Coagulation

COAGULATIONCOAGULATION

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HEMOSTASISHEMOSTASIS

• The body’s intrinsic ability to slow down or stop hemorrhage

• normal hemostasis involves a delicate balance between factors that promote blood coagulation and thrombus stabilization and factors that inhibit blood coagulation and promote thrombus dissolution

clotclot RESOLUTIONFORMATION


COAGULATIONCOAGULATION

• vascular wall

• coagulation factors

• platelet


COAGULATION FIRST STEP

COAGULATION FIRST STEP

•Smooth musclemuscle constriction

luminal diameter reductionretarding blood lossenhancing platelet adherence

•Endothelial cellsVIII-vWF synthesisthromboplastin (III) release

activation of ext pathwayactivation of Factor IX & X

•Subendotheliumcollagen platelet adherence, activation


PRIMARY HEMOSTASISPRIMARY HEMOSTASIS

Platelet

Adherence

Activation

Aggregation

(Contraction)

(Stabilization)


COLLAGEN

von Willebrand Factor

fibrinogen

endothelial cells

Platelet AdhesionPlatelet Adhesionmediated by GP-Ib on platelet surface and vWF

COLLAGEN

GP-Ib


von Willebrand Factorvon Willebrand Factor

• Synthesized & stored in endothelial cells and megakaryocytes (also stored in platelets)

• Forming bridge between subendothelial collagen and Plt• Carrier molecule for Factor VIII Coagulant Protein

(vWF is also known as Factor VIII Related Antigen)• Circulates as series of multimers (in various sizes)• Large, high molecular weight multimers required for normal

hemostasis


COLLAGEN

Platelet ActivationPlatelet Activation

GP-IIb, IIIa

release of and electron dense granules

•Release of platelet’s cytoplasmic products•activation of platelet factor III (PF-3)

PF-3 serves as a binding site for cofactor V & VIII

•production of thrombin


COLLAGEN

Platelet AggregationPlatelet Aggregation

GP IIb-IIIa - fibrinogen interaction

•formation of primary plug•activated platelets synthesize and secrete TXA2

TXA2:

1. promotes plt aggregation

2. vasoconstriction

3. release of plt factor (ADP)

Aspirin inhibits TXA2 and ADP


Coagulation FactorsCoagulation Factors

•Intrinsic Pathway•Extrinsic Pathway•Common Pathway

•majorities are serine proteases•circulate as inactive forms (require activation to function)•majority produced in liver

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot

negative charged surface

tissue factor


Coagulation FactorsCoagulation Factors

•Intrinsic Pathway•Extrinsic Pathway•Common Pathway

•majorities are serine proteases•circulate as inactive forms (require activation to function)•majority produced in liver•many require vit K for synthesis•II, VII, IX, X•protein C, S

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot

negative charged surface

tissue factor


Secondary HemostasisSecondary Hemostasis

1. tissue factor

2. phospholipid complex

3. thrombin activation

4. fibrin polymerization

thrombin, ADP, TXA2

Contraction• contraction of intraplatelet actomyosin• formation of secondary plug• uncover plt membrane receptors

(GPIb, IIIa)

Stabilization• activation of XII thrombin• cross linking of fibrin monomerswww.freelivedoctor.com

ED D

ED D

ED DED DED D

ED DED D

ED D

A ABB

BA A

B

ED

D

E

fibrinopeptide A & B

D domain

E domainthrombinthrombin

Spontaneous aggregation

fibrinogen

fibrin monomer

soluble fibrin polymer

Factor XIIIaFactor XIIIawww.freelivedoctor.com

ED DED DED D

ED DED D

ED DEDE D

Stabilization of Fibrin ClotStabilization of Fibrin ClotStabilization of Fibrin ClotStabilization of Fibrin Clot

Thrombin

Factor XII I Factor XIIIa

ED DED DED D

ED DED D

ED DEDE D

soluble fibrin clot

stabilized fibrin clot


Other Proteins in Blood CoagulationOther Proteins in Blood Coagulation

Prekallikrein

activates XII and prekallikrein

High molecular wt. Kininogen (HMWK) (=binding protein)

supports reciprocal activation of XII, XI and prekallikrein


ANTICOAGULATION & FIBRINOLYSISANTICOAGULATION & FIBRINOLYSIS

Vascular Wall

Anti-Coagulation Factors

Fibrinolytic Factors


ANTICOAGULATION & FIBRINOLYSISVascular Wall

ANTICOAGULATION & FIBRINOLYSISVascular Wall

• Endothelial Cell• prostacyclin (PGl2)• heparan sulfate• thrombomodulin• tissue plasminogen activator (tPA)

• Muscle• muscular dilation


ANTICOAGULATION & FIBRINOLYSISAnti-Coagulation Factors

ANTICOAGULATION & FIBRINOLYSISAnti-Coagulation Factors

• Antithrombin III (with thrombin & heparin)

• negative feedback on thrombin

• inactivates Xa (XIIa, XIa, IXa)

• Prostacyclin (PGl2) from endothelial cells

• vasodilation

• conversion of ADP into products that inhibit plt aggregation

• thrombin + endothelial cells

thrombomodulin binds & activates Protein C

inactivates Va & VIIIa

inhibits thrombin

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot


Protein C• vit K dependent zymogen• produced in liver• inactivates Va and VIIIa

Protein S• vit K dependent binding protein• co-factor for protein C• binds C4b-binding protein

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot


AnticoagulationHeparin


• Heparin activates Antithrombin III (AT III)• AT III inactivates Thrombin and Factor Xa• rapid onset of action

Laboratory monitoring:• aPTT : ~1.5X – 2.5X normal mean• heparin level :

0.2 – 0.4 U/mL by protamine titration

0.35 – 0.70 by Factor Xa inactivation assay

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot




AT AT


II


IIAT


Coumadin (Warfarin) AnticoagulantsCoumadin (Warfarin) Anticoagulants

•inhibits hepatic synthesis of vit K-dependent clotting factors (II, VII, IX, X)•competitive inhibition of g-carboxylation

inactivate “acarboxy” forms synthesized

•onset delayed 3 to 5 days•also inhibits synthesis of protein C & S

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot


Thrombolytic (Fibrinolytic) FactorsThrombolytic (Fibrinolytic) Factors

• Urokinase : released from endothelial cells and monocytes• Tissue plasminogen activator (tPA)

conversion of plasminogen to plasmin

cleavage of fibrinogen & fibrin into fibrin split products

inhibit plt aggregation

thrombin activity

fibrin strands cross linking


Plasmin Degradation of Fibrin ClotPlasmin Degradation of Fibrin Clot

ED DED DED D

ED DED D

ED DEDE D

plasmin plasminplasmin

EDE DED D DD

ED DD D E

D-dimer E-fragment DED complex

Fibrin Degradation Products


Bleeding DisordersBleeding Disorders


ProcoagulantPlateletsFactorsFibrinogenvon Willebrand Factor

AnticoagulantAntithrombin IIIProtein CProtein S

ProfibrinolyticPlasminogentPAFibrin Fragment D-dimer

AntifibrinolyticPAI-1Alpha-2 Antiplasmin

clotclot RESOLUTIONFORMATION


Vessel Abnormalitiesincreased vascular fragility

Vessel Abnormalitiesincreased vascular fragility

• manifested by petechial hemorrhages of skin/mucous membranes• bleeding time, plt count, PT, aPTT --- normal• not life threatening bleeding

1. congenital

a. Ehlers-Danlos syndrome (AD)

b. hereditary hemorrhagic telangiectasia (AD)

2. acquired

a. hypersensitivity vasculitis

(1) drug reaction : immune complex deposit in vessel walls

(2) Henoch-Schonlein purpura

b. scurvy (vit C deficiency)www.freelivedoctor.com

Henoch-Schonlein purpuraHenoch-Schonlein purpura

• generalized hypersensitivity vasculitis• uncertain cause

clinical Sx:• purpura• colicky abdominal pain• polyarthralgia• acute glomerulonephritis


Coagulation Factor AbnormalityCoagulation Factor Abnormality• hematomas/ecchymoses after minor trauma• often severe bleeding

1. congenital : usually single factor deficiency

a. sex-linked

(1) hemophilia A (Factor VIII def.)

(2) hemophilia B (Christmas disease, Factor IX def.)

b. autosomal dominant

(1) von Willebrand’s disease

c. autosomal recessive

2. acquired : usually multi-factor deficiency and clotting abnormalities

a. vitamin K deficiency

b. severe liver diseasewww.freelivedoctor.com

Hemophilia A (Factor VIII deficiency)Hemophilia A (Factor VIII deficiency)

•bleeding into joints crippling arthropathy•sex-linked inheritance•high rate of spontaneous mutation

•25% of pt’s do not have family history of hemophilia

•decreased VIII-C, near normal VIII-vWF•>50% severe deficiency•increased aPTT•normal bleeding time, plt, PT

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot


hemophilia Ahemophilia A


Hemophilia B(Christmas disease, Factor IX def.)

Hemophilia B(Christmas disease, Factor IX def.)

•less common than hemophilia A•similar clinical Sx and inheritance pattern as hemophilia A (sex-linked)

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clot


von Willebrand’s diseasevon Willebrand’s disease• easy bruisability (no bleeding into

joints)• unable to release VIII-vWF• intact VIII-vWF synthesis• VIII-C level is also decreased

(unknown reason)• autosomal dominant

• 1 in 30,000 population• usually diagnosed in childhood or

young adults• increased bleeding time• normal plt, PT• normal or increased aPTT


Vitamin K Deficiency

vitamin K dependent factors : II, VII, IX, X

Vitamin K Deficiency

vitamin K dependent factors : II, VII, IX, X

•acquired disorder•may occur in malnutrition, malabsorption, biliary obstruction, drug

•increased PT•normal bleeding time, plt•normal or increased aPTT

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clotwww.freelivedoctor.com

Severe Liver DiseaseSevere Liver Disease

factors synthesized in liver : II, V, VII, IX, X, fibrinogen

Severe Liver DiseaseSevere Liver Disease

factors synthesized in liver : II, V, VII, IX, X, fibrinogen

• increased PT, aPTT• normal bleeding time, plt

II

XII

XI

IX

VIII VII

X

V

I

XIII

Stable clotwww.freelivedoctor.com

PLATELET ABNORMALITIESPLATELET ABNORMALITIESPLATELET ABNORMALITIESPLATELET ABNORMALITIES1. Thrombocytopenia

a. decreased productionb. increased utilizationc. increased destruction

(1) isoimmune thrombocytopenia(2) idiopathic thrombocytopenic purpura (ITP)(3) thrombotic thrombocytopenic purpura (TTP)(4) drug reaction(5) mechanical destruction(6) hypersplenism

2. Functional abnormalitiesa. congenital

(1) defective adhesion (Bernard-Soulier)(2) defective aggregation (thrombasthenia)

b. acquired(1) aspirin(2) thrombocythemia


ThrombocytopeniaThrombocytopeniaThrombocytopeniaThrombocytopenia

• decreased in number of platelets• bleeding from small vessels (skin, GI, mucous membrane,

GU, brain)• normal or increased bleeding time• decreased platelet• normal PT, aPTT


ThrombocytopeniaThrombocytopeniaThrombocytopeniaThrombocytopenia

decreased production1. diffuse bone marrow disease (aplastic anemia, tumor)

2. megakaryocyte disorder

increased utilization1. DIC


Thrombocytopenia Thrombocytopenia increased destructionincreased destruction


1. isoimmune thrombocytopeniaa) neonatal

[PLA 1 neg. mother] + [PLA 1 pos. baby]

production of anti-PLA 1 Ab (IgG)

b) post-transfusion

[PLA 1 neg. recipient] + [PLA 1 pos. platelet]

destruction of PLA 1 platelets and recipient's own platelets




2. idiopathic thrombocytopenic purpura (ITP)a) acute ITP

• children following a viral infection• self-limiting disease• ? platelet as an “innocent bystander”

b) chronic ITP• adults (often premenopausal females)• may be associated with other “autoimmune diseases”• production of autoantibody against Pt’s own platelets• removal of opsonized platelets by reticuloendothelial system• decreased circulating platelet, but increased BM

megakaryocytes


2. idiopathic thrombocytopenic purpura (ITP)clinical:

• easy bruising and bleeding after minor trauma

treatment:• steroid• splenectomy




3. thrombotic thrombocytopenic purpura (TTP)• abnormal platelet aggregation in microcirculation• microangiopathic hemolytic anemia• fever• transient neurologic deficits• renal failure

hemolytic uremic syndrome (HUS)• platelets start to aggregate in small vessels without

particular reason

HUS


Disseminated Intravascular Coagulation (DIC)

Disseminated Intravascular Coagulation (DIC)

- an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases

- activation of clotting system resulting in wide spread formation of microthrombi throughout the microcirculation

- as a consequence, causing consumption of platelets, fibrin and coagulation factors, and activation of thrombolytic mechanism

Two major triggering mechanisms1. release of tissue factor or thromboplastic substance2. widespread endothelial injury


DICDICTriggering Mechanisms

1. release of tissue factor or thromboplastic substance- placental tissue- granules from leukemic cells- bacterial endotoxin- mucus from adeno CA

2. widespread endothelial injury- Ag-Ab immune complex deposit- extreme temperature- microorganisms


DICDICPathology: - wide spread thrombi

(brain, heart, lungs, kidneys, adrenals, spleen , liver)- microinfarcts

Clinical: - ~50% associated with obstetric complications- ~30% with carcinomatosis

- microangiopathic anemia- dyspnea, cyanosis- convulsions, coma- oliguria, acute renal failure- shock, circulatory failure


DICDICClinical: acute DIC with a predominance of thrombin generation

and consumption of coagulation factors

bleeding tendency(oozing from venopuncutres or operating site)

subacute and chronic DIC

thrombotic tendency


DICDICLab: - fibrinogen

- platelet- PT- aPTT- fibrin degradation product

acute DIC: - prolongation of aPTT, PT and TT- reduction of platelets, AT III and protein C- decreased fibrinogen- elevated fibrin degradation products

chronic DIC: - aPTT and PT may be within normal ranges- slightly decreased platelets- elevated fibrin degradation products and D-

dimer


Platelet Functional Abnormalities Platelet Functional Abnormalities congenitalcongenital

Platelet Functional Abnormalities Platelet Functional Abnormalities congenitalcongenital

1. Bernard-Soulier syndrome• defect in platelet adhesion• autosomal recessive• defect in platelet membrane glycoprotein (GP Ib)

2. thrombasthenia• defect in platelet aggregation• autosomal recessive• defect in platelet membrane glycoprotein (GP IIb & IIIa)• no fibrinogen linking of platelets• easy bleeding and no clot retraction

1

2


Platelet Functional Abnormalities Platelet Functional Abnormalities acquiredacquired

Platelet Functional Abnormalities Platelet Functional Abnormalities acquiredacquired

1. aspirin• inhibits cyclooxygenase

suppression of TXA2 synthesis

• effect lasts for 72 hours

2. thrombocythemia• platelet : >3,000,000/ml• functionally abnormal platelets• occasionally seen in myeloproliferative disorders


Coagulation TestsCoagulation TestsCoagulation TestsCoagulation Tests1. Bleeding Time : in vivo test

measures adequacy of plt functionnormal : <6 min.

2. Platelet Count normal : >200,000/mL3. aPTT : intrinsic pathway (XII, XI, IX, VIII, X, V)

used to guide heparin therapy4. 50/50 mixing study

pt’s plasma + nl. plasmaif mixing correct aPTT = Pt is deficient in intrinsic factor(s)no correction = circulating anticoagulants or inhibitors

5. Prothrombin Time (PT) : extrinsic pathway (II, VII, V, X)monitoring warfarin/coumadin effects


Coagulation TestsCoagulation Tests

6. Fibrinogen Level normal : 200 – 500 mg/dL

7. ADP platelet aggregation

8. Ristocetin aggregation test• test for presence or activity of vWF

9. Thrombin Time (TT) normal : 20 – 30 sec• measures 3rd stage of coagulation• prolonged if

• def or abnormality of fibrinogen• presence of fibrin split products• presence of heparin


History & Physical Examare

most importantmost sensitivemost specific

Tests of Hemostasis

History & Physical Examare

most importantmost sensitivemost specific

Tests of Hemostasis


Coagulation

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