Real-world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi-institutional case series.

INTRODUCTION: The management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies. AIM: To provide real-world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis. METHODS: This is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement. RESULTS: Twenty-four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first-line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%-72% more cost-effective than eptacog alfa. No safety concerns or adverse events were reported. CONCLUSIONS: In this case series, eptacog beta was safe, effective, and economical as first-line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors.

Current status and future prospects of activated recombinant coagulation factor VIIa, NovoSeven®, in the treatment of haemophilia and rare bleeding disorders.

rFVIIa, a human recombinant activated coagulation factor VII, has been used worldwide for more than two decades for the treatment of bleeding episodes and prevention of bleeding in patients undergoing surgery/invasive procedures with congenital haemophilia A or B with inhibitors (CHwI A or B), acquired haemophilia (AH), congenital factor VII deficiency and Glanzmann thrombasthenia (GT), refractory to platelet transfusion. The approved dosage, administration and indication of rFVIIa in the US, Europe and Japan differ, depending on the needs of the patient population and regulatory practices. This review presents an overview of the current status and future prospects, including that from a Japanese perspective, of using rFVIIa in the treatment of approved indications. The efficacy and safety of rFVIIa in the approved indications has been demonstrated in several randomised and observational studies and data from registries. The overall incidence of thrombosis across all approved indications in a retrospective safety assessment of clinical trials and registries, prelicensure studies and postmarketing surveillance studies of rFVIIa use was 0.17%. Specifically, the risk of thrombotic events was 0.11% for CHwI, 1.77% for AH, 0.82% for congenital factor VII deficiency and 0.19% for GT. Emerging non-factor therapies such as emicizumab have changed the treatment landscape of haemophilia A, including preventing bleeding in patients with CHwI. However, rFVIIa will continue to play a significant role in the treatment of such patients, particularly during breakthrough bleeding or surgical procedures.

A ROTEM-guided algorithm aimed to reduce blood product utilization during neonatal and infant cardiac surgery.

BACKGROUND: Neonates and infants undergoing cardiac surgery tend to receive high volumes of blood products. The use of rotational thromboelastometry (ROTEM®) has been shown to reduce the administration of blood products in adults after cardiac surgery. We sought to develop a targeted administration of blood products based on ROTEM® to reduce blood product utilization during and after neonatal and infant cardiac surgery. METHODS: We conducted a retrospective review of data from a single center for neonates and infants undergoing congenital cardiac surgery using cardiopulmonary bypass (CPB) from September 2018-April 2019 (control group). Then, using a ROTEM® algorithm, we collected data prospectively between April-November 2021 (ROTEM group). Data collected included age, weight, gender, procedure, STAT score, CPB time, aortic cross-clamp time, volume, and type of blood products administered in the operating room and cardiothoracic intensive care unit (CTICU). In addition, ROTEM® data, coagulation profile in CTICU, chest tube output at 6 and 24 hours, use of factors concentrate, and thromboembolic complications were recorded. RESULTS: The final cohort of patients included 28 patients in the control group and 40 patients in the ROTEM group. The cohort included neonates and infants undergoing the following procedures: arterial switch, aortic arch augmentation, Norwood procedure, and comprehensive stage II procedure. There were no differences in the demographics or procedure complexity between the two groups. Patients in the ROTEM® group received fewer platelets (36 ± 12 vs. 49 ± 27 mL/kg, p 0.028) and cryoprecipitate (8 ± 3 vs. 15 ± 10 mL/kg, p 0.001) intraoperatively when compared to the control group. CONCLUSION: The utilization of ROTEM® may have contributed to a significant reduction in some blood product administration during cardiac surgery for infants and neonates. ROTEM® data may play a role in reducing blood product administration in neonatal and infant cardiac surgery.

Real-life experiences with goal-directed prohemostatic therapy with fibrinogen concentrate, prothrombin complex concentrate, and recombinant factor VIIa: a retrospective study of 287 consecutive patients.

The Danish Capital Region Blood Bank operates a 24/7 on-call service staffed with physicians specialized in hemostatic management to guide clinicians in hemostatic resuscitation, including administration of prohemostatic therapy (PHT). The outcome of patients who receive PHT as part of hemostatic resuscitation remains unanswered. The objective of this study was therefore to investigate clinical outcome of patients receiving PHT managed by the on-call service. We identified 287 patients who received PHT during 2015-16, of which 161 (59%) received fibrinogen concentrate (FC), 111 (39%) received prothrombin complex concentrate (PCC), and 15 (5%) received recombinant factor VIIa (rFVIIa) as the first product. Patients were critically ill with a 30-day mortality of 31%. Among FC recipients, cardiothoracic admission, non-trauma, and antithrombotics predicted survival. FC recipients had lower platelet count and thrombelastography clot strengths than the other PHT groups and within the group, these factors predicted mortality. The symptomatic thromboembolic event (TE) rate at 30 days was 5%. For PCC recipients, vitamin K antagonists predicted survival, while rivaroxaban predicted mortality. TE rate was 2%. We did not identify factors associated with survival in the small group of rFVIIa recipients. TE rate was 13%. In summary, trauma and coagulopathy predicted mortality in patients who received FC and our data suggest that optimization of PHT algorithms may be possible. Outcome of patients who received PCC was comparable to results reported elsewhere and its use may be safe in a setting as reported here. Recombinant FVIIa was rarely used but had the highest incidence of arterial thromboembolism.

Recombinant Factor VIIa in Pediatric Cardiac Surgery.

OBJECTIVES: Recombinant activated factor VIIa (rVIIa) is used off-label for refractory bleeding after cardiac surgery. This study reviewed the indications, usage rates, and complications of rVIIa. DESIGN: A retrospective case-control observational study. SETTING: A single quaternary pediatric hospital. PARTICIPANTS: All children undergoing cardiac surgery with cardiopulmonary bypass over a three-year period. INTERVENTIONS: Administration of rVIIa as rescue therapy for refractory bleeding after weaning from cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Onethousand, five hundred fifteen cardiopulmonary bypass procedures were reviewed. Patients receiving rVIIa were each matched to two control patients by age, procedure type, and bypass time. Data collected included weight, crossclamp time, anticoagulant and antifibrinolytic dose, return to the operating room for bleeding, thrombotic events, and extracorporeal membrane oxygenation (ECMO) circuit interventions. Forty-two patients received rVIIa (2.8%). Major systemic thrombotic complications were observed in 19% (controls 12.5%) of patients; 80% of recombinant factor VIIa patients requiring postoperative ECMO had interventions for circuit thrombosis (controls 31.25%); 4.76% of rVIIa recipients required reexploration for intractable bleeding (controls 1.39%). CONCLUSIONS: This study added to understanding regarding the use of recombinant factor VIIa in pediatric cardiac surgery and reported increased thrombotic complications, especially for children who progress to ECMO. Prospective studies to better understand the pathophysiology of coagulopathy and hemorrhage in pediatric cardiac surgery and the role of hemostatic agents, such as rVIIa, are required.

Selected severe „haematological“ syndromes in adult intensive care patients.

Haemophagocytic syndrome, diffuse alveolar haemorrhage, catastrophic antiphospholipid syndrome and various types of thrombotic microangiopathies are rare conditions with significant morbidity and mortality. A common feature is late diagnosis, which can affect the success of treatment. The aim of this review article is to summarize the basic diagnostic and therapeutic steps of the present subpopulation of critically ill patients.

FVIIa (Factor VIIa) Induces Biased Cytoprotective Signaling in Mice Through the Cleavage of PAR (Protease-Activated Receptor)-1 at Canonical Arg41 (Arginine41) Site.

OBJECTIVE: Recent studies showed that FVIIa (factor VIIa), upon binding to EPCR (endothelial cell protein C receptor), elicits endothelial barrier stabilization and anti-inflammatory effects via activation of PAR (protease-activated receptor)-1-mediated signaling. It is unknown whether FVIIa induces PAR1-dependent cytoprotective signaling through cleavage of PAR1 at the canonical site or a noncanonical site, similar to that of APC (activated protein C). Approach and Results: Mouse strains carrying homozygous R41Q (canonical site) or R46Q (noncanonical site) point mutations in PAR1 (QQ41-PAR1 and QQ46-PAR1 mice) were used to investigate in vivo mechanism of PAR1-dependent pharmacological beneficial effects of FVIIa. Administration of FVIIa reduced lipopolysaccharide-induced inflammation, barrier permeability, and VEGF (vascular endothelial cell growth factor)-induced barrier disruption in wild-type (WT) and QQ46-PAR1 mice but not in QQ41-PAR1 mice. In vitro signaling studies performed with brain endothelial cells isolated from WT, QQ41-PAR1, and QQ46-PAR1 mice showed that FVIIa activation of Akt (protein kinase B) in endothelial cells required R41 cleavage site in PAR1. Our studies showed that FVIIa cleaved endogenous PAR1 in endothelial cells, and FVIIa-cleaved PAR1 was readily internalized, unlike APC-cleaved PAR1 that remained on the cell surface. Additional studies showed that pretreatment of endothelial cells with FVIIa reduced subsequent thrombin-induced signaling. This process was dependent on ß-arrestin1. CONCLUSIONS: Our results indicate that in vivo pharmacological benefits of FVIIa in mice arise from PAR1-dependent biased signaling following the cleavage of PAR1 at the canonical R41 site. The mechanism of FVIIa-induced cytoprotective signaling is distinctly different from that of APC. Our data provide another layer of complexity of biased agonism of PAR1 and signaling diversity.

Prophylaxis Using a Mixture of Plasma-Derived Activated Factor VII and Factor X (pdFVIIa/FX) in a Patient with Hemophilia B Complicated by Inhibitors and Allergy to Factor IX Concentrates: A Case Report.

Treating patients with hemophilia and inhibitors is often problematic. The presence of inhibitors negatively impacts the effectiveness of treatment to achieve hemostasis especially in patients with hemophilia B, owing mainly to allergic reactions to factor IX (FIX) concentrates and the low success rate of immune tolerance therapy. A 9-month-old boy had intracranial hemorrhage and was diagnosed with hemophilia B. After replacement therapy, he developed inhibitors and an allergic reaction to FIX. Prophylactic therapy was initiated with recombinant activated factor VII (rFVIIa) and later switched to pdFVIIa/factor X (FX; 120 µg/kg as the FVII dose, every other day) because of a recurrence of intracranial hemorrhage. Since then, he remained well without life-threatening bleeding for more than 2 years. Our case suggests that pdFVIIa/FX may be useful for prophylactic therapy in hemophilia B complicated by inhibitors and allergic reaction to FIX concentrates.

Hemorrhagic Complications of Invasive Intracranial Pressure Monitor Placement in Acute Liver Failure: Outcomes of a Single-Center Protocol and Comprehensive Literature Review.

BACKGROUND: Elevated intracranial pressure due to cerebral edema is associated with very poor survival in patients with acute liver failure (ALF). Placing an intracranial pressure monitor (ICPm) aids in management of intracranial hypertension, but is associated with potentially fatal hemorrhagic complications related to the severe coagulopathy associated with ALF. METHODS: An institutional Acute Liver Failure Clinical Protocol (ALF-CP) was created to correct ALF coagulopathy prior to placing parenchymal ICP monitoring bolts. We aimed to investigate the frequency, severity, and clinical significance of hemorrhagic complications associated with ICPm bolt placement in the setting of an ALF-CP. All assessed patients were managed with the ALF-CP and had rigorous radiologic follow-up allowing assessment of the occurrence and chronology of hemorrhagic complications. We also aimed to compare our outcomes to other studies that were identified through a comprehensive review of the literature. RESULTS: Fourteen ALF patients were included in our analysis. There was no symptomatic hemorrhage after ICP monitor placement though four patients were found to have minor intraparenchymal asymptomatic hemorrhages after liver transplant when the ICP monitor had been removed, making the rate of radiographically identified clinically asymptomatic hemorrhage 28.6%. These results compare favorably to those found in a comprehensive review of the literature which revealed rates as high as 17.5% for symptomatic hemorrhages and 30.4% for asymptomatic hemorrhage. CONCLUSION: This study suggests that an intraparenchymal ICPm can be placed safely in tertiary referral centers which utilize a protocol such as the ALF-CP that aggressively corrects coagulopathy. The ALF-CP led to advantageous outcomes for ICPm placement with a 0% rate of symptomatic and low rate of asymptomatic hemorrhagic complications, which compares well to results reported in other series. A strict ICPm placement protocol in this setting facilitates management of ALF patients with cerebral edema during the wait time to transplantation or spontaneous recovery.

The intraoperative use of recombinant activated factor VII in arterial switch operations.

BACKGROUND: The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study. METHODS: We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher's exact test was performed to compare categorical variables. Wilcoxon's rank-sum test was used to compare continuous variables between cohorts. RESULTS: Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005-3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3-12.3] versus 15.9 [15.1-17.2], p < 0.001) and international normalised ratio (0.8 [0.73-0.90] versus 1.3 [1.2-1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls. CONCLUSIONS: In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.

Treatment of Diffuse Alveolar Hemorrhage: Controlling Inflammation and Obtaining Rapid and Effective Hemostasis.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or systemic autoimmune disorders. Pathologic findings show pulmonary capillaritis, bland hemorrhage, diffuse alveolar damage, and hemosiderin-laden macrophages, but in the majority of cases, pathogenesis remains unclear. Despite the severity and high mortality, the current treatment options for DAH remain empirical. Systemic treatment to control inflammatory activity including high-dose corticosteroids, cyclophosphamide, and rituximab and supportive care have been applied, but largely unsuccessful in critical cases. Activated recombinant factor VII (FVIIa) can achieve rapid local hemostasis and has been administered either systemically or intrapulmonary for the treatment of DAH. However, there is no randomized controlled study to evaluate the efficacy and safety, and the use of FVIIa for DAH remains open to debate. This review discusses the pathogenesis, diverse etiologies causing DAH, diagnosis, and treatments focusing on hemostasis using FVIIa. In addition, the risks and benefits of the off-label use of FVIIa in pediatric patients will be discussed in detail.

Pulmonary Hemorrhage in the Neonate.

Pulmonary hemorrhage (PH) is a pathology associated with significant morbidity and mortality, particularly among preterm infants in the NICU. The diagnosis is made when hemorrhagic secretions are aspirated from the trachea concurrent with respiratory decompensation that necessitates intubation or escalated support. The implementation of mechanical ventilation and widespread exogenous surfactant administration have significantly reduced respiratory morbidities. However, when PH develops, death remains the most common outcome. Treatment for PH remains primarily supportive; thus, a thorough understanding of underlying disease processes, manifestations, diagnostic testing, and current evidence is vital to enable early identification and proactive management to reduce morbidity and mortality.

Engineering of a membrane-triggered activity switch in coagulation factor VIIa.

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa.

Feminizing Genitoplasty in a young girl with Glanzmann's thrombasthenia-management of haemostasis.

We report peri- and post-operative management of haemostasis in a 11-year old girl with Glanzmann Thrombasthenia (GT) who had feminizing genitoplasty for genital ambiguity due to Congenital Adrenal Hyperplasia (CAH-21 Hydroxylase deficiency). A blend of Glanzmann Thrombasthenia (GT) and DSD 46XX due to CAH is not reported in literature. Surgery particularly genitourinary reconstruction in patients with GT is challenging due to risk of intra and post-operative bleeding. Haemostasis can successfully be achieved with platelet transfusions, antifibrinolytic (Tranexamic acid) and judicious use of recombinant factor VIIa (rFVIIa) even in a resource limited setting.

Perioperative Hemostatic Management of a Pediatric Patient with Glanzmann Thrombasthenia Undergoing Osteoplastic Craniotomy and Hematoma Removal: A Case Report.

Glanzmann thrombasthenia is an uncommon hereditary disease that involves an abnormal platelet function leading to complicated hemostatic problems. In situations of anticipated hemorrhage, irradiated apheresed platelets are the first line of treatment. In addition, a combination of recombinant factor VIIa and an antifibrinolytic agent such as tranexamic acid can be utilized to minimize bleeding. Here we are present stable management of a pediatric patient with Glanzmann thrombasthenia admitted for traumatic epidural hematoma removal. Due to the condition of the operation site, some blood loss was unavoidable. However, hemostasis was successfully controlled, and the patient was discharged without additional complications.

Missed at first Glanz: Glanzmann thrombasthenia initially misdiagnosed as Von Willebrand Disease.

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by a defect in platelet integrin αIIbß3. Given the rarity of the condition (1/1,000,000), assessment and diagnosis should be undertaken in a specialist centre. We report the case of a 34 year old woman with severe menorrhagia and a childhood diagnosis from another centre of Von Willebrand Disease. She had an extensive bleeding history, with epistaxis, menorrhagia and postoperative bleeding requiring multiple previous transfusions. Repeat haemostatic workup in our centre revealed normal Von Willebrand levels but abnormal platelet aggregation consistent with Glanzmann thrombasthenia. Antibody screening detected both anti-HLA and anti-αIIbß3 antibodies, complicating subsequent haemostatic management. This case highlights the importance of diagnostic accuracy, the potential negative sequelae of misdiagnosis and subsequent therapeutic interventions.

Characteristics Associated With Mortality in 372 Patients Receiving Low-Dose Recombinant Factor VIIa (rFVIIa) for Cardiac Surgical Bleeding.

OBJECTIVE: Activated recombinant factor VII (rFVIIa) has been used to treat cardiac surgical bleeding in an off-label manner. This observational report analyzes the outcomes with use of a low dose and early administration of rFVIIa for cardiac surgical bleeding. DESIGN: A retrospective, observational study. SETTING: Single-center, tertiary care cardiothoracic surgical setting. PARTICIPANTS: A total of 6,862 patients underwent cardiac surgery from January 2012 to January 2018. Of those, 372 patients received rFVIIa perioperatively. INTERVENTIONS: An institutional policy directed low-dose, incremental aliquots of intravenous rFVIIa (0.5-1 mg). Characteristics and outcomes were compared among patients who survived (n = 328) and patients who died (n = 44). MEASUREMENTS AND MAIN RESULTS: The median dose of rFVIIa was low at 13.29 µg/kg. Higher doses were given to patients who died (15.79 µg/kg v 12.99 µg/kg; p = 0.0133). Patients who died received more blood and component transfusions (median 9 products in those who died v 6 products in survivors; p = 0.0022), although the median transfusion requirement for all patients was 6 units per patient. The rate of reoperation was not different in the 2 groups. Mortality was associated with emergent/urgent surgical procedures (p = 0.0282), type of surgical procedure with aortic procedures being highest risk (p = 0.0014), cardiogenic shock (p = 0.0028), postoperative renal failure (p = 0.0035), postoperative cardiac arrest (p = 0.0006), and ischemic stroke (p = 0.0084). CONCLUSION: Mortality after life-threatening cardiac surgical bleeding treated with rFVIIa was more common in aortic procedures and emergent and urgent surgeries. Lower doses of rFVIIa than previously reported may achieve bleeding cessation because overall blood component transfusions were low in this cohort.

Protease-activated receptor 2 promotes actomyosin dependent transforming microvesicles generation from human breast cancer.

Apart from blood coagulation, coagulation proteases are involved inextricably in cancer progression/propagation via intra/inter-cellular signaling, mediated predominantly by protease-activated receptors (PARs). Microvesicles (MVs), a plasma membrane shredded component, has recently been identified as an important contributor to human breast cancer metastasis. However, the role of PAR2 in promoting MVs generation from breast cancer cells remains largely unexplored. The objective of this study is to investigate whether coagulation protease-mediated human breast cancer propagation commences via MVs and also to decipher the underlying signaling mechanism. Here, we elicited that coagulation factor-FVIIa and Trypsin activates PAR2, which governs MVs shedding from MDAMB231 cells by altering actomyosin dynamics. Treatment of cells with PAR2 activators facilitate MVs generation by activating three independent (MAPK, P38, and Rho) signaling cascades. MAPK, signals through activating MLCK followed by MLC phosphorylation to alter myosin organization whereas, P38 reorganizes actin dynamics by the sequential activation of MK2 and HSP27. RhoA-dependent ROCK-II activation again contributes to remodeling myosin II activity. Further, both our in vitro and in vivo analyses showed that these MVs potentiate invasive and migratory property to the recipient cells. Breast cancer patients blood show an elevation of TF-bearing, pro-metastatic MVs than normal. These findings give an insight into the detailed signaling mechanism involved in the production of MVs with transforming ability from PAR2-activated human breast cancer cells. Understanding these mechanistic details will certainly help to identify crucial targets for therapeutic interventions in MVs-associated human breast cancer metastasis.

Off-label use of 4-factor prothrombin complex concentrate is common despite little known benefit: A retrospective study.

BACKGROUND/OBJECTIVE: While four-factor prothrombin complex concentrate (4F-PCC) is FDA-approved for reversal of warfarin-induced major bleeding, its use in real-world settings is unclear. This study's objective was to identify indications leading to 4F-PCC use and associated outcomes at a single university hospital. METHODS: This was a retrospective cohort study of patients receiving 4F-PCC over a 22-month period. A dose was "on-label" if given for reversal of warfarin-induced coagulopathy in patients with major bleeding or requiring urgent surgeries/procedures; other doses were "off-label". RESULTS: A total of 165 doses of 4F-PCC in 154 patients were given. Sixty-one percent of doses were on-label, while 39% were off-label. Intracranial hemorrhage was the most common indication (55% of doses). On-label patients had significantly higher rate of INR normalization and survival to hospital discharge than off-label patients. There was no difference in time to INR normalization, time to hemostasis, or incidence of thromboembolic complications. CONCLUSIONS: Off-label use of 4F-PCC is likely common, occurring in nearly 40% of drug administrations at our center. Larger-scale prospective trials studying specific indications are needed for validation in off-label settings. Until such evidence is available, given potential harms historically displayed by off-label use of other hemostatic agents, limiting off-label 4F-PCC use is recommended.

Factor VIIa administration in orthotopic heart transplant recipients and its impact on thromboembolic events and post-transplant outcomes.

Recombinant, activated factor VIIa (rFVIIa) is used during cardiac surgeries to mitigate refractory coagulopathic bleeding. The purpose of this study was to examine whether rFVIIa use in orthotopic heart transplant (OHT) recipients was associated with a higher incidence of thromboembolic (TE) events compared to patients who did not. A single-center, retrospective, cohort study was performed on OHT recipients who received rFVIIa for refractory coagulopathic bleeding from January 2013 to December 2015. Patients were evaluated for up to 6 months after transplantation and assessed for TE events, rejection, readmissions, graft survival, and patient survival. Categorical variables were analyzed using the Chi square test while student's t or ANOVA testing was utilized for continuous variables. Of the 62 patients who met inclusion criteria, 27 patients received rFVIIa, and 35 patients were selected for the control group. The overall incidence of TE events was not significantly different between patients who received rFVIIa compared to patients in the control group (14.8% vs 11.4%) (p = 0.69). Within 14 days, 14.81% of rFVIIa patients suffered a TE event compared to 5.7% of the control group (p = 0.23). Rejection, readmissions, graft survival, and patient survival were not significantly different at any time points. Use of rFVIIa in heart transplantation showed no difference in the overall rate of TE events, however, there was a nonsignificant trend toward higher risk of early TE development in the rFVIIa group compared to the control group.