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M E D I C I N E M A S T E R C L A S S P R E C L I N I C A L S E R I E S HAEMOSTASIS & COAGULATION CASCADE A P A R N A B I J U CONTENT TO BE COVERED ✓ Basics of haematopoiesis ✓ What are clotting factors? ✓ Stages of haemostasis ✓ Interpreting PT and APTT ✓ Anticoagulants, antiplatelets and fibrinolytics ✓ Bleeding disordersSBA 1 Platelets play an important role in haemostasis. From which of the following precursors do thrombocytes develop from? A. Erythroblasts B. Lymphoid progenitor C. Myeloblast D. Megakaryocyte E. ReticulocyteSBA 1 – ANSWER Platelets play an important role in haemostasis. From which of the following precursors do thrombocytes develop from? D. Megakaryocyte Platelets / thrombocytes are formed when they break off into little fragments from megakaryocytes. HAEMATOPOIESIS • Platelets are derived from cellular fragments of megakaryocytes – part of the myeloid lineage • Thrombopoietin controls proliferation and maturation of megakaryocytes • Formed in bone marrow Source: PulsenotesSBA 2 A 35-year-old female patient with cystic fibrosis has had a week-long history of bloating, abdominal discomfort and greasy stools. She is now presenting with bruising on her arms, after sustaining a minor injury. Poor function of which of the following factors is the cause of this presentation of bruising? A. Factor I B. Factor IV C. Factor VI D. Factor IX E. vWFSBA 2 – ANSWER A 35-year-old female patient with cystic fibrosis has had a week-long history of bloating, abdominal discomfort and greasy stools. She is now presenting with bruising on her arms, after sustaining a minor injury. Poor function of which of the following factors is the cause of this presentation of bruising? D. Factor IX Factors II,VII, IX and X are vitamin K dependent factors.Vitamin K is a fat-soluble vitamin and therefore requires good fat absorption. Patients with cystic fibrosis have poor exocrine function of the pancreas, which leads to reduced lipase and decreased fat absorption. If vitamin K absorption is affected, then there will be poor function of the vitamin K dependent factors. CLOTTING FACTORS • Produced in liver • Require activation to exert their functions • Vitamin K dependent factors are II,VII, IX and X • Remember 1972! • Factor II is also known as prothrombin COMMON / TERMINAL PATHWAY • Prothrombin → thrombin • Fibrinogen (factor I) is converted into fibrin – these fibrin molecules become long fibrin strands, which are cross-linked with the help of fibrin stabilising factor (factor XIII) Stages of haemostasis Vessel spasm Platelet plug formation H A E M O S TA S I S Coagulation cascade stoppage of blood flowss and Clot retraction Clot dissolution HAEMOSTASIS PRIMARY HAEMOSTASIS 1. VESSEL SPASM / CONSTRICTION 2. PLATELEG PLUG • Endothelial injury causes smooth • Platelets bind to exposed sub-endothelial collagen via von muscle contraction Willebrand factor (vWF) at site of injury • Releases ADP, platelet-activating factor and TXA2 – causes further • Vessels release thromboxane A2 platelet aggregation and vasoconstriction (TXA2) – causes vasoconstriction • Formation of primary haemostatic platelet plug vWF binds to GpIb receptors on platelets About vWF: • Produced by megakaryocytes and endothelial cells • Carrier protein for coagulation factor VIII • Helps link subendothelial layer to platelets ADP activates GpIIb/IIIa receptors on platelets – allows platelet aggregation, via fibrinogen molecules Source: Guyton and Hall Textbook of Medical PhysiologySBA 3 Platelets release many important chemical mediators when they are activated, such as ADP and TXA2. Certain antiplatelet medications function by inhibiting receptors on platelets, which these chemicals normally bind to. Which of the following receptors is inhibited by prasugrel and ticagrelor? A. Gp1b B. Gp2b/3a C. P2Y12 D. COX E. Gp6SBA 3 – ANSWER Platelets release many important chemical mediators when they are activated, such as ADP and TXA2. Certain antiplatelet medications function by inhibiting receptors on platelets, which these chemicals normally bind to. Which of the following receptors is inhibited by prasugrel and ticagrelor? C. P2Y12 Clopidogrel, prasugrel and ticagrelor all work by binding to and inhibiting P2Y12 inhibitors on platelets,which normally binds ADP (causes platelet activation and aggregation). Source: Nature Reviews Cardiology HAEMOSTASIS SECONDARY HAEMOSTASIS Source: Guyton and Hall Textbook of Medical Physiology 3. COAGULATION CASCADE • Activation of clotting factors • Formation of fibrin strands, which cross-link to form a fibrin clot • Two pathways of activation – extrinsic and intrinsic Intrinsic pathway – end letter is the starting letter for the next clotting factor! Twelve → Eleven → Nine → Eight → Ten Extrinsic pathway – factor VII and tissue factor Ca2+ (factor VI) is important in many stages too! (Why is citrate added to blood EXTRINSIC products?!) PATHWAY INTRINSIC PATHWAY MEASURES OF HAEMOSTASIS PRIMARY HAEMOSTASIS → bleeding time, platelet count SECONDARY HAEMOSTASIS → PT, APTT FIBRINOLYSIS → D-dimer / FDP Von Willebrand disease affects Reference ranges both primary AND secondary Bleeding time: 3-7 minutes haemostasis! Platelet count: 150-400 x10 /L PT: 10 – 14 seconds WHY?! APTT: 22 – 36 seconds Fibrinogen: 1.9 – 8.0 g/L D-dimer for DVT / PE: <500ng/mL is cut-off for exclusion PT & APTT PT = prothrombin time. Measures extrinsic pathway (factors VII, X,V, II and fibrinogen / I). • INR = international normalised ratio (a standardised version of PT) APTT = activated partial thromboplastin time. Measures intrinsic pathway (factors XII,XI, IX,VIII, X,V, II and fibrinogen). • PT = play tennis (play tennis outside, therefore EXTRINSIC) • PTT = play table tennis (play table tennis inside, therefore INTRINSIC)SBA 4 Anticoagulants are used in the treatment of many conditions such as myocardial infarction and stroke. What is the mechanism of action of unfractionated heparin? A. Inhibits vitamin K epoxide reductase enzyme B. Direct factor Xa inhibitor C. Inhibits cyclo-oxygenase enzyme D. Direct factor IIa inhibitor E. Enhances ability of antithrombin IIISBA 4 – ANSWER Anticoagulants are used in the treatment of many conditions such as myocardial infarction and stroke. What is the mechanism of action of unfractionated heparin? E. Enhances ability of antithrombin III Unfractionated heparin works by potentiating effects of antithrombin III (natural anticoagulant found in the body). HAEMOSTASIS 3. COAGULATION CASCADE CONTINUED • Clotting cascade is restricted to site of injury via 4. CLOT RETRACTION action of natural anticoagulants (proteins C and • Platelets contract, via action of actin and myosin filaments S, antithrombin III) • Edges pulled together • Inhibits certain factors of clotting cascade, prevents clot from getting too big C L I N I C A L P O I N T S 5. CLOT DISSOLUTION • Process called fibrinolysis ANTIPLATELETS FIBRINOLYTIC • Plasminogen (trapped in clot • Aspirin → COX inhibitor Alteplase → tissue during clot formation), is • Clopidogrel, ticagrelor, prasugrel → plasminogen P2Y12 inhibitors activator converted to plasmin, by tPA • Tirofiban, abciximab → GpIIb/IIIa inhibitors • Plasmin breaks down fibrin strands and clotting factors ANTICOAGULANTS • Warfarin → vitamin K epoxide reductase inhibitor, affects vitamin K dependent factors (1972) • Heparin → activates antithrombin III • DOAC → rivaroxaban (direct X inhibitor), dabigatran (direct II inhibitor)MOA OF ANTIPLATELETS Source: Nature Reviews Cardiology VIRCHOW ’S TRIAD • Long-haul flight • Immobility • Varicose veins VENOUS STASIS HYPERCOAGULABLE ENDOTHELIAL STATE INJURY • Pregnancy • Diabetes mellitus • Cancer • Smoking • Autoimmune • Trauma conditions e.g. SLE BLEEDING DISORDERSSBA 5 A 14-year-old boy presents to the GP with bleeding into his knee joint, after falling over whilst playing with his friends. His mother states she is a carrier of an inherited bleeding disorder. Which of the following coagulation factors is deficient in this boy? A. Factor VII B. Factor VIII C. Factor X D. Factor XIII E. ProthrombinSBA 5 – ANSWER A 14-year-old boy presents to the GP with bleeding into his knee joint, after falling over whilst playing with his friends. His mother states she is a carrier of an inherited bleeding disorder. Which of the following coagulation factors is deficient in this boy? B. Factor VIII This boy has an inherited bleeding disorder, likely haemophilia A. He therefore has a deficiency in factor VIII.SBA 6 A 14-year-old girl presents to the GP with excessive bleeding after minor trauma, and also reports very heavy periods. Her mother also had the same issues. Which of the following results will be found on her coagulation screen? A. Decreased bleeding time B. Increased APTT C. Decreased APTT D. Increased PT E. Decreased PTSBA 6 – ANSWER A 14-year-old girl presents to the GP with excessive bleeding after minor trauma, and also reports very heavy periods. Her mother also had the same issues. Which of the following results will be found on her coagulation screen? B. Increased APTT This patient likely has von Willebrand disease.This is inherited in an autosomal dominant manner, and patients will have increased bleeding time and APTT on coagulation studies. HAEMOPHILIA X-linked recessive disorders Predisposition for bleeding Signs and symptoms: • Frequent spontaneous bleeds • Haemarthroses (bleeding into joints) – may Source: BMJ Best Practice lead to joint deformity • Easy bruising • Menorrhagia Haemophilia B Haemophilia A • Deficiency in factor IX • Deficiency in factor VIII • Aka Christmas Disease • Blood results: • Blood results: • Prolonged APTT • Prolonged APTT • Decreased factor VIII • Decreased factor IX • Normal PT, bleeding time, and • Normal PT, bleeding time, and vWF levels vWF levels VON WILLEBRAND DISEASE (VWD) • Most common inherited coagulopathy – autosomal dominant • Deficiency in vWF – impaired platelet aggregation • Also leads to factor VIII deficiency! Blood results: • Increased bleeding time • Prolonged APTT • Normal PT Signs and symptoms: • Mucocutaneous bleeding • Bleeding after minor trauma / surgery • Nose bleeds • Menorrhagia • Easy bruisingREFERENCES • Pulsenotes - https://app.pulsenotes.com/medicine/haematology/notes/haematopoiesis • Guyton and Hall Textbook of Medical Physiology – John Hall, 2021 • Essentials of Pathophysiology, Carol Mattson Porth, 2015 • Nature Reviews Cardiology • Image of haemarthrosis - https://bestpractice.bmj.com/topics/en-gb/468