ACQUIRED COAGULATION ABNORMALITIES

1. ACQUIRED COAGULATION ABNORMALITIES

2. ACQUIRED COAGULATION ABNORMALITIES - causes 1. Vitamin K deficiency 2. Liverdisease • Clottingfactorinhibitors: circulatinganticoagulants complicationsof anticoagulanttherapy 4. Incraesedconsumptionorloss of the clottingfactors: a) disseminatedintravascularcoagulation ( DIC) b) fibrinogenolysis (primaryfibrinolysis)

3. Coagulation abnormalities of vitamin K deficiency • vitamin K isessential for the finalpostribosomalcarboxylation of F II, VII, IX, X and the physiologicanticoagulants, protein C and protein S Laboratoryfeatures: •  PT (prothrombintime) and  F II, VII, IX, X • aPTT (activatedpartialthromboplastintime) may be prolonged in severe, protractedvitamin K deficiency • Levels of PIVKA-II (Proteinsinduced in vitamin K absence) aremoresensitivethan PT

4. Vitamin K deficiency-etiology I. Inadequate supply: 1. Dietary deficiency (leafy green vegetables 90-120mcg) 2. Destroying the gut flora by administration of broad-spectrum antibiotics II. Impaired absorption of vitamin K: 1. Biliary obstruction (gallstone, strictures, tumor) 2. Malabsorption of vitamin K(sprue, celiac disease, ulcerative colitis) 3. Drugs (cholestyramine) III. Pharmacologic antagonists of vitamin K (coumarins, warfarin)

5. Abnormalities of hemostasis and coagulation in liver diseases (1) I. Decreased synthesis of coagulation factors 1. Fibrinogen, protrombin, clotting F V, VII, IX, X, XI, XII, XIII, prekallikrein, high molecular weight kininogen 2. Antiplasmins, antithrombin, protein C and protein S II. Aberrant biosynthesis 1. Of abnormal fibrinogenu 2. Of abnormal analogues of prothrombin, F VII, IX, X

6. Abnormalities of hemostasis and coagulation in liver diseases (2) III. Deficient clearance 1. Of fibrin monomers, fibrinogen degradation products (FDP) 2. Of activated coagulation factors (IXa, Xa, Xia) 3. Of plasminogen acivators IV. Accelerated destruction of coagulation factors 1. Intravascular coagulation 2. Localized coagulation (hepatic cell necrosis) 3. Abnormal fibrinolysis V. Thrombocytopenia and platelet dysfunction (splenomegaly)

7. Treatment • Vitamin K doses 10mg • FFP (invasive procedure) • Prothrombin complex concentrates • Platelet transfusion • Antifibrynolytic agents (dental extraction)

8. Circulating anticoagulants Clotting factor inhibitors are autoantibodies (usually IgG) or alloantibodies (in hemophilia A) that inactivate coagulation factors - Laboratory test: prolonged aPTT

9. Circulating anticoagulants I. Antibodies to factor VIII (prolonged aPTT, normal INR) 1. In hemophilia A 2. Postpartum -several months after parturition in asociation with a first pregnancy 3. Various immunologic disorders (rheumatoid arthritis, SLE, penicillin allergy) 4. Older patients without underlying disease II. Other spontaneous inhibitors (rarely)- against factors: V, IX, XIII, fibrinogen, III. Lupus anticoagulant (in 30% SLE, rheumatoid arthritis, HIV infection, in lymphoproliferative disorders, after drugs hydralazine, quinidine, penicillin)

10. Acquired hemophilia A • Common bleeding sites are soft tissue, skin, and mucous membrane • Treatment – Factor VIII bypassing agents: • Recombinant activated factor VII • Plasma-derived factor eight-inhibitor bypassing agent (FEIBA, also called activated prothrombine complex concentrate) • To eradicate the inhibitor is recommended

11. DIC Disseminated intravascular coagulation • isanacquiredsyndromecharacterizedby systemicintravascularactivationof coagulation, leading to fibrindeposition in the microvasculature and small-vessels, contributing to organ dysfunction • consumption of platelets and coagulationfactors lead to thrombocytopenia and impairedcoagulation and mayresult in bleedingcomplications

12. Clinical conditions that may be complicated by DIC • Sepsis/severe infection • Trauma • Malignancy • Acute leukemias • Kasabach-Merritt syndrome • Vascular abnormalities • Severe alergic/toxic reaction • Obstetrical conditions • Amniotic fluid embolism • Abruptio placentae • HELLP syndrome • Solid tumors

13. ACUTE DIC-CLINICAL PRESENTATION • symptoms of underlying disease • symptom of local thrombosis • hemorrhagic diathesis • shock

14. Diffuse intravascular coagulationMicrothrombosis secondary fibrinolysis ↓ platelets FDP clotting factors Ischemic tissue damage Microangiopathic Bleeding anemia tendency

15. Acute DIC - laboratory features: •  Increased D-Dimer level •  FDP level •  AT level •  platelet level • Bload smear - schistocytes •  fibrinogen level •  TT (Thrombin time) •  aPTT •  PT (Prothrombin time)

16. Acute DIC diagnosis • The basis of the diagnosis is the knowledge of the underlying diseases • Patients suffering from acute DIC need urgent therapy • DIC should always be taken into consideration if a complex coagulation defect in combination with a underlying disease is observed

17. Diagnostic algorithm for the diagnosis of overt DIC (1) • Riskassessment: • Does the patienthaveanunderlyingdisorderknown to be associated with overt DIC? • Ifyes, proceed

18. Diagnostic algorithm for the diagnosis of overt DIC (2) - Order global coagulation tests • Platelet count (>100=0, <100=1, <50=2) • Elevated fibrin-related markers (FDP no increase:0, moderate increase:2, strong increase:3) • Prolonged PT (<3sec.= 0, >3 but <6 = 1, >6sec. = 2) • Fibrinogen level (>1g/L=0, <1g/L=1) If ≥ 5: compatible with overt DIC

19. CHRONIC (compensated) DIC In chronic DIC, the activation of the hemostatic system is minimal since negative feedback mechanisms as well as inhibitors can limit the activation process so that microthrombi do not occur and bleeding episodes are rare phenomena

20. Chronic DIC - etiology 1. Obstetric complications: eclampsia, the death fetus syndrom 2. Vascular disorders: giant hemangiomas (Kasabach Merrit syndrome), Leriche syndrome, Raynaud,s disease 3. Carcinomas 4. Hematology disorders: myelofibrosis, polycythemia vera, PNH 5. Reumathoid disorders: SLE, sclerodermia 6. Kidneys disorders: glomerulonephritis, HUS 7. Another: vasculitis allergica, diabetes mellitus

21. PRIMARY FIBRINOLYSIS (FIBRINOGENOLYSIS) DEFINITION: primary fibrinolysis occurs when plasmin is generated in the absence of DIC ◊ This has been described in hepatic disorders, prostatic carcinomas, and cases without apparent cause ◊ At present, most cases of primary fibrynolysis are iathrogenically induced during thrombolytic therapy

22. Plasminogen intrinsic extrinsic exogenousactivation activation activationfactor XIa, XIIa, kallikrein tPA, uPA streptokinasekininogen or APSAC PlasminFibrinogen FibrinFDP FDP + D-Dimer

23. Acquired coagulation abnormalities - diagnostics I History II Physical examination III Laboratory features - morphology - blood smear - bleeding time - prothrombin time (PT), INR - aPTT - thrombin time (TT) - fibrinogen - fibrin(ogen) degradation products (FDP) - D-dimer - antithrombin

24. PT aPTT Platelet Fibrinogen TT FDP D-Dimer AT count Acute DIC       Chronic DIC N  N  N  N   N     Fibrinogenolysis N   N   N N NHeparin overdosage   N N N N N NDicumarol  N N N  N N N overdosage orprothrombin complex factors defficiency Diferentiation of aquired coagulation abnormalities

25. ACA – DIC THERAPY 1. Treatment of the underlying disorder 2. Treatment of shock 3. Replacement therapy - platelet concentrates - RBC - FFP - Cryoprecipitate (fibrinogen) - Activated protein C (drotrecogin alfa) • Heparin treatment unfractioned heparin or low-molecular weight heparin acrocyanoza, purpura fulminans, dermal necrosis, venous thromboembolism

26. Treatment – thrombosis predominantes • Continousinfusion of UFH • Prophilacticdoses of heparinor LMWH • Especially, severe purpura fulminans, acral ischemia, vascular skin infarction

27. Treatment - bleedings • Transfusion of plateletsorplasma (components) including FFP and/orprothrombincomplexconcentrate (fluid overload) • Severehipofibrynogeneamia (<1g/L): FFP, fibrionogenconcentrate and cryopercipitate

28. CASE PRESENTATION