factor VII deficiency is a rare disorder (1/500,000), with manifestations similar to those experienced by patients with haemophilia. Excessive bleeding during surgical procedure is prevented by factor VII administration. We report two cases of patients presenting a factor VII deficiency who were treated for oncological surgery. In the first patient with a severe congenital factor VII deficiency (8%), a continuous infusion of factor VII prevented the development of perioperative bleeding. In the second case, with a probably acquired factor VII deficiency (33%) related to a leiomyosarcoma, bleeding was prevented by a single preoperative factor VII injection.

Repair of abdominal aortic aneurysm in severe Factor VII deficiency.

Congenital Factor VII deficiency is a rare disorder associated with reduced levels of Factor VII activity. Replacement therapy is necessary to control hemorrhaging or if surgery is needed. We report operative treatment of one case of chronic abdominal aortic aneurysm in a patient affected by a severe form of congenital Factor VII deficiency (endogenous FVII level <1%). The operation was carried out after the administration of Factor VII concentrate raised the Factor VII concentration to hemostatic levels. The patient continued to receive the concentrate every 6 hrs during the first three postoperative days. Dosage was assessed to obtain Factor VII levels not lower than 25%. No postoperative bleeding or thrombotic events were observed. The patient was discharged in excellent condition.

Congenital factor VII deficiency in a patient with an abdominal aortic aneurysm.

A patient with congenital factor VII deficiency underwent surgery for an inflammatory abdominal aortic aneurysm. No references in the literature have been found on the management of this coagulation defect in patients who require vascular surgery. We present one such case, with special reference to the perioperative management of factor VII replacement therapy.

Congenital factor VII abnormality discovered in an infant at a routine checkup.

Congenital coagulation factor VII abnormality in an infant was first discovered because of a decreased normotest value at a routine health checkup at the age of 1 month. No bleeding tendency had been noticed. The normotest value did not respond to an administration of vitamin K. The prothrombin time (PT) was prolonged, and the activated partial thromboplastin time (A-PTT) was in the normal range. Factor VII activity was extremely low, whereas the level of factor VII antigen was relatively low. These data indicate that the propositus is a factor VII reduced variant, a rare variant of congenital factor VII deficiency. The propositus and her brother are homozygotes, and her parents and sister are heterozygotes.

[Gastrectomy for a patient with congenital factor VII deficiency--a case report].

A 76-year-old man with congenital factor VII deficiency was admitted to our hospital for the treatment of gastric cancer. On admission, the hepaplastin test was prolonged reaching to 21% and factor VII activity was reduced to 8%. After preoperative heat-treated prothrombin complex concentrates loading test, factor VII levels had been maintained above 20% by every four-hour infusion of concentrates during operation and the first post operative day. Bleeding tendency didn't occur, but thrombosis occurred at the left femoral vein. Pre and postoperative replacement therapy is essential to the patient with congenital factor VII deficiency for the safety of operation.

[Practical approaches for surgical procedures in congenital factor VII deficiency]. / Attitude pratique en cas d'intervention chirurgicale chez un sujet atteint d'un déficit congénital en facteur VII.

A 33 year old female with a congenital deficit in factor VII underwent four operations, all without any haemorrhage. One of then was carried out using substitutive therapy. She had a non-A non-B hepatitis one month after this treatment. Substitutive therapy depends on the assessment of the risk of haemorrhage, which can be estimated by the concentration of factor VII, the severity of spontaneous haemorrhage, the surgical history, and the planned operation. Since the risk of transmitting viruses with freeze-dried blood products would appear to be virtually nil, since 1985, fresh frozen plasma should be avoided for this type of indication. The doses of concentrated factor VII to be used lie between 20 IU.kg-1 every 4 h and 40 IU.kg-1 every 8 h. Such a dose should be administered in either one or several injections, according to whether the risk of haemorrhage is important or not. Substitutive therapy should be continued as long as the risk persists. Using a test dose of factor VII and, afterwards, measuring its biological activity can help to determine the best time for starting the treatment in order to obtain a level of factor VII greater than the minimum required for surgical haemostasis (10%).

Déficit congénito del factor VII: comunicación de un caso / Congenital factor VII deficiency: communication of a case

Paciente con tendencias hemorrágica leve, que presenta en su estudio de coagulación un patrón típico de déficit de factor VII confirmada por una baja actividad coagulante de dicho factor, de 47%. El resto de los parámetros fueron normales. No hay estudio familiar por residir aquellos en provincia. Se trata pues de una deficiencia congénita de carácter autosómica recisiva del factor VII, diagnosticada por primera vez en el Hospital Central de Sanidad de las Fuerzas Policiales

Arthropathy and surgery in congenital factor VII deficiency.

A 35-year-old woman with severe (less than 1 percent) factor VII deficiency had recurrent hemarthroses involving the left knee, leading to deformity, pain, and virtually complete loss of function. It was elected to perform a total knee replacement. In preparation for surgery, the patient received heat-treated prothrombin complex concentrate containing 870 units of factor VII per vial. A dose of 50 U/kg raised the factor VII level to 115 percent. At surgery, dense adhesions were found within the joint, the articular cartilage was overgrown with pannus extending out to the lateral patella, and there was extensive deformity of the femoral condyle and tibial plateau. The joint was excised and replaced by a cemented Microloc prosthesis. Postoperatively, factor VII levels were maintained above 10 percent by six-hourly infusions of concentrate. Beginning on Day 4, single daily infusions of 25 U/kg were given prior to physical therapy. No bleeding occurred, and the patient was ambulating at the time of discharge 20 days postoperatively. This experience indicates that despite its short half-life (less than four hours), factor VII levels sufficient to prevent bleeding can be maintained in factor VII-deficient patients undergoing major operative procedures.

Defecto congénito de los factores II, VII, y X / Congenital defect of factors II, VII, and X

Se analizan las principales características clínicas y de laboratorio de las deficiencias aisladas y combinadas de los factores II, VII y X. Se señala la importancia del uso de diferentes reactivos y metodologías para poderlos clasificar, sobre todo las variantes, debido a que en estos casos se presentan niveles inmunológicos normales con niveles disminuidos de actividad funcional o coagulante. Se discute brevemente el diagnóstico diferencial de estos trastornos, asi como se esbozan algunas pautas para el manejo del paciente con estas complicaciones hemorragicas hereditarias

Deficiencia congénita combinada de los factores V y VII de la coagulación en una familia mexicana: deficiencia Toledo-Tehuantepec, un nuevo trastomo / Coagulation factors V and VII combined congenital deficiency in a Mexican family: Toledo-Tehuantepec deficiency, a new pathological entity

Se encontró deficiencia combinada de los factores V y VII de la coagulación de los miembros de una femilia originaria de Espinal, Oxaca, en el Istmo de Tehuantepec. Los padres son consanguíneos, y ambos tienen el apellido Toledo. Hay labio leporino en el padre y un hijo. Ningún familiar tiene hemorragias anormales pero sus estudios de coagulación del tiempo de protrombina y de tromboplastina parcial resultaron prologados. El padre es deficiente en factor V, la madre en factor VII, y sus hijos heredaron ambas deficiencias (V y VII), lo que indica una transmisión autosómica dominante y el patrón del estado heterocigoto. Esta deficiencia no se ha descrito previamente, por lo que cabe reconocerla con el nombre Toledo-Tehuantepec