Reversal Of Warfarin Anticoagulation Research Articles

Balfaxar: Another four-factor PCC for warfarin reversal.

Balfaxar (Octapharma), a human plasma-derived four-factor prothrombin complex concentrate (PCC), has been approved by the FDA for rapid reversal of warfarin anticoagulation in adults who require an urgent surgical/invasive procedure. It is the second four-factor PCC to become available in the US; Kcentra, which has been available since 2013, is approved for the same indication and for urgent reversal of warfarin anticoagulation in adults with acute major bleeding. Balfaxar is marketed in Canada and Europe as Octaplex.

EVALUATION OF APPROPRIATE USE OF PEDIATRIC FRESH FROZEN PLASMA IN A TERTIARY CARE HOSPITAL

Fresh frozen plasma (FFP) is the primary source of coagulation factors. Indications of FFP use are very limited such as disseminated intravascular coagulation, massive bleeding, thrombotic thrombocytopenic purpura, biopsy for chronic liver disease, and reversing warfarin anticoagulation with severe bleeding. In clinical practice, FFPs are reported to be used inappropriately either in respect of the particular indication or excessive in adult studies. Therefore, we aimed in this study to evaluate indications of pediatric FFP usage in our tertiary care hospital Patients aged 0-18 years, who were hospitalized in Ankara City Hospital Children's Hospital between September and December 2020, were analyzed retrospectively. Demographic information, diagnosis, FFP transfusion indication, pre-transfusion coagulation results, surgical procedure and bleeding status, and the amount of FFP administered were recorded. Statistical analysis was done with SPSS 18.0 program. 1110 units of FFP were transfused to 324 patients (57% males) in 987 transfusion episodes. The mean age of the patients was 5.4±5.7 years68% of the transfusion episodes had a pre-transfusion coagulation testing. 249 (25%) of the transfusion episodes were given before or after minor or major surgery, and 226 (23%) were for plasmapheresis. The most FFP usage was in pediatric and cardiovascular surgery intensive care and hematology/oncology clinics. 69% of the FFP transfusions were appropriate. Misuse of FFP exposes patients to unpredictable adverse effects such as allergic reactions, infectious complications, hemolysis, fluid overload, and transfusion-induced acute lung injury (TRALI). In this study, the use of FFP in children was evaluated for the first time in our country, and it was found that the 31% of the FFP transfusions was inappropriate. Regular audit and education programs for the efficient use of FFP by hospital transfusion committees can improve transfusion practices.

Single Centre Retrospective Analysis of Patients Who Underwent Emergency Reversal of Warfarin Anticoagulation

IntroductionWarfarin is used in the treatment and prevention of thromboembolic disorders, with the risk of bleeding ranging from 1% to 3% per year resulting in hospitalisation or death. Emergency reversal of warfarin is indicated when warfarin therapy is complicated by bleeding, prior to emergency procedures / surgeries, and in patients who have supra-therapeutic INR with high risk of bleeding. Launceston General Hospital is a 330-bed hospital in regional Australia and we practise warfarin reversal in accordance with the national guidelines. Prothrombinex-VF (PTx-VF) is a 3-factor prothrombin complex concentrate (PCC) used in Australia, which contains factors II, IX, and X mainly. Due to low factor VII levels in PTx-VF, addition of 1 unit of FFP with PTx-VF is generally recommended, however there is lack of supportive evidence. There are a few reports of successful use of 3-factor PCC without the use of FFP. Hence in our hospital, the addition of FFP to PTx-VF for warfarin reversal is based on clinician's preference.Aim of studyTo study the clinical, laboratory, therapeutic and outcome data on patients who underwent emergency reversal of warfarin anticoagulation, and to compare the warfarin reversal (INR values) after administration of PTx-VF vs PTx-VF + FFP.MethodsWe performed a retrospective study of patients who underwent emergency reversal of warfarin in our hospital between January 2011 and December 2013. All the patients who underwent emergency reversal of warfarin with PTx-VF +/- FFP were captured from the blood bank database. Patients who received PTx-VF for indications other than emergency warfarin reversal and those with insufficient data were excluded from the study. The clinical, laboratory and transfusion data of these patients and the warfarin reversal strategies and clinical outcomes across different clinical settings were analysed. Non-parametric statistical analysis was used to compare the differences in post-treatment INR values in the PTx-VF vs PTx-VF + FFP groups and statistical significance was assumed at a P value of less than 0.05.ResultsA total number of 125 patients who underwent emergency warfarin reversal were included in the study. The median age was 77 years (range: 28 - 95) with 78 males (62%) and 48 females (38%). Table-1 presents clinical characteristics of the patients. Three clinical subgroups were identified - major bleeding in 61 patients (49%), emergency surgery in 54 patients (43%) and supra-therapeutic INR with high risk of bleeding in 10 patients (8%). Table-2 compares the clinical, laboratory, management and outcome characteristics in these subgroups. According to clinicians' preference, 56% of patients received PTx-VF alone, while 44% received PTx-VF + FFP. Statistically there were no differences in median INR values performed within 6 - 12 hours after administration of PTx-VF vs PTx-VF + FFP in all patients (P = 0.10), bleeding subgroup (P = 0.08) and emergency surgery subgroup (P = 0.24); and the number of patients in the supra-therapeutic INR subgroup was very small for evaluation. Overall 4 patients died due to warfarin-related complications, all of them in the bleeding subgroup.ConclusionIn our study majority (64%) of patients were above 75 years and the most common (69%) reason for warfarin anticoagulation was atrial fibrillation, which were similar in other studies. We observed that GI bleeding was the most common cause for warfarin reversal. Rapid INR correction with good clinical haemostasis occurred in most of the patients after administration of PTx-VF +/- FFP. The mortality rate in our cohort was 3% (4 of 125), and intracranial bleeding accounted for 75% (3 of 4) deaths. Among 14 patients who experienced intracranial bleeding, either spontaneous or induced by trauma, three (21%) died. There were no significant differences in the post-treatment INR values with PTx-VF alone when compared to PTx-VF + FFP, overall and also in the clinical subgroups. The major advantage of warfarin over DOACs is the rapid reversibility in emergency settings and we demonstrated that our 3-factor PCC (PTx-VF) was effective in emergency reversal of warfarin, without the need for FFP. There are a few limitations in this study since it is retrospective and observational. Hence prospective studies are required for better evaluation of the clinical characteristics, and the efficacy of 3-factor PCC without FFP in emergency reversal of warfarin anticoagulation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The outcomes of three-factor prothrombin complex concentrate (3F-PCC) in warfarin anticoagulation reversal: a prospective, single-arm, open-label, multicentre study.

There is a wide variation on the efficacy of three-factor Prothrombin Complex Concentrate (3F-PCC) in warfarin reversal. We aimed to determine the efficacy and safety of 3F-PCC in warfarin reversal. This multicentre prospective study analysed data from adult patients on warfarin who received 3F-PCC (Prothrombinex-VF®) for anticoagulation reversal between June 2019 to October 2020. Purposive sampling was used in this study. Study endpoints included target INR achievement, adverse drug reactions (ADRs), and in-hospital all-cause mortality. Logistic regression analyses were used to assess independent predictors of study endpoints. One-hundred thirty-seven patients with a median age of 68 (59-76) years were recruited, who were predominantly male (59.9%, n = 82). A total of 102 patients required 3F-PCC for life-threatening (40.9%, n = 56) and clinically significant bleeding (33.6%, n = 46). Initial INRs ranged from 1.55 to undetectable high (> 26). All patients had INR reduction, of which 62% (n = 85) achieved target INR, whereas 12.4% (n = 17) achieved INR below the target range. Median INR was reduced from 4.76 (3.14-8.32) to 1.54 (1.27-1.88) post-3F-PCC (p < 0.001). The use of adjunctive reversal agents and initial INR < 3.6 were the significant predictors for target INR achievement. Six (4.4%) ADRs were observed. Two (1.5%) cases with the suspected acute coronary syndrome were associated with mortality. Ischemic stroke occurred in one (0.7%) patient. The incidence of in-hospital all-cause mortality was 21.2% (n = 29). The rate of INR achievement was 62% in our study without apparent increased risk of thromboembolic events and in-hospital all-cause mortality.

Warfarin-associated intracranial haemorrhage in pregnant woman with double mechanical valve replacement: a case presentation

BackgroundManagement of warfarin-associated major haemorrhage in prosthetic valve diseases is difficult as there is a fine line between haemorrhage and thrombosis. An individual’s propensity towards thrombosis, such as pregnancy, makes this situation even more complicated. Cases like these are very rare in the literature.Case presentationA 26 weeks pregnant, gravida two, para one, 35-year-old patient with prosthetic aortic and mitral valves presented to an external emergency clinic with clouding of consciousness. Her international normalised ratio(INR) was 8.9 at presentation. Brain MRI revealed a left subdural haematoma with no significant mass effect. Warfarin treatment was discontinued. On the second day of follow-up, she was referred to our centre for further evaluation of her clinical deterioration. She was haemodynamically stable on admission to the intensive care unit and followed up with a stable condition until the fourth day when she developed right eye drop and subsequent loss of consciousness. Her haematoma was surgically evacuated, and her condition improved. Eventually, she and a healthy newborn were discharged.ConclusionIntracranial haemorrhage during pregnancy is a relatively rare complication that requires a multidisciplinary management plan. Although the thrombogenic risk is high, it is vital to complete a reversal of warfarin anticoagulation in pregnant women with major bleeding.

Efficacy and safety of four-factor prothrombin complex concentrate fixed, weight-based dosing for reversal of warfarin anticoagulation

ABSTRACT Background Four-factor prothrombin complex concentrate (4F-PCC) is widely used for urgent reversal of anticoagulation with warfarin, but the optimal 4F-PCC dosing approach is unknown. Herein, we sought to determine the efficacy of a novel fixed, weight-based dosing nomogram. Methods We retrospectively studied consecutive adult patients receiving fixed, weight-based 4F-PCC dosing for warfarin reversal between 30 April 2009 and 31 December 2010. The primary outcome was reversal of warfarin anticoagulation, defined as INR ≤1.5 within 6 h. Secondary outcome was the occurrence of thromboembolic events. Results A total of 227 patients (56% male), with a median age of 74 years and a median weight of 76kg were evaluated. The most common indications for 4F-PCC were active bleeding (37.4%: 12.7% intracranial, 12.3% gastrointestinal, 4.0% trauma, 8.4% other), reversal for a procedure (22.0%), reversal for surgery (29.5%) or other (11.1%). 66.1% of patients achieved an INR ≤1.5 within 6 h of 4F-PCC administration. 95.0% (57/60) of patients completed a planned procedure and 95.7% (67/70) of patients completed a planned surgery. The median baseline INR was 2.9 (1.5–10) and decreased significantly to a median of 1.3 (1.0–3.7) (p < .001) post-4F-PCC administration. There was no statistically significant difference in response to a fixed, weight-based dose of 4F-PCC based on pre-PCC INR, as long as the pre-treatment INR was ≤ 4.5. Although the majority of patients in our study (99%) received doses over 1000IU, rates of thrombosis were low (1.8%). Conclusion Fixed, weight-based dosing of 4F-PCC is effective for reversing warfarin anticoagulation in patients with a pre-dosing INR ≤ 4.5.

Reversal of warfarin anticoagulation in geriatric traumatic brain injury due to ground-level falls

BackgroundThe efficacy of prothrombin complex concentrate (PCC) compared with fresh frozen plasma (FFP) for reversal of oral anticoagulants has not been investigated in geriatric patients suffering intracranial hemorrhage (ICH) due...

Prothrombin Complex Concentrates (PCCs) Have Limited Effect on TF-Initiated Thrombin Generation in FXa Inhibitor-Anticoagulated Plasma: In Vitro Comparison between Direct Reversal By Andexanet Alfa and “Work Around” By PCCs

Introduction: Direct oral FXa inhibitors (DOACs, e.g., apixaban [Apix] and rivaroxaban [Riva]) exert their anticoagulant activity by specifically targeting FXa with subnanomolar affinities. Reversal of DOAC-induced anticoagulation can be achieved by immediate and effective sequestration of the inhibitors to relieve inhibition of FXa activity and restore normal thrombin generation (TG). Andexanet alfa (AnXa) is a modified human FXa protein approved in the US and EU for patients treated with Apix or Riva, when reversal of anticoagulation is needed due to life-threatening bleeding. Factor replacement therapies (e.g., 4 factor-PCCs [4F-PCCs]) have demonstrated clinical benefit for vitamin K antagonist-anticoagulated patients by replacing factors II, VII, IX, and X rendered deficient by the anticoagulant. In contrast, the effectiveness and clinical benefit of 4F-PCCs are unclear for reversing DOACs because PCCs do not affect anti-FXa activity. In the present study, we evaluated the effect of individual coagulation factors (FIX, FX, FII), as well as 4F-PCCs on TF-initiated TG (TF-TG) in human platelet poor plasma (PPP), with or without Apix or Riva, and compared it with AnXa under the same conditions. Methods: TF-TG was measured using a calibrated automated thrombogram (CAT, 5 pM TF, Diagnostica Stago). Purified plasma proteins (FIX, FX, FII), PPP, and a commercially available 4F-PCC (Kcentra/Beriplex) were used. 4F-PCC was used with or without pretreatment with the heparinase cup (Haemonetics Corporation) at room temperature for 30 minutes. TF-TG was measured in PPP spiked with purified plasma proteins, 4F-PCC (0-1.0 IU/mL), 4F-PCC + Riva or Apix (0-250 ng/mL), or PPP with AnXa (0-4 μM) + Riva or Apix (0-2000 ng/mL). For comparison, reversal of warfarin anticoagulation by 4F-PCC was performed under similar conditions using individual plasma from warfarin-treated patients (INR = 1.5-6.9) spiked with 4F-PCC (0-1.0 IU/mL). Five CAT parameters were collected, and the endogenous thrombin potential (ETP) and Peak thrombin (Peak) were used for the comparisons. Results: In normal PPP, addition of FX (up to 1.0 IU/mL) had minimal effect on TF-TG parameters, whereas FIX (1.0 IU/mL) mainly increased Peak (~60%). In contrast, FII (1.0 IU/mL) increased both the ETP (~2x) and Peak (~50%). These observations are consistent with the relative plasma concentration and affinity of these coagulation factors as the substrate for the respective enzyme complexes, demonstrating the predominant role of prothrombinase activity in the TF-TG. Addition of 4F-PCC (1.0 IU/mL, equivalent to the therapeutic dose of 50 IU/kg) to PPP caused similar increases of ETP (~2.4x) and Peak (~40%). However, individual plasma protein (FIX, FX, FII) or 4F-PCC up to 1.0 IU/mL was unable to restore normal ETP or Peak in the presence of Apix or Riva (75-250 ng/mL). ETP and Peak increased only when the inhibitor concentrations were sufficiently low (&amp;lt;75 ng/mL), leading to less inhibition of FXa and increased FIIa formation, likely due to an increased FII level from 4F-PCC addition. Similar results were obtained with or without preincubation of 4F-PCC with heparinase prior to spiking in plasma. In contrast, AnXa (0-4.0 μM) dose-dependently reversed Apix- and Riva- (up to 2000 ng/mL) induced inhibition of TF-TG. In the same TF-TG assay, 4F-PCC dose-dependently reversed warfarin anticoagulation in warfarin-treated patients' plasma spiked with 4F-PCC. Conclusions: Specific reversal agents are effective for restoration of TF-TG by either direct sequestration of the FXa inhibitor and restoration of FXa activity (in the case of AnXa with FXa inhibitors) or by replacement of inactive factors due to warfarin treatment (in the case of 4F-PCCs). Addition of coagulation factors or use of 4F-PCCs had limited effect on restoration of normal TG in the presence of a FXa inhibitor. These data demonstrate that AnXa can normalize TF-TG over a wide range of FXa inhibitor concentrations (0-2000 ng/mL), in particular over the range observed in bleeding patients in the ANNEXA-4 study, where 77% of bleeding patients had inhibitor levels ≥75 ng/mL at baseline. In contrast, 4F-PCCs were only able to restore normal TF-TG at low inhibitor levels (&amp;lt;75 ng/mL). These in vitro data are consistent with ANNEXA-4, where AnXa demonstrated &amp;gt;90% immediate reversal of anti-FXa activity and &amp;gt;80% hemostatic efficacy with a wide range of FXa inhibitor levels and multiple bleed types. Disclosures Lu: Portola Pharmaceuticals: Employment, Equity Ownership. Lin:Portola Pharmaceuticals, Inc: Employment, Equity Ownership. Bui:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership.

Prothrombin, alone or in complex concentrates or plasma, reduces bleeding in a mouse model of blood exchange-induced coagulopathy

Prothrombin complex concentrates (PCC) are fractionated plasma protein drugs that reverse warfarin anticoagulation. PCC may control more general bleeding. We sought to identify the dominant procoagulant factor in PCC in vivo. We tested PCC or coagulation factor (F) treatment in CD1 mice made coagulopathic by exchange of whole blood for washed red cells. Anesthetized mice were transfused with murine fresh-frozen plasma (mFFP), PCC, mixtures of human vitamin K-dependent proteins (VKDP) (prothrombin, FVII, FIX, or FX), or purified single human VKDP, immediately prior to tail transection (TT), liver laceration (LL), or intravascular laser injury (ILI). Plasma donor mice were treated with vehicle or control antisense oligonucleotide (ASO-CON) or ASO specific for prothrombin (FII) (ASO-FII) to yield mFFP or ASO-CON mFFP or ASO-FII mFFP. Blood losses were determined spectrophotometrically (TT) or gravimetrically (LL). Thrombus formation was quantified by intravital microscopy of laser-injured arterioles. PCC or four factor- (4F-) VKDP or prothrombin significantly reduced bleeding from TT or LL. Omission of prothrombin from 4F-VKDP significantly reduced its ability to limit bleeding. Mice transfused with ASO-FII mFFP demonstrated inferior haemostasis versus those transfused with ASO-FII following TT, LL, or ILI. Prothrombin is the dominant procoagulant component of PCC and could limit bleeding in trauma.

Results of Octaplex for reversal of warfarin anticoagulation in patients with hip fracture.

Patients with hip fracture who present anticoagulated with warfarin often require reversal of anticoagulation for safe hip fracture surgery. Vitamin K is typically administered for this, but requires 24-48 hours for maximal effect. These patients have an increased delay to surgery and increased mortality. Octaplex is a prothrombin complex concentrate (PCC) that reverses warfarin anticoagulation in less than an hour. This study assesses the effectiveness and safety of Octaplex for reversal of warfarin anticoagulation for hip fracture surgery. We reviewed the medical records of all patients with hip fracture in Calgary who received Octaplex between 2009 and 2015. Timing of admission, Octaplex administration and hip fracture surgery were recorded. Mortality and cardiac, thrombotic and orthopedic complications were assessed. Median time from Octaplex administration to an international normalized ratio of 1.4 or lower was 1.1 hours. The median time from admission to surgery was 22 hours. Thirty-day mortality was 15.2%, with 4 cases of cardiac arrest and 1 respiratory arrest. Patients who received both Octaplex and fresh frozen plasma (FFP) had a lower rate of 30-day survival than those who received only Octaplex (95.7% v. 60.0%, p = 0.002). There were significant rates of cardiac events and 30-day mortality among patients who received Octaplex, but this is unsurprising in this population with multiple medical comorbidities. We caution against administrering both FFP and a PCC in patients for warfarin reversal. Octaplex is effective for rapidly reversing warfarin anticoagulation and reducing delays to hip fracture surgery. Further study comparing Octaplex to reversal using only vitamin K is required.

Reversal of warfarin anticoagulation using prothrombin complex concentrate at 25 IU kg-1 : results of the RAPID study.

Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). The RAPID protocol reduces unwarranted delays without compromising efficacy.

Dose‐associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal

ESSENTIALS: Fresh frozen plasma (FFP) may be associated with a dose-based risk of pulmonary complications. Patients received FFP for warfarin reversal at a large academic hospital over a 3-year period. Almost 20% developed pulmonary complications, and the risk was highest after > 3 units of FFP. The risk of pulmonary complications remained significant in multivariable analysis. Fresh frozen plasma (FFP) is often administered to reverse warfarin anticoagulation. Administration has been associated with pulmonary complications, but it is unclear whether this risk is dose-related. Aims We sought to characterize the incidence and dose relationship of pulmonary complications, including transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI), after FFP administration for warfarin reversal. We performed a structured retrospective review of patients who received FFP for warfarin reversal in the emergency department (ED) of an academic tertiary-care hospital over a 3-year period. Logistic regression was used to explore the relationship between FFP dose and risk of pulmonary events. Two hundred and fifty-one patients met the inclusion criteria. Overall, 49 patients (20%) developed pulmonary complications, including 30 (12%) with TACO, two (1%) with TRALI, and 17 (7%) with pulmonary edema not meeting the criteria for TACO. Pulmonary complications were significantly more frequent in those who received > 3 units of FFP (34.0% versus 15.6%, 95% confidence interval for risk difference 7.9%-8.9%). After stratification by subtype of complication, only the risk of TACO was statistically significant (28.3% versus 7.6%, 95% confidence interval for risk difference 8.2%-16.6%). In multivariable analysis controlling for age, sex, initial systolic blood pressure, and intravenous fluids given in the ED, > 3 units of FFP remained a significant risk factor for pulmonary complications (odds ratio 2.49, 95% confidence interval 1.21-5.13). Almost 20% of patients who received FFP for warfarin reversal developed pulmonary complications, primarily TACO, and this risk increased with > 3 units of FFP. Clinicians should be aware of and prepared to manage these complications.

Feasibility and clinical effectiveness of pre-hospital prothrombin complex concentrates (Octaplex/Beriplex) in anticoagulated patients with traumatic intracranial haemorrhage

Background Incidence and mortality from traumatic intra-cranial haemorrhage (ICH) is increased in patients on warfarin [1]. Prothrombin Complex Concentrates (PCC) rapidly reverse warfarin anti-coagulation and have been shown to reduce haematoma expansion and mortality in warfarinised patients sustaining ICH [2]. We aimed to determine the feasibility of pre-hospital use of PCCs by physicians and their clinical effectiveness in warfarinised patients sustaining traumatic ICH.

Reversal of warfarin anticoagulation for urgent surgical procedures.

Patients treated with warfarin for therapeutic anticoagulation present a challenge for the perioperative management of urgent and emergent surgery. Anticoagulation must be reversed prior to most surgical procedures to prevent intraoperative bleeding. The purpose of this module is to review the options for urgent reversal of warfarin anticoagulation and the indications for each reversal agent. Selection of the appropriate agent is important to reduce unnecessary complications of treatment and to achieve optimal reversal of anticoagulation. When urgent surgery is required for patients taking warfarin, intravenous vitamin K1 should be used for procedures that can be delayed for six to 12hr. Vitamin K1 results in the activation of existing clotting factors rather than requiring the synthesis of new proteins, which allows for its relatively rapid onset of action. Intravenous vitamin K1 acts more quickly than oral administration, with reversal of anticoagulation occurring within six to 12hr vs 18-24hr, respectively. If surgery cannot be delayed, prothrombin complex concentrates (PCCs) should be given, and intravenous vitamin K1 should be infused concurrently to ensure sustained reversal of anticoagulation. The duration of action of both PCCs and plasma is six hours due to the short half-life of factor VII. Prothrombin complex concentrates contain small amounts of heparin and are contraindicated in patients with heparin-induced thrombocytopenia. Plasma should be used only if PCCs are unavailable or are contraindicated. Reversal of warfarin anticoagulation can be achieved in a safe and timely manner when the appropriate agent is selected and administered correctly.

Use of prothrombin complex concentrate in warfarin anticoagulation reversal in the emergency department: a quality improvement study of administration delays.

BackgroundQuick reversal of warfarin anticoagulation is important in life threatening bleeding. The aim of this study is to improve the administration delay when using Prothrombin Complex Concentrate (PCC) for the emergent reversal of warfarin anticoagulation in the emergency department.MethodsAn audit and feedback quality improvement project was conducted in three phases: a retrospective audit phase, an analysis and feedback phase and prospective evaluation phase. The charts of all eligible patients in a single Emergency Department (ED) in Québec, Canada, who received PCC since the introduction of this product in 2009 until October 31, 2011, were retrospectively audited. The administration delay of PCC was calculated from the time of prescription to the time of administration. With the data, we determined where improvements could be attained, and jointly with all stakeholders in the ED and the blood bank, we created an action plan to ensure the timely administration of PCC. The action plan was then implemented and a six-month prospective evaluation study was conducted to determine any improvement.ResultsSeventy-seven charts were reviewed in the retrospective chart audit. The mean administration delay was 73.6 minutes (STD [34.1]) with a median of 70.0 minutes (25–75% IQR [45.0–95.0]). We found that this delay was principally due to the following barriers: communication problems between the ED and the blood bank as well as delivery inefficiencies. An action plan that involved a flowchart to remind all clinicians how to order PCC and a new delivery method from the blood bank to the ED were developed. During the 6 months following the implementation of our action plan, 39 patients received PCC and the mean administration time decreased to 33.2 minutes (STD [14.2])(p < .0001) with a median of 30.0 minutes (25–75% IQR [24.3–38.8]).ConclusionBy implementing an action plan comprising of a flowchart and a new delivery process, this audit and feedback quality improvement project reduced the administration time of PCC by more than half. Future studies to measure the impact of a similar audit and feedback process involving an action plan in other centers should be conducted before this type of quality improvement process is implemented on wider scale.

Prophylactic Fresh Frozen Plasma Infusion is Ineffective in Reversing Warfarin Anticoagulation and Preventing Delayed Intracranial Hemorrhage After Falls.

Elderly patients, with considerable fall risk, are increasingly anticoagulated to prevent thromboembolic disease. We hypothesized that a policy of prophylactic fresh frozen plasma (FFP) infusion in patients having falls would reverse vitamin K antagonists (VKAs) and that reversal would decrease delayed intracranial hemorrhage (ICH). A retrospective review of patients with trauma admitted to a level 2 community trauma center was performed from January 2010 until November 2012. Inclusion criteria were: ground level fall (GLF) with suspected head trauma, on VKA, an international normalized ratio (INR) of >1.5, and a negative head computed tomography (CT). Patients were transfused with FFP to a goal INR of <1.5 while observed. Patients were classified as reversed (REV) if the lowest INR achieved within 4 to 24 hours after initial INR was <1.5 or unreversed (NREV) if lowest INR achieved was >1.5. Chi-square and logistic regression were performed. A total of 194 patients met the criteria. In all, 43 (22%) patients were able to be REV, and 151 (78%) patients remained NREV. Unreversed patients were male and younger (P < .05). There was no difference in mean FFP received. Unreversed patients had a higher initial INR of 3.0 compared to REV patients (2.5; P = .018). One patient developed a delayed ICH and belonged to the REV group. The incidence of delayed hemorrhage was 0.5%. A strategy of prophylactic FFP infusion was ineffective in VKA reversal. We recommend against prophylactic infusion of FFP during a period of observation for patients on VKA with suspected head trauma and a negative initial CT.

Efficacy and safety of Prothrombin Complex Concentrates Weight-Based Dosing for Reversal of Warfarin Anticoagulation

▪Background: Prothrombin complex concentrates (PCCs) are widely used for correcting elevated international normalized ratio (INR) levels in patients anticoagulated with warfarin requiring an urgent reversal. However, the optimal dosing regimen has yet to be defined. In 2008, the Canadian National Advisory Committee (NAC) on blood product utilization recommended a single dose of 1000 IU for all adults over 18 years of age, irrespective of INR levels, and suggested further consultation with a Hematologist if extremes in weight or INR were observed. A revision in 2011, suggested dosing based on the INR elevation as an option and in 2014 the recommendation was updated to include a possible algorithm including both INR and weight. Currently there is insufficient evidence to suggest that one approach is more efficacious than another. Our institution has been using a novel weight-based dosing protocol for PCCs since 2009, which dispenses to a maximum of 3000 IU for adults weighing over 100kg. Herein, we sought to determine the efficacy of our weight-based dosing nomogram.Methods: We conducted a retrospective cohort study of all consecutive adult patients (age > 18 years) who received PCCs using our weight based dosing regimen between April 30, 2009 and December 31, 2010. All patients were anticoagulated with warfarin. Clinical and laboratory information was obtained through chart review. The weight based regimen consisted of 1000 IU for weight less than 40kg, 1500IU for 41 to 60kg, 2000 IU for 61 to 80kg, 2500 IU for 81 to 100kg, and 3000 IU for > 100kg. Doses of PCCs were based on the concentration of factor IX. PCCs utilized at this centre were Octaplex and Beriplex. The primary outcome was reversal of warfarin anticoagulation, as defined by an INR of 1.5 or less to achieve a clinical response within 6 hours. Statistical analysis was done using descriptive statistics and chi squared analysis.Results: A total of 227 charts were included in the study from April 30, 2009 to December 31, 2010. The median age was 74 years old (range 40-95), the median weight was 76kg (range 44-200), and 56% of patients were male. Medical indications for warfarin anticoagulation included atrial fibrillation (68%), DVT (32%) and stroke (21%). The most common indication for PCCs was active bleeding (44%: 13% intracranial, 12% gastrointestinal, 4% trauma, 15% other), reversal for a procedure (22%) and reversal for surgery (30%). Prior to receiving PCCs, 29% of patients were taking Aspirin and 4% were taking Clopidogrel. The percentages of patients treated with each dose were: 1000IU (1.3%), 1500IU (17.6%), 2000IU (41.0%), 2500IU (24.2%), 3000IU (15.9%). A second dose of PCC was given to 0.4% of patients. FFP was given to 7% of patients prior to PCCs administration and 14% of patients post PCCs administration. 63% of patients received vitamin K. Seventy-nine percent of patients achieved an INR of 1.5 or less within 6 hours of PCC administration. There was a statistically significant difference in response based on pre-PCC INRs (see table 1). The median baseline INR was 2.9 (range 1.5- >10) and decreased to a median of 1.3 (range 1.0-3.7) post-PCCs administration. Planned procedures were completed in 93% of 60 patients, and planned surgeries were completed in 94% of 70 patients within 24 hours of receiving PCCs. Four patients (2%) developed a deep vein thrombosis within 30 days of receiving PCCs.Conclusion: Our study demonstrates that weight based dosing is effective in reversal of anticoagulation in patients on warfarin. Laboratory response rates are similar to other studies (Wozniak et al). Although the majority of patients in our study (99%) received doses over 1000IU; rates of thrombosis are low. Future studies comparing different strategies are needed.Table 1INR rangePre-PCCProportion with Post-PCC INR of 1.5 or less (%)P-value1.5-3110/122 (90%)3.1-4.533/43 (77%)0.037*>4.535/62 (56%)<0.001***1.5-3 vs 3.1-4.5**1.5-3 vs >4.5 DisclosuresLazo-Langner:Pfizer Bayer LEO Pharma: Honoraria. Chin-Yee:Alexion Pharmaceuticals: Research Funding.

Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal.

IntroductionProthrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation.MethodsData were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety.ResultsSeventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, p < 0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost.ConclusionsBased on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa.

Prothrombin complex concentrate for rapid reversal of warfarin anticoagulation to allow neuraxial blockade.

The development of Prothrombin Complex Concentrates (PCCs) has led to better outcomes in patients receiving emergency reversal of warfarin. However, most published data describes the use of PCCs in the setting of major bleeding or emergent major surgery, with little information on neuraxial blockade. We describe a case of rapid warfarin reversal using PCC and subsequent surgery under spinal anaesthesia in an 87-year-old lady, for whom general anaesthesia was deemed high risk. Her international normalised ratio (INR) on the morning of surgery was 1.8, precluding neuraxial blockade; however, it was felt that given, the need for imminent surgery, immediate reversal of the warfarin was indicated. We administered a single dose of 23 units/kg PCC and 5 mg vitamin K. Her INR 1 hour following PCC was 1.2, and spinal anesthetic was administered. The patient then underwent excision of melanoma deposits from her leg and groin dissection. There were no complications, the patient recovered satisfactorily, and there were no thrombotic or hemorrhagic events at 30 days postoperatively. This case study demonstrates a novel use of PCCs; in certain patients, PCCs may be safely used for immediate reversal of warfarin to allow for neuraxial blockade, safer anaesthesia, and better outcomes.

Use Of Prothrombin Complex Concentrates In Warfarin Anticoagulation Reversal In The Emergency Department: A Quality Improvement Study Of Administration Delays

Introduction In some bleeding situations, quick reversal of warfarin anticoagulation is important. In the event of a major life-threatening bleeding event, the anticoagulation reversal delay can have an impact on mortality. This study aimed to improve the administration delay when using Prothrombin Complex Concentrate (PCC) for the emergent reversal of warfarin anticoagulation in the emergency department. Methods An audit and feedback quality improvement project was conducted in three phases: a retrospective audit phase, an analysis and feedback phase and prospective evaluation phase. The charts of all eligible patients in a single Emergency Department (ED) in Québec, Canada, who received 4-factor PCC since the introduction of this product in 2009 until October 31, 2011 were retrospectively audited with pre-planned evaluation criteria. The administration delay of PCC was calculated from the time of prescription to the time of administration. After this retrospective chart audit, we determined where improvements could be attained, gave feedback to the ED and the blood bank, and we created an action plan to ensure the timely administration of PCC. The action plan was then implemented in practice to reduce the administration delay. Finally, a six-month prospective evaluation study was conducted to determine if our action plan was followed and improved the administration delays. Results Seventy-seven charts were reviewed in the retrospective chart audit. The mean administration delay was 73.6 minutes (STD [34.1]) with a median of 70.0 minutes (25-75% IQR [45.0-95.0]). We found that this delay was principally due to the following barriers that prevented timely administration of PCCs: communication problems between the ED and the blood bank and reconstitution and delivery inefficiencies. In order to address these barriers, we developed an action plan that involved the following elements: a flowchart to remind all clinicians how to order PCCs and a new delivery method from the blood bank to the ED. During the 6 months following the implementation of our action plan, 39 patients received PCCs and the mean administration time decreased to 33.2 minutes (STD [14.2]) (p&lt;.0001) with a median of 30.0 minutes (25-75% IQR [24.3-38.8]). Conclusion This audit and feedback quality improvement project involving the development and the implementation of an action plan comprising of a flowchart and a new delivery process reduced the administration time of PCC by more than half. Future studies to measure the impact of implementing a similar audit and feedback process involving an action plan in other centers should be conducted before this type of improvement process is implemented on wider scale. Disclosures: No relevant conflicts of interest to declare.