Anticoagulation-related intracranial hemorrhage - Henry Ford Health ...

Anticoagulation related
Intracranial hemorrhage
Tamer Abdelhak, MD
Senior Staff NeuroCritical Care
Program Director NeuroCritical Care Fellowship
Departments Of Neurology and Neurosurgery
Henry Ford Health System
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Disclosure
None
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Objectives
Clotting pathways refresher.
Anticoagulation Associated ICH
Epidemiology, i Mortality.
AC reversal guidelines n Protocols
New Agents.
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Hoffman 2003, 2005, J Thromb Thrombolysis

Every bleeding eventually stops
but how?
Activation of Platelets leading to
Platelet clot.
Activation of clotting cascade leading
to Fibrin clot formation.
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Clotting factors
1- Natural deficiency:
Hemophiliacs, liver disease.
2-Acquired:
Drugs e.g warfarin, heparin…etc
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So is anticoagulation a problem for
us???
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Bleeding
mechanical heart valves (1–8.3%),
atrial fibrillation (0–6.6%),
coronary heart disease (0–19 19.3%),
venous thromboembolism (0–16.7%),
ischemic cerebrovascular disease (2–13%)
The most frequent complication of OAC is
gastrointestinal bleeding,
intracranial hemorrhage (ICH) is the main
cause of fatal bleeding.
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Epidemiology
1-1 1.7% of the population is currently
receiving OAC with vitamin K
antagonists. (Schurgers, Blood 2004)
5–12% of ICH is related to OAC.
(Flaherty&Broderick Neurology 2007)
Rate of OAC-ICH is about 2–9 per
100,000 /y, an incidence 7- to 10-
fold higher than in the untreated
population(Steiner et al Stroke 2006)
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Epidemiology
The incidence of anticoagulant-associated
associated
intracerebral hemorrhage quintupled in
our population during the 1990s.
The majority of this change can be
explained by increasing warfarin use.
Anticoagulant-associated associated intracerebral
hemorrhage now occurs at a frequency
comparable to subarachnoid hemorrhage.
h
(Flaherty&Broderick Neurology 2007)
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Annual incidence rates for intracerebral hemorrhage (ICH),
anticoagulant‐associated intracerebral hemorrhage (AAICH), and
ischemic stroke in the Greater Cincinnati/Northern Kentucky area
The increasing incidence of anticoagulant‐associated
intracerebral hemorrhage.
Flaherty, M; Kissela, B; Woo, D; Kleindorfer, D; Alwell, K;
Sekar, P; Moomaw, C; Haverbusch, M; Broderick, J
Neurology. 68(2):116‐121, January 9, 2007.
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2

Flood is coming
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Why is OAC ICH increasing
problem??
larger number of elderly patients
that receive OAC for cardiovascular
reasons.
The increased use of combined
anticoagulant regimens
The addition of antiplatelets
the expanded use of OAC for
secondary stroke prevention.
Smith et Al 1999 Arch IM
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Is outcome any different between
AA ICH and non AA ICH???
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Answer
Patients with OAT-related ICH have a
mortality rate approaching 60%,
compared to about 40% for their
non-anticoagulated counterparts
( Hart Stroke 1995, Lavoie J Trauma
2004, Mina J Trauma 2003)
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New Data
299 ICHs. Use of warfarin was
associated with a higher mortality
from ICH (OR, 1.62; 95% CI, 0.88
88-
2.98). INRs >3 increased the odds of
dying of ICH by 2.66 66-fold (95% CI,
1.21-5.86). (Fang(
et al Stroke 2012)
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New data
Re LY trial 2.0 years of follow-up (18,113 pts)
154 intracranial i hemorrhages h occurred in 153 participants
i
46% intracerebral (49% mortality),
45% subdural (24% mortality), and
8% subarachnoid (31% mortality).
The rates of intracranial hemorrhage were 0.76%, 0.31%,
per year among those assigned to warfarin, dabigatran 150
mg respectively (P

Reversal is indicated
HOW????
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AHA 2010
1. Patients with a severe coagulation factor deficiency or severe
thrombocytopenia should receive appropriate factor replacement
therapy or platelets, respectively (Class I; Level of Evidence: C).
(New recommendation)
2. Patients with ICH whose INR is elevated due to OACs should
have their warfarin withheld, receive therapy to replace vitamin
i
K–dependent factors and correct the INR, and receive intravenous
vitamin K (Class I; Level of Evidence: C).
PCCs have not shown improved outcome compared with FFP but
may have fewer complications compared with FFP and are
reasonable to consider as an alternative to FFP (Class IIa; Level of
Evidence: B).
rFVIIa does not replace all clotting factors, and although h the INR
may be lowered, clotting may not be restored in vivo; therefore,
rFVIIa is not routinely recommended as a sole agent for OAC
reversal in ICH (Class III; Level of Evidence: C). (Revised from the
previous guideline).
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AHA 2010
3. Although rFVIIa can limit the extent of
hematoma expansion in noncoagulopathic
ICH patients, there is an increase in
thromboembolic risk with rFVIIa and no
clear clinical benefit in unselected patients.
Thus rFVIIa is not recommended in
unselected patients. (Class III; Level of
Evidence: A). (New recommendation)
Further research to determine whether any
selected group of patients may benefit from
this therapy is needed before any
recommendation for its use can be made.
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Vitamin K
slowly reverts INR to its normal values,
needing 2–24 h to be effective.
All patients with OAC-ICH must be given
vitamin K. Otherwise, INR will not be
corrected completely and a rebound
coagulopathy might develop
should be administered IV as the effect is
too slow using the oral route.
( Dentali et al J Thrombosis Hemostasis 2006)
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Fresh Frozen Plasma
IV at a dose of 10-15 mL/kg
requires the concomitant
administration of vitamin K.
Delays due to thawing and
preparation.
volume overload has to be
considered in older patients
small risk of viral
transmission,thrombocytopenia,
anaphylactoid reactions,septicemia
(Goldstein Stroke 2006)
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Prothrombin Concentrate Complex
PCC
Is a mixture of clotting factors II,
VII, IX, X, and protein C and S,
derived from large donor plasma
pools by ion-exchange
chromatography and
cryoprecipitation
(Bershad & Suarez NCC 2009)
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PCC
Bebulin (US) 3 F
Profilnine (US)3 F
Proplex-Ta
Preconativ
Beriplex P/N
Kaskadil
Octaplex
Cofact
PPSB-HT Nichiyaku
Konyne
Prothrombinex-HT
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Comparison
Blood type matching
Thawing time
PCC
No
No
FFP
Yes
Yes
Infection risk Y Y
Thrombosis risk Y Y
Clotting factor
concentration
High
Low
Infusion volume

EBM for use of PCC
Sandler SG, Rath CE, Ruder A. Prothrombin complex concentrates Yasaka M, Oomura M, Ikeno K, Naritomi H, Minematsu K.
in acquired hypoprothrombinemia. Ann Intern Med.
Effect of prothrombin complex concentrate on INR and blood
1973;79(4):485–91.
coagulation system in emergency patients treated with warfarin
Josic D, Hoffer L, Buchacher A, Schwinn H, Frenzel W, Biesert L,
overdose. Ann Hematol. 2003;82(2):121–3.
et al. Manufacturing of a prothrombin complex concentrate aiming
van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk
at low thrombogenicity. Thromb Res. 2000;100(5):433–41.
ME, Schouten TJ, et al. Individualized dosing regimen for
Hellstern P. Production and composition of prothrombin complex
prothrombin
concentrates: correlation between composition and therapeutic
complex concentrate more effective than standard
efficiency. Thromb Res. 1999;95(4 Suppl 1):S7–12.
treatment in the reversal of oral anticoagulant therapy: an open,
McQuillan AM, Eikelboom JW, Hankey GJ, Baker R, Thom J,
Staton J, et al. Protein Z in ischemic stroke and its etiologic
subtypes. Stroke. 2003;34(10):2415–9.
Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko
V, et al. Efficacy and safety of a prothrombin complex
concentrate (Octaplex) for rapid reversal of oral anticoagulation.
Thromb Res. 2004;113(6):371–8.
Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe
warfarin-induced overanticoagulation immediately and completely
in patients presenting with major bleeding. Br J Haematol.
2001;115(4):998–1001.
Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I.
Pharmacokinetics of Beriplex P/N prothrombin complex concentrate
in healthy volunteers. Thromb Haemost. 2007;98(4):
790–7.
Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX
complex in warfarin-related intracranial hemorrhage. Neurosurgery.
1999;45(5):1113–8. discussion 1118–1119.
Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex
concentrate for oral anticoagulant reversal in neurosurgical
emergencies. Br J Neurosurg. 2000;14(5):458–61.
Fredriksson K, Norrving B, Stromblad LG. Emergency reversal
of anticoagulation after intracerebral hemorrhage. Stroke. 1992;
23(7):972–7.
Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM.
Urgent reversal of warfarin with prothrombin complex concentrate.
J Thromb Haemost. 2006;4(5):967–70.
Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann
H. Prothrombin complex concentrate (Beriplex P/N) for
emergency anticoagulation reversal: a prospective multinational
clinical trial. J Thromb Haemost. 2008;6(4):622–31.
Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal
of oral anticoagulation with warfarin by a prothrombin complex
concentrate (Beriplex): efficacy and safety in 42 patients. Br J
Haematol. 2002;116(3):619–24.
Vigue B, Ract C, Tremey B, Engrand N, Leblanc PE, Decaux A,
prospective randomized d controlled trial. Thromb Res. 2006;
118(3):313–20.
Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex
P/N) in severe bleeding: experience in a large tertiary hospital.
Crit Care. 2008;12(4):R105.
Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of
prothrombin complex concentrate for acute reversal of oral
anticoagulation. Thromb Res. 2005;115(6):455–9.
Hellstern P, Halbmayer WM, Kohler M, Seitz R, Muller-Berghaus
G. Prothrombin complex concentrates: indications, contraindications,
and risks: a task force summary. Thromb Res. 1999;95(4
Suppl 1):S3–6.
Schulman S, Bijsterveld NR. Anticoagulants and their reversal.
Transfus Med Rev. 2007;21(1):37–48.
50. Pindur G, Morsdorf S. The use of prothrombin complex
concentrates
in the treatment of hemorrhages induced by oral
anticoagulation. Thromb Res. 1999;95(4 Suppl 1):S57–61.
Makris M, Watson HG. The management of coumarin-induced
over-anticoagulation Annotation. Br J Haematol. 2001;114(2):
271–80.
Crawford JH, Augustson BM. Prothrombinex use for the reversal
of warfarin: is fresh frozen plasma needed? Med J Aust. 2006;
184(7):365–6.
Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston
MA, Sarode R. Suboptimal effect of a three-factor prothrombin
complex concentrate (Profilnine-SD) in correcting supratherapeutic
international normalized ratio due to warfarin overdose.
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Blatt PM, Lundblad RL, Kingdon HS, McLean G, Roberts HR.
Thrombogenic materials in prothrombin complex concentrates.
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et al. Ultra-rapid management of oral anticoagulant therapyrelated
surgical intracranial hemorrhage. Intensive Care Med.
2007;33(4):721–5.
55. Schimpf K, Zeltsch C, Zeltsch P. Myocardial infarction
complicating
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Reduced coagulation activation following infusion of a highly
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57. Aledort LM. Factor IX and thrombosis. Scand J Haematol Suppl.

EBM
Prothrombin Complex Concentrates
for Oral Anticoagulant Therapy-
Related Intracranial Hemorrhage: A
Review of the Literature
Bershad & Suarez, NCC, 2010
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INCH Trial
INR Normalization in Coumarin
associated intracerebral
Haemorrhage
Steiner Thorsten
University Hospitals: Halle,
Mannheim, Erlangen, München,
Heidelberg, Germany
Randomized, open label, parallel
groups, multicenter.
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INCH inclusion
Spontaneous intracerebral and
subdural hematoma diagnosed by CT
within 12 hours after onset of
symptoms
•Patient receiving oral
anticoagulation w INR ≥ 2
•Age ≥ 18 years
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INCH outcome
1ry: INR

Factor VII
Still in use in many places
Single factor replacement.
Activated
t Falling out of favor for expense and
side effects after FAST Trial (Mayer et al
2005 NEJM).
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Protocols
How can we be practical?
We have an ICH in ER and high
INR!!!!!
Tell me what should I do now???
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AAFP
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October 4-7, 2012
Sheraton Denver
Downtown Hotel | Denver, Colorado, USA
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HFHS Anticoagulation Reversal
Protocol
These guidelines are supported by
latest literature from AHA, ACCP and
published articles and expert
consultation.
Let me share our background data
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2000-20102010 HFH NCCU
CoRICH Trial
2971 pts with intracranial bleeds.
122 were identified on warfarin (4.1%).
Mean admission GCS was 10 (3-15),
mean pre-therapy INR 4.20 (1.65-18.78) 18.78) and
mean INR post therapy 1.25 (0.95-1.82). Mean
time elapsed before a post therapy repeat INR
check was 155 minutes (7-1090 min).
Reversal agents used included: vitamin K in 36
patients (87.8%), FFP in 34 patients (82.9%),
activated factor 7 in 19 patients (46.3%) and
prothrombin concentrate complex in 20 patients
(48.7%).
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CoRICH data
When looking at outcomes of these
patients, average ICU length of stay was
12.5 days,
There was a 39% mortality.
Thromboembolic events were
encountered in 4 patients (10%).
Anticoagulation was resumed in 12
patients. The mean return to
anticoagulation 15.6 days (range 2-58
days)
(Abdelhak et al 2012 SCCM)
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HFHS Warfarin reversal protocol
INR 1.7-3:
for ICH 2011/2012
Profilnine 20 u/kg+Factor VII 10
mcg/kg.
INR >3:
Profilnine 20 u/kg+Factor VII 20
mcg/kg.
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Follow up
INR 15-30 minutes after
administration of reversal then q 4
hours.
If first INR unsatisfactory may give
FFP.
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Heparin et al
Protamine sulphate.
1 mg for each 100 units heparin IV.
1 mg for each 1 mg enoxparin 8h.
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Direct X inhibitors
Dabigatran (2009, BI, Pradaxa)
Rivaroxaban (2011, Janssen&Bayer
, Xarelto)
Apixaban (Not FDA approved yet,
Pfizer&BM, Eliquis)
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The new arrivals
Direct thrombin inhibitor.
Oral once or twice daily.
Safer and more expensive than
warfarin.
No need for INR monitoring
Renal excreted.
Reversal : Help us GOD.
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A, Effect of rivaroxaban followed by prothrombin complex concentrate (PCC) or placebo on
the prothrombin time (PT; mean±SD).
Eerenberg E S et al. Circulation 2011;124:1573-1579
Copyright © American Heart Association

A, Effect of dabigatran followed by prothrombin complex concentrate (PCC) or placebo on the
activated partial thromboplastin time (aPTT; mean ±SD).
Eerenberg E S et al. Circulation 2011;124:1573-1579
Copyright © American Heart Association

Seriousely
We don’t know.
PCC 50 u/kg +/- Factor
VII 50 mcg/kg +/-
FFP++++++++
Dialysis i if possible on
the way to the
…………………….
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Summary
AA ICH is an increasing problem with
high mortality.
Urgent Clotting factor replacement is
highly recommended.
Follow up INR important.
t
New agents reversal is not available.
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Henry Ford NeuroICU Team
04/05/2012
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Thank you
04/05/2012
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