Prothrombin complex concentrate

Combination of

Factor II Blood clotting factor,

Factor VII Blood clotting factor,

Factor IX Blood clotting factor

Factor X Blood clotting factor

Trade names Beriplex, Octaplex, Kcentra, Cofact

Routes of administration is by Injection.

Prothrombin complex concentrate is a combination of blood clotting factors II, VII, IX and X, as well as protein C and S,

It is prepared from fresh-frozen human blood plasma.

It is used to reverse the effects of oral anticoagulation therapy when bleeding occurs, requiring rapid action to accelerate coagulation.

Reverses the effects of warfarin and other vitamin K antagonist anti-coagulants and is used in cases of significant bleeding in patients with a coagulopathy (INR > 8.0, and when such a patient must undergo an emergency operation treatment.

Other indications include a deficiency of one of the included clotting factors, either congenital or due to liver disease, and hemophilia.

Contraindicated in patients with disseminated intravascular coagulation, a pathological activation of coagulation, because giving clotting factors would only further fuel this process.

If PCC is given because factor levels are low, it can restore normal coagulation.

PCC products contain heparin, they are contraindicated in patients with heparin-induced thrombocytopenia.

PCC cannot be recommended for first-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data are available.

Clinical settings have demonstrated a significant risk of bleeding with warfarin, which was as high as 1–3% per year of fatal or life-threatening bleeding in high-risk patients.

International normalized ratios (INR) > 4 are associated with an increased absolute risk of intracranial hemorrhage (ICH), which can be as much as 2% per year, and continued elevated INR values for the initial 20 h post-ICH lead to increased risk of hematoma expansion, an independent risk factor of mortality.

Historically, the pref2242ed method for VKA reversal has been vitamin K supplementation combined with blood products or recombinant factors.

Guidelines recommend prothrombin complex concentrate (PCC) use for life-threatening bleeds.

Is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII.

Warfarin inhibits vitamin K epoxide reductase enzyme, thus preventing reactivation of the vitamin K-dependent clotting factors II, VII, IX, and X, and the endogenous anticoagulant proteins C and S.

Reversal of this mechanism is accomplished through administration of vitamin K or exogenous clotting factor supplementation.

Vitamin K, administered intravenously or orally, is the treatment of choice for patients presenting with an elevated INR without signs of clinical bleeding.

Patients with clinically significant bleeding and an elevated INR should receive intravenous vitamin K and an exogenous clotting factor formulation.

The most common products utilized for the reversal of VKAs include fresh frozen plasma (FFP), activated recombinant factor VII (rFVIIa), and PCC.

FFP is a plasma-derived blood product containing all clotting factors, as well as approximately 400 mg of fibrinogen.

FFP has been the standard of care for reversal of VKA-induced coagulopathy in critically bleeding patients.

FFP’s difficulties include the volume associated with its use, risk of transfusion reactions, and time to treatment due to thawing requirements.

Each unit of FFP consists of approximately 250 mL and requires an hour to thaw.

Patients may require up to 2 L of volume.

rFVIIa is recombinant human factor VII that enables hemostasis through activation of the extrinsic pathway, resulting in promotion of fibrin formation and decreasing INR.

rFVIIa is used for VKA reversal, trauma-induced coagulopathy, surgery-induced coagulopathy, cardiothoracic surgery, and ICH.

Dosing recommendations range from 20-90 μg/kg.

rFVIIa has been correlated with a significantly increased risk of arterial thrombosis, including myocardial and cerebral infarctions, due to its potent thrombogenecity.

PCC products are lyophilized, allowing reconstitution, as opposed to thawing, providing a significant advantage in time to administration.

PCC products contain factors II, IX, and X, with variable amounts of factor VII.

Variation in factor VII concentrations in PCC has led to their classification as either three- or four-factor.

PCC concentration of vitamin K-dependent clotting factors is approximately 25 times higher than plasma.

In terms of clotting factor concentration, 2000 mL of FFP is comparable to a dose of PCC.

To combat the risk of thrombosis from concentrated infusion of procoagulant factors, some PCCs contain anticoagulants such as protein C, protein S, and heparin.

Has been used in the treatment of hemophilia.

Its use has recently expanded to VKA reversal in patients either actively bleeding or at a high risk of bleeding.

In acute hemorrhage suggested to be a more effective, beneficial, and cost-effective alternative to currently available treatments.

May have a more potent, sustainable, and rapid INR reversal when compared to agents such as FFP.

Monitoring coagulation status with PCC includes prothrombin time (PT), INR, and partial thromboplastin time (PTT).

PT and INR utilize the extrinsic pathway to determine time required to clot.

PTT measures how quickly the intrinsic pathway is activated.

INR correlates well with the level of inhibition of clotting factor formation.

INR correlation with reversal of clotting factor deficiency is much weaker.

In VKA therapy, INR is utilized under the assumption that after reaching a therapeutic level, there is a similar reduction in factors II, VII, IX, and X.

Along with this reduction in the above factors, the intrinsic pathway is being inhibited to a similar extent.

Therapeutic agents that replenish the extrinsic pathway, such as rFVIIa, may have profound effects on INR but do not adequately supplement the intrinsic pathway, as a result the decrease in an elevated INR may not be associated with a cessation of bleeding.

As a result there is poor correlation with INR reversal, and clinical outcomes.

Despite the above difficulties, INR remains the primary monitor due to availability, familiarity, and lack of a better monitoring parameters.

The success rates of a three-factor PCC in reversal of anticoagulation in 46 patients with ICH: Seventy-five percent reached the goal INR of < 1.5 within 30 min of administration.

Studies suggest, however, resistance to three-factor PCC occurs with increasing INR.

Endogenous factor VII requires only 10–15% of normal concentrations to maintain homeostasis.

Patients presenting with < 15% of factor VII concentrations will require supplementation of factor VII to adequately reverse the associated coagulopathy.

INR represents an accurate reflection of extrinsic pathway function, a population parameter of an INR roughly equal to 4–5 has been associated with a reduction in factor VII concentrations below the threshold of 15%.

Patients presenting with an INR of > 4–5 receiving a three-factor PCC may require supplementation of a factor VII-containing product.

Factors II, V, IX, and X levels were found to significantly increase after supplementation with three-factor PCC, however,factor VII levels did not change.

Low concentrations of factor VII (2–5%) most likely explain the poor INR response to the three-factor agent.

After supplementation with FFP in these patients, factor VII concentrations were elevated to 24%, surpassing the 15% threshold.

Supplementing three-factor PCC with an average of two units of FFP, especially in patients presenting with markedly elevated INRs, supports of the theory that this benefit is most likely due to factor VII supplementation.

FFP contains plasma constituents other than clotting factors, which introduces replenishment of factors VIII, XIII, von Willebrand factor, or fibrinogen.

Four-factor PCC is more likely to completely reverse INR and to do so more rapidly when compared to FFP alone or in combination with PCC.

The key difference in three- and four-factor PCCs is the presence of factor VII.

Although INR is not the best marker for anticoagulation reversal at present, it is the most effective available.

Patients presenting with an INR of > 4 who require emergent reversal of oral anticoagulation may have reduced response to three-factor agents, and should be considered to have supplemention with 1–2 units of FFP due to a perceived factor VII deficiency in patients presenting with an INR > 4 who require emergent reversal of oral anticoagulation.

Although recommended dosing regimen of 25–50 IU/kg was originally developed for the treatment of hemophilia, these doses may be excessive in VKA-treated patients.

Doses as low as 9 IU/kg provide adequate reversal and that there may be a correlation between increasing INRs and requirement of higher doses of three-factor PCC.

Even in patients with markedly elevated INRs, the maximum doses in studies are still lower than the maximum 50 IU/kg utilized in hemophilia.

Individualized dosing of PCC based on patient weight and presenting INR may be most consistent.

Dosing recommendations with three-factor PCCs for patients with clinically relevant bleeding and mildly elevated INR (1.5–3.5), it is reasonable to recommend doses of 25 IU/kg.

Slightly higher doses of 25–50 IU/kg may be recommended in patients presenting with INRs ranging from 3.5 to 5.

Patients presenting with an INR > 5 may need a dose of 50 IU/kg, given as a single dose or two divided doses, in addition to supplemental FFP, while understanding the higher risk of thrombosis.

In a study evaluating 13 patients requiring emergent reversal of INR due to ICH and showed that three-factor PCC in combination with FFP provided a more rapid and consistent INR correction compared to FFP alone.

Despite these benefits, there was no difference in neurological outcomes

Retrospective literature suggests an association with better clinical end points from the use of PCC compared to FFP.

PCC to be more likely to be associated with complete reversal in patients with ICH, as well as hematoma growth.

The only prospective trial with three-factor PCC and FFP showed similar outcomes to studies done with four-factor.

Data suggest equivalence, if not superiority, of PCC over FFP.

ICH, the most common population studied with PCC, may derive the greatest benefit from PCC use.

PCC provides a significantly more rapid correction of coagulopathy and preventing hematoma expansion, and is associated with significantly less volume.

With only three-factor PCC products, FFP maintains a role as a supplemental agent.

WITH four-factor PCC, and with the completion of the PROTECT trial, these results may lead to a further reduction in the utilization of FFP for VKA reversal.

rFVIIa produces a profound reduction in INR due to its mechanism of action, however , there is uncertainty whether a reduction in INR equates to a reduction in bleeding.

When compared to rFVIIa, there is a much smaller reduction in INR with PCC, especially the three-factor product due to the lack of factor VII.

PCC may provide a better clinical response in reference to cessation of bleeding, despite minimal effect on decreasing INR.

A retrospective review of patients presenting with warfarin-induced ICH treated with either rFVIIa or three-factor PCC showed that rFVIIa was significantly more successful at reversing INR to a goal of < 1.3 within 1 h (83% rFVIIa vs. 20% PCC).

Among patients that experienced hematoma expansion after therapy, a significantly larger number received rFVIIa (20% rFVIIa vs. 11% PCC).

This hematoma expansion occurred despite rapid reversal of INR in patients receiving rFVIIa.

rFVIIa may be better at reducing INR, but that long-term outcomes are similar.

The minimal volume associated with PCC is considered a benefit in many patient populations supporting its use over FFP.

PCC contains no fibrinogen.

Data exist supporting the utilization of FFP in trauma patients and its correlation with mortality benefits.

Such data does not exist in the trauma patient still with PCC.

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