Clotting, Hemostasis, Anticoagulation

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Clotting, Hemostasis, Anticoagulation

• Greg Stratmann
• University of California
• San Francisco

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Acknowledgement

• American College of Chest Physicians and
  Astra-Zeneca
• Chest 2004 126204S-233S

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Objectives

• Basics of coagulation
• Coagulation tests
• Anticoagulant drugs
• Management of bleeding

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Objectives

• Basics of coagulation
• Coagulation tests
• Anticoagulant drugs
• Management of bleeding

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Two points only

• 1) Two-step process
• Missed by routine coagulation tests
• 2) Arteries Plt ? Thrombin
• Veins Thrombin ? Plt
• Therapeutic consequences

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Therapeutic consequences

• Arterial thrombosis Antiplatelet drugs
• Venous thrombosis Anticoagulants

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Arterial platelet activation
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Venous platelet activation
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Thrombin ? Thrombin
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• Basics of coagulation
• Coagulation tests
• Anticoagulant drugs
• Management of bleeding

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Monitoring coagulation

• Routine tests
• PT, PTT, fibrinogen, (plt count)
• Viscoelastic tests
• ACT, TEG
• Platelet function test
• PFA-100

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Limitations of PT, PTT

• Misses cell-based 2-step physiology of
  clotting
• Misses LMWH
• Misses pentasaccharide
• Misses all antiplatelet medications
• Poorly predicts intraoperative bleeding

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Role of PT, PTTWarfarin, Heparin Monitoring
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ACTActivated Coagulation Time

• Point-of-care test
• PTT equivalent
• Contact - activated by celite or kaolin
• Sensitive to
• Platelet count function
• Hypothermia
• Factor deficiencies, hemodilution
• Anticoagulants (heparin, warfarin, aprotinin)

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Thromboelastography (TEG)
Low shear stress (mimics venous clotting)
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Thromboelastography (TEG)
R gt 11 min 2-4 U FFP, ?-angle lt 40? 2 cryo MA
lt 40mm 2 Plts
BJA 2001, 86575-8 BJA 1992, 69307-13
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Platelet function analyzer-100

• In vitro bleeding time
• Anticoagulated blood
• High shear mimics artery
• Plt aggregation TEG
• Plt adhesion ? TEG
• Detects vWD

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• Basics of coagulation
• Coagulation tests
• Anticoagulant drugs
• Management of bleeding

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Anticoagulants

• Heparins
• Unfractionated heparin
• Low molecular weight heparin
• Pentasaccharide
• Warfarin
• Direct thrombin inhibitors
• Antiplatelet agents
• Aptamers (RNA) against clotting factors

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AT
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AT
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IIa
AT
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IIa
AT
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AT
IIa
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Heparin

• Pharmacokinetics
• T 1/2 45 min
• Plasma protein binding
• Monitoring
• PTT/ACT
• Side effects
• ? BP (? Ca 2, histamine)
• HIT, osteopenia
• Reversible

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Protamine

• Dose 1.3 mg / 100 U heparin
• Three types of protamine reactions
• All cause systemic hypotension

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Type 1 protamine reaction

• Rapid administration
• Hypotension
• Poorly understood

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Type 2 protamine reaction

• Anaphylactic / anaphylactoid
• ? BP, ? PAP
• Predisposing factors
• Allergy to fish (but not shellfish)
• Vasectomy
• Prior exposure (NPH-insulin, hemodialysis)

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Protamine reaction type 3

• Thromboxane ? ? PAP ? RV-failure ? ? BP
• Mortality
• 36 if CPB not available 1
• 24 with CPB 2
• Tx epi, norepi
• Incidence
• 0 on Aspirin 3
• 1.4 without Aspirin 3
• Prior exposure ? risk

• Anesth Analg 2002 941402-8
• J Vasc Surg 1988 9342-50
• J Cardiothorac Vasc Anes 200317309-13

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Protamine reaction Prevention strategies

• Site Central / peripheral / arterial 1
• Administration rate
• Dont push protamine 2
• 40 of protamine reactions occur at 1ml/min
  infusion rates 1
• Animal model Indomethacin 3
• Alternatives Time, heparinase, rPF4

• J Cardiothorac Vasc Anes 2003, 17309-13
• Anesthesiology 199073415-24
• Circ Res 1988 62905-15

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Heparin-induced thrombocytopenia
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Type 1 versus Type 2

• Non-IgG-mediated
• Self limiting
• Onset 1-2 days after exposure to heparin
• Plt count gt 100 K
• Incidence 20-25

• IgG-mediated
• Progressive (more or less)
• Onset 5-10 days after exposure to heparin
• Plt count often lt 100 K
• Incidence 1-3
• Diagnosis is clinical

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Pathophysiology of HIT
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HIT type 2

• Diagnosis is clinical
• Diagnostic tests
• ELISA Heparin-platelet factor 4-antibodies
• Serotonin-release assay
• Stop ALL heparin
• Alternative anticoagulant

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Alternatives to heparin
?

• Low Molecular Weight Heparin
• Pentasaccharide
• Warfarin
• Ancrod
• Danaparoid
• Direct Thrombin Inhibitors

?
?
?
?
?
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Direct thrombin inhibitors

• Parenteral Hirudin, bivalirudin, argatroban,
  melagatran
• Oral Ximelagatran
• At least as effective as warfarin
• Predictable pharmacokinetics
• No monitoring
• ? liver enzymes

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Reversing warfarin
Br J Haematol 2003 123676-82
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What is a safe INR?

• 1.3 -1.5 1
• lt 1.5 2
• lt 2.0 3

• Chest 2004 126204S-233S
• N Engl J Med 1997 336251-7
• Uptodate.com Jan 2005

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Removal of protective effect -Original risk

• Low
• AF without embolism
• Valve prosthesis other than mitral or cage
  prosthesis

• High
• Venous thrombosis or arterial embolus lt 1 mo ago
• Mitral or cage prosthesis

• Intermediate
• Venous thrombosis lt 2-3 mo ago
• Recurrent venous thrombosis
• AF with prior embolism

N Engl J Med 1997 336251-7
Chest 2004 126204S-233S
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Perioperative Management of Anticoagulated
Patients
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Vitamin K

• Onset 6-8 hrs
• Dose / routes of administration
• 1 mg iv (allergic reactions common)
• 1 mg s.c. 1 (may delay onset)
• 1 mg p.o. 2

• N Engl J Med 1997 336251-7
• Chest 2004 126204S-233S

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Revised 2002 ASRA guidelines
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• Basics of coagulation
• Coagulation tests
• Anticoagulant drugs
• Management of bleeding

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Procoagulant maneuvers

• Cause known
• Cause unknown

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Cause known

• Heparin - Protamine
• Warfarin - Vit K, FFP
• Hemophilia - FVIII, FIX
• vWD - cryoprecipitate, DDAVP
• Platelet disorders - platelets

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Cause unknown

• Temperature
• Avoid acidosis (? plt function, ? plt life)
• Antifibrinolytics
• Coagulation factor therapy (rFVIIa)
• Blood products

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Morbidity from blood products

• Transfusion reactions
• Dilution (Plts, V, VIII)
• Infection
• Hypothermia
• Metabolic (Ca2, 2,3-DPG, acidosis,
  alkalosis)
• Inflammation

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Morbidity from Platelets

• Transfusion 2004, 441143-8

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Antifibrinolytics

• Block lysine binding sites on fibrin Blocks
  tPA, plasminogen and plasmin binding
• Decreases plasmin formation
• Decreases plasmin activity
• Aprotinin superior to TXA and ?-ACA (?
  mortality)

Lancet 1999 354 1940-7
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Factor VII a

• Hemophilia
• 30-90 ?g/kg iv PUSH
• 3 min to response
• No response in 15-20
• Works in cardiac 1, prostate 2, liver 3
  surgery
• Few efficacy / safety data
• 1000 / mg

• Transfusion 2005 4526-34
• Lancet 2003, 361 201-5
• Transplantation 2001, 71402-5

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Factor VII a

• Two ways to use it
• Rescue treatment
• Prophylactic
• Predictable bleeding
• Low dose
• Small patients
• Withhold blood products initially?

• Transfusion 2005 4526-34
• Lancet 2003, 361 201-5
• Transplantation 2001, 71402-5

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Factor 7-0
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Summary

• Basics
• Arterial, venous, 2 step
• Coagulation tests
• PT, PTT, ACT, TEG, PFA-100
• Anticoagulant drugs
• Warfarin, heparin (protamine reactions, HIT),
  LMWH, pentasaccharide, DTI, antiplatelet drugs
• Management of bleeding
• Blood product morbidity, antifibrinolytics,
  rFVIIa