Prothrombin Complex Research Articles

Systematic vitamin K antagonist reversal with prothrombin complex concentrate in patients with mild traumatic brain injury: randomized controlled trial.

Traumatic brain injury (TBI) in patients on vitamin K antagonists (VKAs) is linked to a high rate of intracranial hemorrhage (ICH). Rapid reversal can reduce ICH progression and mortality, but its effectiveness depends on the time between bleeding onset and coagulation normalization. The PREVACT study aimed to assess the efficacy and safety of prompt systematic reversal of anticoagulation in patients presenting to emergency departments (EDs) for recent mild-TBI while receiving a VKA. A randomized, open-label, blinded-endpoint clinical trial was conducted in 21 French EDs. Patients receiving a VKA, having experienced a TBI within the last 6 h, and presenting a Glasgow Coma Score ≥13 were included. Patients were randomized to systematic immediate VKA reversal with 25 IU/kg of four-factor prothrombin complex concentrate (4f-PCC) before any investigation (intervention group) or standard-of-care signifying reversal only if the initial cranial computed tomography (CT) scan indicated ICH (control group). The primary outcome was the rate of ICH detected on a cranial CT scan 24 h post-inclusion. The study was prematurely stopped for logistic reasons after the randomization of 202 patients (101 and 101 in the intervention and control groups, respectively, mean age 90; 51.8% female). On the 24-h cranial CT scan, 6 of 98 patients (6.1%) in the intervention group manifested ICH vs. 12 of 99 patients (12.1%) in the control group [odds ratio: 0.47 (95% confidence interval: 0.14-1.44); P = 0.215]. In patients with recent mild-TBI receiving a VKA, systematic prompt reversal with 4f-PCC did not statistically significantly reduce ICH rate at 24 h. However, the study was prematurely stopped and does not exclude a clinically relevant benefit of the strategy tested. Clinicaltrials.gov (NCT01961804).

Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K-Dependent Coagulation Factors Deficiency.

Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K-dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

Perioperative Management of Pediatric Combined Heart and Liver Transplantation: A 17 year single center experience.

An increasing number of centers are undertaking combined heart and liver transplantation in adult and pediatric patients with congenital heart disease. The primary aim of this study was to describe the perioperative management of a single center cohort, identifying challenges and potential solutions. We conducted a retrospective review of all patients undergoing combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022. Preoperative information included cardiac diagnosis, hemodynamics, and severity of liver disease. Intraoperative data included length of surgery, cardiopulmonary bypass time, and blood products transfused. Postoperative data included blood products transfused in the intensive care unit, time to extubation, length of intensive care unit stay, survival outcomes and 30-day adverse events. Eighteen patients underwent en bloc combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022, and the majority 15 (83%) were transplanted for failing Fontan circulation with Fontan Associated Liver Disease. Median surgical procedure time was 13.4 [11.5, 14.5] h with a cardiopulmonary bypass time of 4.3 [3.9, 5.8] h. Median total blood products transfused in the operating room post cardiopulmonary bypass was 89.4 [63.9, 127.0] mLs/kg. Nine patients (50%) had vasoplegia during cardiopulmonary bypass. Activated prothrombin complex concentrates were used post cardiopulmonary bypass in 15 (83%) patients with a 30-day thromboembolism rate of 22%. Median time to extubation was 4.0 [2.8, 6.5] days, median intensive care unit length of stay 20.0 [7.8, 48.3] days and median hospital length of stay 54.0 [30.5, 68.3] days. Incidence of renal replacement therapy was 11%; however, none required renal replacement therapy by the time of hospital discharge. Neurological events within 30 days were 17% and the 30 day and 1 year survival was 89%. Perioperative challenges include major perioperative bleeding, unstable hemodynamics, and end organ injury including acute kidney injury and neurological events. Successful outcomes for en bloc combined heart and liver transplantation are possible with careful multidisciplinary planning, communication, patient selection, and integrated peri-operative management.

Four-factor Prothrombin Complex Concentrate Use for Bleeding Management in Adult Trauma.

The clinical use of four-factor prothrombin complex concentrate in adult trauma patients at risk of bleeding is supported by evidence for urgent reversal of oral anticoagulants but is controversial in acquired traumatic coagulopathy.

3-Factor prothrombin complex concentrate versus 4-factor prothrombin complex concentrate for the reversal of oral factor Xa inhibitors.

Multiple agents exist for the reversal of oral Factor Xa inhibitor (FXa) associated bleeding, including Coagulation FXa Recombinant, Inactivated zhzo (andexanet alfa) and 4-factor prothrombin complex concentrate (4F-PCC). While classified as a 3F-PCC product, Profilnine contains up to 35IU of Factor VII (per 100IU of Factor IX) in addition to therapeutic levels of Factors II, IX, and X, and has demonstrated a similar impact on prothrombin time and blood product usage in non-warfarin related bleeding. This was a retrospective, multicenter study at four medical centers of adult patients who presented with major bleeding associated with oral FXa inhibitors and received either 4F-PCC (n = 64) or 3F-PCC (n = 61). The primary outcome was hemostatic effectiveness. Secondary outcomes included the incidence of thromboembolism, in-hospital mortality, and length of stay. The most common indication for reversal was intracranial bleeding. For the primary outcome, 84% of all patients were rated as effective with no difference noted between the groups (p = 0.81). No significant difference between groups was found in the multivariable analysis adjusting for baseline differences between groups including race, total body weight, type of bleeding, and the use of antiplatelet therapy. There was no difference in the length of stay, in-hospital mortality, or the incidence of thromboembolism between the groups. Overall, no significant differences were found in the effectiveness or safety of 4F-PCC and 3F-PCC use in the management of oral FXa inhibitor-associated bleeding. Further investigations are warranted to explore the use of 3F-PCC for this indication and its safety and effectiveness.

Current Management of Patients with Proximal Femur Fractures Receiving Antiplatelet and Anticoagulant Therapy

Proximal femur fractures (PFF) pose a major challenge in elderly patients with severe comorbidities and receiving antithrombotic therapy since according to the latest guidelines the surgery should be performed as soon as possible, preferably within 24 hours, to reduce mortality and morbidity. This review outlines the practical approach to surgical management of PFF that relies on increasing evidence of safety of early surgery in patients with PFF receiving antiplatelet and anticoagulant therapy. We have also used information from the existing evidence-based guidelines for elective/planned surgery in patients with antithrombotic therapy. The practical approach can be summarised as follows: • Antiplatelet therapy - discontinuation of acetylsalicylic acid (ASA) and clopidogrel in monotherapy or in combination is not necessary prior to surgery. In case of bleeding, antifibrinolytic therapy is recommended as well as administration of platelet concentrate which is rarely needed. • In patients taking warfarin, reversal of its effects is recommended by early administration of vitamin K to allow surgery to be performed within 24 hours. Prothrombin complex concentrate (PCC) as a second-line drug is reserved for extreme cases only. Warfarin therapy is resumed 24 hours after surgery. • Direct oral anticoagulants must be discontinued 24-48 hours prior to surgery, possibly longer depending on the type of drug, time of administration of the last dose, and renal function. In extreme cases, an antidote (idarucizumab, off-label andexanet) can be administered prior to surgery, or PCC in case they are unavailable. Anticoagulation therapy is resumed in 24-48 hours. • Neuraxial anaesthesia is possible when ASA is taken by the patient and in case of effective warfarin reversal. • In early surgery and rapid restart of anticoagulant therapy, bridging therapy with LMWH is not indicated except for in cases with extreme risk of thrombosis. Key words: proximal femur fracture, antiplatelet therapy, anticoagulant therapy, perioperative management.

Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis.

Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01-1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51-0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58-1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01-2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07-1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI - 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD - 0.89, 95% CI - 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events.

Monitoring the efficiency of reversal on anti-Xa direct oral anticoagulants using point-of-care viscoelastic testing

Bleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually “blinded” with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa.

The anticoagulant effects of milvexian, a novel small molecule factor XIa inhibitor, are neutralized by activated prothrombin complex concentrates and recombinant factor VIIa in human plasma and whole blood in vitro

BackgroundThe development of anticoagulants that provide antithrombotic efficacy without a concomitant bleeding risk remains an unmet clinical need in thrombosis. Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. Epidemiologic data suggest that inhibiting activated factor (F)XI may offer an improved safety profile with respect to bleeding risk compared with current-generation DOACs. Additionally, a phase II trial of milvexian in patients undergoing elective total knee replacement demonstrated robust dose-dependent efficacy with no statistically significant increase in bleeding. Nevertheless, the ability to rapidly and effectively correct FXIa inhibitor–induced anticoagulation may still be important in situations where patients experience uncontrolled bleeding or require emergency surgery. ObjectivesWe assessed the ability to normalize the anticoagulant effects of the novel small molecule FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) in vitro using commercially available prohemostatic agents. MethodsMilvexian-associated anticoagulation and correction was evaluated in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. ResultsActivated prothrombin complex concentrates (PCCs) and recombinant factor (rF)VIIa corrected the anticoagulant effects of milvexian in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. In contrast, other agents including PCCs, rFIX, and rFVIII demonstrated either modest or no correction of milvexian-associated anticoagulation. ConclusionThis study demonstrated that currently available activated PCCs and rFVIIa normalize anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established.

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

Use of coagulation factor concentrates and blood transfusion in cardiac surgery: a retrospective cohort study of adults with hereditary and acquired bleeding disorders

BackgroundCardiac surgery poses a significant risk of perioperative bleeding and allogeneic blood transfusions, particularly in patients with bleeding disorders. Increasingly frequent use of coagulation factor concentrates could impact haemorrhagic risks, thromboembolic events, and costs. We describe the use of coagulation factor concentrates and allogeneic blood products in cardiac surgical patients with hereditary and acquired bleeding disorders to assess pertinent outcomes, including perioperative haemorrhage, thromboembolism, and hospital costs. MethodsWe conducted a retrospective cohort study using the Premier Health Database, including adult cardiac surgical patients diagnosed with hereditary or acquired bleeding disorders compared with those without bleeding disorders. ResultsPatients with acquired bleeding disorders required more extensive use of coagulation factor concentrates and blood products compared with those with hereditary bleeding disorders or without bleeding disorders. The highest exposures to coagulation factor concentrates were found in the acquired bleeding disorders group, with 24% receiving factor VIIa and 11.7% receiving prothrombin complex concentrate. This group also experienced significantly higher rates of complications, including a 15.8% rate of haemorrhage and a 19.2% rate of thromboembolic events. The acquired bleeding disorders group had longer intensive care and hospital stays, and the highest mortality rate (19.2%). The increased use of perioperative replacement of factor VIII and factor IX in the hereditary bleeding disorders group led to increased pharmacy costs but did not significantly impact blood bank charges. ConclusionsAcquired bleeding disorders in cardiac surgery patients are associated with increased use of haemostatic interventions, postoperative complications, and increased healthcare costs. Improved management of perioperative haemostasis and thromboprophylaxis strategies are essential for optimising patient outcomes and reducing expenses.

Major Publications in the Critical Care Pharmacotherapy Literature: 2023.

We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023. PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article. Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion. This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients.

Impact of elevated direct factor Xa inhibitor plasma levels on perioperative blood loss in patients undergoing urgent surgery.

Data on the perioperative bleeding risk associated with elevated plasma levels of direct factor Xa inhibitors (FXa inhibitors) are limited. This study examines perioperative red blood cell (RBC) loss in patients undergoing urgent surgery with a residual FXa inhibitor level exceeding 100 mcg/L and without preoperative FXa inhibitor reversal. This retrospective analysis includes data from 32 patients who underwent urgent noncardiac surgery between 2018 and 2022. This study aims to analyze perioperative RBC loss in patients undergoing urgent surgery with a residual FXa inhibitor level exceeding 100 mcg/L and without preoperative FXa inhibitor antidote-based reversal or unspecific treatment with 4-factor prothrombin complex concentrate (PCC). All patients were managed using a watch-and-wait strategy. The last determination of FXa inhibitor plasma concentration prior to surgery showed a median of 245 mcg/L (IQR 144-345), with a median time interval of 3.8 h (IQR 2.4-7.2) before incision. Median RBC loss during surgery was 49 mL (IQR 0-253), 189 mL (IQR 104-217) until POD1 and 254 mL (IQR 58-265) until POD3. Only one patient required intraoperative treatment with 4-factor-PCC and none required reversal with andexanet alfa. Linear regression models found no significant influence of FXa inhibitor plasma levels on intraoperative RBC loss. Rivaroxaban was associated with higher RBC loss until postoperative Day 1 compared with apixaban. No thromboembolic events were observed. Despite markedly elevated plasma concentrations of residual direct FXa inhibitors, perioperative RBC loss was limited in patients undergoing urgent noncardiac surgery. The intraoperative watch-and-wait strategy with selective intraoperative FXa inhibitor reversal or treatment only when required appears to be an appropriate approach.

Acquired hemophilia A as a disease of the elderly: A comprehensive review of epidemiology, pathogenesis, and novel therapy

AbstractAcquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). This review provides an in-depth exploration of AHA, covering its epidemiology, pathogenesis, clinical presentation, diagnosis, complications, and treatment strategies, focusing on recent advancements. AHA can manifest in both men and women with no prior bleeding history. The annual incidence is estimated to be approximately 1 case per million individuals in the general population. The incidence increases significantly with age: the incidence among individuals aged 60 years or older is approximately 3 to 4 cases per million individuals per year. Typically, patients present with an acquired bleeding disorder that is characterized by an isolated, prolonged activated partial thromboplastin time stemming from FVIII deficiency. Diagnosis relies on the detection of neutralizing antibodies using the Nijmegen-modified Bethesda assay. Hemostatic control strategies involve bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII for bleeding patients. Emicizumab, a novel bypassing agent, exhibits several potential advantages. In the realm of immunosuppressive treatment for inhibitor eradication, the CyDRi regimen emerged as a remarkable advancement, significantly enhancing the outlook for the management of AHA even in the elderly frail population.

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

AbstractIntroductionThe 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.AimTo provide real‐world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis.MethodsThis 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.ResultsTwenty‐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.ConclusionsIn 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.

Characterising practice patterns of human derived, lyophilized coagulation concentrates within the trauma quality improvement program registry.

We seek to describe the current practice pattern use of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FC) in trauma patients. Trauma-induced coagulopathy (TIC) and endotheliopathy of trauma (EOT) contribute significantly to mortality from traumatic haemorrhage. FC, and 4-factor PCC are potential treatments for EOT and TIC, respectively. We obtained data from the Trauma Quality Improvement Program (TQIP) registry and identified patients who received either PCC or FC using procedural codes. We used descriptive statistics to characterise practice patterns of these products. There were 6 714 002 total encounters within the TQIP from 2017 to 2022, of which 10 589 received PCC and 3009 received FC. Of the recipients, there were 35 that received both products. There were 44 that received both. The median age of PCC recipients was 77 (69-84) with 19 patients <15 years of age with the youngest being 2 years of age. There was a general upward trend in the number of facilities with documented use of PCC: 155/744, 168/766, 189/764, 206/780, 234/795, and 235/816, respectively. The median age of FC recipients was 57 (32-75) with 48 patients <15 years of age with the youngest being 1 year of age. There was a minor downward trend in the number of facilities that had documented use of FC: 55, 44, 39, 32, 38 and 40. The administration of PCC and FC remains uncommon, although there appears to be an upward trend of PCC use. Most PCC use appeared to be for anticoagulation reversal in the setting of head trauma. Data guiding the use of these products are necessary as these products become more recognised as adjuncts to traumatic haemorrhage control.

SP7.1 - Risk Profile of Administration of 3- and 4-factor Prothrombin Complex Concentrate in Adult Anticoagulated Trauma Patients: A Systematic Review and Meta-Analysis

Abstract Aims To establish thromboembolic complication (TC, primary outcome) and mortality (secondary outcome) Odds Ratios (ORs) following 3-factor Prothrombin Complex Concentrate (PCC3, Comparator Group [CG] 1) and 4-factor Prothrombin Complex Concentrate (PCC4, CG2) administration, compared to Fresh Frozen Plasma (FFP) alone, in adult Vitamin K antagonist-anticoagulated trauma patients. Methods Systematic database and grey literature searches were performed. Random effects model meta-analyses were undertaken for each of this study’s outcomes, producing ORs and 95% Confidence Intervals (95%CIs). The I2 statistic was used to quantify interstudy heterogeneity. Inverse Variance, Mann-Whitney U and Kruskal-Wallis tests were used to examine interstudy demographic/treatment differences. Risk of bias was assessed with the Newcastle-Ottawa Scale, study quality with the GRADE tool. Results 8 papers met inclusion criteria (CG1 n=3, CG2 n=3), 2 were excluded due to insufficient reported information. TC incidence was not significantly increased following PCC3 administration (ORcombined effect1.57, 95% CI 0.24-10.51, p=0.64). Meta-analysis was not performed on TC incidence in CG2 owing to only 1 paper reporting this outcome. Mortality risk was not significantly increased following PCC3 (ORcombined effect1.61, 95%CI 0.27-9.51, p=0.60) or PCC4 (ORcombined effect2.19, 95%CI 0.96-4.98, p=0.06) administration. Admission Injury Severity Score (ISS) and age varied significantly between papers included in CG1 (mean­ISS=15.5, 95%CI=12.0-20.1, p&amp;lt;0.05, meanage=75.3years, 95%CI=65.5-86.7, p&amp;lt;0.05) and CG2 (meanISS=15.1, 95%CI=13.4-17.0, p&amp;lt;0.05, meanage=79.2years, 95%CI=74.7-84.1, p&amp;lt;0.05). Conclusion TC risk is not overtly increased following PCC3 administration, compared to FFP. The same is true for mortality risk following PCC3 and PCC4 administration. There is substantial room for bias in the results reported, further research is warranted.

Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery

IntroductionFactor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed. Materials and methodsWe conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25–50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism. ResultsPCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3–14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5–46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0–175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4–76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5–100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7–14.5] and 22.9 % [95%CI 15.8–31.8] of patients died. ConclusionsPCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.

Fluid resuscitation in trauma: What you need to know.

There have been numerous changes in resuscitation strategies for severely injured patients over the last several decades. Certain strategies, such as aggressive crystalloid resuscitation, have largely been abandoned because of the high incidence of complications and worsening of trauma-induced coagulopathy. Significant emphasis has been placed on restoring a normal coagulation profile with plasma or whole blood transfusion. In addition, the importance of the lethal consequences of trauma-induced coagulopathy, such as hyperfibrinolysis, has been easily recognized by the use of viscoelastic testing, and its treatment with tranexamic acid has been extensively studied. Furthermore, the critical role of early intravenous calcium administration, even before blood transfusion administration, has been emphasized. Other adjuncts, such as fibrinogen supplementation with fibrinogen concentrate or cryoprecipitate and prothrombin complex concentrate, are being studied and incorporated in some of the institutional massive transfusion protocols. Finally, balanced blood component transfusion (1:1:1 or 1:1:2) and whole blood have become commonplace in trauma centers in North America. This review provides a description of recent developments in resuscitation and a discussion of recent innovations and areas for future investigation.

Clinical, Laboratory Aspects and Management of Factor X Deficiency.

Coagulation factor X (FX), originally named Stuart-Prower factor, plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in F10 may lead to FX deficiency and to impaired coagulation. FX variants are phenotypically classified as being type I, with the concomitant reduction of FX coagulant activity and FX antigen levels or type II, corresponding to a reduction in activity with normal antigen plasma levels. Patients affected with FX deficiency tend to be one of the most seriously affected among those with rare bleeding disorders. They show a variable bleeding tendency strongly associated with FX coagulant activity levels in plasma and may present, in the severe form of the deficiency, life-threatening symptoms such as gastrointestinal and umbilical stump bleeding and intracranial hemorrhages or central nervous system bleeding. Treatment of FX deficiency was originally based on the replacement of the missing factor using fresh frozen plasma, cryoprecipitate and prothrombin complex concentrates; however, a plasma-derived concentrate, shown to be safe and effective in clinical trials, is now available. In addition, novel nonreplacement therapy such as small interference RNA, gene therapy, drug repurposing, and gene editing may also represent novel therapeutic approaches for FX deficiency, but further, much focused studies are needed before considering this emerging therapy in such patients.