Preventing Surgical and Postpartum Hemorrhage in an Active Duty Patient With an Undiagnosed Coagulopathy at a Military Treatment Facility

ABSTRACT Factor VII (FVII) deficiency is a hereditary bleeding disorder that significantly increases the risk of hemorrhage during the intrapartum and postpartum periods as well as during surgery. Management often requires careful pre- and post-operative planning, a multi-disciplinary approach, and management at a tertiary center. Most cases in the literature utilized recombinant FVII for treatment. We present a case of a young active duty female who had an undiagnosed FVII deficiency that became apparent during her expedited delivery for fetal distress. Our patient was admitted for delivery while undergoing a work up for an abnormal coagulation panel. Given high suspicion for FVII deficiency, anticipated hemorrhage, and need for cesarean delivery, she was treated with blood products containing FVII. Two days after delivery her diagnosis was confirmed. Available literature discusses the management of known FVII deficiency in pregnancy; however, to the best of our knowledge, there are no cases of an unknown bleeding diathesis incidentally identified just before delivery and later diagnosed as FVII deficiency. This case highlights the appropriate management of an unknown coagulopathy, the significant challenges associated, and the incorporation of a multi-disciplinary team critical to reducing significant maternal morbidity.

Download Full-text

Factor VII Deficiency in the Negev - a 10 Years' Experience of One Tertiary Center

Blood ◽

10.1182/blood.v126.23.4695.4695 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4695-4695

Author(s):

Yariv Fruchtman ◽

Miri Ben harosh ◽

Joseph Kapelushnik ◽

Julia Mazar ◽

Gili Kenet ◽

...

Keyword(s):

Genetic Diagnosis ◽

Residual Activity ◽

Factor Vii ◽

Bleeding Disorders ◽

Factor Vii Deficiency ◽

Advisory Boards ◽

Wide Range ◽

Tertiary Center ◽

Life Threatening ◽

Fvii Deficiency

Abstract Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare bleeding disorders, with an estimated prevalence of 1:300,000 in European countries. Affected individuals display a wide range of clinical phenotypes, ranging from mild non spontaneous bleeding to life threatening (i.e. central nervous system[CNS] bleeding, gastrointestinal [GI] bleeding or haemarthrosis), whereas up to one-third of individuals with a FVII deficiency are asymptomatic and are mainly diagnosed during family studies or after screening for surgery. Unfortunately, the residual activity of FVII does not predict the individual propensity to bleed, and even in individuals with the same mutation, differences in clotting phenotypes can be seen. As our tertiary center serves a unique population in the Negev, we aimed at studying the prevalence and phenotype of FVII deficiency within the last decade. Methods: We searched all electronic records for the last 10 years depicting rare bleeding disorders by ICD 9 code - 2863 and compared them to the hematologic record of factor VII deficiency depicted in our lab - 50% or less activity. Patients with any record of genetic diagnosis, were compared with clinical findings. Results: The population in the Negev is estimated as 700000 people Most of them are Jewish and 150000 of them are Arab-Bedouins. We found 800 records of rare bleeding disorders (ICD 9-2863), Including 200 with FVII deficiency - 100/200 had FVII levels below 50%. Most (90%) of cases were of Jewish origin (mostly oriental Jews) and only 10% were Arab- Bedouins. Forty patients were asymptomatic with 50-30% FVII activity and 20 patients with 30-10% FVII activity were either asymptomatic or presented with mild bleeding diathesis. Out of 23 cases with lower than 10% FVII activity, 7 were symptomatic and suffered severe life threatening bleedings (2 infant died of perinatal ICH. Five families (3 Bedouin and 2 oriental Jews) were identified with severe FVII deficiencies. The 4 Bedouin patients were identified to be homozygous to unique mutation. Interestingly, most medical records depicted FVII deficiency were of women studies due to fertility problems. Conclusions: The prevalence of FVII deficiency depicted in the Negev is much higher in comparison to literature reports (200/700000) Severe FVII deficiency was found in 23: 700000, consistent with 1: 30000 prevalence. As patients are highly variable, in order to "tailor" treatments according to disease severity, new directions should be pursued to identify those with the most severe phenotypes. Disclosures Kenet: Bayer, Novo Nordisk: Other: Advisory Boards, Speakers Bureau; Opko Biologics: Consultancy, Other: Advisory Boards; BPL; Baxelta: Research Funding; Pfizer: Honoraria.

Download Full-text

Genotype-Phenotype Relationship Among 1200 Unrelated White Patients with Inherited FVII Deficiency: A Three-Center Database Study

Blood ◽

10.1182/blood-2021-153580 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 589-589

Author(s):

Susan Halimeh ◽

Gili Kenet ◽

Piotr Kuta ◽

Maria Shneyder ◽

Tido Bajorat ◽

...

Keyword(s):

Blood Group ◽

Research Funding ◽

Laboratory Data ◽

Factor Vii ◽

Poor Correlation ◽

Severe Bleeding ◽

Symptomatic Disease ◽

Fvii Deficiency ◽

Work Up ◽

White Patients

Abstract Background: Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. A clinical heterogeneity with poor correlation with FVII:C levels has been described. Aim of this study was to identify genetic defects and to evaluate their relationships with clinical phenotype in a large cohort of 1228 white patients with FVII:C below the age-dependent cut-off %. Methods: Probands with confirmed inherited factor VII deficiency were i) genotyped (Sanger method & multiplex ligation-dependent probe amplification [MLPA]) for F7 mutations including common polymorphic variants and were ii) classified according to clinical bleeding scores (BC). In addition, common thrombophilic variants and blood groups were determined. Results: Probands included asymptomatic subjects (referred for laboratory work up of recurrent prolonged prothrombin time; n=415; mean age 30 + 19 yrs.; female 52%) and patients who presented with mild, moderate or severe bleeding episodes (n=805; mean age 34 + 18 yrs.; female 70%). Bleeding symptoms included epistaxis, gum bleeding, GI bleeding, hematuria, postoperative and gynecologic hemorrhage. Median FVII activity (entire cohort) measured with clotting-based assays (ACL TOP 750 and/or BCS-XP) was 49% (range 5-78%) and the median ISTH BS recorded within a period of two years prior to work-up was 1(0-17). The latter was significantly higher in women compared with males (2 versus 1; p < 0.001). The corresponding PBAC-Score prior to hormonal treatment was 163 (25-1200). Blood group 0 was present in 40.6% of cases. Known and novel mutations in the F7 gene, including coding regions, exon/intron boundaries and the promoter region, are found in 534 patients (44%) and common polymorphisms were detected in 666 subjects (95%). Logistic regression analysis adjusted for clinical and laboratory data (blood group, FVII activity, presence of F7 gene mutations and /or polymorphisms, thrombophilia status and further factor deficiencies) revealed that older age (increase per year) at referral (odds/95% CI: 1.01/1.007-1.025) and female gender (odds/95% CI: 3.25/2.35-4.50) in part explain differences in clinical bleeding phenotype associated with FVII deficiency. Conclusion: Overall there is poor correlation between the FVII level and the bleeding phenotype. Older patients and females are more likely to have symptomatic disease as a result of gynecological or muco-cutaneous bleeding. Disclosures Kenet: Alnylam: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Opko Biologics: Research Funding; Pfizer: Consultancy, Research Funding; Shire: Research Funding; Novo Nordisk: Consultancy; Roche: Consultancy; Takeda: Consultancy.

Download Full-text

Characteristics, Treatment, and Outcomes of Patients With Severe or Life-threatening COVID-19 at a Military Treatment Facility—A Descriptive Cohort Study

Military Medicine ◽

10.1093/milmed/usab055 ◽

2021 ◽

Author(s):

Brian P Elliott ◽

Gregory M Buchek ◽

Matthew T Koroscil

Keyword(s):

Severe Disease ◽

Ambient Air ◽

Active Duty ◽

Urban Setting ◽

Arterial Oxygen ◽

Treatment Facility ◽

Blood Oxygen Saturation ◽

Life Threatening ◽

Military Treatment Facility ◽

Active Duty Personnel

ABSTRACT Introduction The treatment of severe and life-threatening COVID-19 is a rapidly evolving practice. The purpose of our study was to describe the characteristics and outcomes of patients with severe or life-threatening COVID-19 who present to a Military Treatment Facility (MTF) with an emphasis on addressing institutional adaptations to rapidly changing medical evidence. Materials and Methods A single-center retrospective study conducted on a prospectively maintained cohort. The MTF is a 52-bed hospital within an urban setting. Patients were included in the cohort if they had laboratory-confirmed severe or life-threatening COVID-19 with positive SARS-CoV-2 reverse transcription polymerase chain reaction. Severe disease was defined as dyspnea, respiratory frequency ≥30/min, blood oxygen saturation ≤93% on ambient air, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, or lung infiltrates involving >50% of lung fields within 24-48 hours. Life-threatening COVID-19 was defined as respiratory failure, septic shock, or multiple organ dysfunction. The cohort included patients admitted from June 1 through November 13. Data were collected retrospectively via chart review by a resident physician. Results In total, our MTF saw 14 cases of severe or life-threatening COVID-19 from June 1 to November 13. Patients had a median age of 70.5 years, with 7% being active duty personnel, 21% dependents, and 71% retired military members. The median time to dexamethasone, remdesivir, and convalescent plasma administration was 4.7, 6.3, and 11.2 hours, respectively. The 28-day in-hospital mortality was 0%. Conclusions Patients who present to an MTF with severe or life-threatening COVID-19 are largely retirees, with only a small fraction comprising active duty personnel. The institution of order sets and early consultation can help facilitate prompt patient care for COVID-19.

Download Full-text

Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study

Thrombosis and Haemostasis ◽

10.1055/s-0041-1726344 ◽

2021 ◽

Author(s):

Caroline S. B. Veen ◽

Elise J. Huisman ◽

Lorenzo G. R. Romano ◽

Celesta W. A. Schipaanboord ◽

Marjon H. Cnossen ◽

...

Keyword(s):

Surgical Procedures ◽

Major Bleeding ◽

Prophylactic Treatment ◽

Bleeding Complications ◽

Bleeding Tendency ◽

Limited Data ◽

Surgical Interventions ◽

Tertiary Center ◽

Low Threshold ◽

Work Up

Abstract Background The most optimal management for patients with bleeding of unknown cause (BUC) is unknown, as limited data are available. Objective Evaluate management and outcome of surgical procedures and deliveries in patients with BUC. Materials and Methods All patients ≥12 years of age, referred to a tertiary center for a bleeding tendency, were included. Bleeding phenotype was assessed and hemostatic laboratory work-up was performed. Patients were diagnosed with BUC or an established bleeding disorder (BD). Data on bleeding and treatment during surgical procedures and delivery following diagnosis were collected. Results Of 380 included patients, 228 (60%) were diagnosed with BUC and 152 (40%) with an established BD. In 14/72 (19%) surgical procedures major bleeding occurred and 14/41 (34%) deliveries were complicated by major postpartum hemorrhage (PPH). More specifically, 29/53 (55%) of the BUC patients who underwent surgery received prophylactic treatment to support hemostasis. Despite these precautions, 4/29 (14%) experienced major bleeding. Of BUC patients not treated prophylactically, bleeding occurred in 6/24 (25%). Of pregnant women with BUC, 2/26 (8%) received prophylactic treatment during delivery, one women with and 11 (46%) women without treatment developed major PPH. Conclusion Bleeding complications are frequent in BUC patients, irrespective of pre- or perioperative hemostatic treatment. We recommend a low-threshold approach toward administration of hemostatic treatment in BUC patients, especially during delivery.

Download Full-text

Congenital Deficiency in Factor VII Revealed by Menorrhagia: Case Report

Asian Journal of Pediatric Research ◽

10.9734/ajpr/2020/v4i130138 ◽

2020 ◽

pp. 1-5

Author(s):

Nadia Mebrouk ◽

Abdelilah Radi ◽

Mohamed Selouti ◽

Amal Hassani ◽

Abdelhakim Ourrai ◽

...

Keyword(s):

Treatment Options ◽

Specific Treatment ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Activity Measurement ◽

Recombinant Activated Factor Vii ◽

Congenital Deficiency ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Fvii Deficiency

Factor VII (FVII) deficiency is the most common among rare inherited autosomal recessive bleeding disorders. It is a multifaceted disease because of the lack of a direct correlation between plasma levels of coagulation FVII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even in homozygous subjects—to severe, life-threatening bleedings (e.g., central nervous system and gastrointestinal bleeding). Menorrhagia is a frequent type of bleeding in FVII deficiency, with a prevalence rate of two in three women aged 10 to 50 years and with a peak prevalence in teenagers. When menorrhagia is observed and once the gynecological causes are excluded, it is important to carry out a hemostasis assessment because, if an anomaly is found, specific treatment can be administered and preventive measures taken. Basic diagnostic work-up includes routine assays, prothrombin level, activated partial thromboplastin time and platelet count, followed by FVII coagulant activity measurement for isolated decreased prothrombin level. To confirm the diagnosis, FVII assay should be repeated at least once. Several treatment options are currently available for FVII deficiency: Recombinant activated Factor VII (rFVIIa), plasma-derived Factor VII, fresh frozen plasma and prothrombin complex concentrates. rFVIIa is the most used replacement therapy. Other medical therapies of menorrhagia includes hemostatic agents and hormonal treatments (combined oral contraceptives, levonorgestrel intrauterine devices), in combination or not with rFVIIa. We report the case of a fourteen-and-a-half-year-old girl who presented menorrhagia of great abundance at the age of thirteen, the exploration of which revealed a congenital deficit in FVII.

Download Full-text

Molecular Mechanisms of FVII Deficiency: Expression of Mutations Clustered in the IVS7 Donor Splice Site of Factor VII Gene

Blood ◽

10.1182/blood.v92.5.1646 ◽

1998 ◽

Vol 92 (5) ◽

pp. 1646-1651 ◽

Cited By ~ 28

Author(s):

M. Pinotti ◽

R. Toso ◽

R. Redaelli ◽

M. Berrettini ◽

G. Marchetti ◽

...

Keyword(s):

Splice Site ◽

Molecular Mechanisms ◽

Catalytic Domain ◽

Point Mutations ◽

Factor Vii ◽

Donor Splice Site ◽

Donor Splice ◽

Expression Studies ◽

Fvii Deficiency ◽

American Society

Abstract In three Italian patients, two point mutations and a short deletion were found in the intron 7 of factor VII gene, clustered in the donor splice site and located in the first of several repeats. The mutation 9726+5G→A, the most frequent cause of symptomatic factor VII deficiency in Italy, as well as the deletion (9729del4) gave rise in expression studies to abnormally spliced transcripts, which were exclusively produced from the cryptic site in the second repeat. The insertion in the mature mRNA of the first intronic repeat caused (9726+5G→A) a reading frameshift, abolishing most of the factor VII catalytic domain, or produced (9729del4), an altered factor with 11 additional residues, the activity of which was not detectable in the cell medium after mutagenesis and expression studies. Studies of factor VII ectopic mRNA from leukocytes and expression studies indicated that the deleted gene produced 30% of normally spliced transcript. Differently, the 9726+5G→A mutation permitted a very low level (0.2% to 1%) of correct splicing to occur, which could be of great importance to prevent the onset, in the homozygous patients, of most of the life-threatening bleeding symptoms. The 9726+7A→G mutation was found to be a rare and functionally silent polymorphism. These findings, which provide further evidence of the interplay of sequence and position in the 5′ splice site selection, throw light on the heterogeneous molecular bases and clinical phenotypes of FVII deficiency. © 1998 by The American Society of Hematology.

Download Full-text

Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII

Thrombosis and Haemostasis ◽

10.1160/th05-05-0342 ◽

2005 ◽

Vol 94 (12) ◽

pp. 1177-1180 ◽

Cited By ~ 19

Author(s):

Geir E. Tjønnfjord ◽

Richard Wallensten ◽

Uri Martinowitz ◽

Gili Kenet ◽

Sam Schulman

Keyword(s):

Continuous Infusion ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Single Case ◽

Thromboembolic Complication ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Activated Factor Vii ◽

Different Types ◽

Fvii Deficiency

SummaryThe administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factorVII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion, aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.

Download Full-text

Bleeding symptoms at disease presentation and prediction of ensuing bleeding in inherited FVII deficiency

Thrombosis and Haemostasis ◽

10.1160/th12-10-0740 ◽

2013 ◽

Vol 109 (06) ◽

pp. 1051-1059 ◽

Cited By ~ 26

Author(s):

Alberto Dolce ◽

Guglielmo Mariani ◽

Matteo Nicola Di Minno ◽

Keyword(s):

Relative Risk ◽

Major Bleeding ◽

Independent Predictor ◽

Demographic Variables ◽

Treatment Evaluation ◽

Factor Vii ◽

Bleeding Symptom ◽

Coagulant Activity ◽

Fvii Deficiency

SummaryIndividuals with inherited factor VII (FVII) deficiency display bleeding phenotypes ranging from mild to severe, with 30% of patients having always been asymptomatic (non-bleeding). In 626 FVII-deficient individuals, by analysing data from the International Factor VII (IF7) Registry and the Seven Treatment Evaluation Registry (STER), we determined whether bleeding type at disease presentation and FVII coagulant activity (FVIIc) predict ensuing bleeds. At disease presentation/diagnosis, 272 (43.5%) individuals were non-bleeding, 277 (44.2%) had minor bleeds, and 77 (12.3%) had major bleeds. During a median nine-year index period (IP) observation, 87.9% of non-bleeding individuals at presentation remained asymptomatic, 75.1% of minor-bleeders had new minor bleeds, and 83.1% of major-bleeders experienced new major bleeds. After adjusting for FVIIc levels and other clinical and demographic variables, the relative risk (RR) for ensuing bleedings during the IP was 6.02 (p <0.001) and 5.87 (p <0.001) in individuals presenting with major and minor bleeds, respectively. Conversely, compared to non-bleeding individuals, a 10.95 (p = 0.001) and 28.21 (p <0.001) RR for major bleedings during the IP was found in those with minor and with major bleeds at presentation, respectively. In conclusion, in FVII deficiency, the first major bleeding symptom is an independent predictor of the risk of subsequent major bleeds.

Download Full-text

Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation

Blood ◽

10.1182/blood-2003-04-1199 ◽

2003 ◽

Vol 102 (12) ◽

pp. 4014-4020 ◽

Cited By ~ 32

Author(s):

Elisabetta Castoldi ◽

José W. P. Govers-Riemslag ◽

Mirko Pinotti ◽

Debora Bindini ◽

Guido Tans ◽

...

Keyword(s):

Thrombin Generation ◽

Clinical Phenotype ◽

Activated Protein C ◽

Coagulation Factor ◽

Factor Vii ◽

Factor V ◽

Factor X ◽

Fv Leiden ◽

Fvii Deficiency ◽

Thrombin Formation

Abstract We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency. (Blood. 2003;102:4014-4020)

Download Full-text

Factor VII Deficiency Remains Post-Puberty Due to Point Mutation in the HNF4 Binding Site in the Coagulant Factor VII Gene.

Blood ◽

10.1182/blood.v106.11.1947.1947 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1947-1947

Author(s):

XingWu Zheng ◽

Theresa M. Tidd ◽

Donna DiMichele ◽

Eleanor S. Pollak

Keyword(s):

Binding Site ◽

Point Mutation ◽

Mutant Allele ◽

Factor Ix ◽

Hemophilia B ◽

Factor Vii ◽

Start Site ◽

Expression Plasmid ◽

Fvii Deficiency ◽

Factor Ix Deficiency

Abstract A novel T to C point mutation at −60 in the gene for coagulant Factor VII results in life-long severe coagulant Factor VII deficiency in post-pubertal twin males. The clinical course of these patients provides an informative in vivo example of the regulation of expression of vitamin K-dependent clotting protein Factor VII. An analogous point mutation in the HNF4 binding site in the Factor IX gene results in the clinical phenotype Hemophilia B Leyden, a sex-linked antigen-negative Factor IX deficiency that resolves post-puberty. The affected Factor VII deficient patients have prolonged prothrombin times (46 and 52 secs), normal aPTTs and decreased FVII levels of FVII:Coagulant activity: < 1% and FVII:Antigen: < 3%. The −60 mutation, ACTTTG → ACTCTG occurs 9 base pairs before the start site of transcription and 59 bps before the before the start site of translation. The twins are compound heterozygotes and also possess a mutation in exon 8 at amino acid 348, a mutation that has previously been reported to cause FVII deficiency. Both affected individuals have recurrent target joint hemorrhage (shoulder, elbow, ankle) requiring replacement therapy 6–12 times/year. Results: Gel mobility shift assays using a radio-labeled probe spanning from −76 to −46 in the FVII promoter region demonstrate the loss of binding of transcription factor HNF-4. Transient transfection assays in HepG2 cells using 186 bps of the mutant and the wildtype promoters (−185 to +1) revealed a loss of expression with the mutant allele. Co-transfection with an HNF4 expression plasmid resulted in an increase in expression of the wildetype construct in HeLa cells, a non-hepatic cell line. However, co-transfection of the HNF4 expression plasmid failed to increase expression with the construct containing the mutant allele sequence. Conclusion: The lack of phenotypic change of the FVII:C in 19 yo twin boys provides dynamic support of the necessity of an overlapping androgen binding site in the homologous Factor IX gene as responsible for the phenotypic resolution of Factor IX deficiency (Hemophilia B Leyden) post-puberty. It is of interest that an increase in FVII:C did not occur with advancing age in FVII deficiency due to this HNF4 binding site mutation.

Download Full-text