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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
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COAGULATIONCOAGULATION
• vascular wall
• coagulation factors
• platelet
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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
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PRIMARY HEMOSTASISPRIMARY HEMOSTASIS
Platelet
Adherence
Activation
Aggregation
(Contraction)
(Stabilization)
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COLLAGEN
von Willebrand Factor
fibrinogen
endothelial cells
Platelet AdhesionPlatelet Adhesionmediated by GP-Ib on platelet surface and vWF
COLLAGEN
GP-Ib
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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
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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
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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
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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
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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
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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
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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
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ANTICOAGULATION & FIBRINOLYSISANTICOAGULATION & FIBRINOLYSIS
Vascular Wall
Anti-Coagulation Factors
Fibrinolytic Factors
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ANTICOAGULATION & FIBRINOLYSISVascular Wall
ANTICOAGULATION & FIBRINOLYSISVascular Wall
• Endothelial Cell• prostacyclin (PGl2)• heparan sulfate• thrombomodulin• tissue plasminogen activator (tPA)
• Muscle• muscular dilation
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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
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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
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AnticoagulationHeparin
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
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AnticoagulationHeparin
AnticoagulationHeparin
AT AT
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II
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IIAT
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IIAT
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IIAT
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IIAT
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IIAT
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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
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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
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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
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Bleeding DisordersBleeding Disorders
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ProcoagulantPlateletsFactorsFibrinogenvon Willebrand Factor
AnticoagulantAntithrombin IIIProtein CProtein S
ProfibrinolyticPlasminogentPAFibrin Fragment D-dimer
AntifibrinolyticPAI-1Alpha-2 Antiplasmin
clotclot RESOLUTIONFORMATION
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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
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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
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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
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hemophilia Ahemophilia A
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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
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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
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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
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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
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ThrombocytopeniaThrombocytopeniaThrombocytopeniaThrombocytopenia
decreased production1. diffuse bone marrow disease (aplastic anemia, tumor)
2. megakaryocyte disorder
increased utilization1. DIC
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Thrombocytopenia Thrombocytopenia increased destructionincreased destruction
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
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Thrombocytopenia Thrombocytopenia increased destructionincreased destruction
Thrombocytopenia Thrombocytopenia increased destructionincreased destruction
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
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2. idiopathic thrombocytopenic purpura (ITP)clinical:
• easy bruising and bleeding after minor trauma
treatment:• steroid• splenectomy
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Thrombocytopenia Thrombocytopenia increased destructionincreased destruction
Thrombocytopenia Thrombocytopenia increased destructionincreased destruction
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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History & Physical Examare
most importantmost sensitivemost specific
Tests of Hemostasis
History & Physical Examare
most importantmost sensitivemost specific
Tests of Hemostasis
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