Prof.Mridul Panditrao dwells upon the peri-operative and emergency problem of massive bleeding, the physiology of coagulation, anf the role of recombinanat activated factor VII. KUWAIT MEDICAL JOURNAL December 2011 176 Review Article Kuwait Medical Journal 2011; 43 (3): 176-188 Massive Bleeding in Trauma and Surgery: Role of rFVIIa ABSTRACT KEY WORDS: recombinant activated factor VII, recommendations Mridul Panditrao1, 2, Minnu Panditrao1, Mohammed Shamsah2 1Department of Anesthesiology and Critical Care, Dr. D Y Patil Medical College (Deemed University), Pune, India 2Department of Anesthesia and Intensive Care, Al-Adan Hospital, Kuwait Address correspondence to: Prof. Dr. Mridul M. Panditrao, MD, DA, Senior Specialist, Department of Anesthesia and Intensive Care, Al-Adan Hospital, Kuwait. Tel: 65 88 90 25, E-mail: drmmprao1@ gmail.com INTRODUCTION Traumatic injury is the leading cause of death worldwide among persons between one and 44 years of age[1,2], fourth leading cause of death over all age groups[3] and accounts for 10% of all deaths[4]. In fact, Global Burden Diseases (GBD) Study has classifiedtheinjuriesasGroup-3,alongwithothertwo broader categories of diseases; communicable, and non-communicable[5]. Despite improvement in care, uncontrolled bleeding contributes to 30 to 40% of trauma related deaths and is a leading cause of potentially preventable early in-hospital deaths[6 – 9]. PHYSIOLOGY OF BLEEDING AND HEMOSTASIS[10,11] As a physiological response to an injury, whether, traumatic or planned (surgical), especially, if there is an integumental (skin or mucus membrane) breach then logically hemorrhage is the result. American College of Surgeons[12] (Advanced Trauma Life Support (ATLS) Team) has classifiedbleeding/hemorrhage intofourclasses (Table1, Annexure1 ). This has further been modifiedrecentlytoincludesomemoreparameters[11] (Table 2, Annexure1), Class I being, non-shock state, such as occurs when donating a unit of blood, whereas class IV being pre-terminal event requiring immediate therapy[13]. Massive hemorrhage may be definedasloss of total EBV within a 24-hour period, or loss of half of the EBV in a 3-hour period. Bleeding secondary to surgical / traumatic cause is usually as a result of combination of vascular injury and coagulopathy[14]. STAGE I: VASOCONSTRICTION As a response to hemorrhage, all the mediators of vasoconstriction: noradrenaline, thromboxanes (TBXs) and mediators of RA system are released, causing intense vasoconstriction. Effects: The firstaidsystemcanlastfromminutesto hours. 1. Vasoconstriction minimizes vessel diameter and slows bleeding 2. TBXA2 leads to smooth muscle relaxation 3. The tamponade effect by the extravasated blood adds to vasoconstriction STAGE II: PLATELET PLUG FORMATION A complex phase formed by three sub-phases 1. Platelet adhesion 2. Platelet release reaction Platelets create extensions and come in contact with each other. They release their contents i.e.,

1. MASSIVE BLEEDING IN
TRAUMA & SURGERY

3. Introduction
Uncontrolled Haemorrhage
Second Leading Cause of Death
Associated Coagulopathy
“What to do next” ?

4. Introduction (Cont)
 Traumatic injury is the leading cause of death in age
group - 5 to 44 years
Krug EG, Sharma GK, Lozano R: The global burden of injuries. Am J Public Health 2000, 90:523-526
 Accounts for 10% of all deaths in spite of improved care
Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997, 349:1269-1276.
 Uncontrolled bleeding contributes to 30% to 40% of
trauma related early deaths
 Especially in the hospital setting
Sauaia A, Moore FA, Moore EE, Moser KS, et al’ Epidemiology of trauma deaths: a reassessment. J Trauma 1995, 38:185-
193.
Holcomb JB: Methods for improved hemorrhage control. Crit Care 2004, 8(Suppl 2):S57-60.
Kauvar DS, Wade CE: The epidemiology and modern management of traumatic hemorrhage: US and international
perspectives. Crit Care 2005, 9(Suppl 5):S1-9.

5. Physiology of Bleeding
 Injury: Definition and Consequence
 Classification of the bleeding/ haemorrhage
{American college of Surgeons [Advanced Trauma Life Support (ATLS) Team]}
 4 classes

6. Classification of the Bleeding
 Class I Hemorrhage up to 15%.
 Class II Hemorrhage 15-30%.
 Class III Hemorrhage 30-40%.
 Class IV Hemorrhage >40%.

7. Class I Hemorrhage
 Up to 15% of blood volume
 No change in vital signs
 Fluid resuscitation is not necessary

8. Class II Hemorrhage
 Involves 15-30% of total blood volume
 Tachycardia, ↓ Pulse pressure
 Peripheral vasoconstriction
 Pallor, Cold
 Acute volume resuscitation with crystalloids
 Blood transfusion is not required

9. Class III Hemorrhage
 involves loss of 30-40% of circulating blood
volume
 Tachycardia, ↓ Blood pressure
 ↓ peripheral perfusion, such as capillary refill
 Mental status worsens
 Fluid resuscitation with crystalloid
 Blood transfusion

10. Class IV Hemorrhage
 Involves loss of >40% of circulating blood
volume
 The limit of the body's compensation is
reached
 Aggressive resuscitation is required to
prevent death

11. Massive bleeding
Defined as the loss of one blood
volume within 24 hours or the loss of
half blood volume within three hours.
Spahn DR, Rossaint R: Coagulopathy and blood component transfusion in trauma. Br J Anaesth 2005, 95:130-139

12. Classification of the Bleeding
(UK)
As Described In The American Way, Except The
Cut Off Points At 5% Lesser. Viz.
10%
10-25%
25-35%
> 35%

13. Haemostasis
Definition
Stages
 Stage I : - Vasoconstriction
 Stage II :- Platelet plug formation
 Stage III : - Coagulation cascade
 Stage IV : - Fibrinolysis

14. Stage I Vasoconstriction
 Mediators of Vasoconstriction are released
 Noradrenaline, TBXS, mediators of RA system
 Vasoconstriction minimizes vessel diameter
& slows bleeding
 TBXA2 leads to smooth muscle relaxation
 The tamponade effect by the extravasated
blood adds to vasoconstriction

15. Stage II Platelet plug formation
1. Platelet adhesion
2. Platelet release reaction
1. Platelets create extensions and come in contact
with each other
2. Release their contents i.e. α granules & dense
granules
3. 5HT & TBXs: - Potentiate vasoconstriction
3. Platelet aggregation
ADP increases platelet stickiness and they go on
adhering with each other to create a platelet plug

16. Stage III Coagulation cascade
 Multifactorial process
 Liquid blood gets converted in to a gel or
coagulum/ clot made up from proteinous
fibers – fibrin
 Various elements of blood are trapped in this
network

17. Stage IV Fibrinolysis
 For checking excessive clot formation and
preventing its spread, factors like
plasminogen, antithrombin III, protein C etc
influence this

18. Coagulation cascade
 Initiation phase
 Amplification phase
 Propagation phase
Hoffman M, Monroe DM: A cell-based model of hemostasis. Thromb Haemost 2001; 85(6):958-965.

19. Initiation phase
 Vessel wall injury takes place
 Tissue factor is exposed to the circulating
endogenous factor VII
 VII gets activated to VII A
 Formation of TF/ VII A complex
 This complex activates the cells bearing TF to
produce
 Factor IX to IX A
 Factor X to X A
 The XA binds to VA on the cell surface
Hoffman M, Monroe DM: A cell-based model of hemostasis. Thromb Haemost 2001; 85(6):958-965.
Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol. 2006 Jan; 26(1):41-8.

20. Upon vessel wall
injury, tissue
factor is exposed
to circulating
endogenous
factor VII/VIIa-
leading to the
TF/VIIa complex
which initiates
coagulation
At the surface of
TF-bearing cells
the TF/VIIa
complex
activates.
•Factor IX to IXa
•Factor X to Xa
Factor Xa binds to
factor Va on the
cell surface

21. Amplification phase
 Factor XA/VA complex activates prothrombin
 Prothrombin Thrombin at sub endothelial
surface
 Thrombin amplifies the process by activating
V,VII and platelets
 Activated platelets bind to factors VA, VIIA,
IX A
Monroe DM , Hoffman M. Transmission of a procoagulant signal from tissue factor-bearing cell to platelets.
Blood Coagul Fibrinolysis. 1996 Jun;7(4):459-64.

22. The factor
Xa/Va complex
activates small
amounts of
prothrombin
to thrombin at
the surface of
sub-
endothelial
cells
This limited
amount of
thrombin
activates
factors V, VIII
and platelets
The activated
platelet binds
factors Va,
VIlla and IXa

23. Propagation phase
 The thrombin activated platelets change their
shape
 Expose negatively charged phospholipids to
which, factor VIIIA/ IXA complex binds
 → factor X activation (XA) on the surface of
activated platelets.

24. Thrombin-activated
platelets change shape
and expose negatively
charged phospholipids
to which the factor
Vllla/IXa complex binds
• This results in factor X
activation on the
surface of activated
platelets
The factor Xa/Va
complex activates large
amounts of
prothrombin resulting
in a "thrombin burst"
which:
•Converts fibrinogen to
fibrin
•Activates fibrin-
stabilising factor- XIII
The amount and rate
of thrombin
generation
determines the
strength of the
haemostatic plug

25. “Thrombin burst”
 XA with VA forms complex leading to
 Activation of large amount of prothrombine
to thrombine
“Thrombin burst”
 Fibrinogen → Fibrin
 XIII → XIIIA (fibrin stabilizing factor)
 “Plugged in”

26. Uncontrolled Haemorrhage
in surgical settings!
 Second leading cause of death from trauma
(surgical or non surgical)
 Profound bleeding with coagulopathy
 Mortality and / or Morbidity:
 Severity of injury
 Degree of systemic coagulopathy
 Co-existing acidosis
can rFVIIA help!!!! ? A ‘novel concept’

27. rFVIIa (NovoSeven®7)
(novo nordisk®)
 Recombinant Protein (50 kDa)
 Structurally similar to Factor VIIa
 Half-life 2 – 3 h
 Recommended Doses
 Factor VIII and IX deficiencies 90 μg/kg
 Haemophilia 300 μg/kg
 Plasma rVIIa level > 10 U/ml
Delonhery TG. Management of bleeding emergencies: when to use recombinant activated factor VII. Expert
opinion Pharmaco Therapeutics: 2006; 7(1) 25-34.

28. Mechanism of Action

29. • rFVIIa works locally at
the site of vascular injury,
where tissue factor (TF) is
exposed and activated
platelets are found
• Binding of factor Vila
or rFVIIa to TF initiates
the coagulation
generating small
amounts of thrombin
• At pharmacological
doses rFVIIa directly
activates factor X on the
surface of activated
platelets resulting in a
"thrombin burst”
• The thrombin burst leads
to the formation of a stable
haemostatic plug which
Recombinant factor Vila (rFVIIa) controls bleeding at the site of vascular injury
only
controls the bleeding6

30. How does it help?
 By directly activating Factor X to Xa
 It bypasses the pathway dependence on VIIIa
&/or IXa mechanism
 Overcomes any deficiency/decreased levels
of Factors VIII and IX
 Directly leads to initiation of “Thrombin
Burst”
 Shortens the time required for Clot formation
 Improves the quality of the ‘Final Clot”

31. FDA approved Indications
 Congenital hemophilia
 Acquired hemophilia
 Especially secondary to formation antibodies
against inherent factor VIII.
 Drug induced e.g. penicillin, chloramphenicol,
phenitoin.
 Autoimmune conditions like rheumatoid arthritis,
SLE, malignancies: solid or haematologic,
lympho-proliferative.
 Pregnancy related and post partum.

32. FDA approved Indications(Cont)
 Rarer bleeding disorders
 Inherited FVII deficiency
 Congenital deficiencies of multiple coagulation
factors
 Glanzmann’s thrombasthenia
 Patients with Factor VII and XI deficiency
 Bernard - Soulier syndrome
 Giant platelet syndrome
 Pre-procedural management in patients
with end-stage liver disease

33. “Off the Label” Indications
Use for Bleeding in Peri-operative period?
 No Randomized Controlled Trials
 No FDA approval
 But some anecdotal/ case reports evidence
 Sketchy, yet tempting!

34. Gynaecological surgeries
 Post menopausal patients (age range 58-72
yrs, N=4)
 Hysterectomies: fibroids, Ca Cx,
Ca endometrium, body or metastatic Ca..
 Dose range of rFVIIa 17-70 µg/kg
 Bleeding resolved after 1st dose in 3 pts (12
hrs.)
 2nd dose was needed in 1 pt. for complete
resolution
Ciacma A et al. rFVIIa effectively controls bleed in gynecological surgery: J of Gyne Surg 2005: 21(1) 13-20

35. Oncological surgeries
 Paediatric surgeries (N=8)
 Resection of brain tumors
 Promising results and better outcome
Heisel M, Nagib M, Madsen L. Use of recombinant factor VIIa ( rFVIIa) to control intraoperative bleeding
in paediatric braintumor patients. Paediatr Blood Cancer: 2004; 43(6); 703-5
 lung cancer patient for thoracotomies (N=3)
 rFVIIa to control massive postoperative hemorrhage
 A bolus of 90µg/kg was given, while in 2 of them it had
to be repeated after 2 hrs at 60µg/kg .
 Absolutely effective without hypercoagulability or
thrombo embolic phenomena.
Koglera VM, Slobodnjakb Z. Successful use of activated recombinant factor VII in life threatening bleeding after
thoracic surgery: Swiss med Wkly. 2007: 137; 407-410.

36. Cardiac surgeries
 Infants and elderly patients (N=18).
 Cardiac surgery
 Either single bolus dose or divided doses
 Bleeding significantly reduced in 16 out of 18
Completely terminated in 9 out of 18
 rFVIIa before removal of an intra-aortic
balloon pump
Midhathada MV, Mehta P, Milton W: Recombinant factor VIIa in the treatment of bleeding. Am.j. Clinical
pathology: 2004; 12(1); 124-137

37. Prostate surgeries
 Patients for Prostate surgeries (N=36)
 rFVIIa pre operatively
 Reduced blood loss and the need for blood
transfusion

38. Orthopedic surgeries
 THR, TKR, posterior spinal fusion
 Patients with various coagulation disorders
 rFVIIa prevented postoperative bleeding

39. Post L.S.C.S. PPH
 2 young females ( both, 29 yrs old) multipara
 Both essentially normal preoperatively
 developed uterine atony , DIC and intra & post
partum hemorrhage
 Conventional treatment failed to control bleeding
 90µg/kg of rFVIIa as a final attempt
 within 15 – 20 minutes
 Bleeding stopped
 Resolution of coagulopathy
 No side effects
Uharcek P, Myneek M, Kellener M: Use of recombinant factor VIIa on the therapy of massive bleeding after caesarian section:
Ceska Gynekol: 2007: 72(3); 200-2
Heilmann L, Wild C, Honjnaeki B: Successful treatment of life threatening bleeding after caesarian section with recombinant activated
factorVIIa. Clin Appl Thromb Hemost. 2006: 12(2); 227-9.

40. Ist open non-randomized study
 Patients with post-partum Haemorrhage
 26 patients with rFVIIa
 22 women without rFVIIa
 Patients who had rFVIIa
 Had significantly higher bleeding!!
 Longer (APTT)
 Longer (PT)
 Lower fibrinogen values
Hence as a “last resort” especially in obstetric
hemorrhage.
Ahonen J, Jokela R, Kortila K. An open non randomized study of recombinant activated factor VIIa in major
postmortem hemorrhage: Acta Anaesthesiol Scand: 2007: 1-7

41. Isreali MRTF Guidelines
 rFVIIA as an Adjunct to concomitant surgical
measures
 If packs to be removed, then, before rFVIIA
administration
 If bleeding is encountered outside OR, then
“second look” must be considered
Martino witz U. Michaelson M. Guidelines for use of rFVIIa . Journal of thrombosis and hemostasis 2005, 3: 1-9.

42. Recommendations
 Replace lost/consumed haemostatic factors with:
 FFP
 Cryoprecipitate
 Platelets
 Red blood cells
 Full blood count, PT, APTT and fibrinogen should be
checked regularly to guide replacement.

43. Recommendations (Cont)
 The use of rFVIIa should be considered if bleeding
continues when:
 Greater than one blood volume has been transfused
 Adequate replacement with FFP, cryoprecipitate
and platelets has been given.
 No identifiable surgical source of bleeding has been
found.

44. Recommendations (Cont)
 If it is felt that rFVIIa may be of benefit
 Normally only be requested by a consultant
anaesthesiologist.
 Normally only to be used following discussion
with a consultant haematologist.

45. Recommendations (Cont)
 One 4.8 mg vial should be given (50-100ug/kg
for a 50-100 kg patient).
 Bleeding does not diminish in 30-60 minutes?
a further 4.8 mg vial
 Bleeding continues after a second dose,
NO THIRD DOSE
 Surgical re-exploration should be considered.

46. Precautions
Thrombotic risk associated with the use of rFVIIa
 Patients with
 A history of Coronary Artery Disease.
 A history of arterial or venous Thrombosis.
 Cerebral Vascular Disease.
 DIC.

47. Summary
 Safe and effective in haemophilia patients
with inhibitors.
 Also effective in a variety of bleeding
conditions in non-hemophilic patients.
 “Universal” or “General” Hemostatic agent ??
 But not always effective in all the conditions
 Life saving in some patients experiencing life-
threatening hemorrhage.

48. Conclusions
 Use of rFVIIA as a life saving measure in some
patients experiencing life-threatening
hemorrhage seems warranted as a ‘last resort’
modality, inclusive of peri-operative patients
 However urgent, randomized controlled clinical
trials are needed to define the appropriate role
of this agent.