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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