Congenital Deficiency in Factor VII Revealed by Menorrhagia: Case Report

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.

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A Retrospective Analysis of Transfusion Management for Obstetric Hemorrhage in a Japanese Obstetric Center

ISRN Obstetrics and Gynecology ◽

10.5402/2012/854064 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Shigetaka Matsunaga ◽

Hiroyuki Seki ◽

Yoshihisa Ono ◽

Hideyoshi Matsumura ◽

Yoshihiko Murayama ◽

...

Keyword(s):

Blood Product ◽

Coagulation Factors ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Blood Product Transfusion ◽

Obstetric Hemorrhage ◽

Recombinant Activated Factor Vii ◽

Product Usage ◽

Activated Factor Vii ◽

Fresh Frozen

Background. Since cryoprecipitate, fibrinogen concentrate, or recombinant activated factor VII is not approved by public medical insurance in Japan, we retrospectively assessed blood product usage in patients with obstetric hemorrhage at our tertiary obstetric center. Material and Methods. 220 patients with obstetric hemorrhagic disorders who underwent blood product transfusion in our institution during a 5-year period were reviewed for the types and volumes of blood products transfused. Results. There was a significant positive correlation ( 0.001) between the volume of RCC (red blood cell concentrate) transfused and that of FFP (fresh frozen plasma), irrespective of underlying obstetric disorders. The median of FFP to RCC ratio in each patient was 1.3–1.4, when 6 or more units of RCC were transfused. Conclusions. In transfusion for massive obstetric hemorrhage in terms of appropriate supplementation of coagulation factors, the transfusion of RCC : FFP = 1 : 1.3–1.4 may be desirable.

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Recombinant activated factor VII for cerebral injury—induced coagulopathy in pediatric patients

Journal of Neurosurgery ◽

10.3171/jns.2003.98.3.0611 ◽

2003 ◽

Vol 98 (3) ◽

pp. 611-616 ◽

Cited By ~ 68

Author(s):

John David Morenski ◽

Joseph D. Tobias ◽

David F. Jimenez

Keyword(s):

Injured Patient ◽

Fresh Frozen Plasma ◽

Cerebral Injury ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Content Type ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Repeated Doses ◽

Fine Print

✓ Brain injury remains one of the leading causes of death and disability in children. Appropriate therapy involves aggressive management of intracranial pressure (ICP) and cerebral perfusion pressure, which often requires placement of an intraparenchymal ICP monitor or intraventricular catheter. These potentially life-saving interventions require normal coagulation function; however, several factors may lead to coagulopathy in the head-injured patient. Standard therapies, which often include multiple doses of fresh frozen plasma (FFP), have a number of drawbacks when used in the pediatric population. The use of FFP requires time to type and crossmatch, thaw, and administer. It imposes a significant volume load on a child in whom cerebral edema remains a problem. Success in using recombinant activated factor VII (rFVIIa) in the hemophiliac population suggests an alternative therapy. Three patients suffered severe coagulopathy after cerebral injury. One patient received rFVIIa after repeated doses of FFP had failed to correct the coagulopathy; the other two patients received rFVIIa as the initial therapy. Treatment with rFVIIa consisted of a bolus of 90 µg/kg. Recombinant activated factor VII rapidly corrected the patients' coagulopathies, which allowed placement of intraparenchymal fiberoptic lines and intraventricular catheters to monitor ICP. The patients suffered no complication from the placement of ICP monitoring devices, as demonstrated on computerized tomography scans obtained within 24 hours after placement. Brain injury—induced coagulopathy may lead to significant secondary injury and delays the invasive monitoring necessary for the aggressive management of intracranial hypertension. Fresh frozen plasma takes time to administer, may require repeated doses of significant volume for the pediatric patient, and may ultimately fail. Preliminary data indicated that rFVIIa provides a rapid and successful correction of coagulopathy in the head-injured patient.

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Recombinant Activated Factor VII for the Rapid Correction of Coagulopathy in Nonhemophilic Neurosurgical Patients

Neurosurgery ◽

10.1227/01.neu.0000068830.54968.a8 ◽

2003 ◽

Vol 53 (1) ◽

pp. 34-39 ◽

Cited By ~ 96

Author(s):

Paul Park ◽

Matthew E. Fewel ◽

Hugh J. Garton ◽

B. Gregory Thompson ◽

Julian T. Hoff

Keyword(s):

Fresh Frozen Plasma ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Coagulation Parameters ◽

Activated Factor Vii ◽

Optimal Dosing ◽

Neurosurgical Patients ◽

Fresh Frozen ◽

Dilutional Coagulopathy ◽

Neurosurgical Intervention

Abstract OBJECTIVE Coagulopathy is a significant contraindication for neurosurgery. Unfortunately, many coagulopathic patients require urgent neurosurgical intervention. Standard use of blood products, including fresh-frozen plasma or prothrombin complexes, to correct the coagulopathy often leads to significant delays in treatment. Recombinant activated factor VII (rFVIIa) is a medication originally designed to treat bleeding in hemophiliacs but also seems to correct a wide variety of coagulopathies rapidly and safely in nonhemophilic patients. METHODS The medical records of nine patients with coagulopathy requiring urgent neurosurgical intervention were reviewed retrospectively. Each patient was given a dose ranging from 40 to 90 μg/kg of rFVIIa before undergoing surgery. Pre-rFVIIa coagulation and post-rFVIIa coagulation parameters were obtained. Once correction of the coagulopathy was verified, each patient underwent the appropriate neurosurgical procedure. RESULTS The average age of the patients was 40.9 years; six were women. The causes of the coagulopathy included anticoagulant medication, liver dysfunction, and dilutional coagulopathy after traumatic hemorrhage. Neurosurgical indications included intraparenchymal/intraventricular hemorrhage, hydrocephalus, diffuse cerebral edema, and epidural hematoma. Post-rFVIIa coagulation parameters obtained as early as 20 minutes after infusion of the medication showed normalization of values. There were no procedural or operative complications and no postoperative hemorrhagic complications. No associated thromboembolic or other complications with the use of rFVIIa were observed. CONCLUSION The use of rFVIIa for the urgent surgical treatment of coagulopathic patients is quite promising. Further studies, including randomized, prospective trials using rFVIIa to address issues such as optimal dosing, efficacy, surgical indications, cost-effectiveness, morbidity, and mortality are needed.

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Clinical Usefulness of Recombinant Activated Factor VII in Patients with Liver Failure Undergoing Invasive Procedures

Annals of Pharmacotherapy ◽

10.1345/aph.1q207 ◽

2011 ◽

Vol 45 (11) ◽

pp. 1433-1438 ◽

Cited By ~ 23

Author(s):

Jill C Krisl ◽

Holly E Meadows ◽

Charles S Greenberg ◽

Joseph E Mazur

Keyword(s):

Liver Failure ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Bleeding Complications ◽

Invasive Procedures ◽

Recombinant Activated Factor Vii ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Dose Dependent ◽

Frozen Plasma

Objective: To evaluate the use of recombinant activated factor VII (rFVIIa) in patients with liver failure undergoing invasive procedures. Methods: An OVID/MEDUNE and PubMed search (1997-June 2011) was performed to identify literature on the use of rFVIIa to reduce bleeding risk in patients with liver failure undergoing invasive procedures. Study Selection and Data Extraction: English-language data evaluating the efficacy of rFVIIa to reverse coagulopathies prior to invasive procedures in patients with liver disease were included. Data Synthesis: Following administration of rFVIIa, prothrombin time (PT) and international normalized ratio (INR) response is within 30 minutes. Doses ranging from 20 to 120 μg/kg have been studied, with a reduction in PT seen in a dose-dependent manner. One study in patients with no bleeding administered 5, 20, and 80 μg/kg sequentially during a 24-day period. All doses provided reversal of prolonged PT within 10 minutes, and the duration was dose-dependent. In a study of 15 patients with fulminant liver failure, requiring intracranial pressure monitor placement, a rFVIIa dose of 40 μg/kg was compared to fresh frozen plasma. In patients who received rFVIIa, the PT and INR normalized, compared to none of the patients in the fresh frozen plasma group. Conclusions: Retrospective and prospective data demonstrate that rFVIIa effectively reverses elevated PT and INR, reducing the risk of bleeding and safely facilitating invasive procedures. Based on available data, a dose of 20-40 μg/kg 30 minutes prior to an invasive procedure should be considered in patients with acute or chronic liver failure at risk for bleeding complications. A major limitation of rFVIIa use is the high cost of therapy. A prospective, randomized trial could help determine the appropriate dose of rFVIIa, timing of dose in relationship to procedure, and usefulness of subsequent doses.

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A Comparison of Prothrombin Complex Concentrate and Recombinant Activated Factor VII for the Management of Bleeding With Cardiac Surgery

Journal of Intensive Care Medicine ◽

10.1177/0885066620984443 ◽

2021 ◽

pp. 088506662098444

Author(s):

Alyson Katz ◽

Tania Ahuja ◽

Serena Arnouk ◽

Tyler C. Lewis ◽

Kassandra Marsh ◽

...

Keyword(s):

Cardiac Surgery ◽

Prothrombin Complex Concentrate ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Dose Requirement ◽

Recombinant Activated Factor Vii ◽

Packed Red Blood Cells ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Chest Tube Output

Bleeding following cardiac surgery that warrants transfusion of blood products is associated with significant complications, including increased mortality at 1 year following surgery. Factor concentrates, such as prothrombin complex concentrate (PCC), or recombinant activated factor VII (rFVIIa) have been used off-label for bleeding in cardiac surgery that is refractory to conventional therapy. The objective of this retrospective study is to assess the hemostatic effectiveness of 4-factor PCC or rFVIIa for bleeding after a broad range of cardiac surgeries. Patients were included if they were at least 18 years of age and had undergone cardiac surgery with bleeding requiring intervention with 4-factor PCC or rFVIIa. There were no differences observed in the number of packed red blood cells (4-factor PCC: 2 units vs. rFVIIa: 2 units), fresh frozen plasma (0 units vs. 1 unit) or platelet (2 units vs. 2 units) transfusions following the administration of 4-factor PCC or rFVIIa. The patients in the rFVIIa group, required more cryoprecipitate than those in the 4-factor PCC group (4-factor PCC: 2 units (range 0-6) vs. rFVIIa: 2 units (range 0-8), p = 0.03). There were no differences in secondary outcomes of chest tube output at 2, 6, 12 and 24 hours, nor was there a difference in reexploration rates or the median length of stay in the intensive care unit. Thromboembolic complications at 30 days were similar between the two groups (4-factor PCC: 13% vs. rFVIIa 26%, p = 0.08). The total median dose requirement for 4-factor PCC was 1000 units (15 units/kg) and 2 mg (20 mcg/kg) for rFVIIa. The results demonstrate feasibility of utilizing the minimum amount of drug in order to achieve a desired effect. Both 4-factor PCC and rFVIIa appear to be safe and effective options for the management of bleeding associated with cardiac surgery.

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Application of recombinant activated factor VII during surgery for a giant skull base hemangiopericytoma to achieve safe hemostasis

Journal of Neurosurgery ◽

10.3171/jns.2002.96.5.0946 ◽

2002 ◽

Vol 96 (5) ◽

pp. 946-948 ◽

Cited By ~ 30

Author(s):

Rüdiger Gerlach ◽

Gerhard Marquardt ◽

Heimo Wissing ◽

Inge Scharrer ◽

Andreas Raabe ◽

...

Keyword(s):

Skull Base ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Neurosurgical Procedures ◽

Recombinant Activated Factor Vii ◽

Content Type ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Severe Difficulty ◽

Tumor Remnant

✓ The authors report on a 64-year-old woman with a huge recurrent skull base hemangiopericytoma, in whom they encountered severe difficulty in attaining intraoperative hemostasis. Standard surgical hemostatic methods and the administration of fresh-frozen plasma and prothrombin complex concentrates failed to stop diffuse bleeding from an inoperable tumor remnant. At a critical point during the operation, the intravenous administration of recombinant activated factor VII, combined with mechanical compression, finally led to satisfactory hemostasis. The rationale for using recombinant activated factor VII in situations of uncontrolled bleeding during neurosurgical procedures is discussed, along with the literature in which the use of recombinant activated factor VII as a maneuver of last resort is reported for hemostasis in other surgical fields.

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Use of recombinant activated factor VII

Medicina ◽

10.3390/medicina45030032 ◽

2009 ◽

Vol 45 (3) ◽

pp. 248

Author(s):

Dagmara Reingardienė ◽

Robertas Lažauskas

Keyword(s):

Prothrombin Time ◽

Liver Diseases ◽

Hemophilia A ◽

Tissue Injury ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Congenital Deficiency ◽

Activated Factor Vii ◽

Life Threatening ◽

Hemostatic Disorders

Recombinant activated factor VII (rFVIIa) has been used in the treatment of various congenital and acquired hemostatic disorders for more than 10 years. Hemostasis is initiated by the FVIIa bound to tissue factor (TF), which constitutes only approximately 1% of total amount of the FVII protein existing in the blood. rFVII becomes activated only after the binding to the TF, released at the site of tissue injury. The efficiency of rFVIIa in the treatment of such life-threatening hemorrhagic states like hemophilia reaches up to 76–84%. rFVIIa is successfully used in the treatment of congenital deficiency of factor VII. It normalizes prothrombin time in the patients with the liver diseases and in cases of overdose of indirect anticoagulants. It is also useful for patients suffering from thrombocytopenia, thrombocyte function disorders, hemophilia A and B with development of inhibitors. rFVIIa allows overcoming uncontrollable hemorrhages, etc. It is supposed that rFVIIa is becoming a universal hemostatic drug.

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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.

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IVH in VLBW Preterm Babies – Therapy with Recombinant Activated F VII?

Klinische Pädiatrie ◽

10.1055/s-0043-119994 ◽

2017 ◽

Vol 229 (06) ◽

pp. 335-341 ◽

Cited By ~ 2

Author(s):

Matthias Knüpfer ◽

Jenny Ritter ◽

Ferdinand Pulzer ◽

Corinna Gebauer ◽

Nadine Wolf ◽

...

Keyword(s):

Very Low Birth Weight ◽

Demographic Data ◽

Fresh Frozen Plasma ◽

Coagulation Cascade ◽

Factor Vii ◽

Control Group ◽

Posthemorrhagic Hydrocephalus ◽

Activated Factor Vii ◽

Fresh Frozen ◽

Group A

Abstract Backround Intraventricular hemorrhage (IVH) remains a dangerous and frequent complication in very low birth weight (VLBW) infants. Activated factor VII (aFVII) activates the coagulation cascade and is a potential tool for stopping active bleeding, including limiting the extent of an IVH. This retrospective treatment observation compared data for infants with IVH progression treated with fresh frozen plasma (FFP) alone or with a combination of FFP and aFVII. Methods/Intervention All infants were subject to cranial ultrasonography at least twice daily. When an IVH was detected, treatment with FFP (5–20 ml/kg every 4–6 h) was commenced and the parents were informed. If the parents endorsed aFVII treatment and the IVH showed progress, aFVII (30–50 µg/kg body weight 4–6 times within 16–24 h) was given. Otherwise, infants were treated with FFP only. We compared the course of IVH between the aFVII+FFP treated infants and a control group (FFP only). Results 35 patients throughout were included in the analysis (17 control and 18 aFVII group). Demographic data was not different between groups. The progress of IVH was significantly less in the aFVII group (p<0.01). During the hospital stay, 2 of the infants in the aFVII group died compared to 4 in the control group. A posthemorrhagic hydrocephalus developed in 3 aFVII and 6 control infants. All other outcome parameters and follow-up-results 2 years after treatment did not differ significantly. Conclusion These data show that in the case of a progressing IVH, aFVII may be a candidate for limiting its extent. A prospective randomized trial is warranted.

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Replacement therapy for bleeding episodes in factor VII deficiency

Thrombosis and Haemostasis ◽

10.1160/th12-07-0476 ◽

2013 ◽

Vol 109 (02) ◽

pp. 238-247 ◽

Cited By ~ 28

Author(s):

Mariasanta Napolitano ◽

Alberto Dolce ◽

Rosario Perez Garrido ◽

Angelika Batorova ◽

Mehran Karimi ◽

...

Keyword(s):

Replacement Therapy ◽

Ad Hoc ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Coagulant Activity ◽

Fresh Frozen ◽

Traumatic Bleeding ◽

Bleeding Episodes ◽

Fvii Deficiency ◽

Using Data

SummaryPatients with inherited factor VII (FVII) deficiency display different clinical phenotypes requiring ad hoc management. This study evaluated treatments for spontaneous and traumatic bleeding using data from the Seven Treatment Evaluation Registry (STER). One-hundred one bleeds were analysed in 75 patients (41 females; FVII coagulant activity <1–20%). Bleeds were grouped as haemarthroses (n=30), muscle/subcutaneous haematomas (n=16), epistaxis (n=12), gum bleeding (n=13), menorrhagia (n=16), central nervous system (CNS; n=9), gastrointestinal (GI; n=2) and other (n=3). Of 93 evaluable episodes, 76 were treated with recombinant, activated FVII (rFVIIa), eight with fresh frozen plasma (FFP), seven with plasma-derived FVII (pdFVII) and two with prothrombin-complex concentrates. One-day replacement therapy resulted in very favourable outcomes in haemarthroses, and was successful in muscle/subcutaneous haematomas, epistaxis and gum bleeding. For menorrhagia, single- or multiple-dose schedules led to favourable outcomes. No thrombosis occurred; two inhibitors were detected in two repeatedly treated patients (one postrFVIIa, one post-pdFVII). In FVII deficiency, most bleeds were successfully treated with single ‘intermediate’ doses (median 60 µg/kg) of rFVIIa. For the most severe bleeds (CNS, GI) short- or long-term prophylaxis may be optimal.

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