New blood products hemorrhagic stroke apr 14 12

New Blood Products and Their
Roles in Hemorrhagic Stroke
Doug Morrison
Medical Director of Transfusion Medicine
Fraser Health

New Blood Products in
Hemorrhagic Stroke - Outline
Recombinant factor VIIa in ICH
Oral Anticoagulant Associated Intracerebral Hemorrhage
Therapeutic options for reversal of Warfarin
Prothrombin Complex Concentrates
Review of CBS National Distribution Data for PCC
Fraser Health Audit of PCCs
Revised NAC guidelines 2011 (TMAG Perspective)
Possible role for urgent reversal of new oral anticoagulants

rFVIIa : Niastase
Hemophilia with inhibitors
congenital
acquired
Acquired von Willebrand’s disease
Congenital Factor VII deficiency
Congenital platelet dysfunction syndromes

Coagulation pathway
Bleeding - FVIIa

Original Article

Efficacy and Safety of Recombinant Activated
Factor VII for Acute Intracerebral Hemorrhage
Stephan A. Mayer, M.D., Nikolai C. Brun, M.D., Ph.D., Kamilla Begtrup, M.Sc., Joseph
Broderick, M.D., Stephen Davis, M.D., Michael N. Diringer, M.D., Brett E. Skolnick,
Ph.D., Thorsten Steiner, M.D., for the FAST Trial Investigators

N Engl J Med
Volume 358(20):2127-2137
May 15, 2008

Study Overview

In a previous phase 2 placebo-controlled
trial, recombinant activated factor VII
(rFVIIa) reduced growth of the
hematoma and improved survival and
functional outcome in patients with
intracerebral hemorrhage
Those findings were not reproduced in
this phase 3 trial, in which rFVIIa
reduced hematoma growth but did not
improve clinical outcomes

Kaplan-Meier Survival Curves

Mayer SA et al. N Engl J Med 2008;358:2127-2137

Conclusion

Hemostatic therapy with rFVIIa reduced
growth of the hematoma but did not
improve survival or functional outcome
after intracerebral hemorrhage
The overall frequency of thromboembolic
serious adverse events was similar in the
three groups; however, arterial events were
more frequent in the group receiving 80 μg
of rFVIIa than in the placebo group (9% vs.
4%, P=0.04).

The Practical Management of
Intracerebral Hemorrhage with Oral
Anticoagulatn Therapy -Review
Risk 0.2 % - 0.6 % per year of treatment - VKA
70% are intracerebral, 30% subararchnoid
OAT-ICH represent 15% of all ICH
Many have supratherapeutic INR; however most
have a therapeutic INR
30 day mortality 12-60% & double that of nonanticoagulated patients
Hematoma volume & GCS major determinants
L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228240

Oral Anticoagulation Therapy
Associated Intracerebral Hemorrhage
(OAT-ICH)
Hematoma enlargement is a major determinant of
the poor prognosis in OAT-ICH
OAT-ICH is associated with greater baseline
volume of ICH, more hemorrhage expansion &
greater mortality than spontaneous ICH
Approx 50% of OAT-ICH patients present a
secondary volume expansion compared to 17% of
non-OAT-ICH patients
L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228-240

(OAT-ICH)
Urgent Reversal of Coagulopathy
Based on the premise that this will reduce the risk
hematoma expansion or re-bleeding and facilitate
surgical intervention, if indicated.
immediate IV administration of vitamin K
Factor replacement
– Prothrombin complex concentrates (PCC), or
– FFP (15-30 ml/kg)


NIKE Principles in the Reversal of
Oral Anticoagulation Therapy
Associated Intracerebral Hemorrhage
N – Normalize the INR
I – Immediate reversal in all patients,
regardless of the size of the hemorrhage
K – vitamin K must be included to avoid
rebound elevation of the INR
E – all levels of INR Elevation require
urgent correction

Therapeutic options for reversal
of Warfarin
Withhold VKA
– Two to three days to reach INR < 1.5

Vitamin K
– Oral: slow decrease in INR over 12-24 hr
– I.V.: onset in 4-6 hr, INR < 1.5 in 12-16 hr

Factor replacement – 30 IU/kg (70kg)
– FFP 2000 ml
– PCC 2000 IU (80ml)

Target INR and coagulation
factor concentration
Minor bleeding or invasive procedures:
– clotting factor levels of 20 – 40% or
– an INR of 1.5 – 2.0

Severe injury/bleeding or major surgery:
– factor levels of 50 – 60% or
– INR of 1.0 – 1.5

Dzik WH. Transfusion Therapy: Clinical Principles and Practice, 2nd edition, AABB Press 2005

% coagulation Factors
100 %

INR and Coagulation Reversal

zone of normal hemostasis

50 %
30 %
zone of
anticoagulation

PT (sec)
INR

12 13 15.5

19 21.8

1

1.7

1.3

2.0

24
2.2

30 32
3.0

Frozen Plasma for Immediate
reversal of Warfarin
15-30 ml/kg 1050 – 2100 ml (70 kg)
Familiar and less expensive
Slow correction due to infusion time
Risks include
–
–
–
–

Volume overload (TACO)
Allergic reactions
TRALI
Disease transmission

Prothrombin Complex Concentrates
(PCCs) for immediate reversal
40 – 120 ml rapidly over 20 – 60 min
Reconstitution required but no ABO or
thawing
Predictable effect
Risks
• Solvent detergent eliminates risk of enveloped virus
• Low risk of thrombosis

PCC – Octaplex® & Beriplex®
Human plasma derived second generation
PCCs
Contain vitamin K dependent factors II,
VII, IX, X, Protein C and Protein S
Used in Europe for several years prior to
August 2008 introduction of Octaplex® to
Canada

PCC Factor levels
One 20mL vial contains:
Component

octaplex

Beriplex

in vivo T1/2

Factor II

220-760 IU

380-800 IU

~60h

Factor VII

180-480 IU

200-500 IU

~4h

Factor IX

400-620 IU

400-620 IU

~17h

Factor X

360-600 IU

500-1020 IU

~31h

Protein C

140-620 IU

420-820 IU

~47h

Protein S

140-640 IU

240-680 IU

~49h

Heparin

80-310 IU

8-40 IU

Sodium citrate

17-27 mM

3 mM

Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789
Beriplex Product Monograph, November 2010
Beriplex Product Monograph, November 2010

Clinical indications for PCCs
Reversal of warfarin therapy or vitamin K
deficiency in patients exhibiting major
bleeding
Reversal of warfarin therapy or vitamin K
deficiency in patients requiring urgent (< 6
hour) surgical procedure.
National Advisory Committee on Blood and
Blood products, September 2008

Clinical use of PCCs
Not recommended for:
– Elective surgery reversal of oral anticoagulation
– Treatment of elevated INRs without bleeding or need
for surgical intervention
– Massive transfusion
– Coagulopathy associated with liver dysfunction
– Patients with recent history of thrombosis, myocardial
infarction, ischemic stroke, or Disseminated
Intravascular Coagulation (DIC)
National Advisory Committee on Blood and Blood
products, September 2008

Clinical use of PCCs
Contraindicated:
– Patients with a history of heparin induced
thromobocytopenia (HIT)

Insufficient evidence for use in pregnant
women or pediatric patients.

Octaplex®
monograph dosing recommendations
to normalize the INR (< 1.2) within 1 hr

INR

2.0 – 2.5

2.5 – 3.0

3.0 – 3.5

> 3.5

ml/kg

0.9 – 1.3

1.3 – 1.6

1.6 – 1.9

> 1.9

IU/kg

22.5 – 32.5

32.5 – 40.0

40.0 – 47.5

> 47.5

70 kg patient

1500 – 2000

2000 – 3000

3000 – 4000

>4000

NAC recommendations are lower, due to the fact
the package insert recommendations will correct
factor levels to normal despite the fact that normal
hemostasis does not require 100% factor levels.

“Activated PCC” - FEIBA
Activated PCCs are different products
characterized by the presence of activated factors
(especially VIIa) and used in treatment of patients
with coagulation factor inhibitors.
FEIBA is licensed and in use in Canada
More thrombogenic than second generation PCCs
– in the 1970’s post operative thrombotic
complications occurred in 46% of Hemophilia B
patients receiving perioperative PCC

PCC Production
All PCCs undergo at least 1 pathogen reduction step:
Nanofiltration
Solvent-detergent treatment
Pasteurization
However, theoretical concerns exist regarding:
Non-lipid enveloped viruses (hepatitis A, parvovirus B19)
Prions (vCJD)
?Emerging pathogens?


PCCs: Concerns
Thrombogenicity
Especially with high risk patients, repeated dosing
Attempt to minimize by inclusion of proteins C & S,
heparin, +/- antithrombin
Meta-analysis of PCC use for rapid VKA reversal found
thrombotic incidence was 1.8% (95% CI = 1.0-3.0%) for
4-factor PCCs (0.7% for 3-factor PCCs)1
Exacerbation of coagulopathy/DIC (esp. in liver disease)
Heparin induced thrombocytopenia
Allergic/anaphylactic reactions
Pathogen transmission
1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438.
1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438.

PCCs in Canada
May 2007: Health Canada approves Octaplex® for rapid reversal
of warfarin or VKD in patients exhibiting major bleeding or
requiring urgent (<6hrs) surgery
July 2008: CBS begins distributing Octaplex®
Sept 2008: NAC Recommendations for the Use of Octaplex®
Nov 2010: Health Canada approves Beriplex® P/N
July 2011: Updated NAC Recommendations for the Use of PCCs
Aug 2011: CBS begins distributing Beriplex® P/N

National Advisory Committee on
Blood and Blood Products
NAC provides professional leadership and advice
in matters directly affecting the practice of
transfusion medicine in hospitals, including
utilization of blood & blood products
NAC reports to the provincial and territorial (PT)
Ministries of Health and Canadian Blood Services
(CBS) via the PT/CBS Blood Liaison Committee
Two representatives are appointed by each P/T
MoH + four CBS representatives.

NAC 2008 PCC
Recomendations
Adult dose: 40mL (2 vials = 1000 IU FIX activity) and
10mg vit K IV
Higher dose may be necessary for extremes of
weight or INR
Maximum total dose: 120mL (6 vials = 3000 IU
FIX activity)
Administered IV at rate not exceeding 23mL/min (2-3 vials/hr)
Post-dose monitoring: INR @ 10-15min, clinical
outcomes day 1 & 30
http://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdf
http://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdf

Fraser Health PCC audit
PCC orders screened by on-call hematopathologist
Generally following NAC recommendations with
individualization of the dosage
– Patients weight & INR
– Nature of the bleeding & degree of urgency
– Recommend PT (INR) 15 min after infusion & repeat if
necessary
– Emphasis on IV vitamin K

2010 FHA Octaplex Audit
Feb – Dec 2010 (11 months – 71 cases)

Feb-Dec 2010 Cases by Site
30
26

# of Cases

25
20
15

11

10
8

10

8

5
3

5

3

3

0
ARH

BH

CGH

ERH

LMH

PAH

RCH

RMH

SMH


Indications for the Use of Octaplex in FHA
% of 71 cases Feb - Dec 2010
12.7%

1.4%

11.3%

40.8%

Pre-procedural
ICH

15.5%

GIB
35.2%

Trauma
Medical/Surgical
Hemorrhage
Epistaxis


Distribution of Octaplex Doses
Feb-Dec 2010

Number of Patients

25
20
15
10
5
0
500

1000

1500

2000

Dose of Octaplex Given

2500

3000+


Weight-based Dosing of Octaplex
Feb-Dec 2010

Number of Patients

35
30
25
20
15
10
5
0
0 to 10

10 to 20

20 to 30

30 to 40

Dose given (units per kg)

>40


Mean Dose of Octaplex Over Time
2000
1769
1600

1500

1500

1286

1454

1544
1385

1200
875
800

400

0
Before Feb-Apr MayFeb 09
09
July 09

AugOct 09

NovFebJulyOctFeb 09 June 10 Sept 10 Dec 10

INR Results post infusion

Patients

< 1.5

1.5-1.7 1.8-2.0

>2.0

< 1 hr
%

38

24
63%

9
87%

4

1

1-4 hr

26

1

64

3
85%
12
86%

3

Total
< 4 hr

19
73%
43
67%

7

1


Clinical Effect of Octaplex in 46 Bleeding
Patients Feb-Dec 2010
60%
50%
40%
30%
20%
10%
0%
Stop

Decrease

Same

Increase

C an't tell


Outcome in 35 Surgical Patients After
Octaplex Feb-Dec 2010
120%
100%

97.2%

80%
60%
40%
20%

2.8%

0%
No excessive bleeding

Excessive bleeding


Thrombotic events & Deaths
71 patients Feb-Dec 2010
20
15
10
5
0
MI

Stroke

DVT/PE

Death

Thromboembolic Events

Ischemic Stroke (4 patients)
– 3 deceased (FH-81, 104, 109)
– 1 survived (FH-139)

Venous thrombosis

(2 patients)

– 1 died from cardiogenic shock with evidence of
thrombosis of tricuspid valve (FH-127)
– 1 survived pulmonary embolus (FH-76)

Myocardial Infarction
– Deceased patient FH-81 above

Deaths

Associated with thromboembolic event (4)
– Ischemic stroke (FH-104 & 109)
– Ischemic stroke & MI (FH-81)
– Thrombosis of tricuspid (FH-127)

Not associated with thromboembolism and
thought secondary to presenting illness (12)

NAC 2011 Recommendations
Octaplex® and Beriplex® to be used interchangeably
Special patient populations: insufficient evidence to recommend use in
patients on direct thrombin or FXa inhibitors (dabigatran, rivaroxaban)
Major change = dosing recommendations:
INR < 3.0 → 40mL (2 vials = 1000 IU)
INR 3.0-5.0 → 80mL (4 vials = 2000 IU)
INR >5.0 → 120mL (6 vials = 3000 IU)
Stressed preference for IV vitamin K over PO (never IM/SC)
Highlighted the lack of strong RCT evidence of clinical efficacy in this
area warrants continued data collection
http://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdf
http://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdf

BC TMAG’s view of revised
2011 NAC guidelines
Endorse the NAC recommendations “for the
treatment of critical bleeding”
– INR < 3.0 → 40mL (2 vials = 1000 IU)
– INR 3.0-5.0 → 80mL (4 vials = 2000 IU)
– INR >5.0 → 120mL (6 vials = 3000 IU)

However, in the absence of critical bleeding,
dosing should reflect the patient’s weight, INR and
urgency of the situation with titration of the dose
whenever possible.

Novel Oral Anticoagulants
Reversible, direct inhibitors of common pathway coagulation factors:
– Thrombin (FIIa) = dabigatran (Pradax®)
– FXa = rivaroxaban (Xarelto®), apixaban
2008: dabigatran and rivaroxaban licensed by Health Canada for posthip and knee replacement thromboprophylaxis
Oct 2010: dabigatran approved by Health Canada for stroke prevention
in patients with atrial fibrillation
All 3 agents have completed or are nearing completion of trials in atrial
fibrillation, acute VTE treatment, and secondary VTE prevention

Novel Oral Anticoagulants
Unlike warfarin, these agents have a broad therapeutic index
Routine laboratory monitoring is not required
Both agents undergo mainly renal excretion with a T1/2 of approx 12 hrs
– Dabigatran (35% protein bound) is amenable to dialysis, but not
rivaroxaban
– Can give activated charcoal for acute (<2hrs) overdose of either drug
But, if a patient anticoagulated with these drugs presents with life
threatening bleeding (i.e. ICH) or requires emergency surgery...
– How do we assess their degree of anticoagulation?
– Can we urgently reverse the anticoagulant effects of these drugs?

Why Dabigatran in Atrial
Fibrillation?
standard dose
no monitoring
no drug interactions
improved outcomes
– Thromboembolism:150 mg bid RR 0.66 (0.52 –
0.82) vs warfarin

decreased bleeding complications

Dabigatran Bleeding Risk

End Point

Warfarin
(%)

Dabigatran 110mg
(%)

Dabigatran 150mg
(%)

Major Bleeding

3.36

2.71

3.11

Dabigatran Bleeding Risk
End Point

Warfarin
(%)

Dabigatran
110mg(%)

Dabigatran 150mg
(%)

Age >75 yrs

0.61

0.14

0.26

Age >75 yrs

1.0

0.37

0.41**

Intracranial Bleeding

**p = 0.28

? Underestimation of real life bleeding risk, due to
comorbidities & use in renal insufficiency and the
need for lower dosing in elderly patients

Laboratory tests for Novel
Anticoagulants
There is currently no single laboratory test
routinely available that provides specific
evaluation of the anticoagulation effect of
Dabigatran or other novel anticoagulants.
Dabigatran excretion is prolonged in
patients with abnormal renal function.
Creatinine/GFR measurement is essential in
bleeding patients.

Anticoagulants
A normal INR and PTT should exclude the
presence of significant levels of Dabigatran
or other novel anticoagulants in most, but
not all, patients.
The most sensitive test for the presence of
Dabigatran is the Thrombin Time – a
normal result excludes the presence of this
drug, but not the other new oral
anticoagulants.

Anticoagulants
There are currently no locally available tests
that accurately quantifies Dabigatran
anticoagulant activity or that of the other
novel anticoagulants.
The most sensitive test for the presence of
Direct Factor Xa inhibitors is the PT/INR.

No Antidote for Dabigatran
PCC (Octaplex/Beriplex) and recombinant
Factor VIIa (rFVIIa) have not been
evaluated in clinical settings, and have
NOT been demonstrated to improve
coagulation assays in experimental and
volunteer studies. These agents have
been shown to decrease bleeding in a rat
tail vein model despite absence of
reversal of coagulation parameters.

Animal & in vitro Data
Rivaroxaban
– Rat tail model: bleeding time prolongation due to rivaroxaban
corrected with 50 IU/kg Beriplex® (7 vial dose for 70kg adult)
but not with 25 IU/kg dose1

Dabigatran
– Rabbit kidney injury model: Beriplex® corrected bleeding time
and amount of blood loss in dose-dependent fashion2
– Rat tail model: bleeding time prolongation due to dabigatran
corrected with 50 and 100U/kg Feiba and 100ug/kg rFVIIa;
PTT elevation partially corrected with rFVIIa but not with Feiba3
– Human plasma: Feiba corrected dabigatran-inhibited ETP4
1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC251
1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC251
2. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486
2. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486
3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 0370
3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 0370
4. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127
4. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127

PCC = 50 IU/kg Cofact® (3500 IU = 7 vials for 70kg adult)
CIRCULATIONAHA.111.029017. Published online before print September 6, 2011

Study Methods (cont.)
12 healthy male paid volunteers
PPP samples taken pre-drug, pre-reversal agent, and postreversal agent at 15 min, 30 min, 1 hr, 2 hrs, 4hrs, 6hrs, 24
hrs
Lab measurements used:
– Rivaroxaban: PT, endogenous thrombin potential (ETP)
– Dabigatran: aPTT, TT, ecarin clotting time (ECT)


Rivaroxaban Results

High-dose PCC completely overcame rivaroxaban inhibition of FXa
in the PT and ETP laboratory assay systems

Dabigatran Results

High-dose PCC had no detectable effect on dabigatran inhibition of
thrombin in the PT and ETP laboratory assay systems
Problem: these assays are merely surrogates for clinical bleeding tendency

Management of Bleeding
Novel Anticoagulants
oral charcoal if ingestion within 2 hours
mechanical compression if possible and
surgical intervention where indicated
crystalloid replacement and hemodynamic
support, ensure maintenance of urine output
(aggressive diuresis)

blood product transfusion as indicated
for anemia, thrombocytopenia or
coagulopathy unrelated to dabigatran
hemodialysis, particularly in the setting of
overdose or renal impairment
Consult Hematology

the use of FFP, PCC, activated PCC or rFVIIa
on a routine basis cannot be recommended as
part of an effective reversal protocol based on
the current medical literature
Nonetheless, there are case reports that describe
the use of FEIBA, rFVIIa or PCCs (Octaplex or
Beriplex) and these agents are being used off-label
to treat ICH in many Canadian hospitals, without
any published evidence of efficacy.

There is slightly more evidence of efficacy
in humans of the use of PCC when dealing
with bleeding associated with Rivaroxaban,
possibly by overwhelming the inhibitor with
Factor X
Anecdotal reports suggest that FEIBA may
be more effective than Octaplex or Beriplex
in the context of Dabigatran

Factor VIIa for Dabigitran
In a controlled trial on healthy subjects the
Melagatran-induced effects on PTT, TGP &
platelet aggregation were not affected
Based on these results it appears that VIIa is
not effective in reversing DTI
FAST study in non-anticoagulated ICH

…So What To Recommend?
Supportive therapy, diuresis +/- dialysis
Consider antifibrinolytic therapy Tranexamic acid
(10 mg/kg IV or 25 mg/kg orally, rounded to the nearest 500 mg.)

For acute life threatening bleeds or urgent (<6hrs) surgery:
– Clinician to discuss case with on-call hematopathologist for
possible administration of “reversal agent”
– Current recommendation of VGH hematology / hematopathology
groups is 3000 IU PCC IV infusion (6 vials = 120 mL)
– Outcomes (bleeding, thrombosis, death) should be monitored
Rationale:
– Attempt to overcome inhibition by increasing IIa and Xa
generation
– Avoid higher thrombosis risk of rFVIIa and FEIBA

Conclusions
Factor VIIa not recommended for treatment of ICH
For urgent warfarin reversal, NAC 2011 recommendations
advocate PCC dosage according to INR:
– INR < 3.0 → 40mL (2 vials = 1000 IU)
– INR 3.0-5.0 → 80mL (4 vials = 2000 IU)
– INR >5.0 → 120mL (6 vials = 3000 IU)
Very little evidence to guide situations that warrant
immediate reversal of new anticoagulants
– Current VGH recommendation = 3000 IU PCC
– This is likely to change as the literature evolves!

Beriplex® vs Octaplex®
Similar content of vitamin K dependent
factors including protein C & S
Plus anti-thrombin III (0.6 IU/ml) &
albumin
Protein Z (36 IU/ml - ?proteolysis of Xa)
Less heparin (0.5 IU/ml vs 6.0 IU/ml)
Pasteurization vs S/D (both nano-filtered)

REVNEWANTICO…
Study in Healthy Volunteers of the Reversion by Haemostatic Drugs of
the Anticoagulant Effect of New Anti-thrombotics (REVNEWANTICO)
– 10 healthy male volunteers, open-label, no control arm
– Each given single dose of 20mg dabigatran or 150 mg rivaroxaban
– Reversal agents:
• Dabigatran = PCC, rFVIIa, Feiba
• Rivaroxaban = rivaroxaban decoy (FXa-GLAless)

– Primary outcome = thrombin generation time normalization
– Secondary outcomes:
• Dabigatran = normalization of TT and aPTT
• Rivaroxaban = normalization of PT and anti-Xa activity

– Completion date: June 2011

http://clinicaltrials.gov/ct2/show/NCT01210755
http://clinicaltrials.gov/ct2/show/NCT01210755

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