Excellent Hemostasis

Hemostasis

HemostasisBlood must be fluidMust coagulate (clot) at appropriate timeRapidLocalizedReversible

Normal HemostasisA well regulated processMaintains 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

Normal sequence of Hemostasis (4 steps)1. Arteriolar vasoconstriction (transient)Reflex neurogenic mechanismsBleeding would resume after vasoconstriction if it werent for the activation of platelets or coagulation systems

2. Exposure of subendothelial ECM when there is endothelial injuryECM, especially collagen, is highly thrombogenicPlatelets adhere and become activatedChange in shapeRelease of secretory productsAggregation of platelets forms hemostatic plugThis is primary hemostasis

First two steps of normal hemostasis

Normal hemostasis continued3. Tissue factor released at the site of injury (by endothelial cells)Works with secreted platelet factorsActivates coagulation cascadeA series of proteins where thrombin is activatedInduces further platelet recruitment and granule releaseEnds in fibrin depositionCalled secondary hemostasis

Normal hemostasis continued4. Formation of permanent plugPrevents further hemorrhagePolymerized fibrin and platelet aggregationCounter regulatory mechanisms (t-PA) limit the plug to the site of the injury

Steps 3 and 4

The Main Players in HemostasisEndothelial cellsPlateletsCoagulation cascade

Endothelial CellsProduce vWF (vonWillebrand factor)A product of normal endothelium found in the plasmaessential for platelet binding to collagen and other surfacesSecrete Tissue factorinduced by cytokines (TNF, IL-1)activates the extrinsic clotting pathway

Endothelial Cells have Prothrombotic EffectVia vWF and tissue factor factors that depress fibrinolysis factors needed for the clot are not destroyed before clot formsCollagen is highlythrombogenic

PlateletsExpress glycoprotein receptors on membranes. Gp Ib,IIb/IIIaHave three types of granulesAlpha granulesFibrinogen, fibronectin, factor V and VIII, PDGF, TGFbDense bodies or delta granulesATP/ADP, ionized calcium, histamine, serotonin, epinephrineLysosomal granules

PlateletsHyalomere and granulomere

Platelets continuedUpon encountering the ECM, platelets undergo three general reactions:1. Adhesion and shape change mediated by vWF and glycoprotein Ib2. Secretion (release reaction)calcium required in coagulation cascadeADP as mediator of platelet aggregationSurface expression of phospholipid complexBinding site for calcium ions and coagulation factors

Platelets continued3. AggregationADP and TXA2 (vasoconstrictor thromboxane A2) are the stimuli for the formation of the primary hemostatic plugAspirin inhibits synthesis of TXA2Fused mass of plateletsCreated by coagulation cascade that produces thrombin Thrombin also converts fibrinogen to fibrin cementing platelets in place

PEMBEKUAN DARAH /SISTEM KOAGULASIProses koagulasi merupakan rangkaian reaksi enzimatik yg melibatkan : protein plasma sbg faktor koagulasi fosfolipid Ca 2+Produk akhir jendalan fibrin

Faktor koagulasi

FactorCommon name(s)IFibrinogenIIProthrombinIIITissue Factor, Tissue ThromboplastinIVCalsium IonVLabile Factor, ProaccelerinVIVIIStable Factor, ProconvertinVIIIHemophilia A factorIXChristmas Factor, Hemophilia B Factor, Plasma Thromboplastin ComponentXStuart Prower FactorXIHemophilia C factor, Plasma Thromboplastin Antecedent (PTA) XIIHageman Factor, Contact FactorXIIIFibrin Stabilizing Factor, Laki-Lorand FactorPKPrekallekrein, Fletcher FactorHMWKHigh Molecular Weight Kininogen, Fitzgerald Factor

Jalur Intrinsik Jalur Ekstrinsik XII VII Kontak XIIa Ca++ HMWK PK K Tromboplastin jaringan XI XIa

IX Ixa VIIa PF3 VIII Tenase Complex Ca ++

Jalur Bersama X Xa V PF3 Prothrombin Converting Complex Ca++ Fibrinogen Protrombin Trombin Fibrin Monomer

Fibrin Polimer Soluble XIII XIIIa Ca++ Fibrin Polimer Insoluble

FibrinogenFibrinThrombinProthrombinXaVaVIIaTFExtrinsic PathwayIXaVIIIaXIaXIIaIntrinsic pathwayXIIIaSoft clotFibrinHard clotVVIII

FibrinogenFibrin

FibrinogenFibrinThrombin

FibrinogenFibrinThrombinProthrombinXaVa

FibrinogenFibrinThrombinProthrombinXaVaVIIaTFExtrinsic Pathway

FibrinogenFibrinThrombinProthrombinXaVaVIIaTFExtrinsic PathwayIXaVIIIaXIaXIIaIntrinsic pathwayXIIIaSoft clotFibrinHard clot

Hemophilia A

Deficiency of/nonfunctional VIII

Hemophilia BDeficiency of /nonfunctional IX

Why do they bleed?

FIBRINOLISISProses penghancuran deposit fibrin oleh sistem fibrinolitik aliran darah terbuka kembaliSistem Fibrinolitik, td :- Plasminogen- Aktifaktor Plasminogen- Inhibitor PlasminSistem Fibrinolitik dicetuskan oleh adanya aktivator plasminogen memecah plasminogen plasmin

Aktivasi plasminogen :jalur intrinsik jalur ekstrinsik jalur eksogen

FibrinFibrin Split Products (FSP)PlasminFibrinolysis

FibrinFibrin Split Products (FSP)PlasminPlasminogen tPAFibrinolysis

Skema Fibrinolisis Intrinsik Ekstrinsik Eksogen (XIIa,Kalikrein) (t-PA) (Urokinase Streptokinase)

Aktivator Plasminogen

Plasminogen Terikat Plasmin Terikat Fibrin FDP

Plasminogen Bebas Plasmin Bebas Fibrinogen V VIII Anti Plasmin

Inhibitors of fibrinolysis

Plasminogen activator inhibitors (PAIs)

a2-antiplasmin (serpin)

PEMERIKSAAN LABORATORIUM HEMOSTASIS1. Rumple Leed (RL)2. Bleeding time / masa perdarahan3. Clotting time / masa penjendalan4. Jumlah trombosit5. Protrombin Time (PT) / Plasma Protrombin Time (PPT)6. Activated Partial Tromboplastin Time (APTT)7. Trombin Time

2. BLEEDING TIME/MASA PERDARAHANTujuan : menilai faktor hemostasis yg letaknya ekstravaskulerMetoda : Ivy - voler lengan bawah (T 40 mmHg) tusuk lancet sedalam 3 mm isap dg kertas saring tiap 30 detik - N : 1 6 menit Duke - telinga - N : 1 3 menit

3. CLOTTTING TIME / MASA PENJENDALANTujuan : Mendeteksi kualitas dan kuantitas faktor koagulasi scr keseluruhanNilai normal : 9 15 menit Gelas arloji : 2 6 menit

4. JUMLAH TROMBOSITTujuan : mengetahui kuantitas trombositCara : Langsung Manual : Brecher Herweden Semi otomatik Otomatik Tak langsung FonioNilai normal : 150.000 400.000 / mm3

5. PROTROMBIN TIME (PT) / PLASMA PROTROMBIN TIME (PPT)Tujuan : Menguji faktor koagulasi jalur ekstrinsik (VII) & jalur bersama (V, X) Memonitor terapi anti koagulan oralCara :Plasma + Ca 2+ + tromboplastin jaringan terbentuk jendalan dideteksi dgn fotodetektor (37 0C)Waktu yg diperlukan utk pembentukan jendalan PTNilai normal : 11 -15 detik ( atau beda dgn kontrol 2 detik )

6. ACTIVATED PARTIAL TROMBOPLASTIN TIME (APTT)Tujuan : Menguji faktor koagulasi jalur intrinsik (VIII, IX, XI, XII) & bersama (V, X) Memonitor terapi heparinCara :Plasma + Ca 2+ + tromboplastin jaringan terbentuk jendalan dideteksi dgn fotodetektor (37 0C)Waktu yg diperlukan utk pembentukan jendalan APTT

Nilai normal : 20 - 40 detik

7. THROMBIN TIME (TT)Tujuan : menguji perubahan fibrinogen menjadi fibrinCara : plasma + reagen trombin bekuan (370 C)Nilai normal : 16 20 detik

Conditions Causing BleedingIncomplete hemostasis is most common cause of bleeding.Vitamin K deficiency severe coagulation defectRequired for synthesis of prothrombin and factors VII, IX and XParenchymal diseases of the liverLiver synthesizes several coagulation factors

Hereditary deficienciesHemophilia A--factor VIII deficiencySex-linked recessive30% due to new mutations and dont have family linkHemarthroses 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 deficiencyClinically indistinguishable from Hemophilia ASex-linked recessiveNeed 50% preoperativelyProlonged PTT, normal PTTX: Factor IX or FFP

Von Willebrands DiseaseVon Willebrands Disease- Most common congenital bleeding disorder.Types I, II, and III.PT normal PTT normal or elevatedProlonged bleeding timeType I most common (70%) with mild sx.Type III causes most bleedingType I and III- reduced quantity of vWFTX: Cryo, DDAVPType II- defect in vWF molecule, enough of it but doesnt work well. TX: Cryo

Platelet DisordersAcquired-H2 blockers, heparin.Bernard-Soulier, a Gp1b receptor deficiency (cant bind to each other)Uremia-Inhibits Gp1b, vWF. TX: dialysis, DDAVP, cryo, plts.Ticlopidine- decreases ADP in platelets, prevents exposure of Gp1b/IIIa receptors.Dipyramidole- decreases ADP induced plt aggregation.Plavix-ADP receptor antagonist.Pentoxifyllin- inhibits plt aggregation

Platelet DisordersHeparin induced thrombocytopenia (HIT)Antiplatelet antibodies results in platelet destruction.Also causes aggregation and thrombosis.Low doses of heparin.LMWH may have less risk.

DICDecreased plts, prolonged PT, PTT.Low fibrinogen, high fibrin split products, high D-dimersOften initiated by tissue factor.Treat underlying cause

ThrombiPlatelet aggregatesFibrinTrapped erythrocytes and leucocytesNot part of this hemostatic processThis is a deep vein thrombosisPostoperative patients confined to bed

Endothelial injury is dominant influenceHeart and arterial circulationHypercholesteremia, cigarette smoke productsRadiation, bacterial endotoxinsResults in exposure of subendothelial collagen, adherence of platelets, release of tissue factor and local depletion of prostacyclin (antithrombin)

Alterations in normal blood flowTurbulenceinjures endotheliumAtherosclerotic plaquesStasis Can create venous thrombiAneurysms cause local stasisDeformed cells of Sickle cell anemia cause vascular occlusions

Stasis and TurbulenceDisrupt laminar flow (cells in middle)Bring platelets into contact with endotheliumPrevent dilution of activated clotting factors by fresh-flowing bloodRetard inflow of clotting factor inhibitors

HypercoagulabilityLeiden Factor- 30% spontaneous venous thrombosis.Most common congenital disorder.Resistance to Protein C, defect on factor VTX: heparin, warfarin.Protein C, S deficiency-5% venous thromboses. TX: heparin, warfarin.

HypercoagulabilityAntithrombin III deficiency- 2-3% thrombosis. Heparin doesnt work. Can develop after previous heparin exposure.TX: ATIII concentrate, FFP(highest conc) followed by heparin.Polycythemia- defect in platelet function, usually thrombotic, but can bleed. Keep HCT

HypercoagulabilityLupus 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.

HypercoagulabilityCardiopulmonary Bypass- factor XII activated, results in hypercoagulable state. TX: heparin, warfarin.Warfarin induced skin necrosis- 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.

HypercoagulabilityMay be genetic or acquiredGenetic mutations in the factor V geneMutant factor V is resistant to anticoagulant effect of activated protein CSmoking, obesity and ageLate pregnancy and postpartum amniotic fluid infusion into circulationDisseminated cancers tumors release procoagulantsAdvanced age, bed rest and immobilization

Hematologic DrugsWarfarin- prevents Vit K dependent decarboxylation of glutamic residues on Vit K dependent factors.Dextran- inhibits platelets and coagulation factors.Sequential compression devices-improve venous return but also induce fibrinolysis with compression (release of tPA).

Hematologic DrugsHeparin- 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.Protamine side-effects are hypotension, bradycardia, decreased heart function.

Hematologic DrugsHirudin- leeches, thrombin inhibitor.Ancrod- Malayan pit viper venom, stimulates tPA release.Amicar-antifibrinolytic, procoagulant, inhibits plasmin. Used in DIC, persistent bleeding following CABG, thrombolytic overdoses.Streptokinase, tPA-need to follow fibrinogen levels, levels

Fate of thrombusPropagationAccumulate more platelets and fibrin and obstruct a critical vesselEmbolizationDislodge thrombi and transported to other sites in vasculature

Fate of thrombus, continuedDissolution/resolutionRemoved by fibrinolytic activityOrganization Induce inflammation and fibrosis and may reopen and allow blood flow

Fates continuedRecanalizationOpenings and even blood vessels created in thrombus

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Excellent Hemostasis