Hemostatic therapy for treatment of oral anticoagulation-related ICH

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Hemostatic therapy for treatment of oral anticoagulation-related ICH

Hemostatic therapy for

treatment of oral

anticoagulation-related ICH

Michael N. Diringer, MD, FCCM, FAHA

Professor of Neurology, Neurosurgery & Anesthesiology

Director, Neurology/Neurosurgery Intensive Care Unit

Washington University School of Medicine

St. Louis, MO USA

FINANCIAL DISCLOSURE: No relevant financial relationship exists

OFF LABEL USE: Everything discussed


Case

• 65 year old woman with a prosthetic

aortic valve taking warfarin

• Presents within 2 hours of onset of a

spontaneous lobar intracerebral

hemorrhage

• INR is 2.3 and ICH volume is 25 cc


The Controversy

Should PCC or rFVIIa be used for

acute treatment of

anticoagulation-related ICH ?


OAC related intracerebral

hemorrhage


Larger size predicts worse

outcome

Zubkov AY, Arch Neurol 2008;65:1320


Expansion more common with longer

time window

• Hematoma expansion in 28% OAC-ICH

patients admitted within 24 hours despite

treatment

Yasaka M, Thromb Haemost. 2003;89:278 –283

• Hematoma expansion up to day 7

Hematoma

expansion

No anticoagulants 16%

On anticoagulants 54%

Flibotte JJ, Neurology, 2004;63:1059


Goal: Rapid correction of

warfarin induced coagulopathy


Choices

• Vitamin K

• Recombinant activated Factor VII (rFVIIa)

• Fresh Frozen Plasma (FFP)

• Prothrombin Complex Concentrate (PCC)


Vitamin K

• Takes hours to days to achieve an

effective response

• Still necessary when using rFVIIa, FFP

or PCC

• More rapid when given intravenously

– Adverse events: 3 per 10,000


Fresh Frozen Plasma (FFP)

• Contains all coagulation factors

• Takes time:

• Requires compatibility testing and

thawing

• Large volume to infuse

• Median 30 hours until INR

≤1.3

Brody DL, Neurocrit Care. 2005;2(3):263-7


Transfusion related acute lung injury

(TRALI)

• Hypoxia and bilateral

pulmonary edema

• Independent predictor of

mortality

• FFP higher risk than other

blood products

Toy P, Blood. 2011 Nov 23. [Epub],

Triulzi DJ, Anesth Analg 2009 108; 770


Other risks of FFP

• Circulatory overload

• Blood-borne infection

– HIV, HCV, HBV

• Allergic reactions


Recombinant activated Factor VII

• 5µg/kg (1 mg for 100 kg patient) corrects

therapeutic INR in minutes

But-

• Replaces only 1 factor – may not correct

coagulopathy

• rFVIIa interferes with INR assay

– INR no longer reflects bleeding tendency

– No way to monitor need for additional

treatment


FVIIa normalizes INR but not bleeding

from punch biopsy

Group n Baseline

After

warfarin

After drug

Placebo 24 1.0 ± 0.1 2.5 ± 0.3 2.5 ± 0.3

5 μg/kg rFVIIa 6 1.1 ± 0.1 2.7 ± 0.3 1.5 ± 0.5

10 μg/kg rFVIIa 6 1.1 ± 0.1 2.6 ± 0.2 1.3 ± 0.1

Skolnick B E et al. Blood 2010;116:693-701


FVIIa normalizes INR but not bleeding

from punch biopsy

placebo

Baseline Coumadin rFVIIa

Skolnick B E et al. Blood 2010;116:693-701


Prothrombin complex

concentrates (PCC)

• Contain prothrombin and factors IX, X,

and usually VII

• Some contain protein C and S

• Immediately available

• Reconstituted in small volume of fluid

• ? Potential to induce thrombosis


Literature review: PCC for warfarin

reversal

• 14 studies (460 patients) who received

PCC for warfarin reversal

• PCCs correct INR faster than FFP

• Seven (1.5%) thrombotic complications

• 3 strokes (occurred >48 hours after

PCC)

• 2 DVTs

• 2 non-Q wave MIs

Leissinger C, Am J Hematol 83:137–143, 2008


Literature review: PCC thrombogenicity

• Conclusions

– With the inclusion of coagulation

inhibitors and other manufacturing

improvements, today's PCCs may be

considered safer than earlier products

– PCCs may be considered preferable

to fresh frozen plasma for emergency

anticoagulant reversal

Sørensen B, Crit Care. 2011; 15(1): 201


FFP vs. PCC in OAC-related ICH

• Retrospective

• 55 patients with ICH while on OAC

• Hematoma growth in 27% within 24 hours

• Hematoma growth less with PCC

• Difference no longer seen if INR

completely reversed within 2 hours

Huttner HB, Stroke. 2006 Jun;37(6):1465-70


PCC in OAC-related ICH

• Prospective

• 92 acute ICH patients on warfarin with INR ≥ 2.0

• Treated with PCC (Protromplex, no FVII) and

vitamin K

• No thrombotic

complications

Imberti A et al. Pathophysiol Haemost Thromb 2007–08;36:259–265


Survey of practice

• Treat a hypothetical case of OACrelated

hemorrhage

• Option to give vitamin K, FFP,

rFVIIa, PCC or combination

PCC rFVIIa

North America 10% 70%

Europe, Asia, South

America

81% 22%

Neal M et al. Thromb Res 2008; 122:864–866

FFP

PCC

rFVIIa


Results from

• Efficacy and Safety Study of BERIPLEX ®

Compared With Plasma in Patients With

Acute Major Bleeding Caused by

Anticoagulant Therapy


Conclusions

• Give vitamin K

• Give PCC

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