Hemostasis Lecture Notes PDF

PHYSIO-LEC: LE 2 | TRANS 2 Hemostasis MARIE FRANZE C. PAMATPAT, M.D. | 09/16/2024 I. Hemostasis OUTLINE C. Intrinsic Pathway 📖 Pr...

PHYSIO-LEC: LE 2 | TRANS 2 Hemostasis MARIE FRANZE C. PAMATPAT, M.D. | 09/16/2024 I. Hemostasis OUTLINE C. Intrinsic Pathway 📖 Prevention hemorrhage I. HEMOSTASIS of blood loss[Guyton] or prevention of [Boron and Boulpaep] A. Vascular D. Common Pathway Constriction E. Fibrinolysis Mechanism of hemostasis II. Formation of Platelet V. Role of Anticoagulants → Vascular connection (vascular spasm) Plug A. Clinical Examples → Formation of platelet plug A. Summary and Disorders → Formation of blood clot B. Role of Platelets VI. Blood Coagulation → Growth of fibrous tissue III. Formation of Blood Tests Clot VII. Summary IV. Coagulation Cascade VIII. Review Questions A. Clotting Factors IX. References B. Extrinsic Pathway SUMMARY OF ABBREVIATIONS ADP Adenosine diphosphate ATP Adenosine triphosphate GP Glycoprotein vWF von Willebrand Factor ❗️ Must know 📣 Lecturer 📖 Book 📋 Previous Trans LEARNING OBJECTIVES ✔ Describe hemostasis and the mechanisms involved. ✔ Compare and contrast extrinsic and intrinsic coagulation pathways. ✔ Explain how the extrinsic and intrinsic pathways lead to the common pathway. ✔ Discuss the coagulation factors involved in each pathway. ✔ Describe the role of anticoagulants in maintaining blood flow. ✔ Discuss the disorders affecting hemostasis. ✔ Describe the different blood coagulation tests. Figure 1. The General Steps of Clotting [Lecturer’s PPT] LE 2 TRANS 2 TG-11&12: R. Cadag, E. Cagurangan, A. Cai, E. Cajucom, R. TE: E. Cagurangan AVPAA: J. Belandres Page 1 of 7 Caliao, V. Caliwag, A. Camacho, A.F. Camacho, L. Camposano, V. Candelaria V. Candelaria, N. Canilang, K. Canlas, J. Capillo, S. Capio, M. Capistrano, A. Cardenas  Table 1. Mechanism of Hemostasis Platelets do not usually adhere to other platelets, blood Mechanism of Hemostasis cells, or endothelial membrane due to the negative charge A blood vessel is severed. Blood and blood on the surface of both platelets and endothelial cells Injury components (ie., erythrocytes, white blood → For endothelial cells: negative charge reflects presence cells, etc.) are leaking out of the breaks of proteoglycans, specifically Heparan sulfate The smooth muscle in the vessel wall Occurs in response to: Vascular → Vessel injury or humeral signs contracts near the injury point, reducing spasm → Increase in shear force at the surface of platelets or blood loss Platelets are activated by chemicals endothelial cells released from the injury site and by contact GPIa/IIa and GPVI adhere first to the endothelial wall, but with underlying collagen. The platelets it is not enough to secure the platelet; hence, the presence Platelet of GPIb-IX-V, which attaches to vWf → more stable become spiked and stick to each other and plug platelet plug the wound site. formation von Willebrand Factor (vWf) 📣 Once activated, releases Thromboxane A2 that acts as vasoconstrictor → Found in Weibel-Palade bodies of endothelial cells and alpha granules of platelets In coagulation, fibrinogen is converted to → Naturally present in blood plasma fibrin, which forms a mesh that traps more → Release is triggered by: Coagulation ▪ High shear force platelets and erythrocytes, producing a clot. ▪ Certain cytokines ▪ Hypoxia 📖 A. VASCULAR CONSTRICTION Trauma to the vessel wall causes smooth muscle in the wall to contract; this instantaneously reduces the flow of → Binds to platelet receptor known as GPlb/la (dimer of GPlb linked to GP la) ▪ GPIb is a component of GPIb-IX-V blood from the ruptured vessel. → Breach of endothelium exposes platelet receptors to Process: Blood vessel trauma → contraction of smooth ligands that are components of subendothelial matrix muscle → reduced blood flow → Ligands include collagen, which binds to GPla/lla, and Contraction of smooth muscle results from: fibronectin and laminin, both of which bind to GPIc/lla ▪ 📣 → Local myogenic spasm Primary contributor → Blood components release local autacoid factors from 📋 ACTIVATION Binding of ligand triggers conformational change in the traumatized tissues and platelets platelet receptors that initiates an intracellular signaling ▪ e.g. thromboxane A2 (vasoconstrictor) cascade, which leads to an exocytotic event known as the → Nervous reflexes will act on the blood vessels to release reaction or platelet activation constrict Signal transduction cascade involves: → Activation of Phospholipase C II. FORMATION OF PLATELET PLUG → Influx of Ca2+ A. SUMMARY OF PLATELET PLUG FORMATION Events that occur when platelets are activated: → Activated platelets exocytose the contents of their Table 2. Summary Of Platelet Plug Formation dense storage granules and alpha granules Stage Summary ▪ Dense granules Mediated by integrins platelet − ADP, ATP, serotonin, and Ca2+ ADHESION receptor ▪ Alpha granules vWF binding to GP Ib/Ia receptor − Host growth factors − Hemostatic factors: vWf, clotting factor V and Binding causes conformational fibrinogen change → Formation of thromboxane A2 by activated platelets Activation of Phospholipase C, using cyclooxygenase to initiate the breakdown of ACTIVATION Calcium influx arachidonic acid to thromboxane A2 Exocytosis of granular contents → Platelet forms pseudopods – marked cytoskeletal and Breakdown of Arachidonic acid to morphological changes as the platelet extends first a Thromboxane A2 broad lamellipodium and then into many finger-like ADP, Serotonin, Thromboxane A2 – → 💬 filopodia Granular content from the dense storage granules and alpha granules contain factors needed for All activate more platelets AGGREGATION vWF binds to GP Ib/Ia to activate homeostasis such as ATP, ADP, vWF, clotting factor V, more platelets and form bridges fibrinogen. Once these factors are released it will cause GP IIb/IIIa bind with Fibrinogen more activation of platelets in such a way that platelet aggregation will start to the platelets that adhere to themselves 📋 ADHESION 📋 Platelets adhere to endothelium due to the presence of AGGREGATION platelet receptors, which are glycoproteins in the Signaling molecules released by activated platelets platelet membrane amplify the platelet activation response Platelet receptors are integral membrane proteins ADP (which binds to P2Y12 receptors on platelets), belonging to a class of matrix receptors known as serotonin, and thromboxane A2 promote platelet integrins aggregation Fibrinogen and vWF will form bridges between platelets PHYSIOLOGY Hemostasis Page 2 of 7  → Possible due to presence of glycoproteins in the membrane of platelets → vWF released by activated platelets binds to platelet receptor GPIb/Ia, thereby activating even more platelets and forming molecular bridges between platelets → Platelet activation also induces a conformational change in GPIIb/IIIa, another platelet receptor, endowing it with the capacity to bind fibrinogen → As a result of this conformational change, the fibrinogen that is always present in blood forms bridges between platelets and thus participates in the formation of a platelet plug → Fibrinogen that is cleaved by thrombin plays a critical Figure 3. Structure of Platelet [Lecturer’s PPT] role in clotting ▪ Later on (in secondary hemostasis), thrombin converts the fibrinogen to fibrin, stabilizing the 💬 They contain remnants of the endoplasmic reticulum 💬 Inside the tubules, they have growth factors platelet plug and mitochondria for the production of ATP and ADP Antiplatelet agents: → Aspirin – Reduces release of thromboxane A2 III. FORMATION OF BLOOD CLOT → Clopidogrel – Inhibit P2Y12 receptors Blood clot – Semisolid mass composed of both platelets and fibrin 📖 B. ROLE OF PLATELETS Platelets (also called thrombocytes) are minute discs 1 to 4 micrometers in diameter. Severe trauma – Clot develops in 15 to 20 seconds Minor trauma – Clot develops in 1 to 2 minutes Formed in the bone marrow from megakaryocytes Clot retraction with serum expression occurs within 20 to 60 minutes → 📣 Normal value: 150,000 to 300,000 per microliter (μl) Normal ranges may still vary according to laboratory reference, literature (i.e., certain references state that → Process: Fibrin stabilizing factor activates platelet thrombosthenin, actin and myosin → compress fibrin the upper limit is 450,000), and/or individual’s age group meshwork into a smaller mass (e.g., if patient is adult or newborn) → Platelets are necessary for clot retraction Anucleated and cannot reproduce IV. COAGULATION CASCADE Cytoplasm contains contractile proteins, fibrin stabilizing Three essential steps in clotting: → 💬 factor, thromboxane A2 They contain remnants of the endoplasmic reticulum 1. Rupture or damage of vessel formation of Prothrombin Activator → → 💬 and mitochondria for the production of ATP and ADP 💬 Inside the tubules, they have growth factors All of these are important for the hemostatic function 2. Conversion of Prothrombin to Thrombin 3. Conversion of Fibrinogen to Fibrin of the platelets 📋 📣 A. CLOTTING FACTORS Almost all clotting factors are formed by the liver → 📣 Glycoproteins on cell membrane surface Presence prevents platelets from adhering to endothelium under normal physiological conditions Vitamin K is an essential cofactor of gamma-glutamyl carboxylase (Factors II, VII, IX,X, and Protein C) → Glycoproteins sticks to the injured vessels to start Table 3. Clotting factors and their Synonyms → 📣 hemostasis process injury It causes platelets to become adhesive to site of Clotting factor Fibrinogen Factor I Synonym(s) Half-life in the blood: 8 to 12 days Prothrombin Factor II Thrombocytopenia vs. Thrombocytosis Tissue Factor Factor III; Tissue Thromboplastin → Thrombocytopenia Calcium Factor IV ▪ Low blood platelet count Proaccelerin; labile factor; Factor V ▪ Ex. dengue Ac-globulin (Ac-G) → Thrombocytosis Serum prothrombin conversion ▪ Elevated blood platelet count Factor VII accelerator (SPCA); proconvertin; ▪ 📣 ▪ Higher risk for clotting If thrombocytosis is super high, in some cases it can cause bleeding because there are no more stable factor Antihemophilic factor (AHF); Factor VIII antihemophilic globulin (AHG); clotting factors. Most of the platelets are consumed antihemophilic factor A for the clotting process and there are none left for Plasma thromboplastin their normal function. Factor IX component (PTC); Christmas factor; antihemophilic factor B Factor X Stuart factor; Stuart-Prower factor Plasma thromboplastin Factor XI antecedent (PTA); antihemophilic factor C Factor XII Hageman Factor Factor XIII Fibrin-stabilizing factor Prekallikrein Fletcher factor PHYSIOLOGY Hemostasis Page 3 of 7  Fitzgerald factor; High-molecular-weight high-molecular-weight kininogen kininogen (HMWK) ❗️ Platelets Factor X or Stuart factor is the most important factor for targeted therapy 📋 ❗️ B. EXTRINSIC PATHWAY Also called as Tissue activation/activator pathway 📋 Factors involved: III, VII, X The extrinsic pathway is said to be the quicker responding and more direct pathway for coagulation as compared to the intrinsic pathway Cascade of protease reactions initiated by factors that are 📋 outside the vascular system. Tissue factor activation: Nonvascular cells constitutively express an integral membrane protein called tissue factor (factor III or tissue thromboplastin), which serves as a factor VII (a plasma protein) receptor Figure 5. Extrinsic pathway for initiating blood clotting [Guyton & Hall] Figure 4. Extrinsic Pathway [Lecturer’s PPT] STEPS IN THE EXTRINSIC PATHWAY 1. Injury to endothelium allows factor VII to come into contact with tissue factor – Tissue factor non-proteolytically → 💬 Traumatized vascular wall with blood It should begin with a traumatized vascular wall coming into contact with blood so there will be release activates factor VII to factor VIIa 2. Tissue factor, factor VIIa and Ca2+ form a tissue of Tissue Factor III (or Tissue Thromboplastin), which factor/trimolecular complex (analogous to tenase) acts as a proteolytic enzyme. 3. Trimolecular complex proteolytically cleaves the Tissue factor + FVII + Ca2+ proenzyme factor X to factor Xa. → Once the tissue factor complexes are mixed with FVII → This leads factor VIIa to undergo a conformational and calcium ions, FX will be converted into its activated change that prevents it from dissociating from the tissue factor → ❗️ form, FXa. NOTE: If a factor is activated, there will be a lowercase letter ‘a’ added after the Roman Numeral → Factor Xa proceeds along the common pathway C. INTRINSIC PATHWAY Form (e.g. Factor X to Factor Xa) The intrinsic pathway is longer and more intricate Factor Xa + Phospholipid + Factor V compared to the extrinsic pathway. ▪ 💬 → Form Prothrombin activator The activated Factor Xa also makes a complex with tissue Phospholipids along with Factor V (which It involves a cascade of protease reactions initiated by circulating blood components. Triggered by contact with negatively charged surfaces is still inactivated at this point). This complex will now (e.g., nucleic acids, phospholipids). be responsible for the formation of the prothrombin Initiates within the blood itself, independent of surrounding ▪ 💬 activator. Initially, Factor V is inactivated, but once the clotting begins and thrombin begins to form through tissues. Involves clotting factors: XII, XI, VIII, Prekallikrein, HMW kininogen, Ca²⁺, phosphatidylserine the prothrombin activator, the proteolytic action of IXa-VIIIa-Ca²⁺-Phospholipid complex → activates factor X. ▪ 💬 thrombin will activate Factor V. Once Factor Va is activated, it actually helps Surface contact activation occurs upon exposure to collagen, glass, or other negatively charged surfaces (e.g., 📣 accelerate the protease activity of thrombin membrane of activated platelets). (somewhat exhibiting positive feedback so that more Once Factor XII comes into contact with collagen or ❗️ thrombin will be formed). Once the prothrombin activator is formed, it will any other negatively charged surface, it will have a new molecular configuration, resulting in its activation. → 💬 proceed to the common pathway. The role of prothrombin activator is to convert prothrombin into thrombin → It triggers the platelets, causing it to release tissue thromboplastin. STEPS IN THE INTRINSIC PATHWAY 1. After coming into contact with a negatively charged surface (e.g., glass or platelet membrane), Factor XII (Hageman factor) is converted into XIIa. 2. XIIa then forms a complex with HMWK (high molecular weight kininogen). → HMWK acts as a cofactor, helping anchor Factor XII to the surface, but the conversion happens at a limited pace. PHYSIOLOGY Hemostasis Page 4 of 7  3. Once a small amount of XIIa accumulates, it transforms → With the help of calcium ions there will be a prekallikrein into kallikrein (which acts as a protease). polymerization of fibrin monomer molecules with each 4. Kallikrein enhances the conversion of Factor XII into XIIa other → fibrin fibers (not yet stable) through positive feedback. → Activated fibrin stabilizing factor 5. Factor XIIa, along with HMWK, cleaves Factor XI into ▪ Form covalent bonds between fibrin monomers to Factor XIa. form a mesh called stable fibrin 6. Factor XIa, combined with Ca²⁺, activates Factor IX ▪ Located inside the cytoplasm of the platelets (Christmas factor) into Factor IXa. Factor IXa, along with Remember that when there is a clot there are entrapped Factor Xa and thrombin, cleaves Factor VIII into VIIIa. platelets, so with the help of thrombin, fibrin stabilizing 7. Factor IXa and Factor VIIIa, together with Ca²⁺ (primarily factor will be released and also activate it to act upon on from activated platelets) and negatively charged the fibrin fibers so that it will help in the cross covalent phospholipids, create the tenase complex. linking between the fibrin polymers to make the fibrin 8. The tenase complex (Factor IXa + VIIIa + Ca²⁺) converts Factor X into Factor Xa. Just like in the extrinsic pathway, Factor Xa, along with 📣 stable. Thrombin acts at different steps in the coagulation process, and its action can cause positive feedback, Ca²⁺, helps form the prothrombin activator, marking the which continues and progresses the coagulation cascade point where the intrinsic and extrinsic pathways merge into the common pathway. Figure 7. Prothrombin Activator [Lecturer’s PPT] Figure 6. Intrinsic pathway for blood clotting [Lecturer’s PPT] 📋 Common Pathway: Intrinsic and extrinsic pathways converge to form the common pathway. Main purpose is 📋 D. COMMON PATHWAY Components: Factors I, II, V, X, XII forming the prothrombin activator. In activation, prothrombin will be converted to thrombin, and thrombin 📋 Convergence of extrinsic and intrinsic pathways First protease: Factor Xa from either of the two pathways will be responsible for the conversion of fibrinogen into fibrin polymer/strands E. FIBRINOLYSIS 📋 STEPS IN THE COMMON PATHWAY As the vessels heal, we have to restore the normal blood 1. Factors Xa and Va with Ca2+ and phospholipids form flow, for that to happen, the clot must be removed. prothrombinase complex When clot is formed, a large amount of plasminogen is → Factor Xa from either intrinsic or extrinsic pathway trapped along with other plasma proteins → Thrombin converts factor V to VII Gradual degradation of the clot is called fibrinolysis 📋→ Factor V is highly homologous to factor VIII Begins with conversion of plasminogen to plasmin 2. Prothrombinase converts prothrombin to thrombin → Catalyzed by tissue plasminogen activator or urokinase-type plasminogen activator 📖 In response to rupture of the vessel , a complex PROTHROMBIN ACTIVATOR → The injured tissues and the vascular endothelium slowly releases the tissue plasminogen activator cascade of chemical reactions occurs in the blood → Once the clot is fully formed and ready to be degraded, involving more than a dozen blood coagulation factors. tissue plasminogen activator will now act on the The net result is formation of a complex of activated plasminogen to convert it into plasm 📋 substances collectively called prothrombin activator Converts prothrombin to thrombin Prothrombin → Fibrin ▪ Accelerates the conversion of plasminogen to plasmin → Plasma protein formed by the liver Plasmin Thrombin → Protease that can break down both fibrin and fibrinogen → The thrombin acts as an enzyme to convert fibrinogen ▪ Digests fibrin fibers, fibrinogen, Factor V, Factor VIII, into fibrin fibers that enmesh platelets, blood cells, and prothrombin and Factor XII → 📋 plasma to form the clot Removes low molecular weight peptides from fibrinogen → form one molecule of fibrin monomer ▪ Stops the coagulation cascade to proceed because the clot is now ready to be degraded PHYSIOLOGY Hemostasis Page 5 of 7  📣 V. ROLE OF ANTICOAGULANTS → One of the most prevalent causes: failure of the liver to After the damaged vascular walls heal, our body needs secrete bile into the GI tract to ensure that the clot-free condition of the blood is → Affects all 3 pathways (Extrinsic, Intrinsic, & Common) restored. For this to happen, anticoagulants play an Hemophilia 📣 important role. Anticoagulant – any substance that opposes (or limits) → 📋 → Almost exclusively in males Hemophilia A is caused by Factor VIII 📣 coagulation to restore the clot-free condition of the blood (Antihemophilic Factor) deficiency The most important factors for clot prevention are: ▪ aka “Classic Hemophilia” → Smoothness of the endothelial cell surface. When there is damage to the surface, platelets will be → 📋 ▪ 85% of cases Hemophilia B is caused by Factor IX (Christmas Factor) deficiency attracted and adhere to it. Hence, the coagulation cascade will proceed again. To prevent this, there should be the presence of glycocalyx because it helps → 📋 ▪ aka “Christmas Disease” Hemophilia C is caused by Factor XI (Plasma Thromboplastin Antecedent) deficiency to prevent platelet adhesion. → Presence of thrombomodulin and thrombin ▪ aka ‘Rosenthal Syndrome” complex. This complex activates protein C that will act → Bleeding usually does not occur except after trauma as an anticoagulant. Thrombocytopenia → Very low platelet count Table 4. Examples of anticoagulants in our body ▪ Normal Value = 150,000 - 450,000 /μL of blood Anticoagulants Function → Small punctate hemorrhages Promotes vasodilation → → Can be idiopathic Prostacyclin smoother flow of blood which DISORDERS OF COAGULATION FAILURE inhibits platelet activation and Thrombus clotting → Aggregates of platelets, erythrocytes trapped within a Nitric oxide Inhibits platelet adhesion and mass of fibrin strands aggregation Thrombocytosis Tissue factor pathway Blocks protease activity for → Excessive number of platelet 📋 inhibitor (TFPI) Factor VIIa → Higher risk for excessive thrombosis Antithrombin III (ATIII) Binds to and inhibits Factor Xa → Normal platelet count: 150,000–450,000/μL of blood and thrombin Thrombosis Forms a complex with thrombin → Increases the risk for excessive clot formation Thrombomodulin to remove thrombin from the circulation coagulation and inhibit → 📣 → Clot formation that may decrease/block blood flow If thrombus is large (high in diameter), it may get stuck in the blood vessel resulting in blockage of blood Protein S acts as a cofactor in flow Protein C and Protein the function of Protein C that Embolus S will inactive clotting factors → A portion of a thrombus that breaks free from the vessel involved in the intrinsic pathway wall and enters the circulation Protein C complex Inactivate Factors Va and VIIIa Binds with antithrombin III to → 📣 → Can block vessels to a major organ If carried through the bloodstream, may block blood flow to other blood vessels remove thrombin Removes activated factor IX-XII → Ex. Pulmonary embolism – blood going to the lungs Heparin short acting anticoagulant- lasts blocked by embolus about 1 ½ to 4 hours only ▪ Treatment: heparin Used for bypass surgery and DISSEMINATED INTRAVASCULAR COAGULATION ❗️ pulmonary embolism Remember: Once thrombin is inhibited, most of the steps in the coagulation cascade that leads to the Large amounts of traumatized tissue → release of large amounts of tissue factor in the blood Numerous small clots seen formation of a stable fibrin fiber will be inhibited as well. Usually in patients with widespread septicemia A. CLINICAL EXAMPLES AND DISORDERS Plugging of small peripheral vessels diminishes delivery of DISORDERS OF CLOTTING Vitamin K Deficiency 📋 oxygen Ex: DIC – occasionally patients begin to bleed, many of the clotting factors are removed because of the continuous → Can cause bleeding tendencies clotting cascade and only little amount of procoagulants → Essential factor to a liver carboxylase stayed in the body to allow the normal hemostasis of the (Gamma-Glutamyl Carboxylase) needed by factors - II, blood so there will be bleeding tendencies → 📋 VII, IX, X, and Protein C Impedes the synthesis of Factors II, VII, IX, X → Occurs more frequently in newborns VI. BLOOD COAGULATION TESTS Bleeding time → 📣 ▪ Vitamin K is administered to prevent bleeding Rarely happens in adults because normally the → 📣 → Normal: 1 to 6 minutes Evaluate platelet function → Depends on the depth of the wound and the degree of microbiota of the gut produce Vitamin K ▪ Eating green leafy vegetables is a dietary source of hyperemia 📣 vitamin K → Especially prolonged by lack of platelets → For an adult to have vitamin K deficiency, it may be Clotting time due to a gastrointestinal or a liver problem → Normal: 6 to 10 minutes PHYSIOLOGY Hemostasis Page 6 of 7  → 📣 No longer used because the time varies widely depending on the method used for measuring clotting 3. The vitamin essential for blood clotting is: a. Vitamin A → 📋 Tests for blood coagulation as a whole. It is used to time that is why it is not used anymore b. Vitamin D c. Vitamin E test the total function of the coagulation cascade of a d. Vitamin K person and it measures the time it takes for fibrin 4. Which factor is responsible for converting fibrinogen strands to form from the initial injury to fibrin? Prothrombin time (PT) a. Factor IXa → PT – indication of the concentration of prothrombin in b. Factor Xa the blood; time required for coagulation to take place c. Thrombin → Shortness of time – determined mainly by prothrombin d. TF/ Factor VIIa complex concentration 5. Which of the following is involved in the dissolution → Normal: 12 seconds of a clot? INR (International Normalized Ratio) a. Plasmin → Used to standardize the measurements of prothrombin b. Fibrinogen time c. Thrombin 📣 → Normal: 0.9 to 1.3 d. Plasminogen 📣📣 → High INR value: High risk of bleeding → Low INR value: Higher chance of having a clot ANSWER KEY Coagulation tests are important for patients come in 1. B. Refer to Table #1 with unexplained bleeding to assess the risk of bleeding 2. A. Thrombocytosis – excessive number of platelet of patients with history of prolonged bleeding (i.e., tooth due to excessive production extraction) and an upcoming major surgery Leukopenia – decrease in the number of white blood cells VII. SUMMARY Anemia – decrease in RBCs Hemostasis pertains to a complex physiological Hemophilia – clotting factors deficiency mechanism that prevents bleeding from a blood vessel. 3. D. Vitamin K serves the factor of liver carboxylase Hemostasis is divided into two parts: that is needed by certain clotting factors. → Primary hemostasis, wherein vascular constriction and 4. C. Thrombin converts fibrinogen to fibrin. platelet plug formation occurs, and; 5. A. Plasmin breaks down fibrin and fibrinogen to → Secondary hemostasis, where coagulation cascade stop the coagulation cascade. occurs. Extrinsic pathway is initiated by tissue injury which results IX. REFERENCES in the release of tissue factor (factor III). This then leads to Pamatmat, Marie Franze C., MD. (2024). Hemostasis. activation of factor VII along with Ca2+ to form a [Asynchronous Lecture Recording]. trimolecular complex, followed by the activation of factor X. Hall, J. E., & Guyton, A. C. (2020). Guyton and Hall Intrinsic pathway is initiated by contact to negatively Textbook of Medical Physiology 14th Edition. Elsevier. charged phospholipids. HMWK activates factor XII leading Boron, W.F. and Boulpaep, E.L. 2nd ed. (2012). Medical to the activation of factor XI. Factor XIa will then activate Physiology. A Cellular and Molecular Approach. factor IX. Factor IX together with factor VIII and Ca2+ will 2027 Trans generate intrinsic tenase. It will activate factor X resulting Synchronous lecture in the activation of the common pathway. Common pathway: Factor Xa combines with factor Va and Ca2+ to form the prothrombinase complex. It will convert prothrombin to thrombin which will convert fibrinogen into fibrin monomers. Factor XIII will then stabilize the fibrin strands. Control of Coagulation: → Tissue factor pathway: inhibit coagulation cascade → Protein C pathway: procoagulant → anticoagulant. → Inhibitors of thrombin: ▪ Antithrombin ▪ Heparin ▪ Warfarin VIII. REVIEW QUESTIONS 1. After a vessel injury, which of the following are the 3 steps of hemostasis? a. Vascular spasm, platelet aggregation, blood clotting b. Vascular spasm, platelet plug formation, blood clotting c. Vascular spasm, platelet adhesion, blood clotting d. Vascular spasm, platelet activation, blood clotting 2. Which of the following conditions would produce a higher risk of blood clots? a. Thrombocytosis b. Leukopenia c. Anemia d. Hemophilia PHYSIOLOGY Hemostasis Page 7 of 7