Novel Therapies for Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema: A Systematic Review of Current Evidence

Case Scenario: Management of Trauma-induced Coagulopathy in a Severe Blunt Trauma Patient

The use of prothrombin complex concentrate (PCC) to reverse acquired (coagulopathy of trauma) and induced coagulopathy (preinjury warfarin use) is well defined. To compare outcomes in patients with traumatic brain injury without warfarin therapy receiving PCC as an adjunct to fresh frozen plasma (FFP) therapy compared with patients receiving FFP therapy alone. All patients with traumatic brain injury coagulopathy without warfarin therapy who received PCC (25 IU/kg) in conjunction with FFP or FFP alone at our Level I trauma center were reviewed. Coagulopathy was defined as an international normalized ratio >1.5. The groups (PCC + FFP vs FFP alone) were matched using propensity score matching on a 1:2 ratio for age, sex, Glasgow Coma Scale score, Injury Severity Score, head Abbreviated Injury Scale score, and international normalized ratio (INR) on presentation. The primary outcome measure was time to craniotomy. Secondary outcome measures were blood product requirements, cost of therapy, and mortality. A total of 1641 patients were reviewed, 222 of whom were included (PCC + FFP, 74; FFP, 148). The mean ± standard deviation age was 46.4 ± 21.7 years, the median (range) Glasgow Coma Scale score was 8 (3-12), and the mean ± standard deviation INR on presentation was 1.92 ± 0.6. PCC + FFP therapy was associated with an accelerated correction of INR (P = .001) and decrease in overall pack red blood cell (P = .035) and FFP (P = .041) administration requirement. Craniotomy was performed in 26.1% of patients (n = 58). Patients who received PCC + FFP therapy had faster time to craniotomy (P = .028) compared with patients who received FFP therapy alone. PCC as an adjunct to FFP decreases the time to craniotomy with faster correction of INR and concomitant decrease in the need for blood product requirement in patients with traumatic brain injury exclusive of prehospital warfarin therapy.

Author(s): Bower, Matthew M; Sweidan, Alexander J; Shafie, Mohammad; Atallah, Steven; Groysman, Leonid I; Yu, Wengui

Efficacy of Prothrombin Complex Concentrate (PCC) for Reversal of Warfarin Effect.

Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Vitamin K Antagonist Reversal in Acutely Bleeding Patients: A Retrospective Study

Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). Forty patients [with international normalized ratio (INR)≥ 2·1] assigned semi-urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR ( ≤ 1·5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high ( ≥ 1·5). Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0·007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1·6 (1·2-2·2) with PCC vs. 2·3 (1·5-3·5) with FFP; 1 h after CPB both groups reached similar values [1·6 (1·3-2·2) with PCC and 1·7 (1·3-2·7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0·001). Both groups differed significantly on the course of factor II (P = 0·0023) and factor X (P = 0·008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. PCC reverses anticoagulation safely, faster and with less bleeding than FFP.

Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. VExperimental in vivo study.

Fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) reverse oral anticoagulants such as Warfarin. We compared the standard dosage of FFP and PCC in terms of efficacy and safety for patients with mechanical heart valves undergoing interventional procedures while receiving Warfarin. Fifty patients were randomized (25 for each group) with mechanical heart valves [international normalized ratio (INR) >2.5]. FFP dosage was administered based on body weight (10-15 mL/Kg), while PCC dosage was administered based on both body weight and target INR. INR measurements were obtained at different time after PCC and FFP infusion. The mean ± SD of INR pre treatment was not significantly different between the PCC and FFP groups. However, over a 48-hour period following the administration of PCC and FFP, 76% of the patients in the PCC group and only 20% of the patients in the FFP group reached the INR target. Five (20%) patients in the PCC group received an additional dose of PCC, whereas 17 (68%) patients in the FFP group received a further dose of FFP (P=0.001). There was no significant difference between the two groups in Hb and Hct before and during a 48-hour period after PCC and FFP infusion. As regards safety monitoring and adverse drug reaction screening in the FFP group, the INR was high (INR > 2.5) in 86% of the patients. There was no report of hemorrhage in both groups. PCC reverses anticoagulation both effectively and safely while having the advantage of obviating the need to extra doses.

The management of coumarin-induced over-anticoagulation Annotation.

Reversal of warfarin era thinking.

A multicenter, retrospective, observational study of 4-factor prothrombin complex concentrate (PCC) and/or fresh frozen plasma (FFP) use within routine clinical care unrelated to vitamin K antagonists was conducted. The PCC was administered preprocedure for correction of coagulopathy (prophylactic cohort) and treatment of bleeding postsurgery (treatment cohort). Of the 445 patients included, 40 were in the prophylactic cohort (PCC alone [n = 16], PCC and FFP [n = 5], FFP alone [n = 19]) and 405 were in the treatment cohort (PCC alone [n = 228], PCC and FFP [n = 123], FFP alone [n = 54]). Cardiovascular surgery was the most common setting. PCC doses ranged between 500 and 5000 IU. Effectiveness (assessed retrospectively) was reported as effective in 93.0% in the PCC-only group (95% confidence interval, 89.1% to 95.9%), 78.9% (70.8% to 85.6%) with PCC and FFP, and 86.3% (76.2% to 93.2%) with FFP alone. In the treatment cohort, international normalized ratio was significantly reduced in all 3 groups. In patients who received PCC, the rate of thromboembolic events (1.9%) was below rates in the literature for similar procedures. PCCs offer a potential alternative to FFP in the management of perioperative bleeding unrelated to oral anticoagulant therapy.

Introduction: It is unclear if administering a 3-factor prothrombin complex concentrate (PCC) with or without fresh frozen plasma (FFP) reverses the international normalized ratio (INR) faster than FFP alone in patients with warfarin-associated intracranial hemorrhage (ICH). Methods: This was an IRB approved retrospective cohort study of adult patients with warfarin-associated ICH and an INR>1.5 who received Profilnine with or without FFP versus FFP alone. Results: Of the 68 patients who met criteria, 32 patients were included in the PCC group and 36 patients were included in the FFP only group. The time to reversal of the INR to ≤1.5 from admission to a hospital was 11.3 hours in the PCC group and 15.4 hours in the FFP group (p=0.023). The time to reversal from treatment administration was 4.2 hours in the PCC group and 9.1 hours in the FFP group (p=0.001). In patients with a pre-treatment INR<3, the mean PCC dose was 34 IU/kg and the time to reversal was 9.2 hours for the PCC group and 15.7 hours for the FFP group (p=0.001). In patients with a pre-treatment INR >3, the mean PCC dose was 34–41 IU/kg and there was no significant difference between groups in time to reversal of the INR. A greater percentage of patients in the PCC group than in the FFP group had an INR ≤1.3 at 24 hours (91% vs 58%, p=0.03). In-hospital mortality was 22% for the PCC group and 8% for the FFP only group (p=0.17). There were 9 patients with documented pulmonary edema after treatment in the FFP only group versus 4 patients in the PCC group (p=0.75). There were 3 thrombotic events documented after PCC treatment (9%). Conclusions: This study demonstrated that a 3-factor PCC administered with FFP corrected the INR faster than FFP alone in patients with warfarin-associated ICH. When stratified by pre-treatment INR, PCC reversed the INR faster for patients with an INR<3, but not for patients with an INR>3. This may be explained by the lower than recommended average PCC dose administered to patients with an INR>4. Significantly more patients in the PCC group had an INR ≤1.3 at 24 hours than in the FFP group.

Efficacy and Safety of Prothrombin Complex Concentrate in Patients Undergoing Major Cardiac Surgery

Fibrinogen concentrate for management of bleeding

Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial