Transfusions in Surgery

Dr. Carolyn Faught

November 28, 2006

FACT

• Approximately 60% of all red cell transfusions are administered to surgical patients

• Therefore need to understand indications and risks of transfusion

Main Objectives

• Be aware of the adverse effects of transfusion

• Discuss “transfusion triggers” in surgical patients

• Treatment of massive transfusion

• Indications for recombinant FVIIa in surgical patients

Blood Components• Blood components made by physical separation

from whole blood:– Packed red blood cells (PRBCs)– Platelets– Plasma ( FFP, cryoprecipitate)– Granulocytes

• Blood derivatives:– Fractioned, virally inactivated product (ie. albumin,

IVIG)– Recombinant products (VIII, IX, VIIa)

Universal donor/Universal recipient

• Group O RBCs: universal donor, can be given to patients of all blood groups, because no A or B antigens on surface of RBCs

• Group AB person is the universal recipient for RBCs, because has no anti-A or anti-B antibodies in plasma

• Group AB plasma can be given to all recipients, as it has no anti-A or anti-B antibodies

• Emergency (uncrossed) products = O neg RBCs and AB plasma

• Still best to give Group specific blood

Blood Products: Universal leukoreduction of all blood products in Canada

• ‘third generation’ filters to remove WBCs from blood (leukoreduction) to less than 5x106 WBC/bag of RBCs

• Leukoreduction reduces CMV transmission, HLA alloimmunization, febrile non-hemolytic transfusion reactions

Adverse Effects of Transfusion

• Transfusion Reactions– Infectious– Non-infectious

• Immunologically mediated• Non-immunologic

– Immediate– Delayed

Infectious risks of transfusion• Bacterial contamination of platelets 1:40,000*• HBV - 1/250,000• HIV - 1/1,900,000• HCV - 1/1,800,000• HTLV1 - 1/1,000,000

Less clear• CJD (Creutzfeldt-Jakob disease)• West Nile 1/4,000

Non-infectious risks• Febrile reactions• Allergic/anaphylactoid reactions• Hemolytic reactions – 1/20,000• Volume overload• Acute lung injury (TRALI)• Serologic sensitization

– Alloimmunization to red cell antigens (delayed hemolytic transfusion reaction)

– Graft-versus host disease– Platelet refractoriness, post-transfusion purpura

• Immunomodulation - ? Increased risk of infection, cancer recurrence

TRALI• Transfusion-Related Acute Lung Injury• Non-cardiogenic pulmonary edema after transfusion• Incidence up to 1:5000 transfusions• Antibodies in donor plasma against HLA or

neutrophils react with recipient leukocytes• Leukoagglutination in lungs, increase in vascular

permeability, fluid enters alveolar spaces

• Need to identify, to remove donor from donor pool

TOH Blood Conservation Program

• 800 patients a year assessed at Civic• Best candidates are hips, backs, prostate, some

gynecologic surgery• Patients assessed 4 wks prior to surgery so they

can benefit• Liberal use of Epo and iron • Autologous or 2 unit collection with TRIMA• If Hb > 130 g/L, no Epo• If Hb < 125-130 g/L, no autologous donation

Transfusion Rates Across Canada

• Locally, transfusion rates are ~ 45% in hips, 35% in prostate, 25% in knee

• Across Canada:– Cardiac: 43.8% female 65% vs male 37%– Hip: 34.4%– ICU (post-op and trauma): 36.9%

Can J Anesth 2005: 52(6); 581-590

Transfusion Practices in Surgery

• Little evidence to support age-old practice of keeping Hb > 100g/L

• General trend towards conservative RBC transfusion practices in elective circumstance

• TRICC Trial largest RCT showed RBC transfusion threshold of 70 g/L was as safe as 100 g/L in terms of morbidity and mortality in the critical care setting

Hebert, P.C., NEJM 340(6), 1999;409-418

Red blood cell transfusion practices amongst Canadian anesthesiologists: a survey

• A threshold above 70 g/L chosen by 48% for general surgery, 56% for orthopedic surgery and 9% for vascular surgery

• History of coronary artery disease associated with threshold of 100 g/L

• Very young age associated with threshold of </= 60 g/L

• Conclusion: general adoption of TRICC trial even in surgical patients

Can J Anesth 2006: 53(4); P 344-352

Platelet storage

Fresh Frozen Plasma (FFP)• Fresh Frozen Plasma

contains the clotting factors necessary for the hemostatic process

• Plasma also has volume expansion and oncotic properties

• Typical adult dose = 10-20 ml/kg, 4-6 units

• Unlikely to be beneficial if PT and/or aPTT <1.5x normal

Massive Transfusion (MT) and Coagulopathy

• Definition: replacement of one blood mass in a 24 hour period

• More practical definition: transfusion of four or more PRBCs within one hour or replacement of 50% blood volume in three hours

• Uncontrolled bleeding causes 40% of deaths in severe trauma

Hemorrhage• Symptoms relate to amount lost

• Blood volume (adult) = 75 ml/kg= 5 liters

• 10% loss: few symptoms

• 20% loss: postural hypotension

• 40% loss: shock

• 50% loss: irreversible shock

Massive Transfusion and Coagulopathy

• Hypothermia – slows activity of coagulation cascade, increases fibrinolysis and alters platelet function

• Dilutional coagulopathy – exacerbated by initial volume contraction, fluid resuscitation and transfusion of factor and platelet-deficient PRBCs

• Fibrinogen < 1.0 g/L when blood loss 142%• DIC

The contribution of red cells to hemostasis

Disseminated Intravascular Coagulation

• Hemostatic defects related to the exaggerated generation of thrombin and fibrin and the excessive consumption of platelets and coagulation factors

• Low incidence in elective surgery• In trauma patients:

• Due to degree of tissue trauma and tissue anoxia

• 40% incidence in brain injury, 25% without head injury

Disseminated Intravascular Coagulation

• Incidence of coagulopathy 98% if all of the following:pH less than 7.10Temperature less than 34CSPB less than 70 mm HgInjury severity score greater than 25

Ferrara A, J Trauma 1997;42:857-61

Management of Coagulopathy in MT

• PT/PTT increase when factors V, VIII and IX < 50%

• Both PT/PTT increased if fibrinogen is low• PT or PTT ratio ≥1.8 means factors are <

30% and leads to high rate of bleeding

• No prophylactic regimen of FFP/platelets concentrates has been shown to be effective in MT

Management of Coagulopathy in MT

• Correct hypothermia• Correct low Hb – optimum Hb in MT to maintain

hemostasis unknown but probably higher than required for O2 delivery

• Correct markedly prolonged INR/PTT with FFP ( ratio > 1.5)• Typical use 4-6 units (800-1500 ml) in average

adult or 10-20 ml/kg; – gross underestimate in severely depleted,

actively bleeding, hypothermic patient and should be 1-1.5:1 ratio of FFP to PRBCs

Management of Coagulopathy in MT

• If fibrinogen < 1.0 g/L despite FFP administer cryoprecipitate: 10-20 units

• Platelets for decreased platelet count with clinical coagulopathy

• Consider rFVIIa if above not sufficient to control bleeding

J.F.Hardy,Can J Anesth 2004;51(4):293-310

Recombinant factor VIIa (Niastase) - Background

• Recombinant factor VIIa developed to treat hemophilia patients with inhibitors– By-passing agent in patients not responding

to factor replacement• Recombinant factor VIIa used for treatment and

prophylaxis of hemophiliacs with inhibitors• Use expanded to other bleeding patients

Factor VIIa in Normal Hemostasis

Hoffman M, et al. Hoffman M, et al. Blood Coagul Fibrinolysis.Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. 1998;9(suppl 1):S61-S65.

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTF VIIaVIIa

XX

XaXa

IIIIIIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIaXaXa

IIaIIa

IIaIIa

XaXaFibrinFibrinClotClot

FVIIa – FVIII and FIX Independant

Hoffman M, et al. Hoffman M, et al. Blood Coagul Fibrinolysis.Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. 1998;9(suppl 1):S61-S65.

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlatelet

TFTF

VaVa

VaVaTFTF VIIaVIIa XaXa

XX IIIIIIaIIa

VV VaVa

IIIIXX

IIaIIaXaXaVIIaVIIa FibrinFibrinClotClot

High-Dose FVIIa Enhances IIa Generation Without TF

44

[FVIIa] (nM)[FVIIa] (nM)

Re

lati

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IIa

Re

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IIa

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22

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NormalNormalHemophilicHemophilic

Monroe DM, et al. Monroe DM, et al. BrBr J HaematolJ Haematol 1997;99:542-547. 1997;99:542-547.

Niastase: Licensed Indications

• Treatment of bleeding in hemophilia patients with inhibitors

• Surgical management of hemophilia patients with inhibitors

• Congenital factor VII deficiency (USA)

• Glanzmann’s Thrombasthenia (UK)

Pharmacology of Recombinant Factor VIIa

• 50,000 MW molecule with t ½ of 2 hrs• Normal concentration of factor VII: 10-20 nm• 1% of factor VII circulates in activated form• Standard dose in hemophilia 90 ug/kg

– maximum concentration 50 nm– 500 x normal concentration of VIIa

• Dosing q 2-3 h to maintain hemostatic levels

Expanded Use of VIIa

• Factor VII deficiency• Other factor deficiencies (FXI, acquired FX)• Von Willebrand’s disease• Thrombocytopenia• Platelet function defects• Reversal of oral anticoagulation• Coagulopathy of liver disease• Surgical bleeding• Surgical prophylaxis • Intracranial hemorrhage• Trauma

VIIa in Partial Hepatectomy: Placebo Controlled RCT

Design:

• RCT comparing 20, 80 ug/kg or placebo in non-cirrhotic patients with 2nd dose for OR > 6 hrs

• Monitored for bleeding for 7 days

Results:

• 185 patients

Lodge et al. Hepatology 2002;36:Abst177

VIIa in Partial Hepatectomy

Placebo 20 ug/kg 80ug/kg

Blood loss 1000 800 700

% transfused 37% 41% 25%

Thrombosis 3 3 3

Trend but no significant difference

Effect of rVIIa on Perioperative Blood Loss During Prostatectomy Friederich. Lancet 2003

Design• 36 pts randomized to placebo or rVIIa (20 ug/kg or 40

ug/kg)• Followed for 10 days post-op

Results Placebo 20 ug/kg

40 ug/kg

Blood loss (ml)

2688 1235* 1089*

RBC units 1.5 0.6* 0*

% transfused 58% 38% 0%*

OR time (min) 180 126 120

RecombinantVIIa for Adjunctive Hemorrhage Control in Trauma

Patients

• 7 patients with coagulopathic bleeding treated under compassionate use program

• Age 17-75

• No atherosclerosis/thromboembolic disease

• Received 20-70 units RBCs + FFP and platelets

Intervention

• 1-3 doses of 60-120 ug/kg of rVIIa

Matinowitz et al. J Trauma 2001;51:431

Recombinant VIIa for Adjunctive Hemorrhage Control in Trauma

Results• Bleeding stopped/reduced in all patients• Further transfusions limited to 1-2 units of

RBCs• Significant shortening of coagulation tests• 4 of 7 patients survived• No thrombotic events

Multicentre RCT of rVIIa in Trauma

• 280 pts with blunt or penetrating trauma• All patients receive 3 doses

– 200 ug/kg followed by 100ug/kg 1h and 3h later

TransfusionTransfusion

ICU/Hosp LOS

Survival

Adverse Events

traumaArrive at ER randomize

0 6 8

Units of RBCs

rVIIa 48h

48h

30d

30d

placebo

Boffard et al. J Trauma. 2005: 59: 8-15

• Non significant reduction in RBC units transfused– Significant reduction in RBC units (2.6 units)

and incidence of massive transfusion (14% vs 33%) in blunt trauma when early deaths excluded

• Similar overall survival - 25% vs 30%– Composite outcome incl organ dysfunction

showed increased trend favouring rVIIa (29 vs. 43%)

• No difference in adverse events

Multicentre RCT of rVIIa in Trauma

Boffard et al. J Trauma. 2005: 59: 8-15

Complications Associated with Factor VIIa

FDA report of adverse events from trials and voluntary reporting from 1999-2005

• 220 thromboembolic complications– 193 in non-hemophiliac patients

• 129 arterial thrombosis• 103 venous thrombosis• Approx. 50% of reports within 24 hrs of

infusion• 43 of 67 deaths reported secondary to

thrombosis