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.

[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.

Factor VII Deficiency: From Basics to Clinical Laboratory Diagnosis and Patient Management.

Factor VII (FVII) deficiency is a rare inheritable bleeding disorder affecting 1/500 000 individuals. Clinical manifestations are heterogeneous, from asymptomatic to severe and potentially fatal bleeding. These clinical manifestations do not correlate well with FVII plasma levels. For this reason, FVII-deficient patient management during surgery or for long-term prophylaxis remains challenging. Laboratory testing for FVII activity is, however, the first-line method for FVII deficiency diagnosis and is helpful for managing patients in combination with clinical history. Additional testing consists of FVII immunoassay and genetic testing. Genetic abnormalities on the FVII gene are heterogeneous and can translate into quantitative or qualitative defects. Some of the latter can react differently with different thromboplastins; this can be misleading for the laboratory as no consensus exists at present on an FVII deficiency diagnosis methodology. Indeed, no single test is able to predict accurately the bleeding risk. This review provides a broad picture of inherited and acquired FVII deficiency with a particular focus on laboratory diagnosis.

An engineered tale-transcription factor rescues transcription of factor VII impaired by promoter mutations and enhances its endogenous expression in hepatocytes.

Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the -94C > G or -61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20-40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.

Isolated acquired factor VII deficiency: review of the literature.

OBJECTIVES: Isolated acquired factor VII (FVII) deficiency is a rare haemorrhagic disorder. We report what is currently known about the pathogenesis, clinical features, diagnosis, treatment and prognosis of acquired FVII deficiency. METHODS: We performed a literature search and included all articles published between 1980 and August 2015. RESULTS AND CONCLUSIONS: Acquired FVII deficiency has been reported in 42 patients. There are well-established clinical diseases associated with acquired FVII deficiency, most notably infections, malignancy and haematological stem cell transplantation. The exact pathogenesis of the diseases is still unknown, but different pathophysiological hypotheses have been suggested. The clinical manifestation of acquired FVII deficiency varies greatly in severity; asymptomatic course as well as severe life-threatening bleeding diathesis and fatal bleedings have been described.

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII.

Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates and low-dose recombinant activated FVII. Clinical data suggest that a mild elevation of plasma FVII levels (>10% normal) results in improved hemostasis. Research dogs with a G96E missense FVII mutation (FVII-G96E) have <1% FVII activity. By western blot, we show that they have undetectable plasmatic antigen, thus representing the most prevalent type of human FVII deficiency (low antigen/activity). In these dogs, we determine the feasibility of a gene therapy approach using liver-directed, adeno-associated viral (AAV) serotype 8 vector delivery of a canine FVII (cFVII) zymogen transgene. FVII-G96E dogs received escalating AAV doses (2E11 to 4.95E13 vector genomes [vg] per kg). Clinically therapeutic expression (15% normal) was attained with as low as 6E11 vg/kg of AAV and has been stable for >1 year (ongoing) without antibody formation to the cFVII transgene. Sustained and supraphysiological expression of 770% normal was observed using 4.95E13 vg/kg of AAV (2.6 years, ongoing). No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, d-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). We observed a transient and noninhibitory immunoglobulin G class 2 response against cFVII only in the dog receiving the highest AAV dose. In conclusion, in the only large-animal model representing the majority of FVII mutation types, our data are first to demonstrate the feasibility, safety, and long-term duration of AAV-mediated correction of FVII deficiency.

AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage.

We explored adeno-associated viral vector (AAV)-mediated gene transfer in the perinatal period in animal models of severe congenital factor VII (FVII) deficiency, a disease associated with early postnatal life-threatening hemorrhage. In young adult mice with plasma FVII < 1% of normal, a single tail vein administration of AAV (1 × 10(13) vector genomes [vg]/kg) resulted in expression of murine FVII at 266% ± 34% of normal for ≥ 67 days, which mediated protection against fatal hemorrhage and significantly improved survival. Codon optimization of human FVII (hFVIIcoop) improved AAV transgene expression by 37-fold compared with the wild-type hFVII cDNA. In adult macaques, a single peripheral vein injection of 2 × 10(11) vg/kg of the hFVIIcoop AAV vector resulted in therapeutic levels of hFVII expression that were equivalent in males (10.7% ± 3.1%) and females (12.3% ± 0.8%). In utero delivery of this vector in the third trimester to fetal monkeys conferred expression of hFVII at birth of 20.4% ± 3.7%, with a gradual decline to > 1% by 7 weeks. Re-administration of an alternative serotype at 12 months postnatal age increased hFVII levels to 165% ± 6.2% of normal, which remained at therapeutic levels for a further 28 weeks without toxicity. Thus, perinatal AAV-mediated gene transfer shows promise for disorders with onset of pathology early after birth.

Imaging and intervention of paraneoplastic effect of a right atrial myxoma on factor VII activity levels.

We present the case of a 64-year-old Pakistani man with right atrial myxoma, recently diagnosed with acquired severe factor VII (FVII) deficiency. The patient presented with a history of chronic hiccups and weight loss. Initial evaluation revealed an isolated prolonged prothrombin time, severely reduced FVII activity level, and a giant right atrial myxoma protruding into the right ventricle on computed tomographic thorax and echocardiography. After surgical resection, the patient maintained normal prothrombin time with increased FVII activity level in the immediate 24 hours postoperatively, and a dramatically high level of FVII activity at the 2-month follow-up. We believe that the paraneoplastic effect of myxoma on the FVII activity levels is previously unreported. In addition, we believe that hiccups as a presenting symptom for a myxoma with an atypical origin from the lateral wall of the right atrium has not been reported.

Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.

Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

Acquired factor VII deficiency associated with Wilms tumor.

We present the case of a 2-year-old female with Wilms tumor whose initial evaluation revealed a prolonged prothrombin time (PT) and normal activated partial thromboplastin time. Mixing studies demonstrated correction of the PT and the Factor VII activity was 17% in the absence of a Factor VII inhibitor. She underwent successful resection of the tumor with fresh frozen plasma support and no excessive bleeding. Post-operative testing demonstrated normal PT at 3 days and 1-month. Although acquired von Willebrand factor deficiency has a known association with Wilms tumor, paraneoplastic factor VII deficiency associated with Wilms tumor is previously unreported.

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.

Steps towards an effective treatment strategy in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is a consequence of a genetic polymorphism that can produce a wide spectrum of disease severity. Mildly affected patients may experience increased bleeding after surgery, trauma or mucosal bleeding, while spontaneous and life-threatening bleeding occurs in patients who are severely affected. Replacement therapy is the mainstay of treatment for patients with FVII deficiency. This has traditionally been achieved using fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or plasma-derived FVII concentrates. However, recombinant activated FVII is now widely used for therapy in these patients. As cases of FVII deficiency tend to be encountered infrequently in most centers, no consolidated evidence-based therapeutic regimens have evolved and the side effects of the available treatments have not been comprehensively evaluated. Consequently, an online registry, the Seven Treatment Evaluation Registry (STER) has been set up. This is a prospective study that aims to evaluate the efficacy and safety of the different therapeutic options with which FVII-deficient patients may be treated. Recruitment of patients into the study is currently underway.

Total hip arthroplasty in severe congenital factor VII deficiency: successful use of recombinant activated factor VII for hemostasis.

Congenital factor VII (FVII) deficiency is a rare hemorrhagic disorder, and, in affected patients, surgery is likely to cause excessive bleeding. In this article, we report the first case of total hip arthroplasty in a patient with severe congenital FVII deficiency in which recombinant activated factor VII (rFVIIa, NovoSeven) was successfully used to manage bleeds. The patient was a 68-year-old woman with severe congenital FVII deficiency, who suffered from a hemorrhagic arthrosis of her left hip joint. We administered rFVIIa as intermittent bolus infusions both perioperatively and postoperatively; dosing was based on the results of a preoperative rFVIIa challenge test. During surgery and the 3-day postoperative treatment period, we observed normal hemostasis with no excessive bleeding or complications.

Lack of bleeding in patients with severe factor VII deficiency.

Factor VII deficiency, although rare, is now recognized as the most common autosomal recessive inherited factor deficiency. It is usually considered to be associated with bleeding only in the severely affected subject and heterozygotes (>10%) are not considered at risk. The general recommendation for surgery is to achieve a FVII level in excess of 15% (0.15 1U/mL). We present three cases of severe factor VII deficiency, each of whom appeared hemostatically competent based on clinical history. Subject 1 is a 33 year-old African-American female with a baseline FVII of <1%, who had a fractured tibia requiring open reduction with internal fixation without any FVII replacement and subsequently underwent successful laparoscopic knee surgery with a factor VII level measured at 6%. Subject 2 is a 58 year-old African-American female with a factor VII level of 9% who underwent an elective left total hip replacement without any factor replacement and had no excessive bleeding, but who sustained a pulmonary embolism postoperatively. Subject 3 is a 19-year-old African-American male with a baseline FVII of 1% with a history of active participation in football without noticeable injury and who underwent an emergent appendectomy without bleeding. These three cases represent individuals with the severe form of FVII deficiency who did not exhibit excessive bleeding when challenged with surgical procedures. The clinical history would appear the most valuable tool in predicting the likelihood of bleeding in these patients, and we suggest that the presumption that all patients with severe FVII deficiency should receive replacement therapy before surgical procedures may not be valid in all cases.

Palliative open heart surgery in an infant with factor VII deficiency.

An infant with factor VII deficiency underwent palliative open heart surgery for pulmonary atresia with an intact ventricular septum. No references had been found on the management of this rare coagulation disorder in infantile cardiac surgery. We describe the peri- and postoperative management with a replacement therapy including a recombinant factor VIIa concentrate. We conclude that an appropriate replacement therapy is needed to control bleeding during open heart surgery with factor VII deficiency.

[The influence of factor VII deficiency on cardiac operations with extracorporeal circulation]. / VII kraujo kresejimo faktoriaus deficito itaka sirdies operacijoms naudojant dirbtine kraujo apytaka.

During preoperative blood coagulation testing the factor VII (FVII) deficiency was found in two patients. No liver disease or cardiac insufficiency was found. No history of bleeding episodes existed. The latent (mild) deficiency of the FVII was diagnosed. The treatment with vitamin K (Vitacon) was administered in order to exclude vitamin K deficiency. The treatment showed no impact on the level of the FVII. Mixing study corrected the deficit (normal PT was found). Both patients underwent cardiac surgery with extracorporeal circulation. The epsilon-aminocapronic acid and fresh frozen plasma were used to prevent bleeding. The postoperative bleeding was compared to average of the year. No difference was found. The patients with mild FVII deficiency may safely undergo cardiac surgery with extracorporeal circulation.

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.

Clinical picture and treatment strategies in factor VII deficiency.

Factor VII is a trace protein required for normal haemostasis. Deficiency of factor VII comprises a highly heterogeneous disease group. Factor VII deficiency can cause bleeding, in particular if factor VII is extremely low, but a few cases lacking factor VII function entirely or subtotally may not present with a history of bleeding. Bleeding problems are not often reported in patients having a factor VII:C level at 10-15% of normal or more. Bleeding is frequently of mucocutaneous type, but the whole array of haemophilic bleeding may also occur. To control bleeding, during surgery in particular, substitution is required in the severe case of factor VII deficiency, but clinical studies documenting which correctional levels of factor VII:C to aim are lacking. It appears that a critical low level (trough) value at 10-15% may be anticipated, but clear documentation does not exist. Substitution programmes may include plasma or plasma derived factor IX concentrates of lower degrees of purity, so-called prothrombin complex concentrates that also are relatively impure, and pure factor VII concentrates. An alternative is a recombinant factor VIIa molecule. However, this concentrate has not received license in a number of countries. Thrombotic manifestations appear to occur more often than expected in the factor VII deficient patients, some have been linked to the use of impure concentrates, others to preexisting thrombophilic risk factors, but some are unexplained and may bear a relationship to the deficiency state of factor VII itself. Controlled clinical trials are highly warranted in this rare bleeding condition.