Blood Coagulation Lecture Notes (PDF)

Blood Coagulation John-Paul Westwood Consultant Haematologist, UCLH Introduction  Understanding Blood Coagulation is important as many disorders are associated with derangements of this system  These include both bleeding and thrombotic disorders  Need to under...

Blood Coagulation John-Paul Westwood Consultant Haematologist, UCLH Introduction  Understanding Blood Coagulation is important as many disorders are associated with derangements of this system  These include both bleeding and thrombotic disorders  Need to understand how the system works to target appropriate treatment:  in treating bleeding disorders  in the use of anticoagulants to treat and prevent thrombosis FHMP Overview ILO and CCs  ILO 4 : Describe the fundamental role homeostasis plays in maintaining normal physiology and awareness that loss of compensation leads to disease with the manifestation of clinical signs and symptoms.  CCs :  5: Haemophilia A and B  8: Other inherited bleeding disorders (e.g. Von Willebrand disease and Factor XI deficiency)  13: Venous thromboembolism - pulmonary embolism and deep vein thrombosis (DVT) FHMP Bleeding ILO  ILO 1: Describe key aspects of haemostasis including the role of the blood vessel, the vascular endothelium, platelets, fibrin clots and fibrinolysis. What is blood coagulation?  Blood coagulation is critical for control of bleeding (Haemostasis) but also has important role in immune defence  Complex network of components, including coagulation factors  Can become activated following injury blood vessel walls, but also in relation to infection/inflammation  Bleeding disorders are associated where there is a failure of Haemostasis  While appropriate activation is vital for Haemostasis, inappropriate or overactivation can lead to Thrombosis  How the coagulation system works  Function: control of bleeding and to allow vessel to be repaired  Primary haemostasis  Vasoconstriction and formation of platelet plug  Secondary haemostasis  coagulation factors are activated, and Thrombin generated  Thrombin then converts Fibrinogen to Fibrin  results in a soluble clot which is stabilised by Factor XIII  VESSEL INJURY Local vasoconstriction Platelet adhesion Activation of coagulation and aggregation Fibrin PLATELET PLUG formation Stabilised by FIBRIN PRIMARY haemost Fibrinolytic activity SECOND asis ARYhaem ostasis REPAIR OF VESSEL DAMAGE  Primary Haemostasis  Injured blood vessel  Exposure of collagen  Platelet adhesion via von Willebrand factor  Activation and degranulation of platelets  Aggregation of platelets Secondary Haemostasis Lynn & Sleby, 2013  EXTRINSIC INTRINSI PATHWAY C XII (PT) PATHWA XI VII Y (APTT) IX Ca, PL VIII X Xa FINAL V Ca, PL COMMO N PROTHROMBIN THROMBIN PATHW AY FIBRINOGEN FIBRIN XIII Ca CROSS-LINKED FIBRIN Control of the coagulation system  This is vital  This occurs through the function of natural anticoagulants (Antithrombin, protein C, protein S)  Process involves inhibition of thrombin formation and breakdown of fibrin clots (called fibrinolysis) Natural Anticoagulants Tissue Factor Pathway Inhibitor (TFPI) Antithrombin Activated Protein C, Protein S Adapted from Lynn & Sleby, 2013  EXTRINSIC FIBRINOLYSIS Fibrinolysis t-PA PAI-1 PLASMINOGEN PLASMIN FIBRIN FIBRIN DEGRADATION PRODUCTS (FDPs) Laboratory testing of coagulation system  In vitro approximation to what is going on in vivo  Screening tests are used to pick up major/moderate abnormalities in the coagulation system but may miss mild defects  Definitive tests can be carried out based on symptoms +/- positive screening tests Screening Tests  Full blood count (platelet count)  Coagulation Profile most common:  Prothrombin Time (PT)  Activated Partial Thromboplastin Time (APTT)  (Fibrinogen, Thrombin Time)  PFA-100 bleeding screen (defects of primary haemostasis) Definitive tests  Measurement of coagulation factors (antigenic levels/ activity)  Eg. Factor VIII level  Von Willebrand Screen (vWF antigen and activity, Factor VIII)  Platelet function testing Bleeding Disorders Bleeding disorders  Occur where there is a failure of haemostasis  This can be inherited or acquired  Acquired may relate to medication/ drug effect  Usually a result of either a deficiency and/or problem with function of one or more components in primary/secondary haemostasis  Bleeding disorders can be very variable in terms of symptoms Defects of primary haemostasis  Low platelets (known as thrombocytopenia)  Platelets that don’t function normally  Von Willebrand Disease Defects of primary haemostasis  Easy +/- spontaneous bruising  Petechiae/purpura  Epistaxes (nose bleeds)  Menorrhagia (heavy periods)  Prolonged bleeding following minor trauma  Operative bleeding  Intramuscular haematoma (rare)  Intracranial haemorrhage (rare)  Joint bleeds (very rare) Defects of primary haemostasis Petechiae Purpura Defects of secondary haemostasis  Problem with one or more coagulation factors  Inherited Haemophilia eg factor VIII or IX deficiency, but there are several others  Acquired Haemophilia (very rare)  Other acquired causes:  Liver disease  Drugs e.g. anticoagulants  Vitamin K deficiency  Consumption of coagulation factors or dilutional effect Defects of secondary haemostasis  Symptoms depend on how severe deficiency is, but can be variable  Can get spontaneous bleeding if deficiency is severe (eg severe haemophilia)  Sometimes milder symptoms, only occurring following trauma or surgery  Haemophilia A & B  Haemophilia A = Factor VIII deficiency  Haemophilia B = Factor IX deficiency  Sex linked - ie gene on X chromosome  Females carriers – usually asymptomatic  Males affected  33% arise by new mutation  Prevalence:  Haemophilia A: 1 in 5000 – 1 in 10,000  Haemophilia B: approx. 5 times less common Haemophilia A & B  Infants  post-circumcision bleeding  intramuscular haematoma  Toddlers children adults  recurrent spontaneous painful bleeds  large joints (haemarthroses)  Muscles  pseudotumours  prolonged life-threatening peri/post-operative bleeding Haemophilia A & B  Coagulation screen abnormal  APTT prolonged  PT and TT normal  Low plasma factor VIII or IX  Blood count normal  Prenatal testing possible  Excellent outcome/QoL with prophylaxis  INTRINSIC PATHWAY (APTT) EXTRINSIC PATHWAY XII (PT) XI VII IX Ca, PL VIII X Xa V Ca, PL FINAL PROTHROMBIN THROMBIN COMMO N FIBRINOGEN PATHWA FIBRIN Y XIII Ca CROSS-LINKED FIBRIN Treatment of bleeding disorders  Generally aimed at correcting defect  Eg Factor VIII for haemophilia A patients  Platelets for patients with platelet function defects  General measures:  Tranexamic acid – to inhibit fibrinolysis Venous Thromboembolism (VTE) Venous Thromboembolism (VTE: DVT & PE)  Annual Incidence ranges 75-269 cases per 100000  3rd most common cause of cardiovascular death worldwide (after CHD, ischaemic stroke) (ISTH 2014)  >500000 deaths in EU & >500000 deaths in US every year (ISTH 2014)  Incidence of VTE doubles with each decade after age 40  Patients 70 yrs or older have incidence up to 700 /100000 (Raskob et al, 2014)  VTE  DVT most common, typically in legs  PE fatal in approx 10% cases  VTE survivors have one year mortality rate of 10% (Naess et al 2007, Flinterman et al 2012)  Leading cause of disability-adjusted life years lost in hospitalised patients (ISTH 2014) What are the risk factors for VTE? Significantly Age ↓ mobility > 60 years Surgery Certain Obesity medical conditions Risk factors Abnormal Dehydration clotting conditions Active Pregnancy cancer History HRT or of VTE The‘pill’ Virchow’s triad (Wolberg et al, 2015) Deep venous thrombosis (DVT) Fatal pulmonary embolism (PE)  Pulmonary embolism (PE): mechanism  Clot forms in a deep vein (eg leg DVT)  If this clot becomes dislodged and passes through the circulation and reaches the lungs, this is called a PE  Can cause chest pain, shortness of breath and haemoptysis (coughing of blood) Venous thromboembolism: complications  Recurrent VTE  20% at 2 years  30% at 10 years  Post-thrombotic syndrome  20-50% Treatment of VTE  Anticoagulation  Heparin (low molecular weight heparin)  Direct Oral Anticoagulants (DOACs)  Warfarin  Thrombolysis  Useful for selected scenarios (eg life threatening PE) Prevention of VTE: Thromboprophylaxis Death Pulmonary hypertension Thromboprophylaxis Pulmonary embolism Post-thrombotic syndrome Symptomatic DVT Asymptomatic DVT Summary  Important to have an understanding of the Coagulation system  Bleeding disorders relate to acquired or inherited defects  Venous Thromboembolism (VTE) is major health problem Interactive Module with practice questions  https://moodle.ucl.ac.uk/mod/url/view.php?id=697 4974 Thank-you for your feedback!  https://uclms-asr.app/learningsurveys