923 April 2015 P rothrombin complex concentrates (PCCs) are recommended in preference to other treatments such as therapeutic plasma for urgent reversal of vitamin K antagonists.1,2 PCCs contain either three or four coagulation factors (factors ii, iX, and X, with or without factor Vii) and, depending on formulation, low doses of coagulation inhibitors such as protein C, protein S, and heparin (table 1). There are considerable variations among countries in the availability and licensing status of PCCs. For example, four-factor PCCs have been used for many years in Europe, where their license is not restricted to vitamin K antagonist reversal—they have broad approval for “treatment and prophylaxis of bleeding in acquired deficiency of the prothrombin complex coagulation factors.” in the United States, however, the first four-factor PCC was only recently approved, specifically for urgent reversal of vitamin K antagonist therapy. The mechanism of action of PCCs is important for understanding their therapeutic applications. Vitamin K antagonists such as warfarin function by reducing levels of four coagulation factors: ii, Vii, iX, and X, with the aim of preventing thromboembolism. For patients with life-threatening bleeding, rapid replacement of these coagulation factors is required, and PCCs serve as a concentrated source of the required coagulation factors. Three-factor as well as four-factor PCCs have been explored for vitamin K antagonist reversal. however, due to the absence of factor Vii, it appears that three-factor PCCs are less suitable than four-factor PCCs for patients with an international normalized ratio (inr) greater than 3.7.3 in trauma and perioperative bleeding, patients present with a variety of coagulopathies. PCCs increase thrombin generation potential by ensuring adequate levels of the key coagulation factors—notably factor ii (prothrombin), whose conversion to thrombin is facilitated by activated factor X and activated factor V. treatment with PCCs may potentially be effective in facilitating hemostasis in trauma and perioperative bleeding. however, the potential role of PCCs in these settings must be considered in the context of other treatment options and the patient’s overall coagulation status. Fibrinogen is generally the first coagulation factor to decrease below critical levels during bleeding.4 The physiological response to trauma includes an increase in thrombin generation,5 whereas fibrinogen levels are typically reduced in trauma patients upon admission to hospital.6 in cardiovascular surgery, it has been shown that fibrin formation is impaired to a greater extent than thrombin generation after cardiopulmonary bypass.7 Coagulation management algorithms based on coagulation factor concentrates have been published in relation to cardiovascular surgery8,9 and trauma (fig. 1).10 Some authors advocate the use of PCC in accordance with implementing such algorithms although it should be noted that, after antifibrinolytic medication, fibrinogen supplementation is recommended as first-line hemostatic treatment.8,10,11 PCCs may subsequently be considered for patients with ongoing bleeding despite restoration of fibrinogen levels. Throughout the management of coagulopathic bleeding, therapy should be tailored to the patient’s coagulation status. Point-of-care assessment, for example using rotEm® (tem international Gmbh, Germany) or tEG® (haemonetics Corp., USA), can help determine which of the available hemostatic therapies (e.g., therapeutic plasma, platelets, coagulation factor concentrates, or cryoprecipitate) should be administered. A deficiency in thrombin generation is more likely to arise later during the course of surgery. The potential risk of thromboembolic complications necessitates a cautious approach when using PCCs in trauma and perioperative bleeding. in these settings— unlike vitamin K antagonist reversal—levels of coagulation

Prothrombin Complex Concentrates in Trauma and Perioperative Bleeding

Background: Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest. Methods: Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment. Results: Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median [interquartile range], 650 mL [325–1075] vs 277 mL [175–608], P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number [percent], 44 [80%] vs 34 [76%], P = 0.594) or in the number of units of red blood cells transfused (median [interquartile range], 2 [1–4] vs 3 [1–5] units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio [OR] 2.39, 95% confidence interval [CI] 0.51–11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03–3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14–3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50–1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59–1.40, P = 0.66). Conclusions: This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted.

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An Exploratory Cohort Study Comparing Prothrombin Complex Concentrate and Fresh Frozen Plasma for the Treatment of Coagulopathy After Complex Cardiac Surgery

Prothrombin complex concentrate (PCC) is a term to describe pharmacological products that contain lyophilized, human plasma-derived vitamin K-dependent factors (F), FII, FVII, FIX, FX, and various amounts of proteins C and S. PCCs can be rapidly reconstituted in a small volume (20 ml for about 500 international units (IU)) at bedside and administered regardless of the patient’s blood type. PCCs are categorized as 4-factor PCC if they contain therapeutic amounts of FVII, and 3-factor PCC when FVII content is low. In addition, activated PCC which contains activated FVII and FX with prothrombin is available for factor VIII bypassing therapy in hemophilia patients with inhibitors. Currently, 4-factor PCC is approved for the management of bleeding in patients taking warfarin, but there has been increasing use of various PCCs in the treatment of acquired perioperative coagulopathy unrelated to warfarin therapy and in the management of bleeding due to novel oral anticoagulants. There is also an ongoing controversy about plasma transfusion and its potential hazards including transfusion-related lung injury (TRALI). Early fixed ratio plasma transfusion has been implemented in many trauma centers in the USA, whereas fibrinogen concentrate and PCC are preferred over plasma transfusion in some European centers. In this review, the rationales for including PCCs in the perioperative hemostatic management will be discussed in conjunction with plasma transfusion.

/pdf/role-of-prothrombin-complex-concentrate-in-perioperative-4c65tds7mx.pdf

Role of prothrombin complex concentrate in perioperative coagulation therapy

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg-1 . This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg-1 ) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.

A European consensus statement on the use of four‐factor prothrombin complex concentrate for cardiac and non‐cardiac surgical patients

Practical Use of Thromboelastometry in the Management of Perioperative Coagulopathy and Bleeding.

Prothrombin complex concentrates are increasingly used during complex cardiac surgery with cardiopulmonary bypass. Reports describing massive thromboembolism after administration of prothrombin complex concentrates are rare. We report a case of a patient developing massive intracardiac and pulmonary artery thrombus formations during infusion of a moderate dose of prothrombin complex concentrate after separation from cardiopulmonary bypass for complex open heart surgery.

Fulminant intraoperative right heart and pulmonary artery thrombosis following prothrombin complex concentrate infusion after complex open heart surgery with cardiopulmonary bypass.

Eugene Sandica

Papers

Fulminant intraoperative right heart and pulmonary artery thrombosis following prothrombin complex concentrate infusion after complex open heart surgery with cardiopulmonary bypass.