OB Hemorrhage - r-Factor VIIa Resources

The treatment of life-threatening post-partum haemorrhage (PPH) still remains challenging, and hysterectomy may be required to control the bleeding. We present 12 cases of severe PPH treated with recombinant factor VIIa (rFVIIa). We briefly describe the causes of the haemorrhage and the medical and surgical interventions before rVIIa administration. In 11 women there was a partial or good response to rFVIIa administration, while in one there was no response. In the four women undergoing a subsequent selective arterial embolization, the bleeding was significantly reduced although not completely stopped. From our experience with these 12 cases, and from previously reported cases, the use of rFVIIa may be of benefit in life-threatening PPH. However, treatment with rFVIIa, in addition to standard surgical and medical interventions, may not be definitive in every patient and a selective arterial embolization may be needed.

BACKGROUND: Empirical off-label use of recombinant activated factor VII (rFVIIa) has been reported to be effective in some cases of severe postpartum haemorrhage (PPH). Successful management of these patients has lead to more wide-spread use of rFVIIa in less severe cases without any evidence for the advantages of its administration.
METHODS: Until November 2006, we had administered rFVIIa to 38 parturients. Based on our initial experience with the first 12 patients, we prepared guidelines for the use of rFVIIa. During the existence of these guidelines, we made a retrospective comparison of the 26 women who received rFVIIa with another 22 women who were treated during the same time period without using rFVIIa.
RESULTS: The total amount of blood loss was significantly higher (11.3 +/- 4.5 vs. 8.0 +/- 3.1 l), and the coagulation screen revealed significantly longer partial thromboplastin time (APTT) and prothrombin time (PT) values and significantly lower fibrinogen values in patients receiving rFVIIa. The need for red blood cells, platelets and fibrinogen concentrate was significantly higher in these women. Although the response was considered good in two-thirds of the women, several patients received rFVIIa with a poor or no response as a result of arterial bleeding.
CONCLUSION: The decision to use rFVIIa resulted from a more profound haemorrhage. We did not gain any evidence to extend the use of rFVIIa into less severe cases of PPH. Furthermore, this policy would result in a profound increase in the overall costs of the treatment. Randomized placebo-controlled trials are urgently needed to optimize the use of rFVIIa in obstetric haemorrhage. PMID: 17488316

OBJECTIVE: To collect data from nine European countries for cases of obstetric hemorrhage between 2000 and 2004 in which recombinant activated factor VII (rFVIIa) was used.
METHODS: The cases were identified through national surveys. Standardized case report forms included sociodemographic details, past medical and obstetric history, and details of the progress and management of labor in which the postpartum hemorrhage occurred. Clinicians were asked to describe subjectively the effect of rFVIIa administration using two mutually exclusive categories: 1) bleeding reduced or 2) bleeding unchanged or worse.
RESULTS: A total of 113 forms were returned (88%) with 97 (86%) classified as treatment, and 16 (14%) as "secondary prophylaxis." Clinicians noted improvements after a single dose for 80% of women in the treatment group, and for 75% in the secondary "prophylaxis" group. However, rFVIIa failed in 15 cases (13.8%). Few serious adverse events were noted related to rFVIIa administration; there were four cases of thromboembolism, one myocardial infarction, and one skin rash.
CONCLUSION: Clinical reports and hematologic data suggest improvement for more than 80% of women after rFVIIa administration and few adverse effects.
LEVEL OF EVIDENCE: II.

OBJECTIVE: Postpartum haemorrhage (PPH) remains an important cause of maternal morbidity and mortality. With regard to morbidity, preservation of the uterus is of paramount importance in fertile women. The objective of the study was to describe the cumulative experience of a cohort of women that were treated with recombinant factor VIIa.
STUDY DESIGN: In this retrospective, descriptive study we approached all departments of obstetrics and gynaecology in the Netherlands to find out if they had used rFVIIa for this indication. Twenty-seven cases were reported to us. To evaluate each case, we used a standardized case record form.
RESULTS: The main cause of PPH was uterine atony (82%). In 21 cases rFVIIa was explicitly given to prevent a hysterectomy. This was successful in 16 cases (76%). Relevant reduction or complete cessation of bleeding after rFVIIa was noted in 24/27 cases (89%). There was a reduction in blood product requirements following rFVIIa administration. The dose of rFVIIa was variable and ranged from 16 to 128mug/kg.
CONCLUSION: There appears to be a role for the use of rFVIIa in PPH unresponsive to conventional therapy. Recombinant FVIIa can be helpful and avoid an emergency hysterectomy.

BACKGROUND: Postpartum hemorrhage is one of the most common causes of maternal mortality and morbidity worldwide. The aims of treatment are to maintain the circulation and to stop the bleeding. The latter is achieved by either medical or surgical management. In intractable bleeding, emergency hysterectomy is usually required.
CASE: A 30-year-old nullipara presented with major postpartum hemorrhage due to uterine atony and vaginal lacerations. The patient developed hemorrhagic shock, resulting in prolonged prothrombin time, prolonged activated partial thromboplastin time, and low levels of factor VIII and fibrinogen. Treatments with uterotonic drugs, suturing, ligation of internal iliac arteries, subtotal hysterectomy, packing of the pelvis, and blood transfusion failed to control diffuse pelvic and vaginal bleeding. Recombinant activated factor VIIa (60-microg/kg intravenous bolus injection) was given as a final attempt to control the bleeding. The bleeding was successfully controlled within 10 minutes after administration. No side effects were noted.
CONCLUSION: Recombinant factor VIIa may be an alternative hemostatic agent in a patient with life-threatening postpartum hemorrhage unresponsive to conventional therapy.

The objective of this review was to evaluate and summarize the current literature on the unlicensed use of the novel agent recombinant activated factor VII (rFVIIa) in the management of major postpartum hemorrhage. After a systematic electronic search without temporal limits on MEDLINE, EMBASE, OVID and SCOPUS, the bibliographic references of all retrieved studies and reviews were additionally assessed for further reports of clinical trials. Unpublished works were also identified by searching abstracts from the most eminent conferences on this topic. In total, there were 31 studies that fulfilled our inclusion criteria. These studies incorporated 118 cases of massive postpartum hemorrhage treated with rFVIIa. The median age of the patients was 31.4 years, and cesarean section appeared to increase the risk of postpartum hemorrhage. At a median dose of 71.6 mug/kg, rFVIIa was reported to be effective in stopping or reducing bleeding in nearly 90% of the reported cases. Based on the evidence from the literature, we give some recommendations on the use of rFVIIa in massive postpartum hemorrhage. Nevertheless, although these reports suggest the potential role of rFVIIa in treating massive postpartum hemorrhage refractory to standard therapy, we advise particular caution in interpreting these results, as they are derived from few and uncontrolled studies. Further evidence is needed using well-designed clinical trials to better assess the optimal dose, the effectiveness, and the safety of rFVIIa in such critical bleeding conditions.

Recombinant activated factor VII (rFVIIa) was originally developed for the treatment of bleeding in patients with haemophilia A or B and inhibitors. Over the past ten years, it has been successfully used to prevent or control bleeding in several other nonhaemophilic bleeding conditions. Among the newer 'off-label' clinical applications of rFVIIa, there is increasing evidence of its effectiveness in treating obstetric and gynaecological bleeding unresponsive to conventional therapy. The existing literature on the use of rFVIIa in obstetrics and gynaecology is summarised in this review. Although supported by few and uncontrolled studies, on the whole, the published data suggest a potential role of rFVIIa in the management of obstetric and gynaecological intractable bleeding. However, further evidence is needed to improve the assessment of its optimal dose, effectiveness and safety in such conditions.

Massive obstetric haemorrhage is a life-threatening emergency that remains a major cause of maternal mortality. Conventional management is aimed at optimising uterine tone, replacing circulating volume and blood products, and surgery to achieve haemostasis. Recently there have been numerous reports of the (unlicensed) use of recombinant activated factor VII in the management of major obstetric haemorrhage. We report our experience of using it in the treatment of major post-partum haemorrhage in four previously healthy parturients. The published reports of recombinant activated factor VII use in post-partum haemorrhage (unrelated to pre-existing coagulopathies) are compared.

Recombinant factor VIIa (rFVIIa) was developed in the early 1990s to provide "bypassing" hemostatic therapy for hemophilia A and B patients with inhibitors. More recently, it has been licensed for use in patients with inherited deficiency of factor VII. Since it was licensed for use in hemophilia with inhibitors in the US, Europe, and other countries for these specific indications, it has been used selectively but in a wide array of clinical settings for uncontrolled hemorrhage in individuals without an inherited bleeding disorder. Many of these uses have been described in the medical literature as case reports or small, uncontrolled series. Several randomized clinical trials (RCT) for these "off-label" medical uses have been published in recent months and will serve as the focus of this review. In particular, a review of an RCT for spontaneous intracranial hemorrhage that has demonstrated clinical efficacy in reducing both mortality and volume of central nervous system hemorrhage will be offered. A brief discussion of hypothesized physiologic mechanisms of supraphysiologic doses of rFVIIa will introduce the clinical discussion of these broad off-label uses. Since rFVIIa is a very expensive therapy, possible strategies for optimizing its use in the these settings will be presented.

OBJECTIVE: We hypothesised that patients with massive postpartum hemorrhage (PPH), defined as blood loss >1,500 ml, may benefit from the use of activated recombinant factor VII (rFVIIa).
DESIGN: Retrospective cohort study. Setting. Department of Obstetrics & Gynaecology, Dow University of Health Sciences. Population. Thirty-four women with a diagnosis of massive PPH. Methods. All patients with PPH who were admitted to the Department of Obstetrics & Gynecology and Surgical Intensive Care Unit of Civil Hospital Karachi, Pakistan, were included in the study. From March 2005 to October 2006, 34 patients fulfilled the criteria of massive PPH, of which 18 received rFVIIa to control bleeding, and 16 patients did not. Availability and cost of rFVIIa were the factors in drug allocation. Main outcome measures. Maternal mortality, correction of coagulopathy, the amount of blood products transfused and preservation of fertility.
RESULTS: Patients receiving rFVIIa had lower maternal mortality (5/18, 28% versus 8/16, 50%, OR 0.04 (0.002, 0.83)), and received a lower number of packed red cell transfusions (4.0+/-4.46 versus 9.61+/-6.7, p value 0.007), against the comparison group. Patients receiving rFVIIa had lower activated partial thromboplastin (median: 13.0; 25-75th percentile: -25.0, -8.0, signed rank p<0.0001), and lower prothrombin times (median: -8.8; 25-75th percentile: -24.2, -4.8), after administration of drug. There was no significant difference in the rate of hysterectomy between the 2 groups (11/18 (61%) versus 6/16 (38%)). No adverse event attributable to rFVIIa was observed in the study.
CONCLUSION: Activated recombinant factor VII can be a life-saving drug in patients with massive PPH.

Massive postpartum haemorrhage is a major cause of maternal and fetal morbidity and mortality. Management mainstays include transfusion therapy, uterotonic agents and surgery. The "off label" use of recombinant activated factor VII appears to have an evolving role in the management of massive postpartum haemorrhage refractory to conventional treatments. The current literature is reviewed.

BACKGROUND AND OBJECTIVE: Massive post-partum haemorrhage continues to be one of the world's leading causes of maternal morbidity and mortality. Any new treatment that potentially helps at risk parturients should be thoroughly investigated. Recombinant factor VIIa (rVIIa) is increasingly being used in the treatment of massive haemorrhage. We performed a case-matched analysis of its use since 2003 in the treatment of massive post-partum haemorrhage at our hospital.
METHODS: Twenty-eight cases of massive post-partum haemorrhage were identified over a 3-yr period since 2003. In six of these cases, rVIIa was used as part of their management. Six case-matched controls were sought. The six women with the greatest requirement for packed red cell transfusion who also had a deranged prothrombin time were included. The groups were then compared for differences. The worst prothrombin time in each group was noted as was the best prothrombin time within 6 h, this was used as our measure of response to treatment.
RESULTS: There was no statistical difference in age, gestation, parity, transfusion requirements, mode of delivery or the severity of the coagulopathy between the two groups. In both groups the prothrombin time improved with management. There was no significant difference in either the magnitude of the improvement in the value of the prothrombin time or the absolute value of the best prothrombin time (P = 0.09). Five out of the six women in the rFVIIa group had normal or low prothrombin times within 6 h yet only one woman who did not receive rFVIIa had a normal prothrombin time within 6 h though this was not significant (P = 0.08).
CONCLUSIONS: This case-matched analysis supports the management of massive post-partum haemorrhage with appropriate resuscitation, surgical intervention and use of blood and blood products. This study does not support the routine use of rFVIIa in the management of massive obstetric haemorrhage. rFVIIa may have a role to play in this management but further studies and analyses will be required

CONTEXT: The US Food and Drug Administration (FDA) licensed recombinant human coagulation factor VIIa (rFVIIa) on March 25, 1999, for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX. Use in patients without hemophilia has been increasing since licensure.
OBJECTIVE: To review serious thromboembolic adverse events (AEs) reported to the FDA's Adverse Event Reporting System (AERS). DESIGN, SETTING,
AND PATIENTS: The AERS database was reviewed from March 25, 1999, through December 31, 2004, for thromboembolic AE reports with rFVIIa. The AERS database includes US and non-US spontaneous AE reports from both approved (specific indications for patients with hemophilia) and unlabeled uses. It also includes serious AEs in patients enrolled in postlicensure clinical trials who received rFVIIa. Manufacturer reporting to FDA is mandatory, but primary notification from clinicians and others to FDA or manufacturers is voluntary for spontaneous reports; therefore, AERS underrepresents actual event occurrences.
MAIN OUTCOME MEASURE: Reported thromboembolic events occurring in patients administered rFVIIa.
RESULTS: A total of 431 AE reports for rFVIIa were found, of which 168 reports described 185 thromboembolic events. Seventeen events occurred in patients with hemophilia and 59 occurred in patients enrolled in postlicensure trials. Unlabeled indications accounted for 151 of the reports, most with active bleeding (n = 115). Reported AEs were thromboembolic cerebrovascular accident (n = 39), acute myocardial infarction (n = 34), other arterial thromboses (n = 26), pulmonary embolism (n = 32), other venous thromboses (including deep vein thrombosis) (n = 42), and clotted devices (n = 10). In 36 (72%) of 50 reported deaths, the probable cause of death was the thromboembolic event. In 144 patients with timing information, 73 events (52%) occurred in the first 24 hours after the last dose (30 events within 2 hours). Sixty-four reports (38%) noted concomitant use of hemostatic agents. Most reports lacked sufficient information to evaluate potential dosage associations.
CONCLUSIONS: Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications and occurred in arterial and venous systems, often resulting in serious morbidity and mortality. Analysis of the relationship between AEs and rFVIIa is hindered by concomitant medications, preexisting medical conditions, confounding by indication, and inherent limitations of passive surveillance. Randomized controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia.

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Ongoing bleeding from patients who have an acquired coagulopathy post-surgery is a common problem. Strategies that are available to combat this problem revolve around the replacement of coagulation factors, platelets, and red blood cells as necessary. These strategies are not always successful and a more direct approach to activating the coagulation system can be more effective and in some instances life saving. We describe the use of recombinant factor VIIa in a patient with ongoing post partum bleeding.

BACKGROUND: Amniotic fluid embolism (AFE) is a rare syndrome that can complicate pregnancy and labor. It often has debilitating and lethal consequences. One serious sequela of AFE is disseminated intravascular coagulation (DIC).
CASE: This report describes an atypical presentation of AFE manifested by sudden fetal bradycardia and complicated by maternal DIC. The DIC was eventually successfully treated with the use of recombinant activated factor VIIa.
CONCLUSION: The use of recombinant activated factor VIIa in cases of massive hemorrhage, such as in our patient, is controversial but has been shown, in some cases, to reverse DIC and be successful. The use of recombinant activated factor VIIa should be considered in patients with massive obstetric hemorrhage in whom standard measures of stabilization are unsuccessful.

Recombinant activated factor VII (rFVIIa, NovoSeven) was used in three patients with massive obstetric hemorrhage due to placenta previa accreta, rupture of the uterus and pre-eclampsia with HELLP. Administration of the drug markedly decreased the bleeding and enabled control of the hemorrhage. rFVIIa seems to be an adjunctive hemostatic measure for the treatment of severe obstetric hemorrhage.

Recombinant activated coagulation factor VII (rFVIIa) was developed initially for treatment of patients with hemophilia and neutralizing antibodies ("inhibitors") to coagulation factors VIII or IX. Owing to the unique and selective mechanism of action of rFVIIa and encouraged by clinical experience with other circumstances of inadequate hemostasis, a broad development program has been pursued to test potential efficacy and evaluate safety of this biologic for indications other than hemophilia. This review summarizes the current development of rFVIIa, focusing on results of prospective, randomized clinical trials.