Hemostasis and ThrombosisHemostasis and Thrombosis

Vic Vernenkar, D.O.

St. Barnabas Hospital

Dept. of Surgery

Normal HemostasisNormal Hemostasis

• A well regulated process

• Maintains blood in a fluid, clot free state in normal vessels

• Induces the rapid formation of a localized hemostatic plug at the site of vascular injury

ThrombosisThrombosis• Pathological state• Inappropriate activation of the normal

hemostatic process – within the non-interrupted vascular

system.

• Thrombus (blood clots) formation– Blocks blood flow to vital areas

Normal sequence of HemostasisNormal sequence of Hemostasis (4 steps)

• 1. Arteriolar vasoconstriction1. Arteriolar vasoconstriction (transient)(transient)– Reflex neurogenic mechanisms– Bleeding would resume after vasoconstriction if

it weren’t for the activation of platelets or coagulation systems

• 2. Exposure of subendothelial ECM when 2. Exposure of subendothelial ECM when there is endothelial injurythere is endothelial injury– ECM, especially collagen, is highly

thrombogenicthrombogenic– Platelets adhere and become activated

• Change in shape• Release of secretory products

– Aggregation of platelets forms hemostatic hemostatic plugplug

– This is primary hemostasisprimary hemostasis

First two steps First two steps of normal of normal hemostasishemostasis

Normal hemostasis continued

• 3.3. Tissue factorTissue factor released at the site of released at the site of injury injury (by endothelial cells)

– Works with secreted platelet factors

– Activates coagulation cascadecoagulation cascade• A series of proteins where thrombinthrombin is

activated• Induces further platelet recruitment and

granule release

– Ends in fibrin depositionfibrin deposition

– Called secondary hemostasissecondary hemostasis

Normal hemostasis continued

• 4. 4. Formation of permanent plugFormation of permanent plug– Prevents further hemorrhage

– Polymerized fibrin and platelet aggregation

– Counter regulatory mechanisms (t-PA) limit the plug to the site of the injury

Steps 3 and 4

The Main Players in HemostasisThe Main Players in Hemostasis

• Endothelial cellsEndothelial cells

• PlateletsPlatelets

• Coagulation cascadeCoagulation cascade

Endothelial CellsEndothelial Cells

• Produce vWFvWF (vonWillebrand factor)– A product of normal endothelium – found in the plasma– essential for platelet binding to collagen and other

surfaces

• Secrete Tissue factorTissue factor– induced by cytokines (TNF, IL-1)– activates the extrinsic clotting pathwayextrinsic clotting pathway

Endothelial Cells have Endothelial Cells have Prothrombotic EffectProthrombotic Effect

• Via vWF and tissue factor

• factors that depress fibrinolysis

• factors needed for the clot are not destroyed before clot forms

Collagen is highlyCollagen is highlythrombogenicthrombogenic

For wound healing

For inflammation

For hemostasis

Endothelial cells have Anti-thrombotic Endothelial cells have Anti-thrombotic properties, tooproperties, too

• Antiplatelet effectsAntiplatelet effects– Intact cells are barrier to

subendothelial ECM– PGI-2 and NO prevent

platelets from adhering

• Fibrinolytic propertiesFibrinolytic properties– Tissue type plasminogen Tissue type plasminogen

activatoractivator (t-PA) • promotes activity to clear

fibrin deposits from endothelial surfaces

• Anticoagulant Anticoagulant propertiesproperties– Membrane associated

molecules• Heparin like Heparin like

molecules and molecules and thrombomodulinthrombomodulin

– Inactivate thrombin and several coagulation factors

Factors that favor or inhibit Factors that favor or inhibit thrombosisthrombosis

SOooo…..SOooo…..

• Endothelial cells modulate the balance of hemostasis

• Endothelial injuryinjury is the dominant influence that leads to thrombosis

PlateletsPlatelets• Express glycoprotein receptorsglycoprotein receptors on

membranes. Gp Ib,IIb/IIIa

• Have three types of granules

– Alpha granulesAlpha granules• Fibrinogen, fibronectin, factor V and VIII,

PDGF, TGF

– Dense bodies or delta granulesDense bodies or delta granules• ATP/ADP, ionized calcium, histamine,

serotonin, epinephrine

– Lysosomal granulesLysosomal granules

PlateletsPlatelets

Hyalomere and granulomereHyalomere and granulomere

Platelets continued

• Upon encountering the ECM, platelets undergo threethree general reactions:

1. Adhesion and shape changeAdhesion and shape change

mediated by vWF and glycoprotein Ib

2. SecretionSecretion (release reaction)– calcium required in coagulation cascade– ADP as mediator of platelet aggregation– Surface expression of phospholipid complex

• Binding site for calcium ions and coagulation factors

Platelets continued

• 3. . AggregationAggregation– ADP and TXATXA22 (vasoconstrictor thromboxane A2)

are the stimuli for the formation of the primary hemostatic plug

• Aspirin inhibits synthesis of TXA2

– Fused mass of platelets• Created by coagulation cascade that produces

thrombinthrombin

• Thrombin also converts fibrinogenfibrinogen to fibrinfibrin cementing platelets in place

ThrombocytopeniaThrombocytopenia• Spontaneous bleeding, prolonged bleeding

time

• Lowered platelet count– Uremia, too much aspirin and rare genetic

disorders– Various marrow failure or injury

• Aplastic anemia, leukemia

– Sometimes immunologically mediated– Destruction of platelets by prosthetic heart valves

• Bleeding into CNS a concern

• Common hematologic manifestation of AIDS

Coagulation CascadeCoagulation Cascade

• A series of conversions of inactive proenzymes to activated enzymes, – culminating in the formation of

thrombinthrombin

• Thrombin then coverts the soluble plasma protein fibrinogenfibrinogen to insoluble fibrous protein fibrinfibrin

Two pathways of Two pathways of

coagulation coagulation cascadecascade

• IntrinsicIntrinsic

– Surface contact

• ExtrinsicExtrinsic

– Tissue injury

Coagulation cascadeCoagulation cascade

Heparin is a cofactor thatAllows antithrombin III to Inactivate thrombin andFactor Xa

Thrombomodulin bindsTo thrombin, making itAn anticoagulant whichThen activates anti-Coagulant protein C.Protein C cleave factors Va and VIIIa

Hemophilia B (ChristmasDisease) results from Deficiency of factor IX

Hemophilia A (classic) is due to reduced amount or reduced activity of Factor VIII

Control of cascade to prevent Control of cascade to prevent clotting elsewhereclotting elsewhere

• AntithrombinsAntithrombins– activated by heparin likeheparin like

molecules on endothelial cells

• Clinical administration of heparin minimizes thrombosis

• Proteins C and SProteins C and S– Vitamin K dependent– Inactivate cofactors Va

and VIIIa

• Plasminogen-Plasminogen-plasmin systemplasmin system– Breaks down fibrin

and inhibits its polymerization

– Products of split fibrin are anticoagulants

Conditions Causing Conditions Causing BleedingBleeding

• Incomplete hemostasis is most common cause of bleeding.

• Vitamin K deficiency – severe coagulation defect– Required for synthesis of prothrombin

and factors VII, IX and X

• Parenchymal diseases of the liver– Liver synthesizes several coagulation

factors

Hereditary deficienciesHereditary deficiencies

• Hemophilia A--factor Hemophilia A--factor VIII deficiencyVIII deficiency– Sex-linked recessive– 30% due to new mutations

and don’t have family link– HemarthrosesHemarthroses common

(spontaneous bleeding in joints)

– Infuse patient with factor VIII from human blood or cryoprecipitate.

– Need 100% levels preop, keep at 30% postop.

• Hemophilia B--factor IX Hemophilia B--factor IX deficiencydeficiency– Clinically indistinguishable

from Hemophilia A

– Sex-linked recessive

– Need 50% preoperatively

– Prolonged PTT, normal PT

TX: Factor IX or FFP

VonVon Willebrand’sWillebrand’s DiseaseDisease

VonVon Willebrand’sWillebrand’s DiseaseDisease- Most common congenital bleeding disorder.

• Types I, II, and III.• PT normal PTT normal or

elevated• Prolonged bleeding time• Type I most common (70%)

with mild sx.• Type III causes most

bleeding

• Type I and III- reduced quantity of vWF

• TX: Cryo, DDAVP• Type II- defect in vWF

molecule, enough of it but doesn’t work well. TX: Cryo

PlateletPlatelet DisordersDisorders

• AcquiredAcquired-H2 blockers, heparin.

• BernardBernard--SoulierSoulier, a Gp1b receptor deficiency (can’t bind to each other)

• UremiaUremia-Inhibits Gp1b, vWF. TX: dialysis, DDAVP, cryo, plts.

• TiclopidineTiclopidine- decreases ADP in platelets, prevents exposure of Gp1b/IIIa receptors.

• DipyramidoleDipyramidole- decreases ADP induced plt aggregation.

• PlavixPlavix-ADP receptor antagonist.

• PentoxifyllinPentoxifyllin- inhibits plt aggregation

PlateletPlatelet DisordersDisorders

• HeparinHeparin inducedinduced thrombocytopeniathrombocytopenia ((HITHIT))

• Antiplatelet antibodies Antiplatelet antibodies results in platelet results in platelet destruction.destruction.

• Also causes aggregation Also causes aggregation and thrombosis.and thrombosis.

• Low doses of heparin.Low doses of heparin.• LMWH may have less LMWH may have less

risk.risk.

• DICDIC• Decreased plts, Decreased plts,

prolonged PT, PTT.prolonged PT, PTT.• Low fibrinogen, high Low fibrinogen, high

fibrin split products, fibrin split products, high D-dimershigh D-dimers

• Often initiated by Often initiated by tissue factor.tissue factor.

• Treat underlying causeTreat underlying cause

ThrombiThrombi

• Platelet aggregates• Fibrin• Trapped erythrocytes

and leucocytes– Not part of this

hemostatic process

• This is a deep vein thrombosis– Postoperative patients

confined to bed

Thrombotic cycle and influencesThrombotic cycle and influences

Endothelial injury is dominant Endothelial injury is dominant influenceinfluence

• Heart and arterial circulation• Hypercholesteremia, cigarette smoke

products• Radiation, bacterial endotoxins• Results in exposure of subendothelial

collagen, adherence of platelets, release of tissue factor and local depletion of prostacyclin (antithrombin)

Alterations in normal blood flowAlterations in normal blood flow

• TurbulenceTurbulence– injures endothelium– Atherosclerotic plaques

• StasisStasis – Can create venous thrombi– Aneurysms cause local stasis– Deformed cells of Sickle cell anemia cause

vascular occlusions

Stasis and TurbulenceStasis and Turbulence

• Disrupt laminar flow (cells in middle)

• Bring platelets into contact with endothelium

• Prevent dilution of activated clotting factors by fresh-flowing blood

• Retard inflow of clotting factor inhibitors

HypercoagulabilityHypercoagulability

• Leiden FactorLeiden Factor- 30% spontaneous venous thrombosis.

• Most common congenital disorder.

• Resistance to Protein C, defect on factor V

• TX: heparin, warfarin.

• Protein C, S deficiencyProtein C, S deficiency-5% venous thromboses. TX: heparin, warfarin.

HypercoagulabilityHypercoagulability

• Antithrombin III Antithrombin III deficiency- 2-3% thrombosis. Heparin doesn’t work. Can develop after previous heparin exposure.

• TX: ATIII concentrate, FFP(highest conc) followed by heparin.

• PolycythemiaPolycythemia- defect in platelet function, usually thrombotic, but can bleed. Keep HCT<48, PLTS<400 before SX. TX: ASA.

HypercoagulabilityHypercoagulability

• Lupus AnticoagulantLupus Anticoagulant- antiphospholipid antibodies. Not all patients have SLE. A procoagulant (prolonged PTT but hypercoagulable).

• Diagnose by seeing prolonged PTT, false positive RPR test for syphilis.

• TX: heparin, warfarin.

HypercoagulabilityHypercoagulability

• Cardiopulmonary BypassCardiopulmonary Bypass- factor XII activated, results in hypercoagulable state. TX: heparin, warfarin.

• Warfarin induced skinWarfarin induced skin necrosisnecrosis- Occurs when coumadin started before heparin. Due to a decrease in protein S,C making patient transiently hypercoagulable. Patients with Protien C deficiency highly susceptible.

HypercoagulabilityHypercoagulability

• May be genetic or acquired

• Genetic mutations in the factor V gene– Mutant factor V is

resistant to anticoagulant effect of activated protein C

• Smoking, obesity and age

• Late pregnancy and postpartum – amniotic fluid infusion

into circulation

• Disseminated cancers – tumors release

procoagulants

• Advanced age, bed rest and immobilization

HematologicHematologic DrugsDrugs

• WarfarinWarfarin- prevents Vit K dependent decarboxylation of glutamic residues on Vit K dependent factors.

• DextranDextran- inhibits platelets and coagulation factors.

• Sequential compressionSequential compression devices-improve venous return but also induce fibrinolysis with compression (release of tPA).

HematologicHematologic DrugsDrugs

• HeparinHeparin- activates antithrombin III.• Reversed with protamine (1-1.5 protamine

per 100u of heparin).• Half-life 60-90 min.• Long term heparin use causes osteoporosis,

alopecia. Does not cross BBB.• ProtamineProtamine side-effects are hypotension,

bradycardia, decreased heart function.

HematologicHematologic DrugsDrugs

• HirudinHirudin- leeches, thrombin inhibitor.

• AncrodAncrod- Malayan pit viper venom, stimulates tPA release.

• AmicarAmicar-antifibrinolytic, procoagulant, inhibits plasmin. Used in DIC, persistent bleeding following CABG, thrombolytic overdoses.

• StreptokinaseStreptokinase, tPA-need to follow fibrinogen levels, levels<100 associated with severe bleeding.

Fate of thrombusFate of thrombus

• PropagationPropagation– Accumulate more

platelets and fibrin and obstruct a critical vessel

• EmbolizationEmbolization– Dislodge thrombi and

transported to other sites in vasculature

Fate of thrombus, continued

• DissolutionDissolution//resolutionresolution– Removed by

fibrinolytic activity

• OrganizationOrganization – Induce inflammation

and fibrosis and may reopen and allow blood flow

Fates continued

• RecanalizationRecanalization– Openings and even

blood vessels created in thrombus