The safety of pharmacologic options for the treatment of persons with hemophilia.

INTRODUCTION: The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available. AREAS COVERED: We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed. EXPERT OPINION: The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.

Risk of thromboembolic events after protocolized warfarin reversal with 3-factor PCC and factor VIIa.

Bleeding events and life-threatening hemorrhage are the most feared complications of warfarin therapy. Prompt anticoagulant reversal aimed at replacement of vitamin K-dependent clotting factors is essential to promote hemostasis. A retrospective cohort study of warfarin-treated patients experiencing a life-threatening hemorrhage treated with an institution-specific warfarin reversal protocol (postimplementation group) and those who received the prior standard of care (preimplementation group) was performed. The reversal protocol included vitamin K, 3-factor prothrombin complex concentrate, and recombinant factor VIIa. Demographic and clinical information, anticoagulant reversal information, and all adverse events attributed to warfarin reversal were recorded. A total of 227 patients were included in final analysis, 109 in the preimplementation group and 118 in the postimplementation group. Baseline patient characteristics were similar in both groups, with the exception of higher average Sequential Organ Failure Assessment scores in the postimplementation group (P = .0005). The most common indication for anticoagulation reversal was intraparenchymal hemorrhage. Prereversal international normalized ratios (INRs) were similar in both groups. Attainment of INR normalization to less than 1.4 was higher, and rebound INR was lower in the postimplementation group (P < .0001; P = .0013). Thromboembolic complications were significantly higher in the postimplementation group (P = .003). Elevated baseline Sequential Organ Failure Assessment score and mechanical valve as an indication for anticoagulation were independently associated with thrombotic complications (P = .005). A warfarin reversal protocol consisting of 3-factor prothrombin complex concentrate, recombinant factor VIIa, and vitamin K more consistently normalized INR values to less than 1.4 as compared to the prior standard of care in a diverse patient population. This success came at the cost of a 2-fold increase in risk of thromboembolic complications.

Prothrombin complex concentrate (Beriplex P/N)-related renal and cerebral infarctions in a patient with warfarin-associated intracerebral hemorrhage.

A 45-year-old man receiving warfarin treatment suffered from an intracerebral hemorrhage. Four-factor prothrombin complex concentrate (PCC) was administered to correct coagulopathy. However, bilateral renal infarcts and a cerebral infarct developed on day 5 and 7, respectively after PCC administration. Although the occurrence of PCC-related thromboembolism is low, health care practitioners should closely follow-up the symptoms and signs of thrombosis after PCC administration.

Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.

BACKGROUND: Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. METHODS AND RESULTS: In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event. CONCLUSIONS: 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study.

BACKGROUND: The rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma. METHODS: After 15 yr of clinical use, findings of a pharmacovigilance report (February 1996-March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed. RESULTS: Since receiving marketing authorization (February 21, 1996), ~647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ~31 000) is in line with the incidence observed with other four-factor PCCs. CONCLUSIONS: In general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Managing incidentally diagnosed isolated factor VII deficiency perioperatively: a brief expert consensus report.

While isolated factor VII (FVII) deficiency is being more frequently diagnosed owing to improved preoperative screening procedures, there is no specific guideline for perioperative management of such patients. To complicate the issue, FVII activity levels seem to correlate less well with the risk of hemorrhage than the patient's past and family bleeding history do. We have devised expert consensus recommendations for managing such patients perioperatively, taking into consideration the personal and family bleeding history, the FVII activity level and the inherent bleeding risk of the procedure itself. We hope that clinicians will find this a useful tool in the decision-making process, thereby limiting the use of recombinant factor VIIa to those who need it most, and preventing possible thrombotic complications in those without a strong indication for its use.

Acquired hemophilia: a rare but life-threatening potential cause of bleeding in the intensive care unit.

OBJECTIVE: There are a number of potential etiologies of severe bleeding encountered in the intensive care unit. Although rare, acquired hemophilia is one such etiology that often presents with major bleeding requiring intensive care. Despite the introduction of effective treatments, the reported mortality rate of patients with acquired hemophilia ranges from 6 to 8% and is in part attributable to sequential delays in diagnosis and appropriate treatment. The purpose of this review is to familiarize the intensive care specialist with this underrecognized cause of bleeding, with an emphasis on diagnosis and treatment. METHODS: As the objective of this article was to provide a concise overview of the diagnosis and management of acquired hemophilia, a directed search of English-language literature was undertaken using the PubMed database, targeting such topics as the differential diagnosis of bleeding in the intensive care unit and the epidemiology, diagnosis, and treatment of acquired hemophilia. Clinical study findings pertaining to the efficacy of specific treatments for acquired hemophilia were summarized. RESULTS AND CONCLUSION: Recognition of acquired hemophilia presents a clinical challenge, given the rarity of this condition, a general lack of familiarity with acquired hemophilia, and the potential for confusion with other more common causes of bleeding in the intensive care unit. Nevertheless, there are sentinel clinical and laboratory findings that should raise suspicion of this diagnosis. The treatment of acquired hemophilia is a multi-step, physiologically focused process aimed at controlling both active and recurrent bleeding. Therefore, prompt diagnosis is central to prognosis. Consultation with a hematologist may facilitate efficient diagnosis and management.

Congenital FVII deficiency and thrombotic events after replacement therapy.

Thrombosis has been occasionally described in congenital FVII deficiency. This report deals with patients with FVII deficiency who presented thrombotic events after substitution therapy. At least 12 patients are reported in the literature. In all but two cases thrombosis occurred after prothrombin complex concentrates or plasma derived FVII concentrates. In two instances pulmonary embolism occurred after the administration of large amounts of whole blood. Concomitant prothrombotic risk factors were present in most of these cases (surgery, immobilization, old age, etc.). Personal files allowed us to add another patient who developed bilateral pulmonary embolism after two vials of an aFVII concentrate. In this case also, concomitant risk factors were present, namely surgery for hysterectomy, immobilization. The pulmonary embolism occurred in spite of the congenital FVII deficiency indicating that no sure antithrombotic protection is assured by this defect. The actual needs of substitution therapy in patients with some variants of FVII deficiency is discussed, together with comments on the therapeutic management of the thrombotic events in these patients.

Recombinant activated factor VII increases stroke in cardiac surgery: a meta-analysis.

OBJECTIVES: Recombinant activated factor VII (rFVIIa) is used in various surgical procedures to reduce the incidence of major blood loss and the need for re-exploration. Few clinical trials have investigated rFVIIa in cardiac surgery. The authors performed a meta-analysis focusing on the rate of stroke and surgical re-exploration. DESIGN: Meta-analysis. SETTING: Hospitals. PARTICIPANTS: A total of 470 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four investigators independently searched PubMed and conference proceedings including backward snowballing (ie, scanning of reference of retrieved articles and pertinent reviews) and contacted international experts. A total of 470 patients (254 receiving rFVIIa and 216 controls) from 6 clinical trials (2 randomized, 3 propensity matched, and 1 case matched) were included in the analysis. The use of rFVIIa was associated with an increased rate of stroke (12/254 [4.7%] in the rFVIIa group v 2/216 [0.9%] in the control arm, odds ratio [OR] = 3.69 [1.1-12.38], p = 0.03) with a nonsignificant reduction in rate of surgical re-exploration (13% v 42% [OR = 0.27 (0.04-1.9), p = 0.19]). The authors observed a trend toward an increase of overall perioperative thromboembolic events (19/254 [7.5%] in the rFVIIa group v 10/216 [5.6%] in the control arm [OR = 1.84 (0.82-4.09), p = 0.14]). No difference in the rate of death was observed. CONCLUSIONS: The administration of rFVIIa in cardiac surgery patients could result in a significant increase of stroke with a trend toward a reduction of the need for surgical re-exploration. The authors do not recommend routine use in cardiac surgery patients. rFVIIa may be considered with caution in patients with refractory life-threatening bleeding.

Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial.

BACKGROUND: Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). OBJECTIVES. To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S. PATIENTS AND METHODS: Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg(-1) PCC doses were infused based on initial INR. Study endpoints included INR normalization (

Experience of recombinant activated factor VII (NovoSeven) in the operating theatre and intensive care unit for the management of intracranial bleeding in nonhaemophilic patients.

OBJECTIVE: Intracranial haemorrhage (ICH) is associated with high morbidity and mortality. Our aim was to explore the use of recombinant activated factor VII (rFVIIa NovoSeven Novo Nordisk, A/S, Bagsvaerd, Denmark) for the management of ICH in the operating theater and intensive care unit. PATIENTS AND METHODS: We reviewed all the records of nonhaemophilic patients entered into the haemostasis.com database who received rFVIIa for ICH. RESULTS: Sixteen suitable patients were identified (mean age: 23.3 years; range: 1-58 years). The total dose of rFVIIa administered ranged from 31 to 270 microg/kg. Indications were stabilization of ICH (n=6), control of peri- or post-operative haemorrhage associated with neurosurgical procedures (n=8), or correction of coagulopathy prior to neurosurgical intervention (n=2). The majority (13/16 [81.25%]) required one dose of rFVIIa. A clinical effect (stabilization of bleed, reduction of peri- or post-operative haemorrhage, or prevention of excessive blood loss during neurosurgery) was seen in 14/16 (87.5%) patients. Some improvement in coagulation status was noted. No thromboembolic events were reported. One patient experienced massive elevation of D-dimer levels-an effect possibly due to rFVIIa. Two patients suffered adverse events unrelated to rFVIIa. Six deaths occurred, all attributable to underlying brain injury. CONCLUSION: This observational study suggests that rFVIIa is of value for the management of ICH in nonhaemophilic patients secondary to a range of aetiologies. These findings justify further investigation.

Surgical interventions in a cohort of patients with haemophilia A and inhibitors: an experiential retrospective chart review.

Strategies for the management of perioperative bleeding in patients with haemophilia and inhibitors have evolved rapidly as a result of the development of the bypassing agents Factor Eight Inhibitor Bypassing Activity, Anti-inhibitor Coagulant Complex (FEIBA) and activated recombinant factor VII (rFVIIa). However, there are currently no established guidelines for perioperative use of bypassing agents, and few controlled clinical studies have been carried out. Thus, case reports, such as those presented here, provide useful anecdotal evidence to guide the treatment of inhibitor patients. The purpose of this report was to describe experiences in the use of bypassing agents in a small cohort of patients with haemophilia A and inhibitors undergoing surgical procedures. Cases from five treatment centres were reviewed. Twenty-two procedures using FEIBA, rFVIIa or a combination of both agents were compiled from seven inhibitor patients (six with an alloantibody inhibitor and one with an acquired autoantibody inhibitor). Eleven procedures used FEIBA monotherapy, two employed rFVIIa monotherapy and nine were performed using combination therapy. Supplemental therapies were required to manage bleeding in some cases. Haemostatic control was achieved in all cases, and treatment regimens were generally well tolerated. One thrombotic adverse event was reported: evidence of disseminated intravascular coagulation (DIC) was found after rFVIIa use in one case, although the direct cause of DIC was unknown. The experiences in this case review demonstrate that both major and minor surgical procedures can be safely performed in patients with haemophilia and high-titre inhibitors under the cover of bypassing agents, with a high expectation of success.

Pharmacologic interventions for the management of critical bleeding.

Hospital pharmacists are often consulted for their knowledge about coagulation and therapeutic interventions for the management of critical bleeding. Many pharmacotherapies are available for this purpose, both systemic and topical, and others are in development. These agents and their mechanisms of action are reviewed, and perspectives are provided regarding their use in various clinical settings. Also provided are associated precautions to promote safe use. Current controversies surrounding pharmacotherapeutic agents used to control serious bleeding (e.g., in various types of surgery, trauma, obstetrics, and intracranial hemorrhage) are also discussed.

Key concepts in the management of difficult hemorrhagic cases.

Goals of hemorrhage management involve promoting coagulation and reducing fibrinolysis to enhance clot formation and stability, and minimizing hemorrhagic expansion to reduce the likelihood of adverse outcomes. The optimal hemostatic regimen to obtain these goals will differ according to the clinical scenario. Two hypothetical cases of patients with hemorrhage are presented that are typical of those encountered by clinical pharmacists who practice in centers that treat trauma or surgical patients or patients in need of emergency or critical care because of serious bleeding. To maximize therapy, the clinician must be aware of how best to clinically apply hemostatic agents, their comparative benefits and disadvantages, and the optimal methods for monitoring their effectiveness and toxicities.

Multiple ischemic strokes associated with use of recombinant activated factor VII.

BACKGROUND: Intracerebral hemorrhage is associated with a high rate of mortality and functional disability. For most patients, no treatment other than supportive care has been shown to improve outcome. Preliminary studies suggest that recombinant activated factor VII may limit early hematoma growth and improve functional outcome. However, ischemic complications may occur in some patients. OBJECTIVE: To report a case of severe cerebral ischemic complications associated with the use of recombinant activated factor VII. DESIGN: Case report. SETTING: Tertiary care medical center. PATIENT: We describe a patient with ischemic stroke who developed hemorrhagic conversion following tissue plasminogen activator administration. INTERVENTIONS: Treatment with recombinant activated factor VII, in addition to standard treatment with cryoprecipitate and platelets. MAIN OUTCOME MEASURE: Brain imaging showing multiple ischemic strokes. RESULTS: The patient subsequently developed multiple acute cerebral infarcts in different vascular distributions. CONCLUSION: Although the exact relationship between treatment with recombinant activated factor VII and the development of multiple ischemic strokes remains uncertain, this case suggests that a cautious approach to treatment with this agent is warranted until more data are available.

Probable right atrial thrombus immediately after recombinant activated factor VII administration.

We report the finding of a probable right atrial thrombus in a 33-yr-old male patient with severe head, chest, and abdominal trauma. Refractory coagulopathy and gross haemodynamic instability ensued, which was only partially controlled with massive blood product transfusion and high-dose inotropic support during laparotomy. Continuous transoesophageal echocardiography revealed a probable atrial thrombus partially occluding the right ventricular inflow tract, which appeared immediately after the patient received 100 microg kg(-1) of recombinant activated factor VII (rFVIIa) via a left internal jugular central line. This is the first report documenting an immediate temporal relationship between rFVIIa administration and a space-occupying lesion compatible with localized thrombosis, despite ongoing severe systemic coagulopathy. We review the clinical use of rFVIIa and discuss possible factors contributing to this event.