Acute coagulopathy following infusion of prothrombin complex concentrate.

An acute coagulopathy developed in a 49 year old woman with severe liver disease after she received an infusion of prothrombin complex concentrate. The concentrate used in the infusion was subsequently studied by observing the effect of the concentrate on the partial thromboplastin times of various plasmas. The evidence suggests that activated coagulation factors, including activated factor X, were present in the concentrate, and probably played a role in initiating the acute change in the patient's coagulation status. Mechanisms whereby liver disease predisposes toward the development of such a coagulopathy are discussed. It would appear that prothrombin complex concentrates should be used in patients with liver disease only with utmost caution.     

Clinical effectiveness and safety outcomes associated with prothrombin complex concentrates

Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of warfarin and used for reversal of novel oral anticoagulants, in patients with acute major bleeding or need for an urgent procedure. The research goal was to evaluate effectiveness and safety outcomes with PCC usage at our institution. A retrospective review of electronic medical records identified patients that received a PCC commercially available in the United States (KCentra^® or Profilnine^®) at twelve hospitals in a tertiary care health system from July 1, 2013 to April 30, 2014. A total of 193 patients received PCC, of which 184 patients received four-factor PCC. The patient population was 48 % male and 75 % Caucasian, with a mean age of 73 years old. Clinical outcomes of interest included time to achieve a target INR ≤1.3, time to Hgb >7 g/dL, and incidence of thromboembolism. A total of 143 patients were on warfarin (74.1 %) at baseline, whereas 18 patients (9.3 %) were taking a novel anticoagulant. Target INR of ≤1.3 was achieved in 125 patients (65.8 %), within a median time of 8.03 h (IQR 3.38–34.07). Among patients with a baseline Hgb <7 g/L (n = 13), the median time to Hgb >7 g/dL was 8.48 h (IQR 6.95–13.00). Eight patients (4.1 %) developed an acute venous thromboembolism following PCC administration. INR reversal was achieved in approximately two-thirds of patients, with a low incidence of venous thromboembolism. Four-factor PCC is a viable alternative to plasma.     

Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate

Summary. We have looked for evidence of coagulation activation in six subjects with haemophilia B by performing a single-blind active control cross-over study comparing a recently developed factor IX concentrate with a conventional prothrombin complex concentrate (PCC). Samples were obtained before infusion and at 0·25, 0·5, 1, 2, 4, 6, 12, 24, 36 and 48 h for assay of factor IX, prothrombin time, fibrinopeptide A (FPA), prothrombin fragment F1 + 2, D-dimer, thrombin–antithrombin complexes (TAT) and antithrombin III (ATIII). Following administration of the PCC there was evidence of coagulation activation in five of the six recipients for up to 6 h after the infusion. The factor IX concentrate induced a moderate degree of coagulation activation in one subject. There was no significant difference between the two products in respect of either recovery or half-life. This study provides further evidence that the new high purity preparations of factor IX concentrates produce significantly less coagulation activation than currently available PCCs. It remains to be established whether this will result in a corresponding reduction in thromboembolic complications in clinical use.     

人凝血酶原复合物临床应用研究进展

<正>凝血酶原复合物(PCC)的制备工艺目前国内外基本相同,都是以新鲜冰冻血浆(FFP)为起始原料,经DEAE A-50凝胶批式吸附(1次或者2次),超滤配制,冷冻干燥,并在制备过程中采用有机溶剂/去污剂(Solvent/Detergent,S/D)灭活脂包膜病毒(如HIV等)〔1〕,干热灭活法(如100℃/30 min,蒸汽60℃/10h)灭活非脂包膜病毒(如PPV,HCV等)〔2〕。成品为冻干粉针剂,运输、贮存、用药方便,病毒安全性高。随着血浆分离技术的不断提高,单     

Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate

Therapeutic options for developing countries have to assure an optimum safety and efficacy and low-cost antihaemophilic concentrates. A single blind randomized crossover study was carried out in 12 previously treated HB patients, comparing the pharmacokinetics (PK), thrombogenicity (TG) and safety of two plasma-derived double-inactivated (solvent/detergent heating at 100 degrees C, 30 min) factor IX (FIX) concentrates, UMAN COMPLEX DI (product A) [plasma-derived prothrombin concentrates (PCC)] and a high purity FIX concentrate AIMAFIX DI (product B, HPFIX). In a non-bleeding state, they received one single intravenous dose 50 IU FIX kg(-1) of PCC or HPFIX, and after a wash-out period of 14 days, the other product. We evaluated acute tolerance and determined PK parameters based on FIX levels measured over a 50 h postinfusion period. We studied fibrinogen, platelets, antithrombin, F1 + 2, TAT, D-dimer, over a 360 min postinfusion period. Ten cases remained in on-demand treatment for 6 months, five with PCC and five with HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No inhibitors were detected. PK values (PCC vs. HPFIX): clearence (CL; mL h(-1) kg(-1)) 5.2 +/- 1.4 vs. 6.5 +/- 1.4; the volume of distribution at steady state (mL kg(-1)) 154.9 +/- 54.9 vs. 197.5 +/- 72.5; mean residence time (h) 29.7 +/- 8.1 vs. 30.7 +/- 9.2; T(1/2) (h) 22.3 +/- 7 vs. 23.5 +/- 12.3; incremental recovery (IR; U dL(-1) U(-1) kg(-1)) 0.96 +/- 0.17 vs. 0.76 +/- 0.13. HPFIX showed significant lower IR and higher CL. There were no differences in PK at 3 and 6 months. In TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found with PCC. Product B PK results agrees with reported results for other HPFIX preparations. Use of PCC product A has to consider its thrombogenic activity.     

Initiation of a fixed-dose four-factor prothrombin complex concentrate protocol

Journal of Thrombosis and Thrombolysis - Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to...     

Cost effectiveness of prophylactic treatment with activated prothrombin complex concentrate in a patient with inhibitor-positive hemophilia A

Patients with hemophilia and high titers of inhibitors are hard to treat during bleeding events and consequently are more likely to incur high treatment costs and to experience deterioration in quality of life. We report here the case of a boy with hemophilia A and high titers of inhibitors who responded well to prophylactic activated prothrombin complex concentrate (APCC) treatment. Previously, he had to be hospitalized frequently because of painful bleeding of target joints of the knee and ankle. At the age of 4 years and 3 months, APCC prophylaxis at a dose of 60 U/kg, three times a week, was initiated together with on-demand therapy with recombinant factor VIIa. This reduced the frequency and severity of bleeding and ended the need for hospitalization. This, together with a decreased requirement for bypass agents, APCC treatment significantly reduced the cost of treatment for this patient.     

Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage

OBJECTIVE: To evaluate the efficacy and safety of intravenous infusions of an improved prothrombin complex concentrate (PCC) formulation. PATIENTS AND METHODS: Twenty-two adults with haemostatic defects due to severe liver disease (Quick's test 50%), which required rapid haemostasis because of bleeding or before urgent surgery or invasive intervention. Laboratory follow-up, including the response and in-vivo recovery of the substituted coagulation factors II, VII, IX and X and protein C took place before, then 10 min, 30 min and 60 min after PCC substitution. Clinical efficacy (avoidance or cessation of bleeding) was assessed using a scale ranging from 'very good' to 'none'. RESULTS: Patients received a median PCC dose of 25.7 IU/kg. The response of factor IX and protein C was 1.2-1.4 (IU/dl)/(IU/kg), the in-vivo recovery was 49.7-57.4%, and the Quick's test increased from 39% to a maximum of 65%. Levels of activation markers of the coagulation system factor VIIa, prothrombin fragment 1 + 2 and thrombin antithrombin complex (TAT) increased, but without evidence of any thromboembolic events. Clinical efficacy was judged as 'very good' in 76% of patients after the first (n = 21) treatment. There were no changes in serological status regarding transmission of HIV, hepatitis A virus, hepatitis B virus and hepatitis C virus. No PCC-related adverse reactions occurred. CONCLUSIONS: The infusion of pasteurized, nanometre-filtered PCC is an effective, well-tolerated method of correcting prothrombin complex deficiency in patients with severe liver disease with haemorrhage, or before an urgent surgical or invasive diagnostic intervention.     

Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy

Warfarin reversal is frequently required in day to day haematology practice. Prothrombin complex concentrates (PCC) have replaced fresh frozen plasma as the agent of choice in warfarin reversal due to its safety profile. Ideal dose of PCC is still not known and many centres have local guidelines on using the product. We have successfully used PCC (Beriplex) at a fixed dose in our hospital, but we still need randomised control trials to identify the ideal dose of PCC which can result in rapid reversal of warfarin with minimum risk of thrombosis.     

Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy

Abstract

Warfarin reversal is frequently required in day to day haematology practice. Prothrombin complex concentrates (PCC) have replaced fresh frozen plasma as the agent of choice in warfarin reversal due to its safety profile. Ideal dose of PCC is still not known and many centres have local guidelines on using the product. We have successfully used PCC (Beriplex) at a fixed dose in our hospital, but we still need randomised control trials to identify the ideal dose of PCC which can result in rapid reversal of warfarin with minimum risk of thrombosis.     

A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate

Summary. A prospective cross-over study was carried out on 19 patients with haemophilia B, comparing the pharmacokinetics of a purified factor IX concentrate prepared by metal chelate affinity chromatography (9MC) with a conventional three-factor prothrombin complex concentrate (9A). The highly purified factor IX concentrate was shown to have a half-life comparable to the PCC; the in vivo recovery of the purified concentrate was significantly greater than that of the complex ( P < 0.01). The 20% change in the value of the International Standard for Factor IX Concentrate, introduced in 1988, might have been expected to lower the recovery values. However, the in vivo recovery for both concentrates was somewhat higher than reported previously, particularly in the older literature.
In nine patients, serial assays for fibrinopeptide A, prothrombin fragment FI+2 and thrombin-antithrombin complexes (TAT) were performed to assess the potential thrombogenicity of the two concentrates. Evidence was obtained that there was significantly less activation of coagulation following administration of purified factor IX (9MC), as compared to the activation that occurred after the PCC.     

Prophylactic treatment of severe factor X deficiency with prothrombin complex concentrate

Factor X (FX) deficiency is an autosomal recessive trait that occurs in fewer than 1 in 500 000 people. Not surprisingly, reports of prophylactic treatment for FX deficiency are exceedingly rare. We now report our experience of the use of prophylactic therapy in a FX-deficient patient. This 18-year-old African-American male presented at the age of 4(1/2) years with an FX level < 1%. Treatment was on demand with prothrombin complex concentrates (PCCs) given at two times the dose per kilogram of body weight for factor IX. He experienced frequent epistaxis, soft tissue bleeding and joint bleeding. The development of a target joint (right ankle) prompted the initiation of prophylactic treatment in the beginning of 1998 to the present with 30 units kg(-1) Profilnine twice per week via a home infusion programme. If breakthrough bleeding occurred, he was instructed to infuse another dose. He was instructed that Profilnine should not be infused in more than two doses in 24 h or on more than three consecutive days. A trough level drawn 48 h post-infusion showed an FX level of 30%. In the initial 12 months with prophylactic treatment, there was no breakthrough bleeding. Subsequently, with an additional 11 months of follow-up, he has reported one bleed. He rates his quality of life improved since starting prophylactic treatment. There have been no thrombotic events. Prophylaxis with PCC for FX deficiency with adequate education and follow-up can be performed capably in the home setting with a resultant decrease in the frequency of bleeding and attendant complications.     

Initiation of a fixed- dose four- factor prothrombin complex concentrate protocol

Journal of Thrombosis and Thrombolysis -     

Heparin-induced inhibitory effects of a prothrombin complex concentrate on global tests of haemostasis.

Prothrombin complex concentrates (PCC) have been used as bypassing agents for the treatment of haemophilia A patients with inhibitor as well as for replacement therapy in congenital and acquired deficiencies of vitamin-K-dependent clotting factors. The efficacy of PCC is variable, however, especially during long-term and high-dose use, and all currently available products of this nature contain heparin. We have examined the haemostatic properties of PCC using reconstituted whole blood made by mixing coagulation-factor-deficient plasma and washed blood cells. In rotation thromboelastometry (ROTEM), the recommended therapeutic dose of Proplex ST corrected the abnormal patterns. At higher concentrations, however, the ROTEM patterns regressed. In addition, specific assays of coagulation factors appeared unreliable in the presence of 2.5 U/ml Proplex ST; the abnormalities were corrected when protamine sulfate was added. The findings suggest that the presence of heparin in PCC might have a greater effect on global haemostasis. Careful attention to the anticoagulant effect as well as thrombogenicity of PCC is required. Monitoring therapy using such as ROTEM analysis could be highly informative.     

Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000–4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47–759) and 159 ng/ml (45–255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9–15·4) and 1·2 (1·0–1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.