Prothrombin Complex Concentrate(PCC)

Prothrombin complex concentrate is a combination of blood clotting factors II, VII, IX and X, as well as protein C, S and antithrombin prepared from fresh-frozen human blood plasma.

PCCs are isolated from fresh-frozen plasma (FFP), which is fractionated into cryoprecipitate and cryoprecipitate-free plasma fractions through a process of slow thawing. PCCs are then eluted from cryoprecipitate-free plasma, and single-factor concentrates are further derived by additional purification steps. It includes strict viral inactivation using solvents, detergents, pasteurization, nanofiltration, and vapor-heated treatment.

Four-Factor Prothrombin Complex Concentrate (4F-PCC) Is Superior to Three-Factor Prothombin Complex Concentrates (3F-PCC) for Reversal of Coumarin Anticoagulation Eva Herzog, Franz Kaspereit et al Blood 2014 124:1472; comparison of 4F-PCC and 3F-PCCs for the reversal of VKA anticoagulation in acute bleeding suggests that replenishment of all vitamin K-dependent coagulation factors including factor VII as achieved using a 4F-PCC may result in superior efficacy compared to the use of 3F-PCCs.

Half life of factor in PCC Facctor II Factor VII Factor IX Factor X Duration(hrs) 60-72 4.5-6 18-24 36-48

Fresh Frozen Plasma • The usual volume of 1 unit is ~250 cc = plasma taken from one unit of blood • Vitamin K dependent factors in concentration of 1 Unit/mL • FFP must be ABO compatible but not Rh factor • 10-20 cc/kg (4-6 units in adults) will increase factors by ~20% • It is frozen within eight hours of collection.

• FFP contains all coagulation factors in normal concentrations. PCC vs FFP • FFP contains all coagulation factors in normal concentrations. • May be transfused up to 5 days after thawing and contains slightly decreased levels of Factor V and decreased Factor VIII levels • Plasma is free of red blood cells, leukocytes and platelets • There are no viable leukocytes so plasma does not carry a risk of CMV transmission

Advantages of PCC vs. FFP More effective and rapid correction of INR(30 MINS) (median time- 17 mins) Greater increase in clotting factors(80-100% of factor II and X whereas 60 -80 % of factor VII and IX) Can be infused faster than FFP and with less volume Fewer complications secondary to fluid overload Shorter preparation time Does not require blood-type matching Expensive FFP Less effective correction(3 hrs) (median time-148 mins) Clotting factor increased to 20-30% Requires time to infuse (as larger volume is required) More chances of overload and TRALI Requires time for thawing Require ABO compatibility Comparatibly cheaper

Clinical indications of PCC treatment of patients with haemophilia B Congenital or acquired deficiency of vitamin K-dependent clotting factors Urgent reversal of over-anticoagulation with warfarin. Peri operative Coagulopathy reversal of coagulopathy of trauma

Dosing schedules of PCC 1. Standardized single dose: 1000 IU (40 mL) regardless of weight or INR(2008 NAC recommendation) 25 IU/kg or 40 IU/kg also been reported in the literature. 2. INR based dosing: 2011 NAC recommendation PCC dose if INR > 5 PCC dose if INR 3-5 PCC dose if INR <3 Dose 3000 IU (120 mL) 2000 IU (80 mL) 1000 IU ( 40 mL)

Complications of PCC Adverse events associated with PCC include allergic reactions heparin-induced thrombocytopenia (HIT, for the preparations containing heparin) thromboembolic complications(stroke, MI, PE, DIC and DVT)

Thromboembolic complications with the use of the PCC Author, year (reference) Study design Inclusion criteria N. of patients Thromboembolic events (%) Evans, 2001 Prospective non-randomised Major bleeding and INR > 14 10 0/10 Preston, 2002 Major bleeding or need for urgent reversal of anticoagulation 42 1/42 (2.4) Lorenz, 2007 Prospective cohort Need for urgent reversal of anticoagulation 8 0/8 Pabinger, 2008 Prospective multicentre Emergency anticoagulation reversal 43 1/43(2.3) Bruce, 2008 24 0/24 Retrospective analysis Severe bleeding 24 0/24 Schick, 2008 Retrospective Major bleeding or urgent anticoagulation reversal 50 0/50 Staudinger, 1999 Prospective Overt bleeding or planned invasive procedures in critically ill patients 16 0/16 Lorenz, 2003 Acute bleeding or surgical/invasive procedures in patients with liver disease 22 0/22 Total 215 2/215 (0.9)

PCC in CLD Chronic liver disease is associated with multiple changes in coagulation status. Activity and levels of vitamin K–dependent coagulation factors (II, VII, IX, and X) and coagulation inhibitors (protein C and S) are decreased Platelet count is also decreased

Levels of tissue factor–expressing cells, von Willebrand factor, and coagulation Factor (F)VIII are often increased. The concomitant reduction of pro- and anticoagulants typically leads to rebalanced hemostasis The low levels of pro- and anticoagulants mean that the balance can be easily disturbed, potentially leading to either bleeding or thrombosis.

Blood Products in Liver Transplant Transfusion of RBCs, FFP, and PLTs has been shown to be associated with increased morbidity and mortality in major liver surgery and transplantation. Prophylactic use of recombinant activated FVII has been recommended This treatment failed to reduce transfusion requirements in LT in a multicenter, randomized trial. Moreover, the incidence of arterial thrombotic events was significantly higher compared to controls (5.5% vs. 3.2%, p = 0.003)

Other hemostatic strategies include point-of-care thromboelastometry guided coagulation management based on first-line therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC). This treatment strategy has been shown to be effective in cardiovascular surgery and severe trauma. Moreover, this strategy has been associated with a reduced incidence of thrombotic or thromboembolic events

Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial Freeha Arshad1, Brigitte Ickx2 et al BMC Surgery 201313:22, DOI: 10.1186/1471-2482-13-22 Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. PCC is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure In contrast to the traditional infusion of FFP to stimulate coagulation in cirrhotic patients

We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. The efficacy and safety of PCC in patients with liver cirrhosis requiring major abdominal surgery, however, has never been demonstrated.

Use Of Prothrombin Complex Concentrates In Patients With Hepatic Coagulopathy: A Single Center Retrospective Guillaume Richard-Carpentier, Normand Blais and Benjamin Rioux-Masse Blood 2013 122:2400; Minor bleeding events in patients with hepatic coagulopathy were controlled by the administration of PCC. This study did not show an association between the correction of INR and the efficacy of PCC to control bleeding. PCC is less effective in patients with Child-Pugh C cirrhosis and acute liver failure. This might be due to deficit in coagulation factors such as factor V and fibrinogen that are not supplemented by PCC. Bleeding associated with hepatic coagulopathy is complex and the role of PCC requires further evaluation in regards to other blood products utilization and interventions. Some thromboembolic events and deaths occurred after PCC administration warranting further studies of these agents in different disorders of hemostasis.

Take home Mesage Use of PCC and fibrinogen concerntrate have advantage over allogenic plasma in its rapid availability and restoration of target factors and has lower risks for volume overload and TRALI. Although careful consideration in dosing of PCC is required because of risks of thrombosis

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Clotting Factors Factor number Descriptive I  Fibrinogen - II  Prothrombin III  Tissue factor V  Labile factor VII  Proconvertin VIII  Antihaemophilic factor IX  Christmas factor X  Stuart–Prower factor XI  Plasma thromboplastin XII  Hageman (contact) factor XIII  Fibrin-stabilizing factor