202411101222

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Tags: pharmacology, Haematology

Prothrombin Complex Concentrate

1u PCC : 1ml FFP

vs FFP

PCCs and plasma have fundamentally different physical properties which do not make them interchangeable as treatments for factor deficiency

PCCs are purified, concentrated products that are derived from plasma and contain concentrated factors II, VII, IX, and X (4-factor PCC; 3-factor PCCs that lack factor VII are available) plus small amounts of anticoagulants (protein C, protein S, and heparin).
As such, they lack the full complement of coagulation factors that are present in plasma but can rapidly provide a higher concentration of clotting factors in substantially lower volumes than plasma

In most clinical situations, a four-factor PCC is considered preferable

An adult dose of FFP is 15 mL/kg, while an equivalent dose of PCC may range from 15 to 50 IU/kg depending on the indication for use

Doses of PCC above 50 IU/kg are generally not recommended due to the risk of thromboembolic complications related to an imbalance of procoagulant (ex, Factor II) compared to anticoagulant factors (ex. Antithrombin).

2022 ESAIC Guidelines on the Management of Severe Postoperative Bleeding recommends PCC preferentially over plasma for the treatment of coagulation factor deficiency

Due to presence of heparin in PCCs, product is contraindicated in cases of known Heparin Induced Thrombocytopenia (HIT)

Hemostasis is based on the potential of the blood to produce thrombin (thrombin generation) and the downstream effects of thrombin on coagulation, anticoagulation, fibrinolysis, and the vascular endothelium

According to the cell-based concept of coagulation, hemostasis begins with the initiation phase, which is characterized by the involvement of tissue factors and phospholipids and leads to the initial production of small amounts of thrombin

The production of thrombin activates platelets, factor V, and factor VIII and leads to the second phase (propagation phase) of coagulation.
In this phase, thrombin production increases rapidly and forms a hemostatic plug.
Hemostasis concludes with the termination phase, in which various inhibitory mechanisms regulate the amount and duration of thrombin production and prevent excessive clot formation

Thrombin generation is most sensitive to prothrombin levels (increased thrombin generation) and antithrombin levels (decreased thrombin generation) but can also be perturbed by hemodilution, coagulation factor consumption, shock-induced systemic acidosis, and hypothermia

Patients with severe trauma and coagulopathy often present with reduced levels of factors V, VII, and X and fibrinogen early after injury

Hemostatic resuscitation approaches to restoring thrombin generation in trauma vary with massive bleeding and focus on fresh frozen plasma (FFP) to replace soluble coagulation factor deficiency and restore hemostasis. However, in vitro and clinical studies suggest inefficient thrombin generation recovery after FFP transfusion alone

no significant differences in morbidity or mortality were observed with higher FFP ratios in cases of severe trauma and major bleeding

Benefits of plasma

• blood volume expansion
• glycocalyx protection

first-line treatment with four-factor prothrombin complex concentrate (4F-PCC), as part of a coagulation factor concentrate-based hemostatic approach guided by viscoelastic point-of-care (POC) coagulation monitoring to reversing TIC, rapidly restores clot strength and reduces the need for allogeneic blood products

One advantage of 4F-PCC over FFP is its ability to deliver high doses of vitamin K–dependent clotting factors to restore hemostasis more effectively and faster

Other adv:

• in austere environments w/ limited access to blood products
• ?higher biologic safety ∵ viral pathogen inactivation
• some formulations can be stored at room temp
  Con:
• limited evidence
• no consensus on indications / timing / dosage regimes / adjunct transfusion therapies
• ?risk of thromboembolism
• differences btwn commercially a/v PCC
  • composition
    • additives
      • heparin
      • antithrombin
  • functional activity
    The study highlights the importance of treating each PCC as a distinct agent, with individualized safety and efficacy profiles, and advises caution when substituting products

Pharmacology

The coagulation activity (measured in IU/ml) of lyophilized 4F-PCC is based on factor IX content, although the concentrations of other factors vary between products, as well as other anticoagulant proteins such as protein C, protein S, and variable amounts of heparin (0.2 to 0.5 IU per IU of factor IX), antithrombin III, and human albumin, which are not therapeutic

Three-factor prothrombin complex concentrate (3F-PCC; e.g., Profilnine SD, Grifols Biologicals Inc., USA) contains factors II, IX, and X and a relatively low concentration of factor VII (less than or equal to 175 IU per 500 IU PCC)

4F-PCC, includes a high concentration of factor VII (180 to 500 IU per 500 IU PCC),  affecting the extrinsic, tissue-factor induced coagulation pathway.
4F-PCC also contains antithrombotic proteins C and S, small amounts of heparin (0.2 to 0.5 IU per IU factor IX), antithrombin III, and human albumin

In healthy individuals, factor II (prothrombin) exhibits an elimination half-life of 60 h. The other procoagulant factors have a half-life of approximately 40 h, whereas the antithrombotic proteins are eliminated in greater than 50 h

rapid administration of 4F-PCC, combined with the prolonged half-life of prothrombin and the imbalance of pro- and anticoagulant proteins, raised concerns about thromboembolic complications

Anticoagulant reversal

Low-dose 4F-PCC (25 IU/kg) has been proposed as a cost-effective alternative to high-dose 4F-PCC (50 IU/kg) for the acute reversal of factor Xa inhibitors, providing effective hemostasis without increasing the risk of thromboembolic events or in-hospital mortality

Use in major trauma

the use of 4F-PCC is indicated for severe bleeding events in which impaired thrombin generation is confirmed by the loss and/or consumption of coagulation factors, as identified through conventional coagulation analysis or viscoelastic testing

4F-PCC is not recommended as a first-line empirical treatment, except in cases of exsanguination or very rapid massive bleeding, where rapid replenishment of coagulation factors, along with volume replacement and erythrocyte transfusion, is the primary objective

It is crucial to consider the patient’s comorbidities, which may increase the risk of thromboembolic events, and to individualize dosing to avoid overdosage.

Andexanet alfa, although associated with higher thrombotic risk, has shown superiority in cases of intracranial hemorrhage.

European guidelines

STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management - PMC
Prothrombin concentrate is reasonable to consider over FFP as first-line therapy for refractory coagulopathy in cardiac surgery in select situations to reduce bleeding

References

PCCs for PharmDs

Four-Factor Prothrombin Complex Concentrate Use for Bleeding Management in Adult Trauma

Magic in a Bottle A Focused Review of Factor Concentrates for the Intraoperative Treatment of Acquired Coagulopathy – Fibrinogen Concentrate, Prothrombin Complex Concentrate, and Recombinant Activated Factor VII - BPRCA