The Biology of Bleeding and Clotting to DeathJeffrey H. Lawson, MD, PhDDirector, Vascular Surgery Research LabDirector of Clinical Trials in Vascular SurgeryDuke University Medical CenterDurham, North Carolina

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SurgeryPost-op Recovery

What Are the Challenges of Hemostasis in Surgery?

1. Who is likely to bleed or clot too much?

2. How do we optimize the physiology of the patient?

3. Which topical agents are effective?

4. Which biologic agents are effective? When? How much?

How not to overshoot?

Thrombosis

Clotting

Bleeding

Hemorrhage

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Bleeding, Clotting, and Surgery

• D&C for 2 years at Duke University = 358 complications

• Total bleeding and thrombosis complications: 197/358 = 55%

• 114 of 358 cases could not be well adjudicated with respect to complications Well-documented data reveal 197/244 = 81%

• Total perioperative bleeding complications: 131/244 = 54%

• Total perioperative thrombosis complications: 75/244 = 31%

• Total deaths: 67

• Bleeding as cause of death: 18/67 = 27%

• Thrombosis as cause of death: 22/67 = 33%

D&C=dilation and curettage.

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VII(VIIa)

TF

TF·VII(VIIa)TF·VIIaCa2:PL

IIa Xa

IXaß VIIa

X

XI

XIa

IXIIa

Va·XaCa2:PL

IIa FN (cross-linked)

VIIIa-IXaß

Ca2:PLXaPL

(IXα)

VIII

Fg

Fn

XIIIa

XIIIII

IIaXa

IXaß

Xa IIa

V

Coagulation Cascade: Tissue Factor Pathway

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The Problem

Most complications are at the dark interface between:

• Biology

• Clinical skill

• Medical therapy

• Sick patients

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Hemostasis

“The arrest of bleeding”

Stedman’s Medical Dictionary

But is hemostasis more than that?

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Hemostasis

In surgery—hemostasis is …

• About bleeding

• About clotting

• About timing

• About balance

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Hemostasis“Life in the Balance”

Bleedingto Death

TraumaMajor SurgeryHemophilia

Clottingto Death

StrokeMIThrombosis

Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

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Hemostasis

“Too thick or too thin”

Dr. Richard McCann

Hemostasis in cardiovascular surgery

“Knowing when to be thick and when to be thin”

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Hemostasis

• Blood coagulation

• Anticoagulation

• Fibrinolysis

• Antifibrinolysis

• Vascular tone and blood flow

• Endothelial cells and platelets

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Keeping on Center

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

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SurgeryPost-op Recovery

Thrombosis

Clotting

Bleeding

Hemorrhage

What About Hemostatic Swings During Surgery?

Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

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Keeping on Center

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

Factor V fallsFactor V falls

t-PA increaset-PA increase

IIase increaseIIase increase

TF increaseTF increase

PAI-1 increasePAI-1 increase

Heparin fallsHeparin falls

InflammatoryInflammatoryCytokinesCytokines

Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

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Keeping on Center

Topical HemostaticsPurified Factors, FFP, Cryo, PLTs Aminocaproic acid,

Aprotinin

Heparin, WarfarinLMWH, Argatroban

t-PA, SK, UPA

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin.

Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

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ThrombosisThrombosis

ClottingClotting

BleedingBleeding

HemorrhageHemorrhage

Physiology and Good SurgeryPhysiology and Good Surgery

Topical Hemostatic AgentsTopical Hemostatic Agents

Systemic Biologic TherapiesSystemic Biologic Therapies

Operative Management

Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.