The Physiology of HemostasisIra A. Shulman, MD Professor and Vice Chair of PathologyKeck School of Medicine of USCMedical Director of Transfusion ServiceUSC Norris Cancer HospitalLos Angeles, California

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Activity Goals

In this presentation, you will learn about:

• Essential scientific components of hemostasis

• The causes of and approximate frequencies of excessive surgical bleeding

• How surgical complications, regardless of surgery type, can be attributed to bleeding and clotting

• The importance of determining which patients are at greatest risk for surgical coagulopathy

• How achieving optimal hemostasis can be viewed as a “balancing act”

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Prevalence of Uncontrolled Bleeding

Surgical Discipline Uncontrolled Bleeding Rate

Cardiovascular 5%-7% post-op1

General 1.9% laparoscopic cholecystectomy2

Obstetric 3.9% (vaginal); 6.4% (cesarean)3,4

Orthopedic 2%-6.3% hip/knee arthroplasty5-7

Urologic 4%-8% TURP8; 3.3%-9.9% URL9

Trauma 30%-40%10,11

1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21. 2. Erol DD, et al. Internet J Anesth. 2005;9:2. 3. Combs CA, et al. Obstet Gynecol. 1991;77:69-76. 4. Combs CA, et al. Obstet Gynecol. 1991;77:77-82. 5. Hull R, et al. N Engl J Med. 1993;329:1370-1376. 6. Leclerc JR, et al. Ann Intern Med. 1996;124:619-626. 7. Strebel N, et al. Arch Intern Med. 2002;162:1451-1455. 8. Daniels PR. Nat Clin Pract Urol. 2005;2:343-350. 9.Rosevear HM, et al. J Urol. 2006;176:1458-1462. 10. Holcomb JB. Crit Care. 2004;8(suppl 2):S57-S60. 11. Sauaia A, et al. J Trauma. 1995;38:185-193.

TURP=transurethral prostatic resection.

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Definition of Hemostasis

Hemostasis: “The arrest of bleeding”Stedman’s Medical Dictionary

Hemostasis: “Life in the balance”

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

• Trauma• Major surgery• Hemophilia

• Stroke• Myocardial infarction (MI)• Thrombosis

Bleedingto Death

Clottingto Death

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Definition of Significant Bleeding

• >2 L blood loss in an adult within first 24 post-op hours1

Volume of acute blood loss/patient weight >30 mL/kg

Volume of acute blood loss >40%-50% total blood volume

• Surgical or vascular component: corrected by surgical

intervention or embolization2

• Coagulopathic component: more difficult to control due

to several interrelated mechanisms2

Consumption of coagulation factors and platelets

Dilution of coagulation factors

Metabolic disorders (eg, hypothermia, acidosis)

1. Despotis GJ, et al. Ann Thorac Surg. 2000;70(suppl 2):S20-S32. 2. Vincent J-L, et al. Crit Care. 2006;10:1-12.

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Reasons for Uncontrolled Bleeding

Patient-related• Advanced age• Small body size• Gender• Pre-op anemia

(low RBC volume) • Antiplatelet or antithrombotic

drugs• Hypothermia• Acidosis• Systemic inflammatory

response syndrome (SIRS)• Comorbidities:

Congestive heart failure Hypertension Chronic obstructive

pulmonary disease Peripheral vascular disease Diabetes mellitus Renal failure

Procedure-related• Prolonged operation• CABG• Emergency/trauma• Surgical-site bleeding• Surgical skill

Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

RBC=red blood cell; CABG=coronary artery bypass graft.

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SurgeryPost-op Recovery

Thrombosis

Clotting

Bleeding

Hemorrhage

Can We Predict Who Will Bleed?

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

• Who is likely to bleed or clot too much?• How do we optimize the patient’s physiology?• Which topical agents are effective?• Which biologic agents are effective?

There Is a Difference Between Who Is at Risk and Who Will Bleed

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Patients at Risk for Surgical Bleeding

Certain patients are at higher risk for surgical bleeding, including:

• Patients taking Long-acting anticoagulant therapy Clopidogrel

• Patients undergoing Repeat surgical procedures Oncologic surgery Aortic surgery Cardiac surgery Neurologic procedures or neurosurgery Radical prostatectomy

• Dialysis patients

• Trauma patients

Ferraris VA, et al. . Ann Thorac Surg. 2007;83:S27–S86; Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www.accessmedicine.com/resourceToc.aspx?resourceID=4. Tanaka KA, et al. Anesthesiology. 2003;98:1513-1515.

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Conditions Associated With Coagulopathy

• Hemophilia

• Platelet disorders

• Liver disease

• Uremia

• Disseminated intravascular coagulation (DIC)

• Dilutional coagulopathy

• Anticoagulant treatment

• Acidosis

• Hypothermia

• Extracorporeal circuits

Ferraris VA, et al. . Ann Thorac Surg. 2007;83:S27–S86.Disorders of Hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www. accessmedicine.com/resourceToc.aspx?resourceID=4.

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Thienopyridines Such as Clopidogrel and Postoperative Bleeding

• Evidence is more compelling than for aspirin1

11 studies of clopidogrel and CABG

All studies show increased bleeding when

clopidogrel given within 5 days of CABG — some

with increased mortality

• ACC/AHA and STS/SCA guidelines recommend

stopping clopidogrel for 5 days before surgery (if

possible)1,2

1. Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461. 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.

CABG=coronary artery bypass graft.

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Traditional Model of Hemostasis

Intrinsic Pathway Extrinsic Pathway

factor XIIHMKPK

factor XI factor XIa

factor IXfactor IXa

factor VIIIaPL, Ca+2

factor Xfactor Xafactor VaPL, Ca+2

prothrombin thrombin

fibrinogen fibrin

factor VIIatissue factor

PL, Ca+2

factor X

Adapted from Hoffman M, et al. Thromb Haemost. 2001;85:958-965.

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Vascular Spasm

Currie D. Available at: http://faculty.etsu.edu/currie/hemostasis.htm. Accessed May 6, 2008.

Blood vessel

Vascular spasm

Region of trauma

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Platelet Plug Formation—Primary Hemostasis

Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8.©2005 Lippincott Williams & Wilkins http://lww.com

Platelet adhesion to subendothelial vWF

vWF=von Willebrand factor; GP=glycoprotein.

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Platelet Plug Formation—Primary Hemostasis

Reprinted with permission from Rinder C. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 8.©2005 Lippincott Williams & Wilkins http://lww.com

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Vascular Endothelium Serves As a “Front Line”Defense Against Pathologic Thrombosis

This figure was published in Semin Hematol, Vol 41(suppl 1), Lawson JH, et al, “Challenges for Providing Effective Hemostasis,” pp 55-64, ©Elsevier 2004.

16Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65.

TF-Bearing Cell

Activated Platelet

Platelet

TF

VIIIa Va

VIIIaVa

Va

VIIa

TF VIIa Xa

X II

IIa

IXV Va

II

VIII/vWF

VIIIa

II

IXa

XIX

X

IXa

IXaVIIa

Xa

IIa

IIa

Xa

Evolving Model of Hemostasis

TF=tissue factor; vWF=von Willebrand factor.

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Fibrinolysis

tPA=tissue plasminogen activator; PAI-1=plasminogen activator inhibitor 1; AP=anti-plasmin;PAP=plasmin-anti-plasmin complexes.

Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7.©2005 Lippincott Williams & Wilkins http://lww.com

Endothelium Endothelium

tPAPAI-1

tPA-PAI-1

PAPAP

D-dimerPlasmintPA + Plasminogen

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Putting It All Together

Reprinted with permission from Chandler WL. In: Spiess BD, et al, eds. Perioperative Transfusion Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:chap 7.©2005 Lippincott Williams & Wilkins http://lww.com

Wound: collagen and tissue factor exposure Fibrin formation, clot stabilization

Platelet binding and coagulation initiation Platelet contraction, wound healing, fibrin removal

Platelet aggregation Wound healed

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Normal Hemostasis Is a Balance

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

• Trauma• Major surgery• Hemophilia

• Stroke• MI• Thrombosis

Bleedingto Death

Clottingto Death

• Blood coagulation• Anticoagulation• Fibrinolysis• Antifibrinolysis• Vascular tone and blood flow• Endothelial cells and platelets

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“Keeping on Center”: Moving Toward Normal Hemostasis

NormalHemostasis

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

Bleeding

Clotting

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

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“Keeping on Center” (cont)

Topical HemostaticsPurified Factors, FFP, Cryo, PLTs

Aminocaproic acidTranexamic acid

Heparin, WarfarinLMWH, Argatroban

t-PA, SK, UPA

NormalHemostasis

Bleeding

Clotting

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

ProcoagulantActivity

AnticoagulantActivity

FibrinolyticActivity

AntifibrinolyticActivity

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

22Adapted from Reed RL, et al. Circ Shock. 1990;32:141-152.

**

**

**

**

**P<.0001 vs clotting time at 37oC.

Temperature (oC) Temperature (oC)

**

**

**

*

*

**P<.0001 vs clotting time at 37oC.

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30

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23 25 27 29 31 33 35 37

Th

rom

bin

Tim

e (s

ec)

Temperature (oC)

**P<.0001 vs clotting time at 37oC.*F<.005 vs clotting time at 37oC.

**

**

*

Effect of Temperature on Test Results of aPTT, TT, and PT

aPTT=activated partial thromboplastin time; PT=prothrombin time; TT=thrombin time.

25

30

35

40

45

50

55

60

65

70

23 25 27 29 31 33 35 37 39

aPT

T (

sec)

10

12

14

16

18

20

22

24

26

23 25 27 29 31 33 35 37 39

Pro

thro

mb

in T

ime

(sec

)*

*

29 volunteers had 2 U RBC removed by apheresis (re-infusion of PRP)

11 received back autologous RBC

18 did not receive back their RBC

Valeri et al. Transfusion 2001;41:977-83.

Effect of 2-unit RBC apheresis or plateletspheresis on bleeding time

0

1

2

3

4

5

6

7

8

9

RBCs Platelets

BT

at

35°

C

ApheresisHct: 41 35 (15%) 40 40Platelet count: 220 200 (9%) 238 163 (32%)

Apheresis Returnof RBCs

Apheresis Returnof RBCs

Does Anemia Induce Reversible Platelet Dysfunction?

Beforeapheresis

0.50

1.00

1.50

2.00

1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY

Te

mp

late

BT

(ra

tio

aft

er:b

efo

re a

ph

ere

sis

)

0.70

0.80

0.90

1.00

1.10

Beforeapheresis

1 Hour TX1 TX2 1 DAY 2 DAY 3 DAY 7 DAY

Per

iph

era

l V

en

ou

s H

ct

(rat

io a

fte

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efo

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)

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• During room-temperature storage in the blood bank, platelets express a number of glycoprotein ligands, making them prothrombotic1-3

• Platelets excrete granules containing cell signaling compounds that are capable of triggering reactions in WBCs, endothelial cells, and other native platelets3,4

• This complex activation biology is recognized as part of the platelet storage lesion4

• In certain circumstances, platelet transfusions might increase risk of stroke or death5

1. Spiess BD. Transfusion. 2007;47:354–356; 2. Seghatchian MJ, et al. Transfus Sci. 1997;18:103-107; 3. Van der Planken MG, et al. Ann Hematol. 1999;78:1-7; 4. Seghatchian J, et al. Transfus Med Rev. 1997;11:130-144; 5. Spiess BD, et al. Transfusion. 2004;44:1143-1148.

The Platelet “Storage Lesion” and the Potential Prothrombotic Effect of Platelets

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Thrombosis

Clotting

Bleeding

Hemorrhage

Physiology and Good Surgery

Topical Hemostatic Agents

Systemic Biologic Therapies

Achieving Optimal Operative Hemostasis

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

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Hemostasis: Final Thoughts

• Many surgical complications, regardless of surgery type, can be attributed to bleeding and clotting

• It is important to determine which patients are at greatest risk for surgical coagulopathy

• Achieving optimal hemostasis involves a balancing act, whereby patients must be kept from bleeding or clotting to death through transfusional and nontransfusional therapies