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Overview of Hemostasis

LabM 419 Clinical Coagulation

Fall 2009

Cara Calvo, MS, MT(ASCP), SH(ASCP) - UW, 2008.

CartoonStock graphic accessed at URL http://www.cartoonstock.com/lowres/ksm0795l.jpg 9/18/08.

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Learning ObjectivesAfter reading article 1* and theCHAPTER at a glance summaries of chapters 40 47 of the course text, after careful study and

following this lecture the learner will be able to:

1. Definethe following key terms: a) hemostasis, b) coagulation, c) fibrinolysis, d) platelet adhesion, e)platelet aggregation, f) thrombus, g) procoagulant, h) anticoagulant, i) thrombocytopenia, j) primaryhemostasis, k) secondary hemostasis, l) serine protease, m) tissue thromboplastin, n) fibrinogen, o)fibrin, p) antithrombin, q) prothrombin time (PT), r) activated partial thromboplastin time (APTT), s)International Normalized Ratio (INR), t) von Willebrands Factor (vWF), u) thrombomodulin (TM), v)cofactor, w) plasminogen, x) plasmin, y) contact proteins, and z) international sensitivity index (ISI).

2. Usethe terms listed in objective one to effectively communicate in written and spoken Englishanytime hemostasis is being discussed.

3. Reviewthe nomenclature of coagulation protein factors.4. Identifythe properties of the vascular system that govern the initiation and the regulation of

hemostasis.5. Differentiateprimary from secondary hemostasis.6. Outlinethe specific events, describe the mechanisms, and name the key biological and chemical

substances whose activity and interactions result in hemostasis .7. Describethe functions of blood cells, including platelets, in hemostasis.8. Explainthe relationships among platelets, vascular tissues, vWF, and fibrinogen that enable blood to

clot.9. Recognizeby name key coagulation factors.10. Summarizethe regulation of hemostasis in terms of physical and biochemical mechanisms.11. Constructa simple diagram of hemostasis that cogently illustrates how a blood clot is formed and

lysed.12. List at least 3 different ways coagulation is controlled and hemostasis maintained.13. Nameand discussthe diagnostic use of each lab test discussed in this lecture.

*An Overview of Hemostasis by Henry O. Ogedegbe, PhD, BB(ASCP)SC, Department of Environmental Health, Molecular and Clinical Sciences, Florida

Gulf Coast University, Fort Myers, FL. Laboratory Medicine, 12/2002, 33:12; 948

953. DOI: 10.1092/QWJQLR8ELGL6X32H

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What is Hemostasis? (page 571)

Complex, highlyregulated physiological

process

Events

Cellular Biochemical

Keep blood in liquid statein vasculature

Prevents blood lossfollowing injury throughclot formation

Graphic accessed at URLhttp://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-

%20Blood%20Clot.jpg on 9/18/2008.

http://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-%20Blood%20Clot.jpghttp://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-%20Blood%20Clot.jpghttp://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-%20Blood%20Clot.jpghttp://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-%20Blood%20Clot.jpghttp://www.sportscreekside.net/images/Club%20X%20Summer%20Camps%202008/Health%20Science%20-%20Blood%20Clot.jpg

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Hemostatic Events

Tissue Injury Vasoconstriction

Neural Platelet-reinforced

Platelet Activation

Adhesion Aggregation

Coagulation Blood Clot

Thrombin generation Fibrin polymerization

Fibrinolysis Blood Clot Dissolution

Vascular Patency Restored

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Importance of Balance in Hemostasis

platelets

Coagulation Fibrinolysis

Body

BleedingThrombosis

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Importance of Balance in Hemostasis

Fibrinogen

Fibrin

thrombin plasmin

Fibrinogen

Fibrin

thrombin plasmin

Hemorrhage Thrombosis

Any disruptionin the balance between clot formation and clot dissolution results in thrombosisdue to hypercoagulation or hemorrhaging due to hypocoagulation.

Too many PLTsToo few/non-functional PLTs

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SecondaryHemostasis

PrimaryHemostasis

Categories of Hemostasis (page 572)

Primary

Vascular System Endothelia

Sub endothelia/collagen

Platelets Secondary

Coagulation System

Plasma Proteins

Cells: Platelets

Fibrinolytic System

Plasma proteins

Cells: Platelets, Endothelia

Graphic accessed at URL http://www.acta-ortho.gr/v55t4_4/Figure1.jpg 9/18/08.

Graphic accessed at URL http://www.kup.at/journals/abbildungen/gross/746.html9/18/08.

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Primary Hemostasis: Vessels

Vascular Endothelia at Rest

Anticoagulant

Endothelial cells

Smooth surface

Thrombomodulin

Permeability barrier

Collagen Connective tissue

Injured Vascular Endothelia

Procoagulant

Vessel contraction

Collagen-mediated PLT

activation vWF-mediated PLT adhesion

P-selectin promotes PLTadhesion

Coagulation activation via TF

Graphic accessed at URL https://reader009.{domain}/reader009/html5/0502/5ae931955e772/5ae93199a8181.jpg9/18/08.

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Primary Hemostasis: Platelets

Source: Megakaryocyte

Function: adhere(non-PLT surfaces),

aggregate(PLT stickingto each other), secrete(granules contents)

Graphic accessed URL http://www.wadsworth.org/chemheme/heme/microscope/pix/giantplatelet_nw.jpg, 2009.

Table 40-4 page 574

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Primary Hemostasis: Platelets

Graphic accessed at URL http://www.strokecenter.org/education/ais_pathogenesis/images/platelet_activation.jpg9/18/08.

Primary

HemostasisFunction

SecondaryHemostasisFunction

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Primary Hemostasis: Disorders

Inherited vascular defects

Ehlers Danlos Syndrome

Collagen synthesis defect

Marfan Syndrome

Fibrillin-1 glycoprotein synthesisdefect

Acquired vascular defects Amyloidosis

Actinic purpura

Quantitative PLT defect

To few

Thrombocytopenia

To many Essential Thrombocytosis

Qualitative PLT defect

Von Willebrands Disease (vWD)

Aspirin therapy

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Graphic accessed at URL https://reader009.{domain}/reader009/html5/0502/5ae931955e772/5ae9319c91d61.jpg8/26/07.

Graphic accessed URL https://reader009.{domain}/reader009/html5/0502/5ae931955e772/5ae9319cc8ac9.jpg , 2009.

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Secondary Hemostasis: Coagulation

Biochemical response(Pathways) resulting infibrin clot

Extrinsic

Intrinsic

Common

Soluble fibrinogen

converted to insolublefibrin

Reinforces PLT plug

Graphics accessed at URLhttp://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001 9/18/08.

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Secondary Hemostasis:

Coagulation Factors

oProcoagulants a.k.a coagulation factorsa.k.a clotting factors

oMajority are glycoproteins

oMajority are synthesized in the liver

Few synthesized in monocytes,endothelia, and megakaryocytes

oEight circulate as zymogens

oFour are cofactors

oCategorized as substrates, cofactors,or enzymes

Nomenclature

oRoman numerals

oa indicates active form

oI, II, III, IV occasionally identified by romannumeral

oTheres no VI assigned

oPLT factor 3, Prekallikrein, & HMWK are notassigned roman numerals

Physical Properties Groupings

FactorCommon Name

FunctionPlasmaConcentration

I* Fibrinogen Fibrin precursor 200 400 mg/dL

II* Prothrombin Thrombin precursor 10 mg/dL

III* Tissue Factor Cofactor none

IV* Ionized calcium Essential Mineral 8 10 mg/dL

V Labile Factor Cofactor 1 mg/dL

VII Stable Factor Serine Protease 0.05 mg/dL

VIII AntihemophilicFactor

Cofactor 0.01 mg/dL

vWF Von WillebrandFactor

VIII Carrier & PLTAdhesion

1 mg/dL

IX Christmas

Factor

Serine Protease 0.3 mg/dL

X Stuart-ProwerFactor

Serine Protease 1 mg/dL

XI PlasmaThromboplastinAntecedent Serine Protease

0.5 mg/dL

XII Hageman Factor Serine Protease 3 mg/dL

XIII Fibrin-stabilizingFactor

Transglutaminase 2 mg/dL

Prekallikrein Fletcher Factor Serine Protease 35 50 mg/dL

HMWK FitzgeraldFactor

Cofactor 5 mg/dL

PLT Factor 3 PhosphotidylSerine

Assembly Molecule none

*Customarily identified by name rather than Roman numeral.

Contact Factors

Vitamin-K Dependent

Thrombin-Sensitive

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Secondary Hemostasis:

Fibrinolysis

Enzymatic degradation of fibrinBegins within a few hours of fibrinpolymerization and stabilization

Tracks at pace of wound healing

Primary protease = plasmin

Catalytic product of plasminogenactivation

Fibrin degradation products(FDPs)

X

Y

D

E

D-D = D-dimer

Graphics accessed at URLhttp://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001 9/18/08.

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Hemostasis Control

Graphics accessed at URLhttp://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001 9/18/08.

ControlAgent Target(s) Action

Vasculature Blood flow Vasoconstriction

Liver Plasma

Removal of

activated factors,plasmin, & FDPs

Thrombin V & VIIIActivates factors

Antithrombin IIIThrombin, XIIa,

Xia, IXa, Xa,Kallikrein,

Plasmin

AT III binds theseserine proteasesand neutralizes

their activity

Examples of Controls of Hemostasis

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Hemostasis: Ancillary Systems

Kinins mediatorsof inflammation

Vasodilation

Increasevasopermeability

Smooth musclecontraction

Bradykinin

Kallikrein

Complement

Graphic accessed at URL http://www.uweb.engr.washington.edu/research/tutorials/bloodcompatibility.html7/15/08.

Graphic accessed at URL http://www.merck.com/media/mmpe/figures/MMPE_13IMM_163_02_eps.gif 9/19/08.

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Laboratory Evaluation of Hemostasis

Hypercoagulable Disorders

Test

Measures/

Detects Ordered

ABN ResultIndications

Antiphospholipidantibodies Presence of AB

DVT/PE suspected,recurrent miscarriage

Antiphospholipidsyndrome

Antithrombin AT activity

Recurrent blood clotswith familial history of

ABN clotting AT deficiency

D-dimer Presence of cross-linked FDPs

Evaluate clot formationduring episodes ofbleeding/clotting

Recent/ongoingabnormal clotting

APCR

Activated V resistanceto APC degradation

Venous thrombosispanel

F/U Confirm Factor VLeiden Mutation

Prothrombin Time (PT) Clotting time Screen and monitoringCoumadin therapy

Need for additionaltesting; dosage

adjustment

Partial Thromboplastintime (PTT)

Clotting time Screen and monitoring

Heparin therapy

Need for additionaltesting; dosage

adjustment

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Laboratory Evaluation of Hemostasis

Bleeding Disorders

Test

Measures/

Detects Ordered

ABN ResultIndications

Prothrombin Time (PT) Clotting time Screen and monitoringCoumadin therapy

Need for additionaltesting; dosage

adjustment

Partial ThromboplastinTime (PTT)

Clotting time Screen and monitoring

Heparin therapy

Need for additional

testing; dosageadjustment

Specific Factor Assay Factor Activity Suspected factordeficiency

Factor deficiency

Platelet Count Number of Platelets Screen for cause ofhemorrhage

Risk of hemorrhage orthrombosis (if elevated)

Platelet Aggregation Platelet Function Suspected cases ofPLT dysfunction/vWD

PLTadhesion/aggregation/s

ecretion disorder

http://labtestsonline.org/understanding/analytes/heparin/test.htmlhttp://labtestsonline.org/understanding/analytes/coagulation_factors/test.htmlhttp://labtestsonline.org/understanding/analytes/platelet/glance.htmlhttp://labtestsonline.org/understanding/analytes/platelet_function/glance.htmlhttp://labtestsonline.org/understanding/analytes/platelet_function/glance.htmlhttp://labtestsonline.org/understanding/analytes/platelet/glance.htmlhttp://labtestsonline.org/understanding/analytes/coagulation_factors/test.htmlhttp://labtestsonline.org/understanding/analytes/heparin/test.html

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Hemostasis = Coagulation & Fibrinolysis

Stoppage of bleeding

Restoration of blood flow following injuryto vasculature

Multisystem interactions

Balanced/Regulated

Derangements of balance leads tothrombosis or hemorrhage

The clinical lab monitors hemostasisthrough various tests

References1. An Overview of Hemostasis by Henry O. Ogedegbe, PhD,

BB(ASCP)SC, Department of Environmental Health,Molecular and Clinical Sciences, Florida Gulf CoastUniversity, Fort Myers, FL. Laboratory Medicine, 12/2002,33:12; 948 953. DOI: 10.1092/QWJQLR8ELGL6X32H

2. Rodak BF, Fritsma GA, and Doig K. (2007). HematologyClinical Principles and Applications. St. Louis, Missouri.Saunders Elsevier.

3. Coagulationpresented by MTS Training Solutions at URLhttp://www.medtraining.org

4. The Fritsma Factor at URL http://www.fritsmafactor.com/Education Modules Hemostasis

5. Lab Tests On-line at URL http://labtestsonline.org/

Summary

Graphic accessed at URL http://www.ganfyd.org/index.php?title=Image:CoagulationAndFibrolyticPathways.png#file9/21/08

Megakaryocyte graphic accessed at URL http://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20megakaryocyte%20x50a.jpeg 9/18/08.

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g y y g p p g p g jp g g y y jp g

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