Acquired disorders of haemostasis Acquired platelets disorders • thrombocytopathy • thrombocytosis • thrombocytopenia – Immune cause: • Auto-immune (ITP) • Alo-immune (fetal, post-transfusion) • HIT • Antiphospholipide syndrome – Non-immune cause: • Decreased production – toxic, infection, medicaments, TU, shortage of folate, B12 • Increased consumption - DIC, TTP, HUS, MAHA, HELLP, Kassabach-Merritt syndrome • Distribution disorders - hypersplenism, hyperthermia Acquired thrombocytopathy • Aim of treatment: – ASA – COX inhibition – clopidogrel, prasugrel, ticagrelor – inhibition of ADP inducet aggregation – direct GP IIb/IIIa blocators • as treatment side-effect: NSAID • uremia – guanidinsukcinyl acid – decreased adhesion, aggregation, metabolism • paraprotein – decreased adhesion, aggregation • myeloprolipherative disorders: – production of hypofunctional platelets, acq. vWSy Acq. thrombocytosis • reactive: – infection, malignancy, inflammation, stress – sideropenia – after splenectomy – active bleeding • essential thrombocytemia: • other myeloprolipherative disease – CML, myelofibrosis, polycytemia vera Acq. coagulopaties • liver disease • malignancy • paraprotein • uremia • K vitamin deficiency (+ warfarin) • UFH + LMWH treatment • OC (oestrogene, gestagene) • sepsis • DIC • acq. specific inhibitors (FVIII) • APS (LA, ACLA) Liver disease • Decreased production of plazmatic factors • Productions of abnormal proteins • Hypersplenism – pancytopenia •  PT,  fibrinogen ,  AT III,  platelets (leu, Hb),  MCV • Hypofunction of monocyto-macrofag systeme in liver • Activation of fibrinolysis • Chronic DIC • Rarely acq. inhibitors Malignancy • demage of vessel wall (infiltration by tumor, hyperviskosity, leucostasis) • trombocytopenia (infiltration of bone marrow, treatment, hypersplenism, DIC) • chronic DIC (paracoagulation activity of tumor cells) – Expression of TF: • by tumor cells • by activated leucocytes – Enzymes with coagulation activity – MAHA • defect of plasmatic coagulation factors (liver infiltration) • activation of fibrinolysis (proteolytic activity of tumor cells) Monoclonal paraprotein • binding to platelets and coagul. factors • interference with binding platelets to endothelium • amyloid – sec. deficiency of FX • as specific antibodies against coagulation factors – inhibitor of vWF, FVIII • inhibition of fibrin formation • hyperviscosity Uremia • Hypofunction of primary haemostasis – platelets (guanidinsukcinyl acid) – metabolism of endothelium ( PGI2,NO) – interference with binding platelets to (sub)endothelium – vessel abnormities – angiodysplasia • imbalance of plasmatic coagul. factors –  FVIII, fbg, AT –  PC, PS –  fibrinolytic activity Shortage of K vitamin • hypofunction of coagul. factors: – II, VII, IX, X – PC, PS • prolongation of PT, less aPTT • in newborns • warfarin • antibiotics, parenteral alimentation, obstructive icterus • treatment: – K vitamin – PCC, FFP Pregnancy:  PS  Fbg, FVII, FVIII, vWF OC: Fbg, FVII, FVIII, vWF  PS, AT III Stress: Fbg, FVII, FVIII, vWF tPA 2AP, Plg Inflamation  Fbg, FVII, FVIII, vWF  1AT, PAI-1, tPA, 2MG, Plg Sepsis • Demage of endothelium • Activation of monocytes, granulocytes, expression of TF • Activation of platelets • DIC •  fibrinogen, procoagulation factors and inhibitors of coagulation •  platelets Acq. thrombophilia • Defect of inhibitors (AT, PC, PS, APCR) • Increase of FVIII, fibrinogenu • increase PAI - 1 • hyperhomocysteinemia Disseminated intravascular coagulation DIC Definition by ISTH: • is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes • it can originate from and cause demage to the microvasculature, which, if sufficiently severe, can produce organ dysfunction Disseminated intravascular coagulation DIC • Systematic activation of coagulation, which generates intravascularly fibrin • Microvascularly thrombotization of various organs • Multiorgan failure DIC - etiology • release of TF: – tissue damage (trauma, burns, obstetric) – by tumor cells – by macrofages and monocytec (sepsis) • endothelial damage: – endotoxin (sepsis) – hemangiomas – vasculitis • contact with foreign surface DIC - clinical manifestations Acute (de-compensated) „overt“ • rapid progress • symptomatic – microthrombotization • serious condition • difficult therapy • high mortality Chronic (compensated) „non-overt“ • slow progress • asymptomatic – hypocoagulation • chronic disease • therapy mostly not needed DIC – organs microtrombotization • skin - haematomas, wound bleeding - necrosis • lung - hypoxia, shortness of breath • Kidney - proteinuria, iligo-, anuria, failure • liver - failure • pituitary gland - fever • supraren. gland - hypotension, ionic dysbalance DIC - laboratory tests Screening tests • fibrinogen • platelets • prothrombin time (PT) • activ. parc. thromboplastin time (aPTT) DIC - laboratory tests Specific tests: Procoagulant activity • EGT, F1+2, FPA, FM, TAT, DD Fibrinolytic activity • DD, FDP, plasmin, PAP Inhibitors consumption • ATIII, PC, α-2-antiplasmin, PS, TAT, PAP Organs failure • creatinin, JT, pH, pO2, LD ISTH: overt DIC diagnostic scoring scheme • Condition is presence of causal disease • platelets(109/l)  100 = 0 50-100 = 1  50 = 2 • fibrin mark. (DD,FDP) neg. = 0 mild = 2 severe = 3 •  PT by  3 s = 0 3-6 s = 1  6 s = 2 • fibrinogen (g/l)  1 = 0  1 = 1 • ≥ 5 point = overt DIC ISTH: non-overt DIC diagnostic scoring scheme DIC – laboratory test - summary •  platelets and  fibrinogen •  ATIII •  DD •  PT, aPTT •  schistocytes • non-coagulant tests (organs failure) –  creatinine, liver tests –  pH, pO2 DIC - treatment • identification and treatment of trigerring disease • substitution: – coagulation factors (FFP) • if PT or aPTT  1,5 R – Fibrinogen • < 1 g/l – platelets •  20 x 109/l, resp. 50-80 x 109/l and bleeding symtomes – nature coagulation inhibitors (ATIII  65%, sepsis (a)PC) • heparin (LMWH) in prophylactic dose – after bleeding cessation • other (antifibrinolytics only in case of hyperfibrinolysis) „DIC-like syndrom“ • MAHA – TTP – HUS – HELLP • HIT/T • cavernous hemangioma • APS (catastrophic form) Acquired inhibitor of FVIII • elderly people (after pregnancy) • incidence 1 / 1 000 0000 / year • 50 %: autoimmune disease, malignancy, pregnancy • 50% idiopatic • bleeding: – muscles and soft tissue – traumatic, surgery, CNS – 8-22% mortality •  aPTT, in mixing test too, • assay of inhibitor FVIII: Bethesda unit • treatment: – bleeding: rFVIIa, aPCC (FEIBA) – eradication by immune suppression (CS, CFA, anti-CD20) Antiphospholipid antibodies • heterogenous auto-antibodies against proteins bound to negatively charged phospholipids on cell membranes Antiphospholipid antibodies - mechanism • inhibition: – release of prostacyclin from the endothelium – protein C activation – fibrinolysis activation by complex prekalikren+FXII • stimulation: – activation of platelets – activation of FX on platelet surface • other effects outside haemostasis Antiphospholipid syndrome clinical criteria Thrombosis: • venous or arterial • proven only histologically • but not superficial thrombophlebitis Antiphospholipid syndrome clinical criteria Pregnancy disorders: • three or more subsequent spontaneous abortions before the 10th week of gestation (excluding other causes) • one or more deaths of morphologically normal fetus (documented by sonography or direct examination) after week 10 of gestation • one or more premature births (34 weeks and earlier) of a healthy newborn in severe pre-eclampsia or severe placental insufficiency Antiphospholipid syndrome laboratory criteria • anticardiolipin antibodies (ACLA): – IgG and/or IgM > 40 U/ml or > 99. percentil) • anti--glycoprotein I antibodies: • IgG and/or IgM > 99. percentil • are present 12 weeks or more weeks apart • it is examined by a standardized ELISA Antiphospholipid syndrome laboratory criteria Lupus anticoagulans: • are present 12 weeks or more weeks apart • evidence of prolongation of the screening test (aPTT, PT) • there is no correction by norma plasma • shortening after addition of excess of phospholipids Antiphospholipid syndrome - diagnosis • presence of at least one criterion: – laboratory – clinical • the symptom has a maximum distance of 5 years from laboratory criteria Types of APS and management • Type I (venous) – LMWH, UFH, W • Type II (arterial) – LMWH, LD UFH, ASA, W • Type III (CNS, retinal) – LMWH, ASA, W, • Type IV (combination) – LMWH, LD UFH, W • Type V (abortions) – LMWH, ASA • Type VI (no clinical criteria) – in pregnancy (ASA, LD W) – in situations at risk for thrombosis (LMWH, LD UFH)