Hemostasis PDF - A Summary

Platelets thrombocytes - small, granulated, non-nucleated bodies - count: 300,000/mm3 (150,000- 450.000) - lifespan: 8 days. precersor cells of platelch...

Platelets thrombocytes - small, granulated, non-nucleated bodies - count: 300,000/mm3 (150,000- 450.000) - lifespan: 8 days. precersor cells of platelch M Thrombopoietin (by liver and kidneys): facilitates megakaryocyte maturation N.B.: 30% stored in spleen: Splenectomy → ↑ platelet count (thrombocytosis). Structure: do not have nuclei and cannot reproduce 1. Plasma membrane: Contains: specialized to help them adhere to sites of injury > - a. coat of glycoprotein: negatively charged to prevent adherence of platelets to endothelium. living of blood vessels > - b. glycoprotein receptors for: collagen, von-Willebrand factor, fibrinogen and * ADP. hey molecules involved in blood clothing ↳ cuncial for pletelet adhesion c. Phospholipids helpclothing > - initiate cascade d. Open canalicular system, for uptake of extracellular calcium and release of substances. 2. cytoplasm, contains: Contractile proteins: actin and myosin enable platelets to change their shape. timp. for clot formation A skeleton of microtubules: keeps the disc shape of platelets. granules Hemostasis = (stop bleeding) Steps: 1. vasoconstriction 2. temporary hemostatic plug (platelets functions) 3. definitive hemostatic plug (clotting factors) I. Constriction of Blood Vessel: Immediately, reduces blood flow and may be so strong → obliterates lumen. mechanism: 1. Nervous: initiated by pain sensation from traumatized vessel. 2. Local myogenic contraction: due to direct trauma. 3. Chemical substances (local humoral substances): - from platelets , As : serotonin and thromboxane A2 4. endothelin: from injured endothelium A.F. 2024 17  Hemostasis I. Vasoconstriction II. formation of temporary hemostalia plus III. formation of definitive hemostatic plug I. Vasoconstriction : - immediate varrowing of the blood vessels at site > - reduces blood flow & loss Mechanism : 1 initiato. Nerous mechanisms pain triggers a nemons response a vessel constriction 2. Local myogenic contraction : direct braume to vascular smooth muscle a contraction promote. 3 Chemical substances : "Platelek release serotonin & thromboxane As a varoconstriction help in · Endothelin released by damaged endothelium constricting the versel I. formation of temporary hemostatic plug 1. Platelet adhesion : adhere to the exposed collagen in subendothelial hissue of damaged blood versets t · " Glycoprotein receptors Von Willebrand factor : : allow platelets to slich glycoprotein that binds to to collegen platelets & collagen aid in platelet adhesion Ca gramules + releases t z. Platelet activation: - become activated by ADP , thrombin a swell and pseudopodia (extension) - stick together. 3 Release reaction (Ca dependent) : 4. Platelet aggregation : loose & recessible process - plateets adhere to eachother ↳ stimulated ADP TXAz by release of , , PAF " requires fibringen receptors on platelets a for bridge. 5 Platelet fusion : Light & irreversible process where high concentrations of ADP thrombin , , platelet enzymes reinforce the plug. Platelet 6 procoagulant activity : exposure of phospholipid surfaces (PF3) activate coagulation faches > - counters these effects to limit clot foration to the site injury II. Formation of Temporary Hemostatic Plug = platelets functions: If injury is small, can stop blood loss completely. Steps: 1. Platelet adhesion: Normally platelets do not adhere to healthy vessels but to subendothelial collagen. depends on: a. glycoprotein receptors of platelets b. Von-Willebrand factor (VWF): glycoprotein in subendothelium (also in plasma bound to VIII). 2. Platelet activation (enhanced by ADP and thrombin): swell and put pseudopodia 3. Release reaction: (Ca dependent): dense granules alpha granules a. Calcium  more release 1) factor XIII  stabilization of fibrin clot b. ADP  activation, aggregation 2) Platelet derived growth factor (PDGF)  and fusion of platelets wound healing by growth of endothelium, c. Serotonin  vasoconstriction smooth muscles and fibroblasts. 3) Platelet activation factor (PAF)  platelet aggregation Thromboxane A2 Prostacyclin = PGI2 produced from arachidonic acid in membrane by cyclooxygenase enzyme by activated platelets endothelium actions a. Vasoconstriction, 1) Vasodilator b. ↑ release reaction 2) ↓ release c. ↑platelet aggregation. 3) ↓ aggregation of platelets NB: increases free Ca++ in keep platelet plug localized to the cytoplasm site of injury ❖ NB: Aspirin is used to prevent myocardial infarction because: Aspirin inhibits cyclooxygenase enzyme: ↓ TxA2 & prostacyclin endothelial cells produce new cyclooxygenase whereas platelets cannot A.F. 2024 18  4. Platelet aggregation:(Loose and reversible) - Caused by Released ADP and thromboxane A2 & PAF - requires fibrinogen receptors GpII/IIIa on platelets: act as a bridge - self-propagating process: platelets adhere to each other leading to further release reactions liberating more ADP, and thromboxane A2, causing more aggregation, 5. Platelet fusion: (Tight &irreversible) - Cause: high concentration of ADP, thrombin and platelet enzymes. 6. Platelet procoagulant activity: exposure of PF3: surface for activation of coagulation factors. III. Blood Coagulation= definitive plug: ❖ coagulation factors: 13 plasma proteins: beta globulins (inactive enzymes) synthesized by liver. activated in a cascade: chain of proteolytic reactions activating each other Factor Name Factor Name I Fibrinogen IV Calcium. II Prothrombin XII glass factor. III Thromboplastin XIII Fibrin-stabilizing factor classified: 11215/7/8/9/10/11/12/13 Fibrinogen group Prothrombin group Contact Group I (fibrinogen), V, VIII, II, VII, IX and X XI and XII XIII 1 5 8 13. , , 2 7 9 10 , , , 11 , 12 activated by thrombin need vitamin K for activated by contact to synthesis electro-negatively charged surface A.F. 2024 19  I formation of definitive hemostatic plug Purpose : formation of a stable clot by converting soluble fibringen a insoluble fibrin Coagulation factors : 13 plasma proteins ( produced by liver I act as cascade beach activating next Factor I : converts to fibrin 1927 Factor II : converts to thrombin Factor # (Calcium) : essential for clothing reactions Clothing mechanism - critical part of hemostasis ; temp. plug-stable clot in 2 steps : 1 conversion. fibringen - fibrin : soluble fibringen - insoluble fibrin Inbinsic pathway : ↳ mesk of Librin strands - traps blood cells/platelet/plasma > - solid stable clot , surface 2. stabilization by factor III : III converts loose F. fibrin strands - zu 1. Activation of Factor II - activated when it comes in contact with-we charged Lighter strands adivatar * premallikrein-Collikrein hininogen Thrombin activates of ↳ a + F #. in the presence G - strengthens the clot 2. Activation Factor of #X : - #a adivatar # -a adivatar 3. Activation of EX : a I - IXa in presence of C #I is activated by thrombin peter in common 4. Activation of I :Xa + Ea + Ca" PLadivata + a Exhinsic pathway : -triggered by external trauma that exposes tissue factor TF I · ↑ thrombin - creates 1. Release of Lissue factor III "Vicious circle" senhancing clot 2. Activation of I TFII : binds toI adivater a formation until a limiting reaction shops if 3. Activation of I: I a + Cadivate a + ~ complex G required step #12 of · in every IP. Common pathway. : begins I is activated - once 1. Conversion prothrombin - thrombin : a + Ea + Ca + PL a Prothrombinase complex Coverno Complex Prothrombin # : Thrombin #Ia 2. Conversion of Fibringen to Fibrin : Thrombinachs on fibringen I a fibrin. 3 Stabilization of Librin clot Thrombin adivator : a · I a cross-links - stabilizes , strengthems stable clot that can withstand blood flow ❖ Serum: - plasma remaining after clotting. - devoid of: fibrinogen group & prothrombin: consumed during clotting - contains excess: serotonin from platelets. Clotting Mechanism: ❖ temporary plug converted into definitive clot - end: "conversion of soluble fibrinogen to insoluble fibrin (threads)" → mesh of strands entrapping blood cells, platelets, and plasma. - Fibrin stabilizing factor (XIII) of platelets converts loose threads into tight strands. N.B.: Factor XIII is activated by thrombin in presence of Ca++. A.F. 2024 20  ❖ Important notes: thrombin activates: factor V & VIII: if critical amount of thrombin → vicious circle → more blood clotting until (limiting reaction) stops it Ca is required for all steps except 1st 2 steps in intrinsic pathway ❖ interaction between intrinsic & extrinsic pathways: Intrinsic pathway extrinsic pathway in vivo and in vitro vivo only slow (1-6 min.). very rapid (15 sec.) In vivo (Injury of a blood vessel): both activated: 1) intrinsic (by exposed collagen) catalyzed by high-molecular weight (HMW) kininogen and plasma kallikrein 2) extrinsic (by tissue thromboplastin). in vitro (test tube): only intrinsic (electronegatively charged surfaces as glass). extrinsic system activates intrinsic: activated VII (extrinsic) activates IX (intrinsic factor) Anticlotting Mechanisms = Limiting Reactions 1. Healthy endothelium: a. barrier between blood and subendothelial collagen, preventing activation of platelets and coagulation factors b. smooth & negatively charged repelling negatively charged platelets &coagulation proteins c. produces: antiplatelet & anticosgulant 1) NO and prostacyclin (PGI2) = antiplatelet agents 2) thrombomodulin binds thrombin reduces dotting effect > - 3) tissue plasminogen activator (part of the fibrinolytic system) dissolves cole > - 2. Continuous normal flow of blood 3. liver: Inactivation of activated clotting factors. 4. Heparin : present in small amounts in the blood and combines with antithrombin III in the blood to inactivate factors IX. X, XI & XII 5. Thromboxane A2 and prostacyclin: causes a clot to form at site of injury only A.F. 2024 21  6. Fibrinolytic System: Thrombomodulin Thrombin digests Librin e fibin degradation produch ↳ Thrombomodulin produced by all endothelial cells (except cerebral microcirculation). Plasmin (fibrinolysin): active component of Fibrinolytic system: lyses fibrin and fibrinogen forming fibrinogen degradation products (FDP): inhibit thrombin. N.B.: - Human t-PA is produced by recombinant DNA: If given soon after onset of myocardial infraction (within 6 hours) it lyses clots in coronary arteries. - Other fibrinolytics: streptokinase and urokinase enzymes. Anticoagulants: substances used to prevent blood clotting. A. In vitro (outside body): 1. Removal of Ca2+ ions: - Oxalates precipitate Ca2+ - Citrates (used in blood transfusions) deionize Ca2+. 2. Silicon coated tubes: prevent activation of factor XII. 3. heparin. A.F. 2024 22  B. In vivo:(inside body): Heparin Dicumarol 1) Origin Mast cells and basophils. Plant 2) Mode of action Facilitates action of Competitive inhibition with AntithrombinIII, (blocks Vit.K in liver: inhibits activity of IXa, Xa, XIa, formation of II, VII, IX & X. XIIa) 3) Site of action In vivo & In vitro Only in vivo. 4) Onset Rapid. Slow 5) Duration Short Long 6) Administration injection Orally 7) Antidote Protamine sulphate 1% Vitamin K. Blood Transfusion increase bleeding Abnormalities of Hemostasis: - - Guse : excessive clothing I. Conditions with increased bleeding: Insufficient platelets A. Thrombocytopenic purpura: hinder formation of a proper platelet plug platelet count < 50,000/mm3 (bleeding time is prolonged) ↳ prolonged bleeding characterized by subcutaneous hemorrhages called petechiae small red/pumple spok on body B. Conditions affecting clotting factors: (prolonged clotting time) 1. Liver disease liver disease impairs clothing factor production > - - a 2. Vitamin K deficiency (essential for factors II, VII, IX and X and proteins C&S). causes: produces Uit ↑. K 1) absent intestinal bacterial (Vitamin K formed by intestinal flora) in: a) new born b) adults with long treatment with antibiotics. 2) Obstruction of biliary ducts: absence of bile needed for absorption (Vitamin K fat-soluble) 3. Hemophilia: prolonged bleeding die - severe bleeding, even after mild trauma. T w lach of dot feclos - Congenital recessive X -linked disease: carried by females but appears in males. A (85% of cases) B C absent factor VIII IX XI A.F. 2024 23  II. Conditions with increased clotting “thrombosis”: 1) slow blood flow: prolonged bed rest after operations and varicose veins 2) Atherosclerosis due to rough endothelium III. Increased bleeding & clotting “dissiminated intravascular coagulation DIC” - Wide spread clotting (increased thromboplastin from traumatized tissues) - consumes clotting factors → bleeding tendency. Causes: 1. Retention of dead fetus 2. Septicemia * bacterial infection in bloodstream Hemostatic Function Tests 1. Bleeding time 2. Tests for blood coagulation coagulation Prothrom activated time bin time partial thromboplastin time (APTT Def. time needed for time needed test for test for intrinsic bleeding to stop for blood to extrinsic system (factors without clotting clot system XII, XI, IX and (depends on (factor VII) VIII) platelets) Normally 1-3 minutes 3-10 minutes 15 seconds 30-40 seconds prolonged thrombocytopenic extrinsic & vitamin K hemophilia in purpura intrinsic and deficiency liver diseases A.F. 2024 24