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Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia LOVE=COAGULATION

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Inflammation thrombosis and bleeding l.jpg
Inflammation, Thrombosis, and Bleeding

Jerrold H. Levy, MD

Professor of Anesthesiology

Deputy Chair for Research

Emory University School of Medicine

Director, Cardiothoracic Anesthesiology

Emory Healthcare

Atlanta, Georgia


Love coagulation l.jpg

LOVE=COAGULATION

Everybody talks about it, only a few people seem to understand it.


Normal hemostasis l.jpg
Normal Hemostasis

II

X

VIII/vWF

VIIa

TF

Xa

IIa

Va

VIIIa

TF-Bearing Cell

TF

V

Va

VIIa

IX

Platelet

II

IXa

X

Xa

IIa

VIIIa

IXa

Va

Activated Platelet

VIIa

IXa

Va

IIa

Xa

VIIIa

II

IX

X

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


Caveats regarding inflammation l.jpg
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 l.jpg
MANIFESTATION OF INFLAMMATION

  • Bleeding

  • Ischemia/reperfusion injury

  • Infection

  • MOS dysfunction

  • CNS dysfunction


Hemostasis l.jpg
HEMOSTASIS

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


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COMPONENTS OF HEMOSTASIS

  • Vasculature

  • Coagulation proteins

  • Platelets


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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


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THROMBIN: Proinflammatory mediator

  • Chemotactic for PMNs, monocytes

  • Mast cell activator

  • Stimulates endothelium

  • Formed via endothelial injury by TF expression, induces cytokine expression


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*

Thrombomodulin

XIIIa

THROMBIN GENERATION/EFFECTS

*

BTG, PF4

Contact (XIIa)

Tissue Factor (TF:VIIa)

activation/consumption

Platelets

IX

*

FV, FVIII, FXI

FXIa, FVa/FVIIIa

TFPI

IXa

FVi, FVIIIi

X

Xa

Protein C

VIIIa,

Ca++

, PL

Va, Ca++

, PL

APC

THROMBIN

Prothrombin

XIII

FPA

bradykinin

PT fragment 1.2

ATIII

Fibrin (M)

EC

Fibrinogen

*

tPA

tPA:PAI1

Fibrin (Ps)

FSP

TAT

*

PAI1

Plasminogen

PLASMIN

-2-antiplasmin

D-dimer

Fibrin (Pi)

Platelet GP1b

PAP complexes

*

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

Endothelial-associated


Slide11 l.jpg

VASCULAR ENDOTHELIUM

Huraux C et al: Circulation 1999;99:53-59


Slide12 l.jpg
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


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120

100

80

60

40

X ± SEM

20

Group 1

Group 2

0

1

2

3

4

5

6

7

8

9

10

11

12

13

ANTITHROMBIN ACTIVITY

Normal Activity

Activity - %

Heparin

Protamine

Measurement Period

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


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PATIENTS ON HEPARIN THERAPY

900

800

678

700

612

600

ACT (sec)

567

500

496

478

453

400

AT III

300

No AT III

200

160

160

100

0

Baseline

Heparin

Heparin

Heparin

ACT

4.1 u/ml

5.4 u/ml

6.8 u/ml

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


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FACTORS AFFECTING ACT

  • Factor deficiency: fibrinogen, XII, VIII

  • Contact activation inhibitors: aprotinin

  • Warfarin therapy

  • Heparin therapy

  • Hypothermia

  • Thrombocytopenia/cytosis

  • Platelet inhibitors


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Aprotinin Use in CABG Reoperations

Donor-Blood-Product Requirements

P < .001

P < .001

Lemmer et al

J Thorac Cardiovasc Surg 1994;107:543-53

Levy et al

Circulation 1995;92:2236-44


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Incidence of Stroke in Repeat CABG Surgery

Number of Patients %

Placebo 5 / 72 7

Aprotinin Pump Prime 1 / 72 1

Low Dose 0 / 70 0

High Dose 0 / 73 0

P = 0.01

Neurologic Deficit (Stroke)

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


I nternational m ulticenter a protinin g raft patency e xperience l.jpg
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


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IMAGE Study

Blood Loss and Blood Product Replacement

Drainage and Transfusion

Patients Requiring Any Blood Product

P <.001

P <.001

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


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IMAGE Study

P = .01

P = .03

P = .72

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


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IMAGE Study

  • Adverse Outcome Placebo Aprotinin

  • Death1.6%1.4% (6/434) (5/436)

  • Myocardial Infarction

  • Definite3.8% 2.9%

    • (16/421) (12/410)

    • Def+probable 9.1% 8.6%

    • (38/418) (35/407)

    • Def+prob+possible 12.0% 12.3%

    • (50/418) (50/408)

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



Inhibition of thrombin par 1 activation by aprotinin l.jpg

X Ischemia-Reperfusion Injury

APROTININ

Inhibition of Thrombin PAR-1 Activation by Aprotinin

Protease (Thrombin)

(Irreversible)

Cell Membrane

G protein

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


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APROTININ: Use in Orthopedic Surgery (1) Ischemia-Reperfusion Injury

  • 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.


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APROTININ: Use in Orthopedic Surgery (2) Ischemia-Reperfusion Injury

  • 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 l.jpg
APROTININ FOR HIGH RISK PATIENTS Ischemia-Reperfusion Injury

  • Repeat sternotomy

  • Jehovah’s witnesses

  • Valve surgery/combined procedures

  • Aortic root surgery/DHCA

  • Dialysis patient

  • Endocarditis

  • Minimally invasive valve surgery

  • Transplants/VADs

  • Recent Plavix


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SUMMARY Ischemia-Reperfusion Injury

  • 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


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