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