System of haemostasis
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- Brian McLaughlin
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1 Disorders of haemostasis - I The new conception of coagulation Lectures from pathological physiology Oliver Racz System of haemostasis Maintains blood fluidity Local clot formation after vessel injury Maintains vessel wall integrity Cooperation of vessel wall cells, thrombocytes, other blood cells, coagulation/anticoagulation factors & the fibrinolytic system Nonhaemostatic functions of the system Inflammation, immunity, glucose and lipid metabolism, angiogenesis, etc 2 History Bleeding after circumcision Talmud Schmidt Morawetz 1905 I. Thromboplastin II. Thrombin III. Fibrinogen IV. Calcium 1937 Quick, laboratory methods DIC, Hardaway, McKay 1964 MacFarlane, Davie, Ratnoff - classic coagulation cascade 1974 The role of vitamin K XXI. century new conception, molecular basis of diseases 3 1
2 DISTURBED INTEGRITY OF VESSEL WALL VASOCONSTRICTION seconds PRIMARY HAEMOSTASIS 3 7 min. COAGULATION 5 10 min. FIBRINOLYSIS 2 3 days RESTORED INTEGRITY OF VESSEL WALL 4 Repetion of physiology Physiology of haemostasis (factors, thrombocytes, pathway of activation) Biochemical characterisation of coagulation factors and the role of vitamin K, anticoagulants The transformation of fibrinogen to fibrin, fibrinolysis and its regulation 5 I Fibrinogen fibrin II Prothrombin thrombin vit K III Tissue factor (thromboplastin) IV Ca 2+ V Proaccelerin accelerin VII Proconvertin convertin vit K VIII Antihaemophilic globulin IX Christmas factor vit K X Stuart factor vit K XI Plasma thromboplastin antecedent (PTA) XII Hageman factor (???) XIII Fibrin stabilising factor (FSF) Prekallikrein kallikrein von Willebrand factor High/low molecular weight kininogen (HMK, LMK) 6 2
3 Basic principle - proteolytic cascade 7 factors belong to group of serine proteases (inactive zymogens) Activation cascade - amplification and possibility of regulation Example: transformation of prothrombin to thrombin by activated factor X S S 7 Basic principle - proteolytic cascade Example: transformation of prothrombin to thrombin by activated factor X Xa S S 8 Basic principle - proteolytic cascade Example: transformation of prothrombin to thrombin by activated factor X Xa S S 9 3
4 The role of vitamin K Rats with vitamin K deficiency PIVKA = protein induced in vitamin K absence Similar to prothrombin - not active Vitamin K is the coenzyme of glutamate carboxylase, which converts glutamic acid γ-carboxyglutamic acid Two COO - s bind Ca 2+ In prothrobin there are 10 such places 10 O -NH-CH-C- CH 2 CH 2 COO - O -NH-CH-C- CH 2 CH- COO - COO - 11 Postsynthetic modification of coagulation factors Glutamic acids PIVKA S-S Enzyme with vit K S-S γ-carboxyglutamic acids 12 4
5 New conception Initiation minimal transformation of prothrombin to thrombin (no clot) Amplification Termination Doubts about the in vivo role of contact system (XII) 13 Initiation of coagulation TF VII X II Monocyte TF = FIII, (thromboplastin) CD142 A TRANSMEMBRANE RECPTOR 14 Amplification of coagulation I Activation of thrombocytes II VIII vwf V X XI flip-flop of IX thrombocyte phospholipids 15 5
6 Amplification of coagulation II Internal amplification loop II VIII vwf XI V X IX 16 Amplification of coagulation III Activation of IX/VIII, formation of tenase II vwf XI IX/VIII V X 17 Amplification of coagulation IV formation of prothrombinase vwf II XI IX/VIII X/V 18 6
7 Amplification & termination Activation of thrombocytes, flip-flop of phospholipids Activation of XI amplification loop Activation of IX and VIII TENASE Tenase activates X and V PROTHOROMBINASE production of huge amounts of thrombin Transformation of fibrinogen to fibrin CLOT Formation of crosslinks in fibrin network (XIII) STABLE CLOT 19 Revision of contact system John Hageman (deficiency of XII) died in 1968 on thrombembolic disease after a trauma He probably did not read the textbooks of physiology! According to current opinion the system has rather nonhaemostatic functions 20 Structure of fibrinogen 6 chains, 2* α, β, γ Proteolytic removal of peptides A,B Polymerisation 21 7
8 Polymerisation of fibrinogen 22 Stabilisation of fibrin and fibrinolysis 23 The anticoagulant system Serpins inhibitors of proteases Inhibitor of initiation - TFPI Antithrombin (III) Protein C together with S are the most important inhibitors of amplification proteolytic degradation of V and VIII 24 8
9 The fibrinolytic plasminogen system PLASMINOGEN 92 kda glykoprotein Two step activation to active form, PLASMIN by tissue PLASMINOGEN ACTIVATOR - tpa Plasmin degrades fibrin clot (and has a lot of nonhaemostatic functions) The process is inhibited by PAI 1, an antagonist of tpa Important the activities of tpa and PAI are oscillating in a broad range effects of stress, adrenaline, antidiuretic hormone, obesity (!) and gene polymorphism 25 FIBRIN CLOT FDP PLASMIN D-DIMERS PAI-1 - tpa + PLASMINOGEN 26 Disorders of haemostasis - II Principles of diagnostics Lectures from pathological physiology Oliver Racz
10 Diagnostics I Rumpel-Leede, test of capillary fragility Bleeding time (standardized methods!) normal: 4-6 min.; pathological: > 10 min. Whole blood coagulation time (Lee-White) normal: 4-8 min. Platelet count (automatic analyzers) norm: *10 9 /l 100*10 9 /l thrombocytopenia 50*10 9 /l risk of longer bleeding after an injury or surgery 40*10 9 /l spontaneous bleeding (or not) 10*10 9 /l danger of fatal bleeding (GIT, NS) 28 Diagnostics II principle of coagulation tests Step 1: Anticoagulated blood (Ca 2+ binding by citrate); Step 2: Removal of RBC, LE, TH (centrifugation) Step 3: Addition of surplus Ca 2+ & activators to plasma Step 4: Measurement of time until the first fibrin filaments are formed Expression of results A. In seconds (international standardized calibrators, QC) B. In relative units compared to norm (time patient/control) C. INR = International Normalized Ratio 29 Diagnostics III coagulation tests - examples Prothrombin time - Quick Oral anticoagulant therapy control (OAC) Plasma + Ca 2+ + tissue thromboplastin Norm: sec Necessary factors: VII, X, V, II APTT = activated partial thromboplastin time Plasma + Ca 2+ + caolin (negat. charge) + phospholipid Norm: sec. Necessary factors: XII, XI, IX, and VII, X, V, II 30 10
11 Prothrombin and APTT assay APTT Prothrombin (Quick) 31 Diagnostics IV - other assays Fibrinogen concentration (2-4 g/l) Fibrin & fibrinogen degradation products D-dimer, degradation product of fibrin clot by plasmin diagnostics of DIC exclusion of deep venous thrombosis and pulmonary embolism (limit 500 µg/l) Special assays aggregometry, adhaesion of thrombocytes Direct measurement of factors Assays of polymorphisms, mutations 32 Disorders of haemostasis - III The most important diseases Lectures from pathological physiology Oliver Racz
12 Syllabus 1. Classification 2. Symptomatology 3. Disorders of primary haemostasis - thrombocytopenia & thrombocytopathy 4. Coagulation disorders 5. Vascular purpuras 6. Disseminated intravascular coagulation - DIC 7. Thrombembolic conditions 34 Classification A. HAEMORRHAGIC DIATHESES A1. PLATELET DISORDERS A2. COAGULOPATHIES A3. DISORDERS OF THE VESSEL WALL (In each group inherited and acquired conditions) B. THROMBEMBOLIC CONDITIONS Congenital thrombophilia and others The association betweeen coagulation & atherosclerosis C. DISSEMINATED INTRAVASCULAR COAGULATION 35 Thrombocytopenia Three mechanisms: A. Insufficient production of megakaryocytes B. Increased destruction of thrombocytes C. Abnormal distribution of thrombocytes 36 12
13 Thrombocytopenia A. Insufficient production of megakaryocytes Bone marrow damage: drugs, toxins, radiation, infection, tumors, leukaemia, fibrosis Congenital insufficiency Cobalamin and folic acid deficiency 37 Thrombocytopenia B. Increased destruction Idiopathic thrombocytopenic purpura (ITP) - autoimmune disease Rh group incompatibility DIC Arteficial heart valves C. Distribution Splenomegalia and hypersplenism 38 Thrombocytopathy A. Congenital thrombastenia - m. Glanzman AR insufficient aggregation of platetelets B. Acquired Acetylsalicylic acid, phenylbutasone Uremia 39 13
14 Hereditary disorders of coagulation* Hemophilia A (1/10 000) Unexpected fluctuation of clinical symptomatology Long repeated bleedings Internal bleedings Intracranial bleeding (can be fatal) Chronic anaemia, icterus Severe damage of joints Hemophilia B (IX- XR) C (XI - AR), less severe *REPEAT GENETICS! 40 f. VIII concentration and symptoms 41 von Willebrand disease In the past considered as a moderate form of hemophilia Von Willebrand factor = big multimeric protein Synthesised in endothel and megakaryocytes Function contact of damaged endothel and platelets, mutual interaction of thromobocytes stabilisation of factor VIII. Concentration in people with blood group AB >
15 von Willebrand Deficiency is probably common (1-3 %) mostly asymptomatic Together with other factors can manifest (acetylsalicylic acid, OAC therapy) as mucosal bleeding, bleeding after tooth extraction, menorrhagia Type I, IIa, IIb, III 43 Acquired coagulation disorders Vitamin K deficiency Newborns, malabsorbtion, obstructve icterus, etc. Anticoagulant drugs Dicumarols (antivitamin K); Heparin (activator of antithrombin, inactivation of X, IX & XI) Streptokinase Liver disease 44 Vascular purpura Relatively common condition skin eruption in infectious diseases in children senile purpura scorbut, scurvy - deficiency of vitamin C Disorder of collagen synthesis (proline - hydroxyproline) and abnormal platelet function. Perifollicular skin, gingival, mucosa muscle, GIT bleeding, hematuria. Skin hyperkeratosis
16 Hereditary disordes of vessel wall Hereditary haemorrhagic teleangiectasy (m. Osler-Weber-Rendu), AD, Epistaxis, teleangiectasy Anaemia, DIC, liver cirrhosis Lack of elastic fibers in vessel wall Other hereditary collagen diseases Marfan - Lincoln, Ehlers-Danlos - Paganini 46 Disseminated intravascular coagulation, DIC Consumption coagulopathy Life threating disorder (Death Is Coming!) Generalised activation of haemostasis Thrombosis and bleeding at the same time, tissue hypoxia 47 DIC - causes Complications of gravidity. Amniotic fluid embolisation. Preeclampsia, eclampsia Sepsis & septic shock G- infections (endotoxin), meningococci, pneumococci, plasmodium malariae Sy Waterhouse-Friederichsen as a consequence of meningitis Neoplastic disease: Lung, gastric, breast, prostata Ca, leukaemia 48 16
17 DIC - causes Liver failure Haemolysis (incompatible transfusion) Trauma (haemorrhagic shock, burns) Rejection of transplanted organs Tropical snake toxins 49 Pathogenesis of DIC A. Generalised activation of coagulation B. Thrombosis Microthrombi in circulation; Deposits of microthrombi in tissues and their damage C. Decreased haemostasis Decrease of platelet number, factor concentration Activation of fibrinolysis D. Bleeding E. Disorder of nonhaemostatic functions of the system 50 GENERALISED ACTIVATION OF COAGULATION MICROTHROMBI EMBOLISATION DECREASE OF PLATELETS & COAGULATION FACTORS ACTIVATION OF FIBRINOLYSIS BLEEDING 51 17
18 GENERALISED ACTIVATION OF COAGULATION MICROTHROMBS EMBOLISATION DECREASE OF PLATELETS & COAGULATION FACTORS ACTIVATION OF FIBRINOLYSIS BLEEDING 52 Symptoms and forms tissue ischaemia, gangrena of fingers bleeding (after injections); kidney failure, anuria; haemorrhagic necrosis of adrenal cortex - sy Waterhouse-Friderichsen; haemolytic anaemia, haemoglobinuria; Beginning acute or subacute Stages: Compensated, decompensated and manifest 53 Case study 54 18
19 Thrombosis, thrombembolia, thrombophilia Factors endothel (aterosclerosis, inflammatio) thrombocytes coagulation pro & contra, fibrinolysis (tpa/pai!) circulation (stasis) Forms venous thrombosis arterial (MI) intracardial (mitral stenosis) diffuse (DIC) Occlusive nonocclusive clots Embolia lung, brain, paradox, microembolisation 55 Our case study As an editor of a medical journal I visited our publisher, a cca 50 y old lady. Complaining about respiratory condition, therapy resistant And also swelling of the legs Nothing serious? 56 Our case study Complaining about respiratory condition, therapy resistant And also swelling of the legs Nothing serious? Immediately sent to hospital: D-dimers extremely high X-ray repeated small embolisation 57 19
20 Trombophilia complex disease Immobilisation Stasis Varices Gravidity, hormonal anticonception Trauma, burns Malignant tumors ATHEROSCLEROSIS DEFICIENCY OF ANTICOAGULANT FACTORS ANTITHROMBIN, 1965 PROTEIN C, 1981 INCREASED ACTIVITY OF PROCOAGULANT FACTORS (VII) DECREASED FIBRINOLYSIS 58 APC resistance (Activated Protein C) Factor V Leiden (R506Q), 2 10 % europoid population 4 7fold increase risk of thrombosis in heterozygotes (SK 5 %), Geographic gradient form south to north Also other mutations - F V Cambridge, Hongkong Polymorphism of protein C gene and other genes of coagulation/fibrinolysis factors Functional APC resistance Increase of f VIII, decrease of protein S in gravidity, during hormonal anticonception, inflammation, obesity, malignant tumors 59 APC X/V Leiden 60 20
21 Trombophilia complex disease Immobilisation Stasis Varices Gravidity, hormonal anticonception Trauma, burns Malignant tumors ATHEROSCLEROSIS DEFICIENCY OF ANTICOAGULANT FACTORS ANTITHROMBIN, 1965 PROTEIN C, 1981 INCREASED ACTIVITY OF PROCOAGULANT FACTORS DECREASED FIBRINOLYSIS 61 Bleeding vs clotting! Haemophilia: 1 in (Sk 400) Other bleeding disorders (Th) not so rare or clinically silent (vwd) Thrombophilia 1 in 10 or even more in older, obese, sick people!!! In EU more than deaths, often nondiagnosed!!! 62 Bleeding vs clotting! Thrombophilia 1 in 10 or even more in older, obese, sick people!!! (ATRIAL FIBRILLATION, MALIGNANCIES, BURNS, DIABETES, INFECTIONS, POST SURGERY.. Both in DIC Both in MI secondary prevention anticoagulant treatment WALKING THE TIGHTROPE 63 21
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