Roles of Four-Factor Prothrombin Complex Concentrate in the Management of Critical Bleeding

Four-factor prothrombin complex concentrate (4F-PCC) is the term used to describe a pathogen-reduced, lyophilized concentrate that contains therapeutic amounts of at least 4 coagulation factors: Factor II (FII), Factor VII (FVII), Factor IX (FIX), and Factor X (FX). 4F-PCC has proven to be an effective hemostatic agent compared to plasma transfusion in several prospective randomized trials in acute warfarin reversal. In recent years, 4F-PCC has been used in various acquired coagulopathies including post-cardiopulmonary bypass bleeding, trauma-induced coagulopathy, coagulopathy in liver failure, and major bleeding due to anti-FXa (anti-Xa) inhibitors (eg, rivaroxaban and apixaban). As transfusion of frozen plasma (FP) has not been found efficacious in the above critical bleeding scenarios, there is increasing interest in expanding the use of 4F-PCC. However, efficacy, safety, and clinical implications of expanded use of 4F-PCC have not been fully elucidated. Prothrombin time and international normalized ratio are commonly used to assess dose effects of 4F-PCC. Prothrombin time/international normalized ratio are standardly use for warfarin titration, but they are not suited for real-time monitoring of complex coagulopathies. Optimal dosing of 4F-PCC outside of the current approved use for vitamin K antagonist reversal is yet to be determined. In this review, we will discuss the use of 4F-PCC in four critical bleeding settings: cardiac surgery, major trauma, end-stage liver disease, and oral anti-Xa reversal. We will discuss recent studies in each area to explore the dosing, efficacy, and safety of 4F-PCC.     

Is there a difference in efficacy,safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants?

PurposeThe aim of this study was to compare the efficacy, safety, and cost-effectiveness of 3-factor prothrombin complex concentrate (3F-PCC) vs 4-factor prothrombin complex concentrate PCC (4F-PCC) in trauma patients requiring reversal of oral anticoagulants.Materials and methodsAll consecutive trauma patients with coagulopathy (international normalized ratio [INR] ≥ 1.5) secondary to oral anticoagulants who received either 3F-PCC or 4F-PCC from 2010 to 2014 at 2 trauma centers were reviewed. Efficacy was determined by assessing the first INR post–PCC administration, and successful reversal was defined as INR less than 1.5. Safety was assessed by reviewing thromboembolic events, and cost-effectiveness was calculated using total treatment costs (drug acquisition plus transfusion costs) per successful reversal.ResultsForty-six patients received 3F-PCC, and 18 received 4F-PCC. Baseline INR was similar for 3F-PCC and 4F-PCC patients (3.1 ± 2.3 vs 3.4 ± 3.7, P = .520). The initial PCC dose was 29 ± 9 U/kg for 3F-PCC and 26 ± 6 U/kg for 4F-PCC (P = .102). The follow-up INR was 1.6 ± 0.6 for 3F-PCC and 1.3 ± 0.2 for 4F-PCC (P = .001). Successful reversal rates in patients were 83% for 4F-PCC and 50% for 3F-PCC (P = .022). Thromboembolic events were observed in 15% of patients with 3F-PCC vs 0% with 4F-PCC (P = .177). Cost-effectiveness favored 4F-PCC ($5382 vs $3797).ConclusionsThree-factor PCC and 4F-PCC were both safe in correcting INR, but 4F-PCC was more effective, leading to better cost-effectiveness. Replacing 3F-PCC with 4F-PCC for urgent coagulopathy reversal may benefit patients and institutions.     

Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation

PurposePrevious trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria.MethodsThis was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed.ResultsNinety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P= .01) and major surgery within 14 days (P= .02), as well as the presence of >6 thrombotic risk factors (P= .01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K.Conclusions4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound.     

Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants

Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient’s interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention.     

Prospective Evaluation of a Fixed-Dose 4-Factor Prothrombin Complex Concentrate Protocol for Urgent Vitamin K Antagonist Reversal

BackgroundFour-factor prothrombin complex concentrate (4F-PCC) is the standard of care for reversal of vitamin K antagonists (VKAs). Research has demonstrated noninferior efficacy with the use of lower, fixed-dose strategies for 4F-PCC dosing.ObjectivesWe compared a fixed-dose 4F-PCC protocol to weight-based dosing at our institution.MethodsThis was a multicenter, noninferiority, interventional, quasiexperimental cohort study including subjects who were administered 4F-PCC for VKA reversal. The retrospective cohort consisted of subjects given a weight-based dose of 4F-PCC dependent on international normalized ratio (INR). The prospective cohort was managed with a fixed-dose protocol. The fixed dose was 1500 units of factor IX unless subjects weighed >100 kg or had a baseline INR >7.5, in which case the dose was 2000 units of factor IX. The primary endpoint was achievement of a postinfusion INR of <2. Secondary endpoints included achievement postinfusion INR <1.5, mean 24-h INR, 7-day mortality, and 7-day venous thromboembolic events.ResultsTwenty-four subjects were enrolled in the prospective cohort and 30 in the retrospective cohort. A postinfusion INR <2 was achieved in 96% of subjects in the retrospective cohort and 95% in the prospective cohort (p = 0.0035 for noninferiority). A postinfusion INR <1.5 occurred in 90% of subjects in the retrospective cohort and 75% in the prospective cohort (p > 0.4 for noninferiority). There were no significant differences in 24-h postinfusion INRs, mortality, or venous thromboembolic events.ConclusionThe use of a fixed-dose 4F-PCC protocol is safe and effective for the rapid reversal of VKA-associated anticoagulation.     

A review of guidelines on anticoagulation reversal across different clinical scenarios – Is there a general consensus?

Anticoagulation is key to the treatment/prevention of thromboembolic events. The primary complication of anticoagulation is serious or life-threatening hemorrhage, which may necessitate prompt anticoagulation reversal; this could also be required for nonbleeding patients requiring urgent/emergent invasive procedures. The decision to reverse anticoagulation should weigh the benefit–risk ratio of supporting hemostasis versus post-reversal thrombosis. We appraise the available guidelines/recommendations for vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal in the management of major bleeding, and also assess recent clinical data that may not yet be reflected in official guidance. In general, available guidelines are consistent in their recommendations, advocating administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) rather than fresh frozen plasma to patients with VKA-associated intracranial hemorrhage and life-threatening bleeding, and specific reversal agents as essential therapy for DOAC reversal in those same severe conditions. However, guidelines also recommend off-label use of PCCs for DOAC reversal when specific reversal agents are unavailable. Limited recent evidence generally support the latter recommendation, but guidelines are likely to evolve as more data become available.     

Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor

Approximately 1 in 3–4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all-cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs’ anticoagulation quality [a target time in therapeutic range (TTR) of ≥70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a “borderline” or insufficient stroke risk to trigger the use of OAC. However, observational data from real-world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts.     

Four-factor prothrombin complex concentrate dose response relationship with INR for warfarin reversal

IntroductionFor reversal of warfarin-induced coagulopathy, FDA labeling of four-factor prothrombin complex concentrate (4F-PCC) endorses a dosing strategy based on body weight and baseline INR. Recent literature suggests lower, fixed doses of 4F-PCC may be equally efficacious. The present evaluation aims to characterize the relationship between 4F-PCC dose and degree of reduction in INR.MethodsThis is a retrospective, single-center review of 4F-PCC administrations for warfarin reversal between May 2014 and August 2017. The primary endpoint evaluates the relationship between doses of 4F-PCC and INR measurement after reversal, represented as a linear regression. Exploratory endpoints characterize the relationships of both body weight and baseline INR, the components determining initial 4F-PCC dose, with INR after reversal. Additionally, for records presenting with an INR of 2–3.9, mean INR after reversal was characterized as a function of two 4F-PCC dose cohorts (< 30 and ≥30 IU fIX/kg).ResultsA significant linear relationship between 4F-PCC dose and INR after reversal (INR after 4F-PCC = 1.3651–0.00004(4F-PCC Dose), p = 0.0071, R² = 0.0630) was observed. Body weight and baseline INR were not correlated with INR after reversal. The subgroup analysis of records with presenting INR of 2–3.9 demonstrated no difference in mean INR after reversal with 4F-PCC for those receiving <30 IU fIX/kg and those receiving ≥30 IU fIX/kg.ConclusionThis evaluation found no clinically relevant relationship with 4F-PCC doses and degree of INR reversal. Further prospective study is required to determine optimal dosing schemes of 4F-PCC for warfarin reversal.     

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage

BackgroundFour-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH).Study design and methodsWe completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging.ResultsThere was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC.ConclusionThere was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.     

Thromboelastometry-guided anticoagulation reversal in a patient with ventricular assist device with intracranial hemorrhage

Intracranial hemorrhage (ICH) is a known complication in patients with ventricular assist devices (VAD). We present a case of a 42-year-old male with a VAD and on warfarin who presented to the emergency department with ICH necessitating anticoagulant reversal. An attenuated dose of 15 units/kg of 4-factor prothrombin complex-concentrates (4F-PCC) was given and the patient’s coagulation profile was subsequently assessed using rotational thromboelastometry (ROTEM®) to determine appropriateness of reversal. ROTEM® analysis showed adequate reversal at the time of assessment and the patient ultimately returned home without further functional deficits, highlighting the role of ROTEM® to guide anticoagulation reversal in the VAD patient population.     

Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?

See also Douketis JD, Spyropoulos AC. Vitamin K to reverse the anticoagulant effect of vitamin K antagonists: can you teach an old dog new tricks? This issue, pp 496–8. Summary. Background: After a vitamin K antagonist (VKA) overdose, 1–2 mg of oral vitamin K can lower the International Normalized Ratio (INR) to the therapeutic range. Objective: To establish whether oral vitamin K can substitute for heparin bridging and decrease the INR to ≤ 1.5 before elective surgery. Methods: Patients on long‐term VKAs were randomized either to heparin bridging after the last VKA dose on day – 5 before surgery (group H) or to VKA treatment until day – 2, followed by 1 mg of oral vitamin K on the day before surgery (group K). Blood clotting variables were assessed on days –5/–2, 1 and 0, and postoperatively. If the target INR was not achieved 2 h before incision, surgery was deferred or performed after injection of prothrombin complex concentrate (PCC). Results: In 30 of 94 included patients, baseline INR was outside the chosen range (18, INR < 2; 12, INR > 3.5), leaving 34 eligible patients in group H and 30 in group K. The groups were balanced in terms of body mass index, VKA treatment duration and indication, scheduled surgery, preoperative and postoperative hemoglobin, and blood loss. The INR was significantly higher in group K on days – 1 and 0 than in group H. An INR ≤ 1.5 was not achieved in 20 group K patients (66%). Surgery was postponed or performed after PCC injection in 12 of these 20 patients. Conclusions: Oral vitamin K (1 mg) cannot substitute for heparin bridging before surgery. In addition, one‐third of patients on VKAs were exposed to a risk of bleeding (overdose) or thrombosis (underdose), thus highlighting the need for new oral anticoagulants.     

Challenges of stroke prevention in patients with atrial fibrillation in clinical practice

Strokes and transient ischaemic attacks in patients with atrial fibrillation (AF) can be largely prevented. Risk stratification and appropriate prophylactic regimens help to alleviate the burden of AF-related thromboembolism. Guidelines recommend routine anticoagulation with oral vitamin K antagonists (VKAs) for patients at moderate-to-high risk of stroke, and acetylsalicylic acid (ASA) for those at low risk of stroke. ASA is less effective at reducing the risk of stroke than VKAs; however, ASA does not require monitoring or dose adjustment. Trials of anticoagulants show consistent benefits of oral VKAs for primary and secondary stroke prevention in patients with AF. Nevertheless, VKAs do require frequent coagulation monitoring and dose adjustment because of their variable dose-response profile, narrow therapeutic window, increased risk for bleeding complications and numerous food and drug interactions. This review aims to provide an overview of the clinical challenges of anticoagulant therapy for the prevention of stroke in patients with AF.     

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate

BackgroundControversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria.MethodsThis was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa.ResultsA total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient.ConclusionsAdministration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.     

Experiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding

Background

Current reversal options for warfarin-related bleeding are limited but include fresh frozen plasma, recombinant factor VIIa, or a prothrombin complex concentrate (PCC). There are little data discussing the use of activated 4-factor PCC for warfarin reversal.

Objectives

This review will summarize our experiences with FEIBA (Baxter, Deerfield, IL), an activated 4-factor PCC, for the reversal of warfarin-related bleeding in a community hospital.

Methods

A protocol was put in place in March of 2011, which outlined the use of FEIBA for the emergent reversal of warfarin-related coagulopathy. A low fixed dose was given based on international normalized ratio (INR). For an INR less than 5.0, 500 U of FEIBA was administered. For an INR greater than or equal to 5.0, 1000 U of FEIBA was given. Intravenous vitamin K was given concurrently regardless of INR.

Results

Sixteen patients were treated with FEIBA per the protocol. Average patient age was 73 years. Intracranial hemorrhage was the most common indication for reversal. Mean pre-treatment INR was 3.56 (1.3-6.8); mean post-treatment INR was 1.16 (1.01-1.32). Two of the patients required a second 500-U dose, per the protocol, for an INR that had not yet normalized. Bleeding appeared clinically controlled in 93% of cases. Eighty-seven percent of patients survived to discharge. There were no signs or symptoms of thrombosis in any of the cases.

Conclusions

Emergent reversal of warfarin utilizing a fixed, low dose of FEIBA appears to be efficacious, consistent, and safe. Further comparator studies with other reversal agents are needed.     

Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage

ObjectiveThe objective of this study was to determine the effectiveness and safety of four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitors in patients with traumatic intracranial hemorrhage (ICH).MethodsThis was a retrospective cohort study of patients taking factor Xa inhibitors with traumatic ICH between March 1, 2015 and August 31, 2017 at two trauma centers. The primary outcome was in-hospital mortality in patients who received 4F-PCC (4F-PCC group) compared to those who did not (no reversal group). Secondary outcomes included functional recovery, hospital and intensive care unit (ICU) length of stay (LOS), and thromboembolic complications.ResultsThere were 62 patients included in the study. Injury Severity Score (ISS) was significantly higher in the 4F-PCC group (17.6 vs. 12.1, p = 0.019). The 4F-PCC group had a significantly higher mortality (22.9% vs. 3.7%, p = 0.034) and longer ICU LOS (2.5 vs. 1.4 days, p = 0.0024). The no reversal group had a significantly higher incidence of ischemic stroke/transient ischemic attack (TIA) (0% vs. 14.8%, p = 0.019). After controlling for ISS, there was no significant difference in mortality (p = 0.20), ICU LOS (p = 0.64), or ischemic stroke/TIA (p = 0.94). There was no difference in hospital LOS, discharge disposition, final Activity Measure for Post Acute Care daily activity score, VTE, or MI.ConclusionPatients with a higher ISS received 4F-PCC preferentially, which led to an apparent mortality benefit the no reversal group. After adjusting for baseline differences between groups, there was no difference in mortality, functional recovery, hospital and ICU LOS, or thromboembolic complications.     

Anticoagulation for venous thromboembolism: what if they bleed?

Acute venous thromboembolism (VTE) is treated with parenteral administration of heparin or derivatives, in conjunction with oral vitamin K antagonists (VKAs) to reach and maintain INR values between 2.0 and 3.0 for at least 3 months; the duration of a further period of treatment for secondary prevention of recurrences is still matter of debate. If bleeding occurs during treatment the decision will be based on: a) type of bleeding (major or minor), and b) thrombotic risk if anticoagulation is withheld (characteristics of patients and time elapsed from the index VTE). In case of major bleeding anticoagulation should be stopped and reversed. A first but insufficient measure is i.v. vitamin K administration. Fresh frozen plasma is widely used; however, large volumes are needed (at least 15 mL/kg body weight) with risk for fluid overload. Prothrombin complex concentrate infusion, with 3 or (better) the 4 pro-coagulant factors, is a more efficient (fast and safe) measure. In patients at high thrombotic risk (first month or other conditions) and absolute contraindication for anticoagulation a caval filter is recommended, to avoid as much as possible life-threatening pulmonary embolism.     

Non-Vitamin K Oral Anticoagulants for Stroke Prevention in Special Populations with Atrial Fibrillation

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with “non-valvular AF”, and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.     

Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding

Introduction  

Prothrombin complex concentrates are recommended for rapid reversal of vitamin K anticoagulants. As they normalize levels of vitamin K dependent clotting factors and re-establish hemostasis, they may also be used as adjunctive therapy in patients with major bleeding. The aim of this study was to retrospectively evaluate the efficacy of prothrombin complex concentrates in the surgical setting.     

Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.

BACKGROUND AND OBJECTIVES: The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect. PATIENTS AND METHODS: A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls. RESULTS AND CONCLUSIONS: In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.