Inflammation, Thrombosis, and Bleeding

1
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

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LOVECOAGULATION

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

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Normal Hemostasis
II
X
VIII/vWF
VIIa
TF
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
IIa
Xa
VIIIa
IXa
Va
Activated Platelet
VIIa
IXa
Va
IIa
Xa
VIIIa
II
IX
X
Hoffman et al, Blood Coagul Fibrinolysis
19989(Suppl 1)S61
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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.

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MANIFESTATION OF INFLAMMATION

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

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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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THROMBIN GENERATION/EFFECTS

BTG, PF4
Contact (XIIa)
Tissue Factor (TFVIIa)
activation/consumption
Platelets
IX

FV, FVIII, FXI
FXIa, FVa/FVIIIa
TFPI
IXa
FVi, FVIIIi
X
Xa
Protein C
VIIIa,
, PL
Ca
Va, Ca
, PL
APC
THROMBIN
Prothrombin
XIII
FPA
bradykinin
PT fragment 1.2
ATIII
EC
Fibrin (M)
Fibrinogen

tPA
tPAPAI1
Fibrin (Ps)
FSP
TAT

PAI1
Plasminogen
PLASMIN
-2-antiplasmin
D-dimer
Fibrin (Pi)
PAP complexes
Platelet GP1b

Despotis GJ et al, Anesthesiology 1999911122-51
Endothelial-associated
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VASCULAR ENDOTHELIUM
Huraux C et al Circulation 19999953-59
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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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ANTITHROMBIN ACTIVITY
Normal Activity
Activity -
Heparin
Protamine
Measurement Period
Zaidan JR et al, Anesth Analg 198665377-80
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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 2000901076-9
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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 lt .001
P lt .001
Lemmer et al J Thorac Cardiovasc Surg
1994107543-53
Levy et al Circulation 1995922236-44
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Neurologic Deficit (Stroke)
Levy et al, Circulation 1995922236-44
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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
Patients Requiring Any Blood Product
Drainage and Transfusion
P lt.001
P lt.001
Alderman, Levy, Rich et al, JTCS 1998116716-30
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IMAGE Study
P .01
P .03
P .72
Alderman et al, J Thorac Cardiovasc Surg
1998116716-30
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IMAGE Study
Adverse Outcome Placebo Aprotinin Death 1.6
1.4 (6/434) (5/436) Myocardial Infarction
Definite 3.8 2.9 (16/421)
(12/410) Defprobable 9.1 8.6
(38/418) (35/407) Defprobpossible 12.0
12.3 (50/418) (50/408)
Alderman et al, J Thorac Cardiovasc Surg
1998116716-30
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Role of the Tissue Factor Thrombin Pathway in
Myocardial Ischemia-Reperfusion Injury
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Inhibition of Thrombin PAR-1 Activation by
Aprotinin
Protease (Thrombin)
(Irreversible)
Cell Membrane
G protein
Coughlin SR, Proc Natl Acad Sci USA
19999611023-7
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APROTININ Use in Orthopedic Surgery (1)

• Janssens M High-dose aprotinin reduces blood
  loss in pts undergoing THR surgery.
  Anesthesiology 1994 80 239.
• Murkin JM Aprotinin decreases blood loss in
  patients undergoing revision or bilateral total
  hip arthroplasty. Anesth Analg 1995 80 3438.
• Murkin JM Aprotinin decreases exposure to allog
  blood during primary unilateral THR. J Bone Joint
  Surg Am 2000 82 67584.
• Capdevila X Aprotinin decreases blood loss and
  transfusions in pts undergoing major orthopedic
  surgery. Anesthesiology 1998 88 507.

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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 35760.
• 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 66975.
• Amar D Antifibrinolytic therapy and periop blood
  loss in cancer pts undergoing major orthopedic
  surgery. Anesthesiology 200398337-42.
• Samama CM Aprotinin vs placebo in major ortho
  surgery a randomized/DB/, dose-ranging study.
  Anesth Analg 95287-93, 2002.

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APROTININ FOR HIGH RISK PATIENTS

• Repeat sternotomy
• Jehovahs 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

• 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