1. Assessment of perioperative bleeding risk
When to look further

2. A critical balance Bleeding risk ? Widespread preoperative screening
Type of operation
Consequences of excessive bleeding
? Widespread preoperative screening
Expense
False positives
Procedures delayed

3. Conditions not to miss Haemophilia A Haemophilia B
Von Willebrands disease
Deficiency of Factor VII, VIII, IX, X, XI
Factor specific inhibitors
Platelet dysfunction
Hypofibrinoginemia/dysfribrinoginemia

4. Operations not to miss Intrtacranial Spinal Tonsillectomy
Cancer related surgery

5. History is absolutely critical
Guides the need for laboratory investigations

6. Clinical Clues Previous surgical bleeding
Transfusion
Return to theatre
Readmission for haematoma/bleeding
History of significant spontaneous bleeding
Recurrent epistaxis , recurrent GIT bleeding
Haemarthrosis, retroperitoneal bleeding, muscle bleeds

7. Clinical clues 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

8. Family history Bleeding disorder Deaths from ICH
Surgical Bleeding – Transfusion, return to theatre
Detailed history
Prompts- circumcision
Tonsillectomy, appendicectomy
fractures

9. Drugs Antiplatelet agents Anticoagulants
Drugs associated with thrombocytopenia
Herbal medications
Garlic
Ginseng
Ginko biloba

10. Laboratory screen
FBE
PT/APTT/fibrinogen
vWF Ag
Platelet aggregometry

11. Abnormal coagulation tests
Prolonged APTT
Any prolongation
? Corrects on mixing – factor deficiency
? Fails to correct- factor specific inhibitor or non specific inhibitor
Liver function tests
heparin like drugs
DIC

12. Prolonged APPT Mixing studies Corrected mix Non corrected mix
Factor assays VIII, IX, X, XI XII
Liver function
Vit K
Non corrected mix
Lupus anticoagulant
Factor specific inhibitors

13. Abnormal coagulation tests
Prolonged PT
Any prolongation
? Corrects on mixing – factor deficiency
? Fails to correct- factor specific inhibitor
LFTS,
Warfarin,
DIC
Vit K defcifiency

14. Prolonged PT Mixing studies Corrected mix Non corrected mix
Factor assays VII
Liver function tests
Vit K
Non corrected mix
Factor specific inhibitors
Lupus anticoagulant unlikely

15. 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.

16. Hutchinson revised a questionnaire originally written by Rappaport
Hutchinson revised a questionnaire originally written by Rappaport. Reviewing these questions with each patient or parent will identify many bleeding disorders.
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)?

18. Use of Recombinant factor VIIa in massive bleeding
Novo Seven

19. Definition Massive Blood Loss
Commonly defined as replacement of patient’s total blood volume or transfusion of >10 units of blood within 24 hours
eg in a 70kg adult - translates to an estimated replacement of 4-5L of blood lost, or the transfusion of 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

20. Issues in massive transfusion settings
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

21. Impaired Haemostasis
Impaired haemostasis is a frequent finding in trauma & may be multifactorial
dilutional coagulopathy
dilutional thrombocytopenia
disseminated intravascular coagulation
hypothermia
acidosis
platelet dysfunction
volume expanders

22. Haemostatic effects of colloids
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

23. Dilutional Coagulopathy
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: x 0.6 x (100-45) plasma = 1650 ml plasma
= 8 units of FFP - but...

24. Dilutional Coagulopathy
On-going losses
Do not always need 100% activity of clotting factors for haemostasis - e.g.
Factor V need only 30%
Factor X need only 30%
Factor XI need only 20%
Fibrinogen need only 40%

25. Dilutional Thrombocytopenia
thrombocytopenia is the most common haemostatic abnormality during and after massive transfusion
microvascular bleeding eg oozing from mucosa, wounds & puncture sites
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.

26. Pharmacological techniques/agents
Antifibrinolytic agents
Aprotinin
tranexamic acid
EACA (epsilon-aminocaproic acid)
Desmospressin (DDAVP)
Fibrin sealants
rVIIa (NovoSeven)

27. Massive Blood Loss/Transfusion Episodes

28. Practice Guidelines for component therapy in Massive Blood Loss
FFP: if APTT,INR >1.5 x normal
2 or more units of FFP
mL/kg
Platelets: Platelet count < x10*9/L
if platelets < 100 then 1platelet pool
if platelets <50 then 2 platelet pools
Cryoprecipitate: Fibrinogen < 1.0 g/L
10 units cryoprecipate

29. NovoSeven given

30. Activated Platelets
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”

31. rFVIIa production hFVII Gene Amplification hFVII gene
Multiple copies
of hFVII gene
rFVIIa production
Incorporate into BHK cells
hFVII
gene
Expression of rFVII in culture medium

32. Only approved funded indication in Australia
Control of bleeding and surgery prophylaxis in patients with inhibitors to coagulation factors FVIII or FIX

33. Impaired Haemostasis in Massive Bleeding
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

34. Potential benefit of rFVIIa :
Bleeding in :
Coagulopathy associated with trauma or surgery
thrombocytopenia
platelet-function disorders
liver failure/ transplantation
intracerebral haemorrhage
BMT

35. Contraindications
hypersensitivity to mouse, hamster or bovine proteins

36. Current cost of one dose of NovoSeven: (as at 1/7/2005)
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 ($ for each 1.2 mg vial)
= $ (without GST)

37. Recombinant Factor VIIa (NovoSeven)

38. Dose/Presentation/ Administration
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

40. The Lancet
Vol 354
July 10, 1999

41. Recombinant activated factor VII for adjunctive hemorrhage control in trauma
Uri Martinowitz et al
J Trauma 51(3)
7 Massively bleeding trauma pts
Average of 40 units of blood each
Rx NovoSeven
Bleeding almost stopped in all cases
Reduction of APTT/PT

42. 1st USA case report of FVIIa in trauma
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:
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

43. Safety profile of recombinant factor VII Harold Roberts et al
Seminars in Hematol 41:
10 years of usage in haemophiliacs with inhibitors & bleeding
>400,000 doses
Expanding usage in cardiac surgery & trauma setting
No increase in thrombosis rate

44. No of reported thrombotic events in haemophilia patients with inhibitors
Total of 1939 treated bleeding episodes
298 separate patients
0.8% event rate
CVA 2
AMI 7
DIC 2
DVT 6

45. Safety profile of rFVIIa
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

46. NovoSeven / Thrombosis
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 pre-existing cerebrovascular disease
1 occipital infarct following craniotomy
1 DVT / PE in Glanzmann’s pt

47. Blood Coag Fibrinolysis 14: 713-717 2003
Recombinant activated factor VII for the treatment of life-threatening haemorrhage
John Eikelboom et al.
Blood Coag Fibrinolysis 14:
Use national -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

48. Royal Perth Hospital Patient Characteristics
18 massively transfused, coagulopathic 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

49. Coagulation Profile before and after rVIIa†
*Median, range
† First result after rVIIa given
‡Paired Wilcoxon signed rank sum test

50. Transfusion before and 24 hours after rVIIa

51. Currently at RMH 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

53. 10/8/8/10 rFVIIa Management of patients with
Critical Bleeding and Coagulopathy
If bleeding and
coagulopathy continue
after conventional therapy
(usually: 10 units RBC,
8 units FFP,
8 units platelets,
10 units cryoprecipitate)
10/8/8/10
Appropriate
Medical interventions
prevent and reverse hypothermia
prevent and reverse acidosis
correct coagulopathy
heparin reversal
- warfarin reversal
- consider antifibrinolytic agents
(i.e. surgery, angiographic embolisation)
Identify and manage surgical bleeding
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
If no response in
20 minutes
Consider 2nd
dose of rFVIIa
(100 µg/kg)
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

54. 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

55. NovoSeven Summary Effective in 90 % of cases (case reports)
Not derived from blood
Not antigenic
Effective when other Rx has failed
Unaffected by blood supply shortages
Currently off-label for trauma / CT Surgery
Incidence of serious adverse events <1%
Caution
Elderly
Those with pre-existing thrombotic risk factors
Intra-cranial pathology / surgery
DIC / sepsis