HEMOSTASIS OF BLOOD
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EXPLAINS THE PROCESS OF HEMOSTASIS IN DETAIL AND LUCID WAY
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HEMOSTASIS OF BLOOD
- 3. This process of forming clots in the walls of damaged blood vessels and preventing blood loss while maintaining blood in a fluid state within uninjured vascular system is known as “HEMOSTASIS” Blood must be maintained in a fluid state in order to function as a transport system On the other hand it must also be able to solidify to form clot following vascular injury
- 4. NORMAL HEMOSTASIS Pre-injury NORMAL ENDOTHELIUM INHIBITORY EFFECTS ON PLATELETS INHIBITORY EFFECTS ON COAGULATIO N FACTORS FIBRINOLYSIS Post-injury VASO- CONSTRIC TION PRIMARY HEMOSTASIS COAGULATION CASCADE VASCULAR SYSTEM PLATELETS PLASMA PROTEINS
- 6. The heparin-like molecules enhance the inactivation of thrombin (and other coagulation factors) by the plasma protein antithrombin III Thrombomodulin binds to thrombin, modifying the substrate specificity of thrombin, so that instead of cleaving fibrinogen, it instead cleaves and activates protein C, an anticoagulant Tissue factor pathway inhibitor (TFPI) directly inhibits tissue factor–factor VIIa complex and factor Xa.
- 8. SYMPATHETIC PARASYMPATHETIC As pressure rises and especially for rapid increases in pressure: •baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in: 1.a vasodilatation of the veins and arterioles in the peripheral vascular beds. The vessel wall is innervated by both sympathetic and parasympathetic neurons. The sympathetic outflow to peripheral blood vessels originate in the reticular formation of brainstem. As we know sympathetic neurons utilizes norepinephrine as neurotransmitters to act on alpha receptors and beta receptors. Postjunctional alpha-1 stimulation leads to smooth muscle cell contraction and vasoconstriction. Under normal physiologic condition neurally released norepinephrine acts on alpha receptors on blood vessels, causing vasoconstriction in systemic circulation, whereas activation of beta-1 adrenergic receptors in coronary circulation results in
- 9. VASCULAR ENDOTHELIUM INJURY ENDOTHELIN RELEASE REFLEX NEUROGENIC MYOGENIC & ENDOTHELIN VASOCONSTRICTION {Transient} Narrows the lumen of the vessel to minimize the loss of blood Brings the hemostatic components of the blood (platelets and plasma proteins) into closer proximity to the vessel wall Enhances contact activation of platelets Von Willebrand factor Collagen fibers Platelet membrane glycoprotein Ib
- 16.
Editor's Notes
- clot: a clump of platelets and blood proteins (also known as a thrombus) that form a plug at the site of an injured blood vessel to prevent excessive bleeding. A clot may also form inside a blood vessel and block that vessel, which is called a thrombosis or a blood clot.
- FIRST MECHANISM IS: INHIBITORY EFFECT ON PLATELETS: AN INTACT ENDOTHELIUM RELEASES VARIOUS CHEMICAL MEDIATORS LIKE NITROUS OXIDE, PROSTACYCLIN, HEPARIN LIKE MOLECULES WHICH PREVENT PLATELET ADHESION SO HOW PROSTACYCLIN DOES ALL THESE???? Prostacyclin is produced in endothelial cells by action of cyclooxygenase and prostacyclin synthase. Prostacyclin activates platelet adenyl cyclase leading to generation of Camp. This increase in Camp activates camp dependent protein kinase and blunts the calcium ion rise associated with platelet stimulation and thus inhibits platelet aggregation. ONE MAY ASK HERE WHY PALETELETS ITSELF CANT PRODUCE PROSTACYCLIN.. WELL PLATELETS LACK THE ENZYME PROSTACYCLIN SYNTHASE INSTEAD THEY HAV THROMBOXANE SYNTHASE ENZYME… NOW IN A SIMILAR MANNER NITROUS OXIDE ACTIVATES PLATELET GUANYL CYLASE LEADING TO GENERATION OF Cgmp WHICH ULTIMATELY INHIBITS PLATELET AGGREGATION A CLINICAL APPLICATION OF PROSTACYCLIN IS DURING HEMODIALYSIS WHERE IT IS USED TO PREVENT PLETELET AGGREGATION. DOSE: 0.5mg
- IN BLOOD the heparin-like molecules like HEPARAN SULPHATE COMBINES WITH PLASMA PROTEIN ANTITHROMBIN-III. THIS COMPLEX INACTIVATES THROMBIN AND FACTORS IXa Xa. INTERSTING CLINICAL POINT HERE IS: THIS IS THE SAME MECHANISM THROUGH WHICH EXOGENOUSLY ADMINISTERED HEPARIN{ANTICOAGULANT} FUNCTIONS…SO IN OTHER WORDS HEPARIN INHIBITS FACTOR II,IXa AND Xa… Antithrombin is a glycoprotein produced by the liver. ANOTHER MECHANISM IS MEDIATED BY Thrombomodulin. Thrombomodulin is protein cofactor expressed on endothelial cell surfaces WHICH binds to thrombin, modifying the substrate specificity of thrombin, so that instead of cleaving fibrinogen, it instead cleaves and activates protein C, an anticoagulant..ACTIVATED PROTEIN C INTURN COMBINES WITH PROTEIN S AND INACTIVATES FACTOR Va AND VIIIa.. Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa (Xa). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex. PROTEIN C DEFICIENCY: Protein C is a 62-kD, vitamin K-dependent glycoprotein synthesized in the liver. It circulates in the blood as an inactive zymogen at a concentration of 4 μg/mL. Severe protein C deficiency (i.e. protein C activity <1 IU dL). Infants with severe genetic protein C deficiency usually present within hours of birth with rapidly progressive PURPURA FULMINANT and DIC… THIS PROCESS OF DISSOLUTION OF BLOOD CLOTS NECESSARY TO RESTORE NORMAL BLOOD FLOW IS KNOWN AS FIBRINOLYSIS Endothelial cells synthesize tissue-type plasminogen activator, a protease that cleaves plasminogen to plasmin; plasmin, in turn, cleaves fibrin to FIBRIN DEGRADATION PRODUCTS AND LEADS TO BREAKDOWN OF CLOTS… NORMAL VALUE OF FDP: 10 micrograms per milliliter (mcg/mL) INCREASED FDPS: DIC, THROMBOEMBOLIC STATES, TRANSFUSION REACTION An INTERESTING PHARAMACOLOGICAL ASPECT OF FIBRINOLYSIS PATHWAY IS: DRUGS THAT ARE USED TO ACTIVATE AND INHIBIT FIBRINOLYSIS ACTIVATORS LIKE STREPTOKINASE, UROKINASE & rtTPA ARE USED IN AMI, DVT, PULMONARY EMBOLISM, STROKE, PERIPHERAL ARTERIAL OCCLUSION TO RECANALISE OCCLUDED ARTERIES. STREPTOKINASE DOSAGE: Deep Vein Thrombosis250,000 IU/30 min.100,000 IU/hr for 72 hr INHIBITORS OF FIBRINOLYSIS LIKE EPSILON AMINO CAPROIC ACID, TRANEXEMIC ACID ARE USED IN OVERDOSE OF FIBRINOLYTICS AFTER CARDIOPULMONARY BYPASS SURGERY AFTER TOOTH EXTRACTION IN HEMOPHILIACS MENORRHAGIA TRANEXAMIC ACID: Systemically : 1 gram (30 mg/kg) orally four times a day starting 1 hour preoperatively EACA: Regimen of 50mg/kg body weight. 25% (250 mg/ml) oral rinse every 6 hours for 7-10 days.
- ENDOTHELIN IS FIRST SYNTHESIZED AS PREPROENDOTHELIN THAT IS CONVERTED TO PROENDOTHELIN BY ENDOPEPTIDASE. PROENDOTHELIN IS THEN SUBJECT TO HYDROLYSIS IN VASCULAR WALL BY ECE INTO ENDOTHELIN-1. ENDOTHELIN-1 THEN BINDS TO Gq-protein RECEPTOR ON VASCULAR SMOOTH MUSCLE CELLS WHICH ACTIVATE PHOSPHOLIPASE-C. THIS INTURN LEADS TO INCREASE IN INOSITOL PHOSPHATES(IP3) AND DIACYLGLYCEROL CAUSING INCREASED INTRACELLULAR CALCIUM IONS. THIS CAUSES VASOCONSTRICTION.
- The collagen binding assay [VWF:CB] measures the binding of VWF to collagen…The VWF:CB assay has been shown to be of value in the identification of VWD Type 1, Type 2A and Type 2B VWD…The reference range for the VWF:CB assay is in the range of 50-194 U/dL
- ONCE VWF ATTACHES TO COLLAGEN, THE CIRCULATING PLATELETS BINDS VWF THROUGH GpIb RECEPTORS. HERE VWF ACTS AS A BRIDGE BETWEEN SUBENDOTHELIAL COLLAGEN AND GpIb PLATELET RECEPTORS. THIS IS KNOWN AS ADHESION. Platelets also adhere directly to exposed collagen via GPIa and GPVI receptors…. A CLINICAL POINT TO BE REMEMBERED IS: THE DEFICIENCY OF VWF LEADS TO VWD WHICH IS THE MOST COMMON CONGENITAL CAUSE OF BLEEDING. THE DEFICIENCY OF THIS GPIB RECEPTORS CAUSES BERNARD SOULIER SYNDROME. UPON ATTACHMNT WITH VWF, SUBSEQUENTLY PLATELETS UNDERGO ACTIVATION THROUGH i} SHAPE CHANGE AND ii} BIOCHEMICAL CHANGE SHAPE CHANGE: THE DISCOID SHAPE OF PLATELETS CHANGE TO SPINY SPHERE WITH LONG PSEUDOPOD PROJECTIONS. THIS IS BROUGHT ABOUT BY CONTRACTION OF MICROTUBULES THEREBY CONCENTRATING ORGANELLES IN THE CENTRE OF CELLS & INCREASING SURFACE AREA
- NEXT HAPPENS BIOCHEMICAL REACTIONS.. THE ADHERANT PLATELETS ARE ACTIVATED BY BINDING OF ADP,COLLAGEN,THROMBIN AND EVEN ADRENALINE WHICH INITIATE AN INTRACELLULAR PHOSPHORYLATION CASCADE THAT LEADS TO DEGRANULATION, WHERE BOTH ALPHA GRANULES AND DENSE BODIES ARE RELEASED.THIS IS KNOWN AS RELEASE REACTION. THE ALPHA GRANULES EXPRESS ADHESION MOLECULE P-SELECTIN ON THEIR MEMBRANES AND CONTAIN FIBRINOGEN, FACTOR V & VIII,PDGF.. THIS P-SELCTIN MOLECULE ATTRACTS AND ADHERES LEUKOCYTES IN THE CLOT TO PREVENT INFECTION… DENSE BODIES/GAMMA GRANULES CONTAIN SEROTONIN, ADP AND ATP,IONIZED CALCIUM..{SAC} FINALLY THIS PLATELET ACTIVATION INCREASES SURFACE EXPRESSION OF PHOSPHOLIPID COMPLEXES WHICH PROVIDE A BINDING SITE FOR CALCIUM AND COAGULATION FACTORS IN INTRINSIC PATHWAY.. AS THE ADP IS RELEASED FROM DENSE BODIES IT BINDS TO ITS PLATELET RECPTOR { INHIBITED BY CLOPIDOGREL} INDUCES A CONFORMATIONAL CHANGE OF GPIIB-IIIa RECEPTORS{ INHIBITED BY ABCIXIMAB, TIROFIBAN} ALLOWING THEM TO BIND FIBRINOGEN{ PREVENTED BY EPTIFIBATIDE} WHICH INDUCES CROSS-LINKING OF PLATELETS….THIS IS KNOWN AS AGGREGATION…. DEFICIENCY OF GPIIB/IIIA LEADS TO GLANZMAN THROMBASTHENIA… THROMBOXANE A2 IS SYNTHESIZED BY PLATELET MEMBRANE VIA COX PATHWAY WHICH ALONG WITH FIBRINOGEN FORMS THE “PRIMARY HEMOSTATIC PLUG”{ ASPIRINIRREVERSIBLE COX INHIBITOR}
- THE PROCESS OF COAGULATION INVOLVES A CASCADE OF REACTIONS IN WHICH ACTIVATION OF ONE FACTOR LEADS TO ACTIVATION OF NEXT CLOTTING FACTORS..THIS ENZYME CASCADE REACTION I ALSO KNOWN AS “ WATERFALL SEQUENCE” This model proposed by Macfarlene (1964)… appeared in the journal Nature and was shortly followed by the waterfall model reported by Davie and Ratnoff (1964) in the journal Science. The “cascade” and “waterfall” models suggested that the clotting sequences were divided into 2 pathways. Coagulation could be initiated via an “intrinsic pathway,” so named because all the components were present in blood, or by an “extrinsic pathway,” in which the subendothelial cell membrane protein, tissue factor (TF), was required in addition to circulating components.
- CELL BASED MODEL: PROPOSED B HOFFMAN et al.in 2001 at the duke university, north carolina According to this model of coagulation we do not have two separate discrete pathways instead coagulation is brought about by three overlapping stages occurring on the surface of two different types of cells. Initiation Phase The basic initiator of coagulation is the tissue factor which are proteins present on the surface of cells outside the vascular system 4.eg: fibroblast or smooth muscle cells. These TF bearing cells binds with factor VII and activates it. This complex of TF and factor VII a activates factor X and factor IX. Factor Xa along with Va then activates factor II to thrombin. These thrombin sparks formed will then shift their activity to the surface of platelets….. AMPLIFICATION PHASE: The thrombin formed in the initiation phase activates platelets by binding with protease activated receptors (PAR) present on platelet cell surface. On activation of receptors it leads to activation of PLATELETS Thrombin cleaves the VIII and VWF complex. This VWF binds with GPIb on the platelet surface hence forming bridges between platelets and help in aggregation effect of platelets. Thrombin also activates XI to XI a and factor V to Va. Hence the platelets now form an active procoagulant surface with factors VIIIa, Va and XIa. Propagation Phase During this phase the IXa formed in the initial phase binds with VIIIa forming the tenase complex which inturn leads to formation of factor Xa. This Xa along with factor Va activates prothrombin to thrombin which in turn converts fibrinogen to fibrin…
- REFERENCES: 1. ROBBIN’S BASIC PATHOLOGY 9TH EDITION 2. ROBBIN’S PATHOLOGICAL BASIS OF DISEASE, 7TH EDITION 2. RUBIN’S PATHOLOGY, 6TH EDITION 3. PATHOLOGY ILLUSTRATED, MACFARLANE, 5TH EDITION 4. Textbook of Coronary Thrombosis and Thrombolysis, R. C. Becker 5. MEDICAL PHARMACOLOGY, KD TRIPATHI, 6TH EDITION 6. BRITISH JOURNAL OF PHARMACOLOGY, 88, 1986,AZUMA H ET AL…. 7. JOURNAL OF PROG. CARDIOVAS DIS, 30, 1987 8. Blood: Principles and Practice of Hematology, Volume 1