Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director,

Inflammation, Thrombosis, and Bleeding

Jerrold H. Levy, MDProfessor of AnesthesiologyDeputy Chair for Research

Emory University School of MedicineDirector, Cardiothoracic Anesthesiology

Emory HealthcareAtlanta, Georgia

LOVE=COAGULATION

Everybody talks about it, only a few people

seem to understand it.

Hoffman et al, Blood Coagul Fibrinolysis 1998;9(Suppl 1):S61Hoffman et al, Blood Coagul Fibrinolysis 1998;9(Suppl 1):S61

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlateletTFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTF VIIaVIIa XaXa

XX IIIIIIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIaXaXa

IIaIIa

IIaIIa

XaXa

Normal Hemostasis

CAVEATS REGARDING INFLAMMATION

• Inflammation has multiple humoral, cellular components, and undergoes amplification.

• Defining clinical outcomes from inflammation is difficult.

• Hemostatic activation/thrombin generation is an inflammatory response, and tissue injury is key.

MANIFESTATION OF INFLAMMATION

• Bleeding• Ischemia/reperfusion injury• Infection• MOS dysfunction• CNS dysfunction

HEMOSTASIS

The stoppage of bleeding, hemorrhage, or blood flow through a blood vessel or body part.

COMPONENTS OF HEMOSTASIS

•Vasculature•Coagulation proteins•Platelets

CAVEATS REGARDING COAGULATION/THROMBOSIS

• Arterial clot is due to platelet-fibrinogen interactions. Heparin does not completely block this.

• Venous clot and venous thromboembolic phenomenon are prevented by thrombin inhibitors

THROMBIN: Proinflammatory mediator

• Chemotactic for PMNs, monocytes

• Mast cell activator• Stimulates endothelium• Formed via endothelial injury by

TF expression, induces cytokine expression

D-dimer

Prothrombin

PT fragment 1.2

XaXIXa

IX

Contact (XIIa)

PAI1

Plasminogen PLASMIN

FSP

Tissue Factor (TF:VIIa)

VIIIa, , PLCa++

Va, Ca++

Platelets

APC

BTG, PF4

tPA:PAI1

PAP complexes

-2-antiplasmin

tPA

EC

FVi, FVIIIi

Thrombomodulin*

*

*

*

*

* Endothelial-associated

Fibrinogen

FPA

THROMBIN

, PL

Protein C

XIII

activation/consumption

bradykinin

TFPI FV, FVIII, FXI FXIa, FVa/FVIIIa

Fibrin (Ps)

Fibrin (M)

Fibrin (Pi)

XIIIa

Platelet GP1b

TAT

ATIII

THROMBIN GENERATION/EFFECTS

Despotis GJ et al, Anesthesiology 1999;91:1122-51

VASCULAR ENDOTHELIUMHuraux C et al: Circulation 1999;99:53-59

DIC• Triggered by TF/endothelial injury• Produces fibrin deposition in

microvasculature and MOS dysfunction• Path: Microangiopathic hemolytic anemia• Lab: platelets, fibrinogen, PT, PTT, D-dimers, ATIII

Group 1Group 2

X ± SEM

Act

ivit

y -

%

Zaidan JR et al, Anesth Analg 1986;65:377-80

Normal Activity

20

0

120

100

80

60

40

Heparin Protamine

1 2 3 4 5 6 7 8 109 11 12 13Measurement Period

ANTITHROMBIN ACTIVITY

PATIENTS ON HEPARIN THERAPY

160

567612

678

160

453478

496

0

100

200

300

400

500

600

700

800

900

BaselineACT

Heparin4.1 u/ml

Heparin5.4 u/ml

Heparin6.8 u/ml

AC

T (

sec)

AT III

No AT III

Levy JH et al, Anesth Analg 2000;90:1076-9

FACTORS AFFECTING ACT

• Factor deficiency: fibrinogen, XII, VIII

• Contact activation inhibitors: aprotinin

• Warfarin therapy• Heparin therapy• Hypothermia• Thrombocytopenia/cytosis• Platelet inhibitors

Aprotinin Use in CABG Reoperations

Lemmer et al Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53J Thorac Cardiovasc Surg 1994;107:543-53

10.3

2.2

0

5

10

15

RBC FFP Plt Cryo Total

Donor-Blood-Product RequirementsDonor-Blood-Product Requirements

Levy et al Levy et al Circulation 1995;92:2236-44Circulation 1995;92:2236-44

11.9

1.6

0

5

10

15

No.

Units Tra

nsf

use

d

RBC FFP Plt Cryo Total

PP < .001 < .001PP < .001 < .001

Neurologic Deficit (Stroke)

Levy et al, Circulation 1995;92:2236-44Levy et al, Circulation 1995;92:2236-44

Number of PatientsNumber of Patients %%

PlaceboPlacebo 5 / 725 / 72 77

AprotininAprotinin Pump PrimePump Prime 1 / 721 / 72 11

Low DoseLow Dose 0 / 700 / 70 00

High Dose High Dose 0 / 730 / 73 00

PP = 0.01 = 0.01

Incidence of Stroke in Repeat CABG SurgeryIncidence of Stroke in Repeat CABG Surgery

International Multicenter Aprotinin Graft Patency Experience

•796 (91%) Patients assessable for blood loss, usage•703 (81%) Patients assessable by angiography

for saphenous vein-graft patency (at mean of 10.8 days postop)

•831 (95%) Patients assessable for MI by ECG and cardiac enzyme evaluation

IMAGE Study

58%

40%

Placebo Aprotinin

Patients Requiring Any Patients Requiring Any Blood ProductBlood Product

Alderman, Levy, Rich et al, JTCS 1998;116:716-30

1168

664

0

1

2

3

4

Un

its T

ran

sfu

sed

0

500

1000

1500

Th

ora

cic

Dra

inag

e (

mL)

PlaceboAprotinin

Drainage and TransfusionDrainage and Transfusion

P <.001P <.001

P <.001P <.001

Blood Loss and Blood Product ReplacementBlood Loss and Blood Product Replacement

IMAGE Study

10.9

15.4

9.5 9.412.4

23

0

10

20

30

% P

atie

nts

with

Occ

luded

SV

G

All Centers US Centers Non USCenters

Placebo Aprotinin

Alderman et al, J Thorac Cardiovasc Surg 1998;116:716-30

PP = .03 = .03

PP = .72 = .72

PP = .01 = .01

IMAGE Study

Adverse OutcomeAdverse Outcome PlaceboPlacebo AprotininAprotininDeathDeath 1.6%1.6% 1.4%1.4%

(6/434) (6/434) (5/436)(5/436)Myocardial InfarctionMyocardial Infarction

DefiniteDefinite 3.8%3.8% 2.9% 2.9% (16/421) (16/421)

(12/410)(12/410)Def+probableDef+probable 9.1%9.1%

8.6%8.6% (38/418)(38/418)

(35/407)(35/407)

Def+prob+possibleDef+prob+possible 12.0%12.0% 12.3%12.3%

(50/418)(50/418) (50/408)(50/408)

Alderman et al, J Thorac Cardiovasc Surg 1998;116:716-30

Role of the Tissue Factor – Thrombin Pathway in Myocardial Ischemia-Reperfusion Injury

Inhibition of Thrombin PAR-1 Activation by Aprotinin

Cell Membrane

G protein

Protease (Thrombin)

(Irreversible)

Coughlin SR, Proc Natl Acad Sci USA 1999;96:11023-7Coughlin SR, Proc Natl Acad Sci USA 1999;96:11023-7

APROTININX

APROTININ: Use in Orthopedic Surgery (1) • Janssens M: High-dose aprotinin reduces blood loss

in pts undergoing THR surgery. Anesthesiology 1994; 80: 23–9.

• Murkin JM: Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 1995; 80: 343–8.

• Murkin JM: Aprotinin decreases exposure to allog blood during primary unilateral THR. J Bone Joint Surg Am 2000; 82: 675–84.

• Capdevila X Aprotinin decreases blood loss and transfusions in pts undergoing major orthopedic surgery. Anesthesiology 1998; 88: 50–7.

APROTININ: Use in Orthopedic Surgery (2) • Hayes A The efficacy of single-dose aprotinin 2 million KIU

in reducing blood loss and DVTs in THR surgery. J Clin Anesth 1996; 8: 357–60.

• Kasper SM A retrospective study of the effects of small-dose aprotinin on blood loss and transfusion needs during total hip arthroplasty. Eur J Anaesthesiol 1998; 15: 669–75.

• Amar D: Antifibrinolytic therapy and periop blood loss in cancer pts undergoing major orthopedic surgery. Anesthesiology 2003;98:337-42.

• Samama CM: Aprotinin vs placebo in major ortho surgery: a randomized/DB/, dose-ranging study. Anesth Analg 95:287-93, 2002.

APROTININ FOR HIGH RISK PATIENTS

• Repeat sternotomy• Jehovah’s witnesses• Valve surgery/combined procedures• Aortic root surgery/DHCA• Dialysis patient• Endocarditis• Minimally invasive valve surgery• Transplants/VADs• Recent Plavix

SUMMARY• Thrombin generation modulates the

thrombotic effects of vascular injury and pharmacologic intervention

• Thrombin activation of PAR-1 receptors activates pathologic mechanism of injury

• Aprotinin inhibits pathologic hemostatic activation by blocking PAR-1 receptors

• Safety data from clinical studies including orthopedic surgery have not demonstrated a prothrombotic effect of aprotinin