ACQUIRED COAGULATION ABNORMALITIES

ACQUIRED COAGULATION ABNORMALITIES - causes 1. Vitamin K deficiency 2. Liver disease Clotting factor inhibitors: circulating anticoagulants complications of anticoagulant therapy 4. Incraesed consumption or loss of the clotting factors: a) disseminated intravascular coagulation ( DIC) b) fibrinogenolysis (primary fibrinolysis)

Coagulation abnormalities of vitamin K deficiency vitamin K is essential for the final postribosomal carboxylation of F II, VII, IX, X and the physiologic anticoagulants, protein C and protein S Laboratory features:  PT (prothrombin time) and  F II, VII, IX, X aPTT (activated partial thromboplastin time) may be prolonged in severe, protracted vitamin K deficiency Levels of PIVKA-II (Proteins induced in vitamin K absence) are more sensitive than PT

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)

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

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)

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

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

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)

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

Disseminated intravascular coagulation DIC Disseminated intravascular coagulation is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to fibrin deposition in the microvasculature and small-vessels, contributing to organ dysfunction consumption of platelets and coagulation factors lead to thrombocytopenia and impaired coagulation and may result in bleeding complications

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

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

Diffuse intravascular coagulation Microthrombosis secondary fibrinolysis ↓ platelets FDP clotting factors Ischemic tissue damage Microangiopathic Bleeding anemia tendency

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)

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

Diagnostic algorithm for the diagnosis of overt DIC (1) Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC? If yes, proceed

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

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

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

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

Plasminogen intrinsic extrinsic exogenous activation activation activation factor XIa, XIIa, kallikrein tPA, uPA streptokinase kininogen or APSAC Plasmin Fibrinogen Fibrin FDP FDP + D-Dimer

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

Diferentiation of aquired coagulation abnormalities PT aPTT Platelet Fibrinogen TT FDP D-Dimer AT count Acute DIC         Chronic DIC N  N  N  N   N     Fibrinogenolysis N   N   N N N Heparin overdosage   N N N N N N Dicumarol  N N N  N N N overdosage or prothrombin complex factors defficiency Diferentiation of aquired coagulation abnormalities

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

Treatment – thrombosis predominantes Continous infusion of UFH Prophilactic doses of heparin or LMWH Especially, severe purpura fulminans, acral ischemia, vascular skin infarction

Treatment - bleedings Transfusion of platelets or plasma (components) including FFP and/or prothrombin complex concentrate (fluid overload) Severe hipofibrynogeneamia (<1g/L): FFP, fibrionogen concentrate and cryopercipitate

CASE PRESENTATION