MASSIVE BLEEDING IN TRAUMA &

SURGERYRole of rFVIIa

CONSULTANTDEPARTMENT OF ANESTHESIOLOGY

&INTENSIVE CARE

PUBLIC HOSPITAL AUTHORITY’S RAND MEMEORIAL HOSPITAL

FREEPORT, BAHAMAS

Dr. MRIDUL. M. PANDITRAO

Uncontrolled Haemorrhage

Second Leading Cause of Death

Associated Coagulopathy

“What to do next” ?

Introduction

Introduction (Cont)

Traumatic injury is the leading cause of death in age group - 5 to 44 years

Accounts for 10% of all deaths in spite of improved care

Uncontrolled bleeding contributes to 30% to 40% of trauma related early deaths

Especially in the hospital setting

Krug EG, Sharma GK, Lozano R: The global burden of injuries. Am J Public Health 2000, 90:523-526

Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997, 349:1269-1276.

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.

Physiology of Bleeding

Injury: Definition and Consequence

Classification of the bleeding/ haemorrhage {American college of Surgeons [Advanced Trauma Life Support (ATLS) Team]}

4 classes

Classification of the Bleeding

Class I Hemorrhage up to

15%.

Class II Hemorrhage 15-30%.

Class III Hemorrhage 30-40%.

Class IV Hemorrhage >40%.

Class I Hemorrhage Up to 15% of blood volume

No change in vital signs

Fluid resuscitation is not necessary

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

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

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

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

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%

Haemostasis

Definition

Stages

Stage I : - Vasoconstriction Stage II :- Platelet plug

formation Stage III : - Coagulation

cascade Stage IV : - Fibrinolysis

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

Stage II Platelet plug formation

1. Platelet adhesion2. 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 aggregationADP increases platelet stickiness and they go on adhering with each other to create a platelet plug

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

Stage IV Fibrinolysis

For checking excessive clot formation and preventing its spread, factors like plasminogen, antithrombin III, protein C etc influence this

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.

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 surfaceHoffman 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.

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 XaFactor Xa binds to factor Va on the cell surface

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.

The factor Xa/Va complex activates small amounts of prothrombin to thrombin at the surface of sub-endothelial cellsThis limited amount of thrombin activates factors V, VIII and platelets

The activated platelet binds factors Va, VIlla and IXa

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.

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- XIIIThe amount and rate of thrombin generation determines the strength of the haemostatic plug

“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”

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’

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.

Mechanism of Action

Recombinant factor Vila (rFVIIa) controls bleeding at the site of vascular injury only

• 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 controls the bleeding6

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”

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.

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

“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!

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

resolutionCiacma A et al. rFVIIa effectively controls bleed in gynecological surgery: J of Gyne Surg 2005: 21(1) 13-20

Oncological surgeries Paediatric surgeries (N=8)

Resection of brain tumors Promising results and better outcome

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.

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

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.

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 pumpMidhathada MV, Mehta P, Milton W: Recombinant factor VIIa in the treatment of bleeding. Am.j. Clinical

pathology: 2004; 12(1); 124-137

Prostate surgeries

Patients for Prostate surgeries (N=36)

rFVIIa pre operatively Reduced blood loss and the need for

blood transfusion

Orthopedic surgeries

THR, TKR, posterior spinal fusion Patients with various coagulation

disorders rFVIIa prevented postoperative

bleeding

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 effectsUharcek 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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Thank you!