Transcript Assessment of perioperative bleeding risk

Assessment of
perioperative bleeding risk
When to look further
A critical balance
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Bleeding risk
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Type of operation
Consequences of excessive bleeding
? Widespread preoperative screening
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Expense
False positives
Procedures delayed
Conditions not to miss
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Haemophilia A
Haemophilia B
Von Willebrands disease
Deficiency of Factor VII, VIII, IX, X, XI
Factor specific inhibitors
Platelet dysfunction
Hypofibrinoginemia/dysfribrinoginemia
Operations not to miss
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Intrtacranial
Spinal
Tonsillectomy
Cancer related surgery
History is absolutely
critical
Guides the need for laboratory
investigations
Clinical Clues
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Previous surgical bleeding
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Transfusion
Return to theatre
Readmission for haematoma/bleeding
History of significant spontaneous
bleeding
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Recurrent epistaxis , recurrent GIT bleeding
Haemarthrosis, retroperitoneal bleeding,
muscle bleeds
Clinical clues
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Menorrahgia
 Floods, clots, period> 7 days, home from
school/work
 Iron deficiency
 Hysterectomy for menorrhagia
Post partum bleeding not due to obstetric
causes
Petechia, easy bruising
Family history
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Bleeding disorder
Deaths from ICH
Surgical Bleeding – Transfusion, return to
theatre
Detailed history
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Prompts- circumcision
Tonsillectomy, appendicectomy
fractures
Drugs
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Antiplatelet agents
Anticoagulants
Drugs associated with thrombocytopenia
Herbal medications
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Garlic
Ginseng
Ginko biloba
Laboratory screen
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FBE
PT/APTT/fibrinogen
vWF Ag
Platelet aggregometry
Abnormal coagulation tests
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Prolonged APTT
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Any prolongation
? Corrects on mixing – factor deficiency
? Fails to correct- factor specific inhibitor or
non specific inhibitor
Liver function tests
heparin like drugs
DIC
Prolonged APPT
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Mixing studies
Corrected mix
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Factor assays VIII, IX, X, XI XII
Liver function
Vit K
Non corrected mix
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Lupus anticoagulant
Factor specific inhibitors
Abnormal coagulation tests
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Prolonged PT
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Any prolongation
? Corrects on mixing – factor deficiency
? Fails to correct- factor specific inhibitor
LFTS,
Warfarin,
DIC
Vit K defcifiency
Prolonged PT
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Mixing studies
Corrected mix
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Factor assays VII
Liver function tests
Vit K
Non corrected mix
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Factor specific inhibitors
Lupus anticoagulant unlikely
Controversy re the role of routine preop
screening for U/L bleeding disorder
Bolger
et al found 6 coagulation disorders in 52 pts
undergoing preop screening for adenotonsillectomy.
recommended preop screening in all patients
In
a retrospective review of 994 patients, Manning et al
found that preop PT/PTT failed to identify any patients
with occult coagulopathies.
Burk
et al performed a retrospective review of 1603
patients undergoing adenotonsillectomy. Preoperative
screening , a careful bleeding history is used to identify
any potential bleeding disorders and guide further
laboratory disorders.
Hutchinson revised a questionnaire originally written by Rappaport.
Reviewing these questions with each patient or parent will identify
many bleeding disorders.
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Has the patient ever bled for a prolonged period of time after biting
the tongue, cheek, or lip?
Does the patient develop spontaneous bruises larger than 4 to 5 cm
in diameter?
Has the patient experienced prolonged bleeding following minor
surgical procedures such as circumcision, skin biopsies, or dental
extractions? Has bleeding recurred 24 hours after the cessation of
hemorrhage?
What medications has the patient been taking during the last 10
days? Has the patient ingested any antiplatelet agents such as
aspirin?
Does the patient have any blood relatives with any known bleeding
disorder? Have any other these relatives had prolonged bleeding
requiring the use of blood transfusions?
Does the patient have any systemic medical disorders that might
result in excessive bleeding (Lupus, liver or renal disease)?
Use of Recombinant factor
VIIa in massive bleeding
Novo Seven
Definition Massive Blood Loss
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Commonly defined as replacement of patient’s
total blood volume or transfusion of >10 units
of blood within 24 hours
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eg in a 70kg adult - translates to an estimated
replacement of 4-5L of blood lost, or the transfusion of 1620 units of packed RBC
2nd definition: replacement of 50% of
circulating blood volume in <3hrs or bleeding
>150ml/min
(Normal blood volume approximately 7% of
ideal body weight in adults)
70 ml X Kg
Issues in massive transfusion settings
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Haemostatic defects
“Unknown” patients
Appropriateness of usage - especially of non-red cell
support
Stocks / Inventory management
Communication
Rapid performance of investigations & compatibility
tests
Rapid issue of blood products
Haematological advice/consultation
Documentation
Impaired Haemostasis
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Impaired haemostasis is a frequent finding
in trauma & may be multifactorial
 dilutional coagulopathy
 dilutional thrombocytopenia
 disseminated intravascular coagulation
 hypothermia
 acidosis
 platelet dysfunction
 volume expanders
Haemostatic effects of colloids
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all semi-synthetic colloid solutions produce some
impairment of haemostasis
Primarily due to haemodilution of clotting factors
Gelatins (e.g. Haemaccel & Gelofusin) - least impact
on haemostasis
Dextrans - more significant haemostatic
derangements - max dose 1.5g/kg to avoid risk
bleeding
lowMW dextrans increase microvascular flow &
have specific effects - FVIII activity reduced,
plasminogen activation and fibrinolysis increased,
clot strength reduced & platelet function impaired
Dilutional Coagulopathy
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72 kg Adult trauma victim
5 litre whole blood volume
Pre-trauma haematocrit 45%
Initial plasma volume 5000 ml x (100-45)
= 2750 ml plasma
Haemorrhage of 60% of whole blood
volume
Represents loss of: 5000 x 0.6 x (10045) plasma = 1650 ml plasma
= 8 units of FFP - but...
Dilutional Coagulopathy
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On-going losses
Do not always need 100% activity of
clotting factors for haemostasis - e.g.
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Factor V need only 30%
Factor X need only 30%
Factor XI need only 20%
Fibrinogen need only 40%
Dilutional Thrombocytopenia
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thrombocytopenia is the most common
haemostatic abnormality during and after
massive transfusion
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microvascular bleeding eg oozing from
mucosa, wounds & puncture sites
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platelet count of 50 x 109/L during active
bleeding should be sufficient for normal
haemostasis provided platelet function intact.
count of 50 x 109/L expected when red cell
concentrates equivalent to 2 blood volumes
transfused. However, marked individual
variation.
Pharmacological techniques/agents
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Antifibrinolytic agents
 Aprotinin
 tranexamic acid
 EACA (epsilon-aminocaproic acid)
Desmospressin (DDAVP)
Fibrin sealants
rVIIa (NovoSeven)
Massive Blood Loss/Transfusion Episodes
Ongoing Uncrossmatched Blood
Issued ie RCC's
Ongoing Blood &
Blood Products
Issued ie RCC's,
FFP, Plts & Cryo
2 units uncrossmatched O
Neg used
More
Uncrossmatched
Blood requested
>10 Units
in 8 Hrs
Thaw 5-10 Units Cryo & Issue
3 Units AB FFP & 5 Units (1pool )Plts
Call Haematology
Registrar or Consultant
Contact !
ie Page
Practice Guidelines for component therapy in
Massive Blood Loss
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FFP:
if APTT,INR >1.5 x normal
 2 or more units of FFP
 10 -15 mL/kg
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Platelets: Platelet count < 50 - 100 x10*9/L
 if platelets < 100 then 1platelet pool
 if platelets <50 then 2 platelet pools
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Cryoprecipitate: Fibrinogen < 1.0 g/L
 10 units cryoprecipate
Date
16/6/05
CH
NovoSeven given
Comment
0330
Time issued
from RMH Blood
Bank
RCC
0700
1200
1400
6
1530
1630
1730
1900
0200
4
FFP
5
9
PLATELETS
10
10
CRYO
10
20
INR
1.0
1.6
1.5
1.4
1.3
.0.7
0.7
APTT
29
64
47
47
39
87
40
FIBRINOGEN
2.8
2.1
2.0
3.2
3.2
3.7
3.8
Hb
128
55
68
Clotted
67
92
96
PLT COUNT
163
170
168
207
181
207
TCT (TCTP)
Activated Platelets
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Activated by small amount of thrombin
generated by TF-VIIa complex
Activation leads to negatively charged
phospholipids being exposed on platelet surface
Forms the platform for augmentation of
coagulation
 IXa generated binds to platelet surface and
with VIIIa forms Xase complex
 Xase complex leads to generation of
increased thrombin “Thrombin Burst”
hFVII
Gene
Amplification
Multiple copies
of hFVII gene
rFVIIa
production
Incorporate
into BHK cells
hFVII
gene
Expression of
rFVII in culture medium
Only approved funded indication in Australia
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Control of bleeding and surgery prophylaxis in patients with
inhibitors to coagulation factors FVIII or FIX
Impaired Haemostasis in Massive
Bleeding
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Multifactorial
 Dilution of platelets and coagulation factors
following transfusion and volume expanders
 Loss of haemostatic factors
 Consumption in clot formation
 Disseminated intravascular coagulation (DIC)
 Hypothermia
 Acidosis
 Platelet dysfunction
 Haemostatic impairment due to semisynthetic
colloids
All these lead to impaired thrombin generation
Potential benefit of rFVIIa :
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Bleeding in :
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Coagulopathy associated with trauma or
surgery
thrombocytopenia
platelet-function disorders
liver failure/ transplantation
intracerebral haemorrhage
BMT
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Contraindications
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hypersensitivity to mouse, hamster or
bovine proteins
Current cost of one dose of NovoSeven:
(as at 1/7/2005)
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e.g. dose in massive blood loss setting
e.g. 70 kg patient
(round up weight to 72 kg)
give 100 μg per kg
= 7200 μg = 7.2 mg
= 6 vials each of 1.2 mg
= 6 x ($1208.26 for each 1.2 mg vial)
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= $7249.56 (without GST)
Recombinant Factor VIIa (NovoSeven)
Dose/Presentation/ Administration
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powder for reconstitution, stored at 2-8C
sterile water for injection for reconstitution
(2.2mL with 1.2mgvial)
vials 1.2mg, 2.4mg, 4.8mg - usual stock 1.2mg
dose recommended 100mcg/kg rounded to
nearest whole vial
administered as IV bolus over 2-5minutes
time to peak concentration 15 minutes
elimination half life 2-3 hour
Treatment of traumatic bleeding
with recombinant factor VIIa
Gili Kenet, Raphael Walden, Arieh Eldad, Uri Martinowitz
Surgical intervention failed to stop life-threatening bleeding caused
by injury complicated by severe coagulopathy. Administration of
recombinant factor VIIa immediately corrected the coagulopathy and
bleeding stopped.
THE LANCET • Vol 354 • November 27, 1999
The Lancet
Vol 354
July 10, 1999
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Recombinant activated factor VII for
adjunctive hemorrhage control in trauma
Uri Martinowitz et al
J Trauma 51(3) 431-439 2001
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7 Massively bleeding trauma pts
Average of 40 units of blood each
Rx NovoSeven
Bleeding almost stopped in all cases
Reduction of APTT/PT
1st USA case report of FVIIa in trauma
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Successful use of recombinant activated factor VII for
trauma-associated hemorrhage in a patient without
pre-existing coagulopathy
Patricia O’Neill et al
J Trauma 52: 400-405 2002
24 yo female stabbed 6 times to right chest /
epigastrium / limbs
Aggressive volume expansion / surgery / transfusion
support
Prolonged surgery to hepatic lacerations
After 108 units of red cells, 78 units FFP, 18 units
cryoprecipitate, eqiv 60 units platelets / further
surgery x 2 / gelfoam packing / angiographic
embolisation – the bleeding continued
One dose of rFVII given – bleeding ceased
immediately
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Safety profile of recombinant factor VII
Harold Roberts et al
Seminars in Hematol 41: 101-108 2004
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10 years of usage in haemophiliacs with inhibitors
& bleeding
>400,000 doses
Expanding usage in cardiac surgery & trauma
setting
No increase in thrombosis rate
No of reported thrombotic events in
haemophilia patients with inhibitors
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Total of 1939 treated bleeding
episodes
298 separate patients
0.8% event rate
CVA
 AMI
 DIC
 DVT
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2
7
2
6
Safety profile of rFVIIa
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Requires tissue factor from injured site for
activity – thus effect confined
0.2% thrombosis rate in haemophiliac group
Fatal thrombosis rate of 4 in 5522 cases
(0.07%)
One thrombotic cerebral infarction in 10
patients treated for SAH
NovoSeven / Thrombosis
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AMI 5 pts of 7 > 70 years
1 AMI occurred 3 days post dose (also on tranexamic
acid)
1 AMI following continuous infusion of FVII for dental
procedure
6 Cerebral thrombotic events. 3 patients had preexisting cerebrovascular disease
1 occipital infarct following craniotomy
1 DVT / PE in Glanzmann’s pt
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Recombinant activated factor VII for the treatment
of life-threatening haemorrhage
John Eikelboom et al.
Blood Coag Fibrinolysis 14: 713-717 2003
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Use national email-out to gather cases
21 patients (22-79 years)
Multi-trauma / cardiac or vascular surgery / liver
transplantation
Median pre-Factor VIIa usage of 22 units of red cells
Median INR 1.6 Median APTT 55s
In 24 hours post FVIIa median red cells usage was 2 units
16/21 alive at 30 days
No thrombotic complications
Royal Perth Hospital
Patient Characteristics
• 18 massively transfused, coagulopathic
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patients
(no pre-existing coagulopathy)
Median age 44 (range 22-79)
Females 5 (28%), Males 13 (72%)
Cause of bleeding/surgical procedure
 7 cardiac/vascular surgery
 5 orthoptic liver transplant
 2 chronic liver disease with coagulopathy
 2 multitrauma
 1 fatty liver of pregnancy, caesarian section
 1 severe haemorrhagic pancreatitis
Coagulation Profile before and after rVIIa
Before
rVIIa*
†
After
rVIIa*†
INR
1.6(1.4-3.6) 1.0(0.9-1.2)
APTT
54 (31-180)
40 (30-94)
Fibrinogen 1.8 (1.2-4.3) 2.6 (1.5-4.6)
*Median, range
† First result after rVIIa given
‡Paired Wilcoxon signed rank sum test
P-value‡
<0.0001
0.0009
0.09
0
Packed cells
20
40
60
Transfusion before and
24 hours after rVIIa
before
after
Currently at RMH
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When NovoSeven is requested / recommended
Direct consultation with haematology consultant and
treating consultant with patient
Usually only considered after failure of aggressive non-red
cell blood product support to achieve haemostasis
MPH: treating consultant advised to contact health fund/
hospital management to get agreement for payment
Funding issues/ process: to be resolved
Increasing frequency of requests
RMH Guidelines for recombinant Factor VIIa
Recombinant Factor VIIa may be considered in the following situation (each of these criteria should
be met):
1.
Massively transfused patients (more than 10 units of red cells in 24 hours or
replacement of blood volume within 3 hours) with ongoing bleeding and coagulopathy
2.
Persistent bleeding despite:2.1 Appropriate blood component transfusion (fresh-frozen plasma, platelets,
cryoprecipitate) to try and correct coagulopathy
2.2 Pharmacologic measures (DDAVP, anti-fibrinolytic agents)
2.3 General haemostatic measures (including efforts to correct hypothermia,
hypocalcaemia)
2.4 Surgical intervention where appropriate.
3.
The treating Consultant (Surgeon, Anaesthetist, Intensive Care Physician) must
consider the condition of the patient to be such that he/she is likely to die of ongoing
bleeding. The Unit/Divisional Head must also agree with this decision. This should
be documented in the patient medical records.
4.
A full blood count and coagulation profile (APTT, INR, and fibrinogen) should be
available prior to considering the use of recombinant factor VIIa and should be
repeated after the product is administered to assess response
The decision to use recombinant Factor VIIa should be made in consultation with the
on-call haematologist. Further blood component transfusion (fresh frozen plasma,
platelets, cryoprecipitate) may need to be given after recombinant factor VIIa, as
appropriate.
5.
Identify and manage surgical bleeding
(i.e. surgery, angiographic embolisation)
Management of patients with
Critical Bleeding and Coagulopathy
If bleeding and
coagulopathy continue
after conventional therapy
Appropriate
Medical interventions
- prevent and reverse hypothermia
- prevent and reverse acidosis
- correct coagulopathy
- heparin reversal
- warfarin reversal
- consider antifibrinolytic agents
(usually: 10 units RBC,
8 units FFP,
8 units platelets,
10 units cryoprecipitate)
10/8/8/10
rFVIIa
100 µg/kg
(rounded to whole vial)
Laboratory Tests
Repeat blood tests after each
4-6 units RBCs
PT, APTT > 1.5 X control  4 units FFP
Fibrinogen < 1g/L
 10 units cryoprecipitate
Platelet count < 75 X 109/l  4 units of platelets
Consider calcium chloride
Note:
• Use of rFVIIa in children and pregnancy requires special consideration of risk/benefits
• Early use may be considered in high-risk groups e.g. patients with cirrhosis and undergoing liver surgery
If no response in
20 minutes
Consider 2nd
dose of rFVIIa
(100 µg/kg)
Recombinant factor VIIa for life threatening post-partum haemorrhage
J Ahonen and R Jokela. Recombinant factor VIIa for life threatening post-partum haemorrhage
British Journal of Anaethesia (2005) 1-4
NovoSeven Summary
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Effective in 90 % of cases
(case reports)
Not derived from blood
Not antigenic
Effective when other Rx
has failed
Unaffected by blood
supply shortages
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Currently off-label for
trauma / CT Surgery
Incidence of serious
adverse events <1%
Caution
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Elderly
Those with pre-existing
thrombotic risk factors
Intra-cranial pathology /
surgery
DIC / sepsis