Hematology Physiology: Hemostasis & Coagulation Cascade PDF

Last edited: 10/24/2021 1. HEMOSTASIS: COAGULATION CASCADE Hemostasis: Coagulation Cascade Medical Editor: Mariel Antoinette L. Perez OUTLINE I) INTRODUCTION II) FIVE STEPS OF HEMOSTASIS III) APPENDIX I...

Last edited: 10/24/2021 1. HEMOSTASIS: COAGULATION CASCADE Hemostasis: Coagulation Cascade Medical Editor: Mariel Antoinette L. Perez OUTLINE I) INTRODUCTION II) FIVE STEPS OF HEMOSTASIS III) APPENDIX IV) REVIEW QUESTIONS V) REFRENCES I) INTRODUCTION (1) HEMOSTASIS Word Etiology o “hemo” – blood; “stasis” – stop Localized blood stopper Usually occurs when there’s damage to blood vessels o E.g., ruptured, lacerated, leaking out A sequence of five steps (2) NATURAL ANTI-COAGULATION OF BLOOD Before studying the process of hemostasis, it’s important to understand what keeps the blood naturally thin o Prevents blood from becoming thrombotic, coagulating on its own, and forming a clot There are three general layers to take note of: o Endothelial cells  secrete chemicals Nitric Oxide (NO) Prostacyclin (PGI2) o Subendothelial cells  underneath the endothelial layer  made up of connective tissue, specifically collagen  collagen-rich layer o Smooth muscle cells with specific types of receptors  nociceptors = pain receptors Figure 1 Natural Nanti coagualtion mechanisms (1) Platelet Inactivation II) FIVE STEPS OF HEMOSTASIS There are two things in the blood: plasma and cells o Cells (or formed elements) such as White Blood Cells (WBCs), Red Blood Cells (RBCs), and platelets o Platelets  Microscopic (tiny), cytoplasmic fragments  Derived from megakaryocytes  Naturally inhibited by NO and PGI2 keeps platelet inactive to prevent it from binding onto the surface of the endothelial cell (2) Heparin Sulfate Glycosaminoglycan present on the membrane Natural anti-coagulant Binds and activates protein Anti-Thrombin III (ATIII) o Degrades and inactivates clotting factors II, IX, X  Clotting factors are naturally just circulating in the bloodstream (3) Thrombomodulin Binds with protein called Thrombin (Factor II/ FII) o Activates Protein C  Degrades and inactivates factors V and VIII HEMOSTASIS: COAGULATION CASCADE HEMATOLOGY: Note #7. 1 of 6  (1) VASCULAR SPASM (2) PLATELET PLUG FORMATION (1) Trigger With the endothelial cells damaged, o There will be a decreased release of NO and PGI2 injured blood vessel  endothelial damage  Platelets will not be inactivated o May also cause damage to the underlying tissue  Allow platelets to attach to endothelium o Blood may leak out and decrease blood volume o Damaged heparin sulfate will not be able to keep (2) Purpose clotting factors inactivated o Damaged thrombomodulin will not be able to activate Prevent blood loss from occurring by contracting or protein C  cannot keep FV and FVIII inactivated constricting blood vessels (1) Platelet Activation (3) Mechanism Platelets are activated when GP1b binds with vWF (i) Endothelin o GP1b (glycoprotein-1b)  Secreted by injured endothelial cells  Platelet receptor that specifically binds to vWF  binds on to receptor on smooth muscle o von Willebrand Factor (vWF)  activates intracellular PIP2-Calcium mechanism  secreted by injured endothelial cells  smooth muscle contracts  triggers vessel (2) Platelet chemical release vasoconstriction  decreases blood vessel diameter  prevents blood loss Once activated, will release the following o Adenosine Diphosphate (ADP) (ii) Myogenic Mechanism o Thromboxane A2 (TXA2) o Serotonin (5-hydroxytryptamine or 5-HT)  Direct contact or injury to smooth muscle causes smooth muscle contraction (3) Platelet Aggregation (iii) Nociceptor Activation Platelets have receptors on their membrane that specifically bind with ADP and TXA2  Inflammatory chemicals are released when there’s ADP & TXA2 stimulates platelets to come and aggregate inflammation at area of injured vessel E.g., histamine, leukotrienes, prostaglandins, Platelets bind with other platelets via their GP2b/3a, with  These chemicals stimulate the nociceptors fibrinogen bridging them together  Nociceptors (pain receptors) will initiate pain  Pain reflex induces vasoconstriction (4) Vascular Spasm Effect Enhancement TXA2 and serotonin bind to the smooth muscle o Cause contraction o Triggers ↑vasoconstriction of injured blood vessels o Enhances the vascular spasm effect (5) Clinical Significance Aspirin: TXA2 release Clopidogrel, Prasugrel, Ticagrelor: ADP release Abciximab: inhibits GP2b/3a inhibitors Von Willebrand Disease: VWF production Figure 2 Vascular Spasm Figure 3 Platelet plug formation 2 of 6 HEMATOLOGY: Note #7 HEMOSTASIS: COAGULATION CASCADE  (3) COAGULATION CASCADE o Activates XIII  XIIIa  Requires Ca2+ Intrinsic pathway o Independent of the extrinsic pathway Factor XIIIa  For example, someone’s blood in a test tube is not o Also known as Fibrin Stabilizing Factor heparinized (no heparin coating) o Crosslinks fibrin stands together Glass has rough, charged surface  hence, Crosslinked fibrin XIIa from the intrinsic pathway gets activated o Creates a fibrin mesh  This shows that the intrinsic pathway can occur in  Mesh will hold down the platelet plug in place a test tube independent of the extrinsic pathway.  Mesh prevents platelets from dislodging and going o Takes 4-6 minutes to different areas to cause an embolism Extrinsic pathway o Thickens the blood passing through the area to slow o Dependent on some of the factors and proteins within down the blood flow and prevent blood loss the intrinsic pathway (3) Extrinsic Pathway o Takes 30 seconds Note: An “a” after the roman numeral indicates an Blood vessel injury triggers release of Tissue factor activated factor. (Factor III) Factor III activates Factor VII  VIIa (1) Intrinsic Pathway o requires Ca2+ and PF4 Liver constantly creates clotting proteins that are normally VIIa can activate IX  IXa inactivated while circulating in the blood VIIa can converge into or stimulate the common pathway Activated platelets express phosphatidyl serine groups on o Requires Ca2+ and PF4 their membrane, causing a negative charge Negative charge will interact with and activate Factor XII Note: Tip for Remembering the Coagulation Cascade (Hageman Factor) o XII  XIIa X marks the spot in the middle = Factor X Left (intrinsic pathway) count downwards XIIa activates XI  FXIa o 12  8 (skip 10) XIa activates IX  IXa Right (extrinsic pathway) IXa forms a complex with VIIIa o 3 + 7 = 10 o Complexation requires PF3 and Ca2+ Common Pathway VIIIa-IXa activates X  Xa o 5 x 2 x 1 = 10 (2) Common Pathway (4) Clinical Significance X  Xa is the start of the common pathway Hemophilia A→↓in factor VIII Xa, Va, and Ca2+ will activate prothrombin activator Hemophilia B→↓in factor IX o converts prothrombin (II) to thrombin (IIa) Hemophilia C→↓in factor XI Thrombin reacts in two ways: Heparin, Factor X inhibitors (Rivaroxaban)→↓factor X o Links together Fibrinogen (I) into Fibrin (Ia)  Fibrinogen is soluble Heparin, Factor II Inhibitors (Dabigatran)→↓thrombin or  Fibrin is insoluble in the plasma also known as Factor II Helps turn liquid blood into a jelly-like Warfarin→↓ formation of Thrombin, Factor VII, Factor IX, substance to slows down blood flow in the Factor X area and prevent loss of RBCs HEMOSTASIS: COAGULATION CASCADE HEMATOLOGY: Note #7. 3 of 6  (5) FIBRINOLYSIS (4) CLOT RETRACTION & REPAIR (1) Breaking Down Fibrin Mesh (1) Platelet Contraction There’s a need to get rid of the clot Platelet contraction is stimulated once the platelet plug is o The clot may be big enough that it could occlude anchored to injured vessel wall by fibrin mesh blood flow and possibly cause ischemia Platelets contains contractile proteins o Actin and myosin7 Endothelium expresses protein Tissue Plasminogen Activator (TPA) When platelets contract, they pull the damaged edges of TPA converts Plasminogen into Plasmin the injured blood vessel close to each other o Plasminogen is naturally occurring in the bloodstream This squeezes some serum out of the injured vessel (2) Platelet-Derived Growth Factor (PDGF) Secretion Plasmin breaks down Fibrin mesh into Fibrinogen and If smooth muscle cells are damaged, PDGF triggers Fibrin degradation products like D-Dimer mitosis or proliferation of smooth muscle cells o This process recanalizes the clotted vessel Damage to connective tissue, PDGF forms connective (2) Clinical Significance tissue patches to regenerate collagen fibers TPA Drugs (3) Vascular Endothelial Growth Factor (VEGF) o ↑Plasminogen to Plasmin Secretion  Increased rate of blood clot breakdown Regenerates the new endothelial lining o Given to patient who have stroke or some type of The blood vessel then starts to go through healing & ischemic attack within hours remodeling Elevated D-Dimers can be indicative of blood clots and inflammation o Specific blood tests can be done to determine if patient has had some type of clot formation Antifibrinolytics (TXA)→↓Plasminogen to plasmin→↓break down of blood clot and stabilizes clot Figure 4 Clot Retraction Figure 5 Fibrinolysis 4 of 6 HEMATOLOGY: Note #7 HEMOSTASIS: COAGULATION CASCADE  III) APPENDIX Figure 6. Summary of Hemostasis Figure 7. Coagulation Cascade HEMOSTASIS: COAGULATION CASCADE HEMATOLOGY: Note #7. 5 of 6  IV) REVIEW QUESTIONS 1) Which is not a natural way of the body to prevent blood from becoming thrombotic? a) Heparin Sulfate b) Nitric Oxide c) Thromboxane d) Prostacyclin 2) Which of the following is more stable? a) Fibrinogen b) Fibrin c) They are equally stable 3) What is the third step of hemostasis? a) Platelet Plug Formation b) Coagulation Cascade c) Vascular Spasm d) Fibrinolysis CHECK YOUR ANSWERS V) REFRENCES Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017 Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ: Pearson; 2020. Boron WF, Boulpaep EL. Medical Physiology.; 2017. Urry LA, Cain ML, Wasserman SA, Minorsky PV, Orr RB, Campbell NA. Campbell Biology. New York, NY: Pearson; 2020. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine. New York etc.: McGraw-Hill Education; 2018. Sabatine MS. Pocket Medicine: the Massachusetts General Hospital Handbook of Internal Medicine. Philadelphia: Wolters Kluwer; 2020 6 of 6 HEMATOLOGY: Note #7 HEMOSTASIS: COAGULATION CASCADE