Anticoagulant Reversal Handbook | Page 7

Overview with transfusion reactions such as allergic reactions , febrile non-haemolytic transfusion reactions , transfusionassociated circulatory overload ( TACO ), and transfusion-related acute lung injury ( TRALI ) as well as pathogen transmission . ^{11 , 14 , 15} Studies have also shown that a significant change in the INR following FFP transfusion is expected at INR levels of ≥1.7 . ¹⁶ In addition , because each unit of plasma raises the activity of clotting factors by only 2.5 – 5 %, the recommended dose to reverse VKA effect is 15ml / kg , which equates to three to four units of FFP in a 70kg patient . ^{13 , 17} This large volume of fluid increases the time taken for infusion and also raises the risk of volume overload , which might be significant in patients with cardiac or renal diseases . ^{13 , 18} The time required for blood compatibility testing and thawing also contributes to the delay in initiating reversal treatment . A cohort of patients with intracerebral haemorrhage showed that the median time interval between admission to the neuro-intensive unit and INR normalisation with FFP administration was 30 hours , during which many of these patients had a haematoma expansion . ¹⁹ Thus , FFP should only be considered when PCC is not available , in patients who have already received full dose of PCC but still need INR correction , or in patients with history of allergy or adverse reaction to PCC or its components . However in these situations when FFP should be administered , concomitant vitamin K administration is recommended to sustain the

14 , 15 anticoagulation reversal ( Figure 2 ).

The use of rFVIIa is neither recommended nor approved for reversal of VKA-associated coagulopathy . Although rFVIIa is associated with rapid INR correction at a rate comparable to PCC , there are very limited data to support clinical benefits compared with other reversal strategies . Because INR is very sensitive to factor VII , the quick INR correction might not reflect the true adequate coagulation status due to uncorrected levels of the other vitamin K-dependent coagulation factors ( that is , factors II , IX and X ) that are necessary for normal haemostasis . The increased risk of thrombosis along with the cost of rFVIIa

11 , 17 must also be taken into consideration .

PCCs are non-activated concentrates of vitamin K-dependent coagulation factors II , IX , X and variable amounts of factor VII . PCCs are categorised into

20 , 22 , 24 , 25

Table 1 : Comparison of FFP , 3F-PCC and 4F-PCC

Cross matching and thawing

Components All coagulation factors , fibrinogen , plasma proteins , protein C and S ( not quantified and may vary )

three-factor ( 3F-PCC ) and four-factor ( 4F-PCC ), which has significant amounts of factor VII compared with 3F-PCC ,

15 , 17 , 20 which has little to no factor VII . Furthermore , Kcentra ^® in the US ( Beriplex / Confidex in the EU ; CSL Behring , Marburg , Germany ), the most recently approved 4F-PCC , contains significant amounts of the naturally occurring anticoagulants proteins C and S and a small amount of antithrombin III and heparin . ²¹ 4F-PCC is very effective for urgent VKA reversal and is the preferred treatment of choice with more reliable INR correction compared with FFP and 3F-PCC ( Table 1 ). However , because the effect of PCCs is transient , coadministration of vitamin K is required for sustained VKA reversal . Weight- and INR-based dosing is recommended for 4F-PCC over standard dosing ( Table 2 ). A follow-up INR can be checked 15 – 60 minutes after PCC administration . Some disadvantages of PCCs include high cost

Factors II , IX , X , may have low levels of VII , proteins C and S ( negligible amounts )

Factors II , VII , IX , and X , proteins C and S ( quantified levels of factors )

Risk of infection or TRALI

Present Negligible Negligible

* Slower in patients with high risk of volume overload ( that is , cardiac and / or renal disorders )

Table 2 : Dosing guideline per baseline INR ²³

Baseline INR

4F-PCC dose ^* , IU ^** of factor IX per kg body weight

Maximum dose ^*** ( units of factor IX )

2 to < 4 25 Not to exceed 2500 4 – 6 35 Not to exceed 3500 > 6 50 Not to exceed 5000

*

Dosing is based on body weight . Dose based on actual potency as stated on the packaging , which will vary from 30 to 31 factor IX units / ml . Nominal potency is 500 units per vial , approximately 25 units per ml after reconstitution .

_**

IU = international units .

_***

Dose is based on body weight up to but not exceeding 100kg . For patients weighing more than 100kg , maximum dose should not be exceeded . and small prothrombotic risk ( trial experience shows the thromboembolic risk of PCCs is comparable to that of plasma ). PCCs should be avoided if a history of heparin-induced thrombocytopaenia is present .

Conclusions In summary , bleeding is a common complication of VKA therapy . VKA reversal is essential in severe and life-threatening events . Along with IV vitamin K , administration of 4F-PCC is the preferred reversal approach in urgent cases . l

References

1 . Trevor AJ , Katzung BG , Kruidering-Hall M . Drugs used in coagulation disorders . In Trevor AJ et al ( eds ) Katzung and Trevor ’ s Pharmacology and Examination Board Review , 11th edn . 2015 ; McGraw-Hill Education : New York , NY .

2 . Zehnder JL . Drugs used in disorders of coagulation . In Trevor AJ et al ( eds ) Katzung and

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