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
FFP
3F-PCC
4F-PCC
Required
Not required
Not required
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 )
Dose
Weight based ( 10 – 20ml / kg )
INR and weight based
Volume infused
Large ( 1unit / 200 – 250ml )
Small
Small ( 500units / 20ml )
Administration time
200 – 300ml / hour *
10 – 15 minutes
INR reduction
Hours ( varies based on
Depends on pre-INR levels
Significant
infusion time and number of units given )
( more effective in INR < 4 )
Time from infusion to surgery
Longer ( 8.5 hours )
Limited literature
Shorter ( 3.6 hours )
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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