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Examination of hemostasis

Examination of hemostasis. Stanislav Matou š ek . Hemostatic disorders. + thrombosis and embolism ( e.g. DVT or MI or stroke ) Virchow ’s trias – Endothelium dysfunction , stasis , blood factors Procoagulational changes in the blood = HYPERCOAGUABILITY DISORDERS.

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Examination of hemostasis

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  1. Examination of hemostasis Stanislav Matoušek

  2. Hemostatic disorders • +thrombosis and embolism (e.g. DVT orMI or stroke) • Virchow’s trias – Endothelium dysfunction, stasis, blood factors • Procoagulational changes in the blood =HYPERCOAGUABILITY DISORDERS • -excessive bleeding • hemorrhagic diatheses = bleedingstates • //Endothelium and vessel wall – purpuras/vasculopathies • //Platelets – thrombocytopeniasand -pathias (common) • //Plasmatic coagulation system – coagulopathies

  3. Causes and signs of bleeding disorders Lack or defect of platelets Blood vessel disorder Lack of plasmatic factors Mostly bruises and bleeding to joints Excessive bleeding Mostly petechiae

  4. Disorders of primary hemostasis Platelets and vessels

  5. Platelet thrombus Exposition of procoagulation phospholip. (pf3) Coagulation cascade thrombin fibrin web Vasoconstriction in injured vessel adrenalin serotonin - - - Vessel injury PDGF ADP Bleeding myocytes&fibroblasts - Platelets activated Collagen Exposal + + + + membr. fosfolipidy Platelet adhesion Platelet aggregation Desquamated epithelium kys. arachidonová Exposal ofvonWilebrand’sfactor endoperoxidy PGG2 PGH2 + + - von Wilebrand’sfactor thromboxan A2 Endothelium PAF granulocytes, baso-, macrophages eicosanoids PGG2 PGH2 membranephospholipids Arachidonic acid prostacycline PGI2

  6. Thrombocytopenia • 1) Production decreased↓ • 2) Consumption increased ↑ • A) with increased activity of thrombin • B) imuno-thrombocytopenia • C) other • 3) Combination of both mechanisms

  7. Platelet count • 200 – 400 x 103/µL (109/L) = 200 000 – 400 000 /µL The risk of spontaneous bleeding is low if the number of platelets is > 30 000 /µL and blood vessels and coagulation system are intact

  8. I) Thrombocytopenia from insufficient production • Aplastic disorder • Congenital • Acquired • Bone marrow damaged by medicaments (chemotherapy), chemicals (benzene), radiation, infection (HIV), autoantibodies • Infiltrationof bone marrow (carcinomas, lymphomas, leukemia) • Myelodysplastic syndrome, Myelofibrosis • Defect in megakaryocyte maturation • vit. B12 and folate deficiency Bone marrow aspiration(less megakaryocytes in aplastic)

  9. 2) Thrombocytopenia from increased consumption • A) Increased activity of thrombin • Disseminated intravascular coagulation –DIC • activation in infections/malignities (extracellular proteases)-chronic DIC • B) Imunothrombocytopenia (e.g. autoantibodies) • Idiopathic thrombocytopenic purpura- autoantibodies produced with unknown cause • Acute vs. chronic • Secondary ( SLE, lymphomas, HIV) • After medicaments • …. • Heparininduced • C) Other • Hypersplenism, artificial valve • TTP = Thrombotic thrombocytopenic purpura Activity of thrombin, clotting tests PT and aPTT

  10. Thrombotic thrombo-cytopenic purpura • ? Cause is probably damage to endothelium - release of von Willebrand factor - decreased degradation of vWf by its protease (antibodies against the protease, congenital?)

  11. Purpura

  12. 3) Combination of low production and increased consumption • Liver cirrhosis

  13. platelet dysfunction = thrombocytopathy • Congenital • Acquired • aggregation inhibitors therapy (aspirin, ticlopidin) • platelets covered by IgA or IgM (multiple myeloma) • Dextran (infusion, often given in bleeding) • Uremia (Kidney failure) • Essential Thrombocytosis (one of myeloproliferative diseases analogy of polycythemia vera) Normal number of platelets, bleeding time ↑ Clinically: Generally, it is difficult to stop bleeding (e.g. during surgery),

  14. Bleeding time (Duke) • Standardized puncture of the earlobe, or standardized incision to the forearm with cuff inflated to 40 Torr . • We measure the time until the bleeding stops • 2-5 min (2-9 min in forearm) • Increased in platelet dysfunction and in vonWillebrand disease (but not in Hemophilia)

  15. vonWillebrand disease • Missing or defective vonWillebrand factor • The factor is important in platelet adhesion (primary hemostasis) and serves also as a carrier for factor VIII (decrease of concentration of factor VIII leads to defect in coagulation) • Combined bleeding of petechial and hemophilic type • Congenital or acquired • Prevalence 1%, but generally mildsymptoms (heterozygotes) • Prolonged bleending time (Duke) and aPTT

  16. Vasculopathies / purpuras • congenital • e.g. Ehlers-Danlos syndrom (defect of collagen) • Acquired • scurvy(vitamin C deficiency) • glucocorticoid excess • Purpura senilis • Henoch-Schoenlein purpura (children after an upper respiratory infectionxx DD DIC in meningococcal infection!)

  17. Tourniquet test (Rumpel-Leede capillary-fragility test) • A blood pressure cuff is inflated to a point little bit above diastolic blood pressureduring 5 min (10 min). • Positive, if more that 5 petechiae per square inch are found. • Vasculopathies, dengue fever diagnosis (more than 20 petechiae).

  18. Scurvy

  19. Secondary hemostasis disorders Plasma coagulation system

  20. + Kallikrein XII (Hageman) + XIIa (Hageman) + - - - - - - - - - - - - - - - - - - - - - - - IX von Willebrand factor Subendothelium (contact with collagen surface) VIII VII XIa + + { + + } von Willebrand factor X VIIa IXa Ca++ III Tissue thromboplastin + VIIIa Ca++ + Platelet phospholipides } Platelet phospholipides (pf.3) Xa II prothrombin + Ca++ XIII (fibrin stab. f.) V Va + + Ca++ Ca++ Platelet phospholipides (pf.3) Platelet phospholipides IIa thrombin + XIIIa (fibrin stab. f.) I fibrinogen Fibrin web Covalent bonds Fibrin web Weak bonds + + Prekallikrein HMWK Intrinsic pathway Intrinsic activation only by collagen contact XI + Extrinsic pathway Exogenous activ. by tissue factor

  21. Anti Vit. K Anti Vit. K Anti Vit. K Anti Vit. K { III (tissue tromboplastin) + Ca++ Membrane phospholipides } Platelet factor 3 (platelet phospholipides) II prothrombin + Ca++ Platelet phospholipides IIa thrombin I (fibrinogen) Fibrin web fibrin monomer + + Intrinsic pathway (contact with collagen) XIIa (Hageman) + Extrinsic pathway (tissue factor) XIa (PTA) + } Hemophilia B VIIa (konvertin) IXa (Christmas) Hemophilia A Ca++ VIIIa (AF) + } Xa (Stuart-Prower) Va (accelerin) Ca++ + IIa (thrombin) XIIIa (fibrin stab. f.)

  22. X-linked Great- grandson Queen Victoria of Britain Carrier of Hemophilia Tsarevich Alexei Sufferer of Hemophilia Tsar Nicolai II of Russia

  23. { (activated) Partial Tromboplastin Time PTT,aPTT, APTT III (tissue tromboplastin) + Ca++ Prothrombin Time, PT, (Quick) Membrane phospholipides Platelet factor 3 (platelet phospholipides) I (fibrinogen) Fibrin web fibrin monomer + + Intrinsic pathway (contact with collagen) XIIa (Hageman) + Extrinsic pathway (tissue factor) XIa (PTA) + } VIIa (konvertin) IXa (Christmas) Ca++ VIIIa (AF) + } Xa (Stuart-Prower) Va (accelerin) + IIa (thrombin) XIIIa (fibrin stab. f.)

  24. { III (tissue tromboplastin) + Ca++ Membrane phospholipides Platelet factor 3 (platelet phospholipides) I (fibrinogen) Fibrin web fibrin monomer + + Intrinsic pathway (contact with collagen) XIIa (Hageman) + Extrinsic pathway (tissue factor) XIa (PTA) + } VIIa (konvertin) IXa (Christmas) Ca++ VIIIa (AF) + } Xa (Stuart-Prower) Va (accelerin) + IIa (thrombin) Thrombin time XIIIa (fibrin stab. f.)

  25. aPTT Citrate or oxalate plasma, We add phospholipids, Ca++, caolin or other negatively charged surface Time until clot formation (depends on the lab) ~ 25 - 39 s Monitoring of heparin therapy, intrinsic and common pathway, hemophilia

  26. Prothrombin Time (Quick test) • Citrate or oxalate plasma, • We add phospholipids, Ca++, and tissue thromboplastin Time until clot formation (depends on the used thromboplastin) • ~ 12-15 s • INR = PTtest/ PTnormal (norm 0.8 – 1.2) • Monitoring of anti vitamin K anticoagulant therapy (warfarin), extrinsic and common pathway

  27. Evaluation of clotting screen

  28. Inhibition of coagulation

  29. { + III (tissue tromboplastin) + Ca++ Membrane phospholipides Platelet factor 3 (platelet phospholipides) I (fibrinogen) Fibrin web fibrin monomer + + Intrinsic pathway (contact with collagen) Antithrombin 3 XIIa (Hageman) + Antithrombin 3 Extrinsic pathway (tissue factor) XIa (PTA) + } Antithrombin 3 VIIa (konvertin) IXa (Christmas) Protein C Ca++ VIIIa (AF) + } Antithrombin 3 Xa (Stuart-Prower) Protein C Va (accelerin) + Antithrombin 3 IIa (thrombin) XIIIa (fibrin stab. f.)

  30. Antithrombin 3 Antitrombin 3 Antithrombin 3 Antithrombin 3 Protein C Antithrombin 3 Protein C Antithrombin 3

  31. Antithrombin 3 Protein C Antithrombin 3

  32. Heparin Antithrombin 3 Non-active Antithrombin 3 Non-active Antithrombin 3 Non-active Antithrombin 3 Antithrombin 3 Heparin Antithrombin 3 Antithrombin 3 Antithrombin 3 Antithrombin 3 IXa (Christmas) Xa (Stuart-Prower) XIa (PTA) XIIa (Hageman) Platelet factor 4 Heparin Antithrombin 3 IIa (trombin)

  33. { + III (tissue tromboplastin) + Ca++ Membrane phospholipides Platelet factor 3 (platelet phospholipides) I (fibrinogen) Fibrin web fibrin monomer + + Intrinsic pathway (contact with collagen) Antithrombin 3 XIIa (Hageman) + Antithrombin 3 Extrinsic pathway (tissue factor) XIa (PTA) + } Antithrombin 3 VIIa (konvertin) IXa (Christmas) Protein C Ca++ VIIIa (AF) + } Antithrombin 3 Xa (Stuart-Prower) Protein C Va (accelerin) + Antithrombin 3 IIa (thrombin) XIIIa (fibrin stab. f.)

  34. Fibrinolysis =thrombolysis

  35. Thrombolysis Inhibitor of Plasminogen Activator Plasminogen activator Protein C Inactivates Inhibitor of Plasminogen Activator + protein C activator + Inhibitor of Plasminogen Activator Aktivátor plazminogenu Protein S non-active protein C Protein S Protein S Protein C Protein C VIIIa (AF) Va (akcelerin) IIa (thrombin) Thrombomodulin Endothelium

  36. Hypercoaguability (thrombophilic) disorders

  37. Most common hypercoagubility disorders • Mutation of factor V – Leiden mutation / insensitivity to protein C • Defect in Antithrombin III • Defect in Protein C • Defect in Protein S

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