Primary and secondary hemostasis Primary (platelet aggregation and activation) - Formation of platelet plug - Vasoconstriction molecules are released - It is important to stop bleeding from capillaries, arterioles and venules • Secondary (coagulation) - Series of reactions of coagulation factors ending by fibrin formation - Crucial for large vessels and to prevent protracted bleeding - Primary and secondary hemostasis can be studied as separate processes in vitro - They are interconnected Platelet function during hemostasis • Adhesion to damaged vessel wall • Storing and releasing ADP, eicosanoids and proteins • Aggregation with other platelets • Surface for coagulation reactions Primary hemostasis - trombocyte adhesion The injury of vessel wall leads into the exposure of collagen Collagen binds von Willebrand factor (vWF) After binding collagen, vWF changes conformation and is able to bind platelet receptor glycoprotein lb (GP lb) on WHIe brand factor Coliagen binding site Thrombocyte activation - post receptor cascade • Most often phospholipase C (PLC) activation -> cleaves PIP2 into IP3 and DAG • Ca2+ release from endoplasmic reticulum • Some receptors (P2X) are linked with Ca2+ membrane channels • ^Ca2+in the cytoplasm • Ca2+ comes from both endoplasmic reticulum and extracellular fluid Thrombwian Inhibition of thrombocyte activation • Induced by l^cAMP or l^cGMP • They activate specific protein kinases(PKA and PKG) • PKA induces Ca2+ transport from cytoplasm into microsomes and extracellular space • PKA and PKG also inhibit Ca2+ release from endoplasmic reticulum (IP3-mediated) • cAMP and cGMP are formd using cyclases and degraded using phosphodiesterases Activators and inhibitors of adenylyl cyclase Activators (i.e. anti-aggregation) - prostaglandin D2 - prostacyclin (PGI2) - adenosine • Inhibitors (i.e. pro-aggregation) - prostaglandin E2 - catecholamines (via a2 receptors) - ADP Activated thrombocyte Increase of intracytoplasmic Ca2+ leads into platelet shape change and degranulation. ADP, thrombin and other vasoconstrictor molecules are released from the granules Via COX activation (both isoforms), TXA2 is synthetized (platelet activator and strong vasoconstrictor) Ca2+ also induces the change of glycoprotein llb/llla conformation into activated state (Gp llb/llla is the most abundant receptor on platelet surface) Activated thrombocyte also expose negatively charged phosphatidylserine, which supports coagulation cascade BREAK IN BLOODVESSEL coagulation rxns «>"«gon^ thrombin — fibrinogen fibrin TXA2 f ADP ADP TXA2 **" A thrombin glycoprotein llb/llla VWF growth factors etc Non-specific: bleeding time (in vivo) Platelet count in |il of blood Light transmission aggregometry (LTA) vs. impedance Either the maximum aggregation rate or its integral p 1 minute is measured number = Is aggregation) after adding an agent - Arachidonic acid - ADP - Thrombin receptor agonist - Gplb agonist - collagen Clot retraction Activated platelets steadily pull back their extremities (filopodia) Through this active process, they pull the fibrin fibres (created by secondary hemostasis from fibrinogen), which are attached to filopodia through Gp llb/llla Fibrin also binds other cells (e.g. fibroblasts) and the retraction thus enables the gluing and repair of the vessel wall Retraction facilitates the fibrinolysis using own plasmin and tPA (see further), but it limits the access of exogenously administered fibrinolytics Platelet+Fibrin 0 Platelet 240 s 700 s Filopodia Fiber kink r % www.rpthjournal.org/article/S2475-0379(22)02274-9/fulltext Coagulation retraction test • The amount of serum released from a given volume of full blood is measured following clot formation and subsequent retraction (usually over 120 min) • The test is used to assess the primary hemostasis (retraction depends mainly on the platelet function), but is further influenced by: • retraction: trombocytosis, 1^ fibrinogen, 4^ hematocrit, ^ fibrinolysis (loss of rigidity) • 4/ retraction: trombocytopenia, 4^ fibrinogen, 4^ hematocrit, secondary hemostasis disorders • No retraction: trombasthenia (Gp llb/llla disorder), fibrinogen deficiency Choose a substance with probable anti-aggregation effect i i i i A. Arachidonic acid B. Guanylyl cyclase inhibitor C. Cyclooxygenase activator D. Phosphodiesterase inhibitor E. Fibrinogen B Coagulation Can be basically started by two mechanisms: 1) Tissue factor („extrinsic pathway") 2) Contact with negatively charged surface ^intrinsic pathway") Extriniic Pathway Intrinsic Pathway The fork Blood Clot The two pathways are well defined in vitro, but not in vivo (they are useful for diagnosis but do not correspond with physiology) Reactants and catalyzers of coagulation reactions Most coagulation reactions have following components 1) Activated enzyme - serine protease (lla, Vila, IXa, Xa, Xla, protein C, plasmin, tPA) 2) Cofactor - puts together the enzyme and the substrate (TF, Va, Villa, protein S, TM, fibrin) 3) Ca2+ 4) Negatively charged surface (fastens the reaction by increasing reactant concentration) 5) Substrate (other factor) Exception: thrombin - does not need a cofactor for most reactions Coagulation cascade in vitro Contact activation (intrinsic) pathway Damaged surface 1 XII Tissue factor (extrinsic) pathway TFPI Tissue factor <-Trauma I........................Antithrombin X Prothrombin (ID , Va •►Thrombin (Ha) Common pathway Fibrinogen (I) Fibrin (la) Active Protein C A Protein 5 XlIIa XIII Protein C + thrombomodulin Cross-linked fibrin clot Coagulation factors are usually serine proteases or their co-factors But: contact system is not necessary for the coagulation (but coagulation factors of intrinsic pathway starting by XI are) Factor XII has ambivalent function -it also promotes fibrinolysis through plasmin activation Contact system (HMWK, factor XII) also participates in the inflammatory response Current model in vivo (cascade initiation) TF + Vila I IXa + Villa Antithrombin Tissue factor -pathway inhibitor (TFPI) H Xa + Va h Protein system I II —IIa (Thrombin) Fibrinogen 1' Fibrin initiation of coagulation and platelet activation platelet aggregation Activation of neighbouring platelets, thrombin formation „tenase complex" „prothrombinase complex" propagation of cogulation Tissue factor (TF, factor III) • Membrane protein occuring in all cell types excluding the endothelium and circulating blood cells • In normal conditions the TF does not come into a contact with coagulation cascade • After endothelial damage (trauma, bacterial toxins...) TF reacts with factor VII and coagulation cascade is started • To start the reaction, a small amount of activated factor Vila is necessary (present in the circulation), which, when bound in a complex with TF, catalyses an activation of more VII-TF complexes • Thromboplastin = TF + phospholipids; partial thromboplastin = phospholipids only K-dependent factors and Ca2+ binding Factors II, VII, IX, X and protein C possess gama-karboxyglutamic acid (Gla) domains at their N-terminus Gla is formed from glutamate using vitamin K as the oxidative agent Gla domains act as chelates and bind Ca2+ They bind the negatively charged phospholipid membranes and change the protein conformation f\f\J\- CO prolHrombin -ooc COO-Prolbrombrri Factor VIII and vWF vWF is responsible for platelet adhesion It also serves as a plasmatic carrier of factor VIII, that is otherwise quickly degraded ADAMT513 platelet^ mm subendoihcliUiTT ADAMTS 13 - protease cleaving vWF multimers Thrombin functions P ROCQ AG U LA NT ACTIONS FIBRINOGEN — FIBRIN FXIU — FXIIIa FV -» FVa FVIII FVIIIa FX1 -f FXIa TAFI TAFIa ANTICOAGULANT ACTIONS PC APC ATI II —► TAT HCII TF EXPOSURE ON Legend: TAFI - thrombin activatable fibrinolysis inhibitor TM - thrombomodulin PC - protein C APC - activated PC ATIII - antithrombin III TAT - complex thrombin-ATIII HCII - heparin cofactor II MONONUCLEAR CELL ^COLLAGEN ■^JCLOT ACTIVATED PLATELETS THROMBOMODULIN Thrombin activates factors XI, VIII and V (Coagulation is thus maintained even when there is no more TF - propagation phase) Coagulation inhibition 1) TFPI produced by endothelium forms a complex with factor Xa that is inhibited the complex reacts with a complex TF-Vlla, which stops the formation of factors IXa and Xa through this pathway (feedback loop via factor XI continues) 2) Protein C with a cofactor protein S it binds to factors Va and Villa that are cleaved and deactivated protein C is activated by thrombin and thrombomodulin (TM, produced by endothelium protein S is either free or bound to the transporter protein C4B ratio between the free and bound protein S (normally approx. 40%) is a sensitive regulator of coagulation 3) Antithrombin III inactivates all serine proteases of coagulation cascade its effect is much strengthened by polysaccharides heparan and heparin (endogenous or exogenous) heparin and related molecules are inhibited by platelet factor 4 (PF4) released from activated thrombocytes Fibrinolysis Enabled by plasmin - serine protease - in the circulation, plasmin is present as inactive plasminogen - when converted into plasmin, it cleaves fibrin into fibrin degradation products (FDP) - out of FDP, D-dimers are important as the markers of fibrinolysis Plasminogen is activated by tissue plasminogen activator (tPA) -secreted by the endothelium, or by urokinase (UK, uPA) - secreted by the epithelium Plasmin is present in the blood clot bound to fibrin (fibrin also acts as a cofactor for tPA) Plasmin molecule Inhibition of fibrinolysis Plasminogen activator inhibitor 1 (PAI-1) - inhibits tPA a2-antiplasmin - cleaves and deactivates free plasmin - But not the plasmin bound to fibrin Fibrinolysis is ensured by plasmin that is bound in blood clot and tPA from nearby endothelial cells In a case of plasmin or tPA leak into the circulation they are readily inactivated by PAI-1 and a2-antiplasmin - Fibrinolysis stays restricted to the blood clot Tests of coagulation cascade • PT - prothrombin time [s]* - TF (factor III) and Ca are added into decalcified blood plasm - PT measures the function of extrinsic pathway (it is often used for the monitoring of warfarin effect) - it is also known as Quick's test • aPTT - activated partial thromboplastin time [s] - by adding Ca, kaolin (clay) and cephalin (phospholipid), factor XII is activated - aPTT measures the function of intrinsic pathway (it is often used for the monitoring of heparin effect) • TT - thrombin time [s] - by adding thrombin and Ca, fibrinogen is activated - measure the conversion of fibrinogen into fibrin *PT is often expressed as international normalized ratio (INR), dimensionless quantity Extrinsic VIII APTT r Final i Common *C Pathway V X II Fibrinogen i Fibrin clot v. Choose the right statement about thrombin... A. Activates platelets using P2Y12 receptors B. Cleaves fibrin after binding thrombomodulin C. Helps fibrinolysis by indirect mechanisms D. Conversion of prothrombin into thrombin is fastened by heparin E. Activates factors V, VIII, XI a XIII 1 1 1 1 I! Practical anesthesia ✓ 1) preparation of v. jugularis - application of 2ml of hypotonic solution 2) laparotomy - v. cava caud. ligation 3) thoracotomy - puncture of heart chambers - collection of blood 4) excision of ligated segment 1) Weight of thrombus 2) aPTT + heparin 4U/kg 1) preparation of v. jugularis - application of 2ml of hypotonic solution 2) laparotomy - v. cava caud. ligation 3) thoracotomy - puncture of heart chambers - collection of blood 4) excision of ligated segment Disorders of hemostasis • Bleeding diatheses - Disorders of primary hemostasis - Disorders of secondary hemostasis (coagulopathies) - Combined disorders • Hypercoagulation (thrombophilia) • Combined hypo- and hypercoagulation (TTP, DIC) Disorders of primary hemostasis Problems of either vessel wall (vasculopathies) or platelets (thrombocytopathies/thrombocytopenias) Clinically, they usually manifest by petechiae Prolonged bleeding time (but this is nonspecific) Often epistaxis, hematuria, menorrhagia, gingival bleeding or bleeding into GIT Vasculopathies - examples inborn • telengiectasia hereditaria (m. Rendu-Osler) - AD, attenuation of vessel wall segments -» teleangiectasias (skin, mucosa, lungs, urogenital tract) • Ehlers-Danlos and Marfan syndrome - defect of connective tissue (colagen), • m. Kasabach-Merrit ( - Vascular malformations with blood i stasis —► DIC acquired • purpura senilis (fragile vessels) • bacterial toxins (scarlet fever) • lack of vit. C (scorbut) • imunocomplexes (Henoch-Schonlein purpura) Thrombocytopenia Normal concentration of the platelets is approx. 150 000-450 000/u.l The thrombocytopenia is clinically manifest when the number of platelets is < 50 000/lil Below 20 000/u.l spontaneus bleeding may occur Causes: 1) Impaired production (aplasia, myelodysplasia -> myelofibrosis) 2) Increased consumption (TTP/HUS, DIC) 3) Destruction by the immune system (ITP, systemic autoimmune diseases, drug-induced thrombocytopenia) 4) Impaired distribution (hypersplenism) 1.50- 1.00 - 2 0.50 b 0.25 - 10 20 30 doba krvácení (min) Thrombocytopathies Inborn: adhesion and aggregation disorders: • Bernard-Soulier syndrome (loss of function of GP lb receptor) • Glanzmann thrombastenia (loss of function of GP llb-llla receptor) Degranulation disorders • Hermansky-Pudläk syndrome • Chediak-Higashi syndrome Acquired: paraproteinemia (Ig inhibit fibrinogen binding to the thrombocytes) renal failure (guaidin succinate and phenol accumulation) dysfunction in myeloproliferative syndromes drug-induced thrombocytopathy (often this is actually the goal of the treatment) von Willebrand disease • Either lack or dysfunction of plasmatic vWF • Both primary and secondary hemostasis is affected • Several types: - Type 1 - low circulating vWF - Type 2 - loss of function of vWF • several subtypes • In type 2N, vWF lacks the binding site for fVIII -same manifestation as hemophilia A - Type 3 - lack of vWF and factor VIII - Pseudo-vW disease - dysfunction (gain of function) of GP lb -> accelerated removal of circulated vWF Disorders of secondary hemostasis Coagulation cascade dysfunction Clinically, they usually manifest by bleeding into body cavities, organs, retroperitoneum, joints, muscles Symptoms: joint deformities, nerve comperssion by a hematoma Abundance and redundancy of coagulation factors (needed for normal values of coagulation tests) Table 6.2, Rare factor deficiencies Factor Plasmo Level Needed Half-Life Therapy Concentration for Heinostasis (hours} l 200^100 mg/dl 100 mg/dl 120 Cryoprecipi Laic » ] 0 mg/dl 25% 50^80 Plasma V 1 mg/dl 20^25% 24 Plasma, plaielets VII 0.05 mg/dl 1 5% 6 Plasma, rVMA VIII 0.01 mg/dl 100% 12 Con cen Ira re, desmopressin IX 03 mg/dl 100% 24 Concenirate X 1 mg/dl 1 0-20% 25-60 Plasma, estrogens XI 0.5 mg/dl 40-60% 40-80 Plasma XIII 1-2 mg/dl 1-3% 159 Plasma Alpha, 5-7 mg/dl 30% (?) 48 Aniifibrinolylic anliplasmin agents Plasminogen 0,005 mg/dl Aniifibrinolylic acii valor 1 agents DeLoughery et alv 2004 Hereditary coagulopathies hemophilia A (Xq-chromosome linked) - defective fVIII • fVIII is a cofactor in the activation of fX in a reaction catalyzed by fIXa • lowering the fVIII concentration down to >25% of normal level does not cause coagulopathy, lowering town to 25-1% - mild coagulopathy, <1% severe coagulopathy • >150 single nucleotide mutations in the fVIII gene - variable phenotype!!! • prevalence in the male population 1:5000 to 1:10000 hemophilia B (Xq-chromosome linked) - defective fix • ~10 times lower prevalence than hemophilia A • >300 mutations in the fIX gene (85% single nucleotide, 3% short deletions and 12% long deletions) defects of other factors rare, usually autosomal recessive inheritance, clinically relevant in severe deficiency - hemophilia C (defective fXI) - autosomal recessive, Ashkenazy and Iraqi Jews - carriers of 2 causal mutations in around 9% of population, rarely in other populations („bottleneck effect") » Unlike in hemophilia A and B, there is no clear correlation between the severity and levels of circulating fXI, incomplete penetrance - dysfibrinogenemia (defective fl) - defective a2-antiplasmin - etc... Hémophilie A : historique Prince Albert de Saxe-Koburg Reine Victoria dAngleterre {1319-1901) _I c Empereur d'Allemagne Frederic III T Edouard Louis IV Victoria VII Grand-due ďAngleterre de Hessen Leopold Alice Alfred Arthur d'Albanie {mortä 31 ans) CT Empereur Prince GuJífaurne II Henri de Prusse Irene Frederic Alexandra de Hessen (mort a 23 ans) de Hessen er Tsar Nicolas I Helene de Waldeck __J Beatrice Henri de Battenberg Alice Waldemer Sigismund Henri [mort ä (rnort ä 4 ans) 46 ans) r Alexandre Leopold Morits de Teck (mortä (mortä Athlone 23 ans) 23 ans par _i accident) O* Victoire AlphonseXIII Eugenie d'Espagne de Battenberg i—r O' Fille Garcon Conductrice Hémophile Tsaréviteh Alexei (assassineä Tage de 13 ans) .....----- M Rupprecht (mort ä 21 ans suite ä un accident de la route) Alphonse Jaime (mort ä 31 ans aprěs un accident de voiture) Juan Gonzales (mort ä 20 ans apres un accident de voiture) Juan Carlos d'Espagne Acquired coagulopathies * Most often accompany the liver failure (coag. factors are synthesized in the liver - moreover the thrombocytopenia can occur as a result of thrombopoetin deficiency) • Anticoagulant therapy (the overdose is particularly frequent in warfarin - inhibits the vitamin K reduction) Hypercoagulation and thrombosis Pathological activation of hemostasis in vascular lumen or in heart chambers (X hemostatic plug) It can lead into the vascular occlusion locally and/or into the embolization and occlusion on distant sites When the thrombus occur in the venous system, it embolizes into the lungs CT tm O tm epcr LI^Qm Aoj, oj^Q o tm Venous Thrombosis Valve, tm O 'ľ' O "i JHHHBHaaaaiÍBP T O TO TO toottocmumansc rmtmommtmo EPCR - endothelial protein C receptor Red vs. white thrombus Red dominance of secondary • hemostasis • rich for fibrin and erythrocytes blood stasis - veins, heart • chambers, emboli • prevention: mainly anticoagulants • Mixed • Arterial aneurysms White dominance of primary hemostasis Rich for platelets (but fibrin is relatively abundant, too) Arterial thrombi prevention: mainly antiplatelet drugs Arterial thrombi Venous thrombi Pulmonary emboli □ Fibrin fibers □ Fibrin sponge Fibrin bundles □ Platelets Microvesicles □ White blood cells □ Biconcave RBCs Intermediate RBCs □ Polyhedrocytes H Balloon - like RBCs CD Echinocytes □ Space Fate of the thrombus Virchow's triad Three main factors predisposing to thrombosis 1) slowing of the blood flow - e.g. stasis during the immobilization, atrial fibrillation, heart failure 2) Damage of the vessel wall - e.g. ruptured atherosclerotic plaque, artificial surfaces, ■endothelial damage -4/trombomodulin 3) Thrombophilic states Rudolf Virchow (1821-1902), German pathologist and politician Thrombophilic states Inborn • Protein C dysfunction (paradoxical hypercoagulation at the start of warfarin treatment -K-dependent !) • Protein S dysfunction • Resistance of factor V to protein C (Leiden mutation - most frequent hereditary thrombophilia) • Antithrombin III dysfunction • Dysfibrinogenemia • Hyperhomocysteinemia (?) • Antiphospholipid syndrome Acquired • Malignancies • Post-operational states • Hyperoestrogenous states (gravidity, peroral contraceptives) • Heart failure • Hyperviscosity (e.g. In polycytemia vera) • Locally everything that leads into blood flow stasis or vessel wall damage Hyperestrogenous states Mechanisms • 1s endothelial production of vWF • nI/ protein S • 1s coagulation factors • Concommitant ^tPA and TAFI (unknown effect) • In combined treatment, the character of changes depends also on progesterone component Effects 1s risk of venous thrombosis Supraaditive risk in Leiden mutation (probably because of protein S - protein C -factor V interaction) Low impact on arterial thrombosis Antiphospholipid syndrome increased risk of thrombosis associated with prolonged aPTT presence of antiphospholipid antibodies frequent abortions unclear pathogenesis possible mechanisms: • induction of TF expression in monocytes 1 • platelet activation via Gp lb • endothelial dysfunction (4, TFPI, ^ PAI-I) • decrease of protein C activity • ß2Gp I loss of function (inhibits fXIa generation by thrombin) Hyperhomocysteinemia homocysteine is an intermediary product of methionine transformation in methionine cycle - homocysteine is either metabolized to cysteine - or it is remethylated back to methionine (in folate cycle) 5,io- methylene THF Hhcy can be induced by genetic and/or nutritional factors - mutations in enzyme-coding genes - low supply of vitamin B6, B12 and folic acid (B9 Protein Tetrahydro-tolaie (THF) 39) MTHFR 5-methyl THF t Folic Acid Methionine ■ S-adenosyl-methionine 'CH-. S-adenosyl-homocysteine Homocysteine Adenosine B6 CS -Serine HHcy is an independent risk factor of atherosclerosis and thromboembolism, fertility disorders and some developmenta and neurological disorders (vertebral clefts) But: those are probably mediated by endothelial dysfunction, not hypercoagulation Lowering homocysteine does not lead into lowering the thrombosis risk Cystathione Cysteine Sulphate Forms (A) monogenic homocystinuria Deficiency of cystathionine-ß-synthase leads the marked increase of homocysteine levels i homozygotes, rare disease (B) Mild hyperhomocysteinemia Common polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene into n Combined disorders of hemostasis Combination of overactive and insufficient hemostasis Overactivation leads into microthrombi formation and to ischemia Exhaustion of platelets/coagulation factors follows accompanied with bleeding Primary hemostasis: thrombotic microangiopathies Secondary hemostasis: DIC Thrombotic microangiopathies A universal feature of thrombotic microangiopathies is an occlusion of small arteries with following thrombocytopenia and hemolytic anemia Coagulation factors are not decreased (x DIC) The role of big vWF multimers, which can induce the aggregation without previous binding to collagen Activation of more platelets at one multimer of vWF is possible The vWF multimers are normally cleaved by ADAMTS13 protease Fragmented erythrocytes Figure 1 'fy.fa V# https://www.arkanalabs.com/diagnose-this-august-22-2022/ ADAMTS 13 - zinc-containing metalloproteinase produced in the liver and in the endothelium - high shear stress (esp. in microcirculation favours the cleaving of von Willebrand factor into monomers, which decreases its ability to activate platelets (prior collagen binding is necessary) - fVIII act as a cofactor in vWf cleaving, the vWf monomers than act as a plasmatic carrier for fVIII - ADAMTS13 is deactivated by thrombin, fXa, fXIa, and plasmin that also cleaves the vWF ADAMTS1J / " endothelium / '--^^ J f <0 O ot damage subendolholi urn •Thrombotic thrombocytopenic purpura •patients with classical TTP have autoantibodies against ADAMTS13 •in rare cases there is an inborn lack of ADAMTS 13 •acute and chronic forms with common recurrences Secondary thrombotic microangiopathies •Often unclear pathogenesis •4/ADAMTS13 is a common denominator (often secondary) •Hemolytic-uremic syndrom (HUS) •Drug-induced thrombotic microangiopathy (DITMA) •HELLP syndrome Hemolytic-uremic syndrome (HUS) •combination of hemolysis, thrombocytopenia and acute renal failure •in principle, it is a localized form of TTP •induction by bacteria - notably by enterohemorrhagic Escherichia coli - endothelial damage by Shiga toxin •others: Shigella, Streptococcus pneumoniae •about 10% is an atypical HUS - endothelial damage by complement •remission usually occurs in three weeks (provided the acute renal failure is compensated), sometimes, chronic kidney disease may develop •Drug-induced thrombotic microangiopathy •Various mechanisms of action (often, drugs either form deposits in kidneys / perivascular area, or induce immune mechanisms) •Anti-tumour treatment (VEGF inhibitors, chemotherapy-oxaliplatina, mitomycine) •Hemolysis, Elevated Liver enzymes, Low Platelets •thrombotic form of preeclampsia, similarly to preeclampsia placental vasoconstriction instead of vasodilation •placental microvascular disorder with the ischemisation of placenta, acute development (1-3 days) •generalized vazospasm in the mother •activated thrombocytes produce TXA2 -^vasoconstriction •consumption of coagulation factors with the platelets, often DIC Disseminated intravascular coagulopathy (DIC) Combination of excessive and insufficient coagulation DIC is a consequence of excessive thrombin formation The process is usually started by the systemic exposition to TF 2 phases: 1) Formation of microtrombi (with local ischemia) 2) Bleeding as a result of consummation of coagulation factors Vitamin K defficiency typically manifests by: i i i A. Thrombosis B. Hematoma C. Petechiae D. Purpura E. DIC 1 1 Treatment of insufficient hemostasis • thrombocytes • etamsylate (stimulates platelet activation) • terlipressin (ADH derivative -vasoconstriction) • frozen plasma • coagulation factors • vitamin K • antifibrinolytics Strategies of antiplatelet Key vWF Fibrinogen Fibronectin Collagen a granule Strategies of anticoagulant treatment Extrinsic Tenase FVII Tissue Factor t FVII a intrinsic Tenase Contact activation FXIIa ^- FXII FXI Rivaroxaban Apixaban Fondaparinux y* Prothrornbtnase I *Z ................j» ......... )an.........FXa * I FVa4_ FV . // I—L—r t Da big air Bn (via A T) Prolhrombin t W ^ Thrombin Heparinolds (via AT) Fibrinogen 1 Fibnn FXI II a FltifMlgtaUa Fibrinolytics Urokinase, streptokinase (act circulation) tPA (restricted to thrombus) reteplase (modified tPA)