Hemostasis

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Hemostasis Blood clot formation Clotting factor Platelet 

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Hemostasis (,hemo’=blood:sta=,remain’) is the stoppage of bleeding, whichisvitally important when bloodvesselsaredamaged. Following aninjury to bloodvessels several actionsmay help prevent blood Coss,including: Vessel injury Platelet plug Fibrin yt Endothelial cells Vascular Platelet plug Blood spasm formation clotting (b) (c) Collagen fibers Formation of aclot (a) 

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Localvasoconstriction Start of bleeding ™ isduetolocal spasm of the smoothmuscle ‏سوب‎ (symp. reflex) 8 ۱۱۱۸ Constriction of vessel canbemaintained ‎by platelet‏ سح ‎vasoconstrictors‏ ۵ 

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Formation of platelet aggregate = Injured bloodvessel releases ADP, which attracts platelets (PLT) = PLTcommingincontact withexposed collagen reCease:serotonin, ADP, TXA2,whichaccelerate vasoconstrictionand causes PLT toswelCand becomemore sticky 

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Themicrographshowsactivatedplateletsadhering to some damaged cells Platetets 

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Formation of clot / ۱ 1 [Factor XII\ = Intheformation of \ \ © theclot,anenzyme Fe XI \ 1 | scien 1 8 calledthrombin Factor IX 1 0 1 ۳ ° 7 ‘ 5 intoinsoluble 5 protein, fibrin 8 6 = Fibrinaggregatesto formameshlike networkat thesite of vascular damage 

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Coagulation mechanismis composed ofan extrinsic andintrinsicpathway,whicheventually mergeinto one " Theintrinsicsystemis morecomplexandpresent ‏للا‎ ‎onlyin higher’ Cifeforms @ foes TF Tauber (e.g. birds and reptiles 0 PL Phosphalpids possess only extrinsic PK ۰ system) Kalco = Thecomplex sequence of oan orn events that produce fibrinare dividedinto three stages Fain (cossinkod) 

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Extrinsic mechanism Intrinsic mechanism Factor <P 1 Factor XI co fristmas factor 2 7. When bloodcomesin | contact withinjured عدادكا- علاوة رمه 2 -1 1 ال ممم thromboplastin (F III) interactswith proconvertin (FVII), andCa* activating Stuart factor (FX). €Extrinsicpathway: ‏سس‎ tuart factor StageI: Formation of ‎1١‏ اک ‎ ‎activator ‎ ‎ ‎ 

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Extrinsic mechanism Intrinsic mechanism Factorxil <P Intrinsicpathway: L 2.Exposedcollagen Factor Xi activates Hageman {ear factor (FXII). Activated ‎gatinates plasma‏ ا ل ‎enzyme-plasma‏ ‎thromboplastin‏ ‎ti- ss antecedent (PTA! FXI,‏ ‎Rate oe‏ ‎whichin the presence of‏ رل ‎Ca**activates Christmas‏ ‎ ‎ ‎ ‎factor (FIX). FIX interactswith tuart factor antihemophilic factor (F JIII),Ca2* StageI: Formation of NEED) Cass toforma, ‏م‎ complex that activates activator Stuart factor (FX). ‎ ‎ ‎ ‎ 

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Extrinsic mechanism Intrinsic mechanism Factor x <BR | 3.Common pathway: Factor XI fear Activated FXinthe ‎ae presenck Sta forms‏ > الملل ‎complexeswith‏ | ‎Anti- —_ accelerin (FV) toform‏ : ‎mmophilic‏ ‏1أ 0115 انةان]0 را ‎Factor ill Fctor‏ ‎activator‏ ۳ ‎ ‎Stuart factor ‎ ‎StageI: Formation of ‎—Frothromsin ‎activator ‎ ‎ ‎ ‎ 

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INTRINSIC PATHWAY EXTRINSIC PATHWAY Tissue Factors (prot & Exposed Collagen ae ۷۱۱ 3 from damaged cells ‏وا اس ویر‎ ۳-۳ vil Ee ‏ال ير‎ ns Ix 4 ۱۷۱۱۱۵ © PROTHROMBINASE> Xill _~ | Cross- _iilla inked Fibrin 

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StageII:conversion of prothrombin to thrombin = Prothrombin inactive precursor of enzyme thrombin = Inthepresence of prothrombinactivatorandCa* prothrombinisconvertedtothrombin = Thrombinitselfincreasesitsown rate of formation (positive feedbackmechanism) 

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ب 51] 0ن نالا ۰۲۹۸۵۲ 6۵۷۷۷ : ‎٩86117‏ fibrin-stabilizing = Fibrinogen-plasma protein produced by the liver = Thrombinconverts fibrinogen tofibrin = Thrombin alsoactivates fibrin-stabilizing factor (F XIII), whichin the presence of Ca", stabilizes the fibrin polymer throughcovalent bonding of fibrin monomers 

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Calciumions = Averequiredfor promotionand acceleration of almost all bloodclotting reactions ™ Except :activation of XIlandXI (intrinsicmechanism) 002 http://mww.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.ntm 

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ی ۱ یس ‎factor‏ 

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Fibrinolysis ‘Summary of the coagulation and fibrinolysis cascades Expat Reviews n Molocar Mecn ©2008 Cami Unie Pass 

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Clot Dissolution 1. Plasminisformedfromplasminogen -enzymecalled activator (e.g.enzymesfromurine, tears, saliva or bacterial enzyme streptokinase) 2 Plasminasanenzymeisinvolvedin breaking down fibrin into soluble fragments (fibrinolysis) ; Activator eg.tePIT— Plasminogen ‏متم و‎ Fibrin —sebublefragments Plasminogenmaybeproduced by eosinophils 

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Positive feedback loop Clot disso! ال كك 

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Anticoagulants Hirudo medicinalis produce Hirudin that inhibits Thrombin 

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Anticoagulants = Although tissue breakdownand platelets destructionare normal events intheabsence of trauma,intravascular clotting does not usually occur because: - theamounts of procoagulants releasedarevery smal ~ naturalanticoagulantsarepresent (Antithrombin IIL, Heparin, Antithromboplastin, Protein CandS, fibrin fibers) 

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115 نأل 0:0 0 عا :0111 زر ۵ ۵ )۲۴و10 111 ای ها = Heparinfrombasophilsandmast cells potentiates effects of antithrombin III (together they inhibit IX,X,XI,xXIland thrombin) = Antithromboplastin (inhibits ,tissuefactors” tissue thromboplastins) = ProteinCandS -activatedby thrombin! degradefactor Va andVIlla 

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Abnormalities of hemostasis ‎te 1‏ مد ابش ‎peg,‏ = ‎ 

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‎the number of‏ نجع بك 5 "ا ‎PLTs- thrombocytopenia‏ ‎™ thiscauses spontaneous bleeding Thrombocytopenia ‎asa reaction tominor trauma ‎Blotchy rash = itmay result from: ‎decreased production (toxins, ‎radiation, infection, leukemias) ‎increased destruction (autoimmune processes) ‎~ increased’PLTs consumption (DIC) ‎ ‎Hemorrhagicspots (petechiae) 

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Thrombocytopenia = Lethal when PLTs<10G/L ™ Bleeding occurs when PLTs<50G/L = Norm: 150-400G/L 

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Hepaticfailure 77 = most of the clotting factorsareformedin theliver ۱ ‏ون‎ Pe Subconjunctival hemorrhage 

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Disseminatedintravascular coagulation (DIC) = Widespreadcoagulation > throm bovis small bloodvessels increas and depletion of coagul« factors — generalized bleeding = Itmay result from: bacterialinfections (endot 1 - disseminatedcancers procoagulants) ~ complications of pregn ~ severecatabolicstates 2 cer viet cancer metastases (PET imaging) 

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Hemophilia A (Cack of F VIII) and B (Cack of F IX) aretransmittedgenetically andaffect onlymales. Females carry the gen but do not show symptoms. ‘Von Willebrand's disease Coss of Carge component 1 

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Hemophilia A (lack of F VIll; 85%) ™ Spontaneous or traumatic subcutaneous bleeding = Bloodintheurine = Bleedinginthemouth, Cips, tongue ™ Bleedingtothejoints, CNS, gastrointestinal tract dhemophitia after tnjectionin, buttock يمي = 

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™ Son of thelast Tsar of Russia -Aleksy Romanow suffered from Hemophilia A 

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Tests of coagulation ۳ 3 << 

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۷ PLS ۷ Ua Intrinsic and extrinsic coagulation pathways Kaolin Thromboplastin Phospholipids (PL) (Tissue factor + PL) Calcium Calcium 58 ‏دیب رس‎ “Extrinsic” Pathway dah, (PT prolonged) ivated P: ectonged) Prothrombin Time Thromboplastin Time N: 9.9 - 13 sec N: 25-35 sec Common Pathway (aPTT and PT prolonged) CLOT 

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Prothrombin time (PT) test -norm77 -75 sec evaluates oxtwinmsiesystem (VIL,X, VIT fibrinogen) cited plasma 58 eae - (ites ‏الل‎ ‏لبن زر‎ Pastor ta he syakesis of Pucctoad Se oe or x - ‏مد جرا‎ - ‏و وضو(‎ ۳0 - تحص ما رم - ی probed PP tekouies ‏رای و‎ fo ‏ل مس2‎ oy oP Paste OM, 1), 0, ‏وعمس عادم‎ 0 Prothrombin 

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International NormalisedRatio (INR) 8 De rend or he OP tr expremerd Pherapeuic teri: ‏ادوص‎ xe arto (probe reba clot ee Saou i Por potiect phere dhuided by tke Por pvr pkexra); © ppledtion: Doctor ocd cco ‏مدني‎ ‎© Correvivs Pastor (lotersratizcrdd terwpy (ey. Dafaria); Geewitviy Tedex) to opphed to he 8 ct thot heparta wl oot probrory IDR ‏تایه سر بس) اجه یلجت ما وتات‎ waht the KDR a TOR. For ‘apy we monitor aPTT and/or aPTT ratio 

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ActivatedPartial Thromboplastin Timetest @PITT) -norm: 25-35 sievaluates imtrimsiesystem (VIII, IX, XI,XIL,X, VIL fibrinogen) 17 eels = an isolated prolongation of ‏عي کر و‎ the «PTT (PT normal) suggests deficiency of citrated plasma factor VIII, IX, XI or XII = prolongation of both the wa Ma APTT and ۳۲ suggests factor | PIV) ‏ا ۵ اا‎ (fibrinogen) deficiency, all of which are rare = PTT is normal in factor VII ‏سک‎ deficiency (PT prolonged) Fitsinogen”Sribsin clot and factor XIII deficiency Prothrombin Oost cowwed cose oF proboaged APT — heporiall! 

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Thrombin time (TT)-norm: 74-75 sec Prolonged TT: ™ Heparin (much more sensitive to heparin than aPTT) ™ Hypofibrinogenemia 

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0511:0110 ]0 5ع كلانه لاع نأعع نأ 5 ‎coagulation tests‏ Thrombocytopenia Von Willebrand’s disease Drugs (Aspirin, NSAIDs, high dose penicillins, etc.) Cirrhosis, Uremia, PLTs dysfunction Low or absent fibrinogen Dysfibrinogenemia, hypofibrinogenemia Heparin Vil, X, V, Hl, fibrinogen deficiency Antibodies Warfarin; Vit K defficiency (mild to severe) Excessive Heparin Factor deficiency (except Vil) Antibodies to clotting factors Heparin Excessive Warfarin 

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۷ PLS ۷ Ua Intrinsic and extrinsic coagulation pathways Kaolin Thromboplastin Phospholipids (PL) (Tissue factor + PL) Calcium Calcium “Intrinsic” ‏دیب‎ “Extrinsic” Pathway «ere [ Prolonged) Cae Thromboplastin Time N: 25-35 sec Common Pathway (aPTT and PT prolonged) CLOT 

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= Thetimetakenfor bloodto Whole blood cot mainly reflects the clotting time 1 generation of thrombin ™ The surface of the glass tube CLOT FORMATION initiates the clotting process. This test is sensitive to thefactors involvedintheintrinsic pathway = Theexpectedrangefor clotting timeis 4-7o MAS. 

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Whole blood clotting time -procedure: ™ Clean the tip of thefinger withanalcohol = Prick thefinger tip withanautomaticlancet = Note thetimewhen bloodfirst appears ontheskin ™ Touchthe tube to the drop of blood = Breakgently 7cmof thetubeat theendof2min, andevery 30sec theseaftery, ‏سس‎ = When fibrin is formed between the two broken pieces of tube the coagulation or clotting time is noted 

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Bleeding time © Thisisa test that measures thespeedin whichsmall bloodvessels close off (thecondition of the bloodvesselsand platelet function) ™ This test isuseful for detecting bleeding tendencies ™ The bleeding stops within 7toomimutes. Thismay vary fromlabtolab, dependingdnnowtnetest ismeasured * Using theearlobemethod,a normal bleeding timeis between gandominutes. 

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Bleeding time procedure: ™ Clean theearlobewithan alcohol ™ Pricktheearlobewithanautomaticlancet ™ Notethetimewhen bloodfirst appearsontheskin ™ After halfaminute (30sec) place the edge of the filter paper on the topof the drop of blood. ™ Performtheoperationat half minute (30sec) interval ™ Theendpoint or bleeding timeis thefirst half minutewhen no bloodis seenon thefilter paper. 

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Abnormal Bleeding Time = Prolonged bleeding timemayindicate: * Avascular (bCoodvessel) defect ° Aplatelet function defect (see platelet aggregation) * plateletscount defect (Cow platelets) = Drugs that mayincrease timesinclude dextran,indomethacin,and salicylates including aspirin). 

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Intrinsic Pathway surface ‎Xt‏ سار ‎Extrinsic Pathway vil ‎ ‎ ‎ ‎ ‎ ‎Vila + TF ‎ ‎vascular injury, ‎x ‎ ‎ ‎Prottrombin@~ TS ‎Thrombin ‎xill ‎Fibrinogen —** Fibrin monomer ‎Xilla ‎Fil ‎ibrin ahs copyright 1996 M.W. King Cross-linked fibrin polymer ‎ 

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The new model of ____ haemostasis =a OS @. 

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1. Initiation phase Injury of vessels wall leads to contact “between blood and subendothelial cells Tissue factor (TF) is exposed and binds to FVila or FVII which is subsequently converted to FVila The complex between TF and FVila activates FIX and FX FXa binds to FVa on the cell surface 

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2. Amplification phase The FXa/FVa complex converts small amounts “of prothrombin into thrombin The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXla converts FIX ۹ to ۴۱۵ 9 3 Activated platelets \ \ bind FVa, FVIlla and ‏ملاع‎ 

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3. Propagation phase The FVIlla/FIXa complex activates FX on the “SUirfaces of activated platelets, FXa in association with FVa converts large ne amounts of prothrombin Fibrinogen into thrombin creating “thrombin burst”. The “thrombin burst” leads to the formation la of a stable fibrin clot. el | Prothrombin 

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Summary: * Haemostasis starts with the interaction between TF and FVila on the surface of subendothelial cells. * The small amount of thrombin generated during the amplification phase activates platelets locally on whose surface the subsequent reactions take place. * The resulting thrombin burst results in the formation of a stable clot. 

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Tissue factor (TF)/FVIla, or TF/rF Vila interaction, "4Hecessary to initiatiate haemostasis At pharmacologic concentrations rFVI directly activates FX on the surface of locally activated platelets. This activation will initiate the "thrombin burst” independently of FVI and FIX. This step is independent of TF. The thrombin burst leads to the formation of a stable clot NovoSeven® Mode of Action Eptacog alfa (activated) Prothrombin 

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Conclusion: « In high 00565 ۲۳۷۱۱۵ binds to the surface of the locally activated platelets where it leads to the formation of a "thrombin burst” 

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Prescribing Information Movoseven® Eptacog af (ectvatea) Abbreviated Prescribing information: NoweSeven Recombinant Coagulation Fact Va Va) Presentation: Ponce or njeuon wit accompanying sauon fo feconsttuion Vater for jection) vaiablem packs cantaning 12,249" .8'mg "fio. Uses: ‏ا و ی ام ی‎ and bevantian of bleeding ducing tae o ‏ماه درب کی‎ in batts wh agar haeroaphi th iors a= cngental FV ‘Setceny-Glaremann’stworasthera wih antvaies to GP Iba andlor Hd, ons wth pes presen eractainess to plate wanstuson. Dosage: Sie fini dsstved inthe ncompsnying sven before Use After ecaattisn the saliten confers 0.6m ein. Acre bywtravences Bees ‘ection aver 2.5 minutes must ho be mixed wih infusion selina or guenin a ip. Haemophilia. or 8 wih brs o acquired Macmoplis il ‘bse of 90n9 per kg boy weight burason ssn ntrel betwee, repeot njecans dependent n seventy ‏وتو موم موه مود له‎ Bevtermes for mil to moserate bleesingcpsouesUincusing ameiatrytesument 1 dose 3 haut eras (S049 per tg outa aenewe ‘iil dose ‏بای وی شم ور‎ dove every to hour unt isa mpravement Wf ortinued therapy inacaed,Sosegentrval canbe ineeasct Stecesivey. Major bleeding epaade moy be rested for 23 weeks onge if ciscaly waar: For eanveprocedaressugery sds nial dose Sour lets for 8:7 ya Dosage tetrel my ten be e‘ensed os hour father 2 weeks reaent maybe po 4 weeks an hesing hes Sette actor Ul dficieney Fa bleesing epsedes and formas procesuesourgerysaminster 16 30,9 perk bon. cuety &-0 haus att hacen Scheved. Adopt dose and weueney ts inahadual larmnd’s Dvarbasten For Heating oplodes ar fr vasiveprocedesaugery ans 900 {tango 80-1209) pe gh. Svery 2 hours 13-5 hour. alae ties doses shou be sdeinisered to socure etecive ‏یمیس‎ Por atone whe reno ‏ماه رم‎ re fest ne treatment. Contra-inications: Know npersraiiy to acave substance, excipient ote muse, hamster” ‘ovine protein. Precautions For severe eds NoveSeven shoud ery be sdmintared in haspitalsspeciolsed inthe eaten of patients wth ‘taguon factor Vil or Bubs cose calanerstion wih sphysianspecateed a Ueatinet of Rachophla, Ambulatory eater shuld not ‏سم‎ 2a hoes Posey of tvernbagenens or induction of Ole conetona fc tan aca could We cape tn cculshng blo, ‏میم که‎ | disease crsh jury, septcacma, DIC Since NevoSeven may canten ce emus af muse, Souine ana hamster prteia there 9 ‘emote possiy of he developmen af hyperaciatety Monitor Fl sefcent patent or pratrambin time ond Fullcoagulant acy: suspect ‏لماه‎ ‎‘mats Fs actoty false reach expected evel a lecing nat contol wth ecommended doses. Avo srmukanou ue of pratrambin comple oncenntes adtvated or ht Use im pregnancy: Oaly administer to pregnant women f cary needed Nat khow excrete inhuman mike seeese auton wnen samunsterng Novceeven is Rursiog wornen: Side Biers: Aaversefencos ctous ond horses) epertad cu post marten Sere Rte Hoon A a0 aca een. ‏لس سدق مه وروی ددع رس‎ mes an cone <Soordersnclusing cerebral infarction and cerebral chaera: kin ashes: venous brombote evens: haemahase ‘Sens adverse reactions incu: Arar tome eves suchas myocar inarion or choca carenrovsscular disorders and bowel infarction ‘enous thrombotic events (auc at tvcritophitit docp wei treribose and pansy ert tthe vet apr o cases peters were preispoced to such ever No sportaneous reparts f anaphylactic reactions, bk patents with haar faerie eacton shou be corfu monitored titer wentnant wth NoveSeven. These patensprevowly ested with human sin anor lana dave Fit Mentor PUK detent pats fr FV tinacies One case ngioneurc osdemaertdnpalint wth Glnarnng’s oribashera ster ‏اا‎ NoveSeven, Marketing ‘Ruthoriation numbers: Novoseven ‏تا نک‎ Eu/ioe)b06/001 Naveseven 120 ¥lU Eu /Seoe/o02 Novoseven 240 KU E1/S/008/003 Leg ‘Category: Pot Banc Hits Price Novaseven 12 tng Ee64.72Novaseven 24 ng ELIZ3-44 NovaSeven #8 mg E2e90 98 Fer eran Fl resting infemaion eas be aban (rom: Movo Node ted Gross Pak Uighton Rous Crawley West Sussex ANDI AT Te 01293 613555 Fs: Sinan ei 53s Ome a prenaraton’ Moy 2004 Ret N7/03/0398 

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A35-year-oldman complains of chronic physical fatigue,which began 3-4~weeks ago. Hesaidhefelt tired all of the timeeven throughhis occupationasa software developer wasmentally but not physically demanding. He breathedcomfortably at rest but, when heexerted himself, he experienced difficulty in breathing andhadhardtime catching his breath. Healsocomplained of smore than usual” mental fatigue, confessinganincreasing inability toconcentrateandfocushisattentionontasksat hands. Colleagues noticedhis pallor andhisinattentivenessat brainstorming sessionsandsuggestedhe reschedule hisannual physical examination for anearlier date. He complained of vagueabdominal painandsense of abdominal fullness. His appetitewas depressed, andhe thought perhaps his physicaland mental symptoms were caused by poor diet. However,attempts to increaseeating resultedin nausea. His stools, he said,were sometimes looseandtarry. Eventually, increasedheart palpitationsandchest pain made himseekmedical advice 

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Laboratoryfindings revealed the following: Laboratory test Patient | Normal RBC (red blood cell count) BS T/L 4۰5-6۰01 HCT (hematocrit ratio) 28% 40-52% Hb (hemoglobin) 8.0g/dL 13-17g/dL MCV (mean corpuscular 7011 78-951 volume) MCH (mean corpuscular 22.8pg 29pg hemoglobin) MCHC (mean corpuscular 28% 34% hemoglobin concentration) 

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Case history questions: 1 What generat medical condition is suggested by the person'ssymptoms? 2. What fundamental changein function of blood relatedtothered blood cells couldsimultaneously affect thefunction of several systems (cardiovascular, respiratory, gastrointestinal,andothers)? ‎What specific diagnosis is supported by thelaboratory‏ ,و ‎findings?‏ ‎4. How could the stool berelatedtothelaboratory findings? 

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Answers: 7, Anemia 2. Areductioninoxygen-carrying capacity of the bloodandthusa reduction in the delivery of oxygen tovarious body tissues 3, Anirondefficiencyanemia 4. Most cases ofiron-defficiency anemia result frominternal blood Coss. Dark, tarry loose stools suggest bleeding fromthe gastrointestinal tract andwarrant further tests to determine the exact cause