acquired thrombosis

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Transcript of acquired thrombosis

  • Inherited and Acquired Thrombotic DisordersAugusto B. Federici Hematology and Transfusion MedicineL. SACCO University Hospital of Milanaugusto.federici @ unimi.it

  • Regulation of Hemostasis Blood hemostasis is composed by a

    series of integrated and regulated processes

    Coagulation factors are always

    balanced by coagulation inhibitors and fibrinolysis

  • Definitions of Thrombosis Thrombosis is the results of a series

    of abnormal reactions of hemostasis, conducting to increased formation of clots and vessel occlusion Arterial and venous thrombi can be

    formed and can be spread out into the circulation (embolism). When venous system is interested = VTE

  • CAUSES OF THROMBOSISThe Virchow TriadA) Vessel Wall Damage: Endothelial damage Atherosclerosis

    B) Blood reology: Increased stasis and viscosity

    D) Blood components: Cell adhesion (platelets) Hyper-coagulation Hypo-fibrinolysis

  • CAUSES OF THROMBOSISRisk FactorsA) Hereditary Thrombophilia: Congenital defects of physiologic inhibitors of blood coagulationB) Acquired Thrombophilia: Immobility Inflammation Malignancy Surgery Drugs (estrogens)

  • THROMBOPHILIAIt may be defined as a condition characterized by an increased risk of thromboembolism at relatively young age.It may secondary to congenital, or acquired causes and some of them may be detected by laboratory investigation.

  • Congenital or Acquired Conditions Associated with VTEAntithrombin deficiencyProtein C deficiencyProtein S deficiencyFibrinolysis defectsHeparin cofactor II deficiencyTFPI deficiency

  • Congenital or Acquired Conditions Associated with VTEModerate hyperhomocysteinemiaAPC ResistanceHigh factor levels (II, VIII, IX, XI, Fib.)High TAFI

  • Congenital or Acquired Conditions Associated with VTEAntiphospholipid syndromeDysfibrinogenemia

  • CAUSES OF THROMBOSISInherited defects of InhibitorsDefects associated with thrombosis Antithrombin III (1%) Protein C (5%) Protein S (3%) Dysfibrinogenemia (0.8%) Factor V Leiden (20%) Prothrombin gene mutation (6%) Homocysteinemia (10%)

  • CAUSES OF THROMBOSISAcquired defects in DVTDefects associated with Deep Vein Thrombosis (DVT): Elevated FVIII (16%) Elevated FXI (11%) Antiphospholipid antibodies (10%)

  • AT III DEFICIENCIESBiochemistry and Genetics AT III : a 58 kDa glycoprotein with

    plasma concentrations of 150 ug/mL is a serin protease inhibitor (serpins) that functions by forming a 1:1 complex with thrombin, Xa, IXa, XIa The 19 kb gene (7 ex, 6 int) is located

    on chromosome 1 (1q23-q25)

  • AT III DEFICIENCIESClassification of Inherited Defects Type I: low functional and low antigen ATIII

    1a: normal but reduced synthesis rate 1b: decreased abnormal ATIII (i.e. Pro407Leu) Type II: low functional, but normal antigen ATIII

    2a: Decreased activity (heparin binding) 2b: Decreased activity (Ser394Leu, Ala384Pro) 2c: Isolated low heparin binding activity (Arg47Cys, Pro41Leu)

  • AT III DEFICIENCIESAcquired & Associated Consumption coagulopathy: DIC Liver Dysfunction Renal Disease Malignancy : Leukemias Malnutrition & gastrointestinal loss Drugs: Estrogens, Hep, L-asparaginase Other: Vasculitis, hemodialysis,

    infections, plasmapheresis,

  • PROTEIN C DEFICIENCIESBiochemistry and Genetics Protein C: a vitamin K-dependent

    glycoprotein with Mr of 62 kD synthesized in the liver The 11 kb gene (9 exons) is located

    on chromosome 2 (2q14-21)

    PC defects are autosomally inherited:

    homozygous or compound heterozygous may be severely affected

  • PROTEIN C DEFICIENCIESBasic and Clinical Effects Reduced proteolytic cleavage of FV

    and FVIII: increased thrombin generation Venous thrombo-embolism occurs

    in patients with PC defects especially when associated with other defects: ATIII, PS, FV and II mutations & acquired defects

  • PROTEIN C DEFICIENCIESAcquired & Associated Consumption coagulopathy: DIC Liver Dysfunction Renal Disease Malignancy : Leukemias Drugs: Estrogens, Hep, L-asparaginase Other: Vasculitis, hemodialysis,

    infections, plasmapheresis,

  • PROTEIN S DEFICIENCIESBiochemistry and Genetics Protein S (PS): a vitamin K-dependent

    glycoprotein with Mr of 69 kD that serves as a cofactor of APC PS exists in plasma in two distinct forms:

    Free PS (40%) and PS-C4BP

    The 80 kb gene (15 exons) is located

    on chromosome 3

  • PROTEIN S DEFICIENCIESClassification of Inherited Defects Autosomal dominant defect Type I: low functional and low antigen PS:

    Low PS-free, low clotting (Most common heterozygous defects of PS) Type II: low functional, but normal antigen PS:

    Normal levels of total PS and free PS, but low functionally PS clottingType III: normal total PS, but low free and functional PS

  • PROTEIN S DEFICIENCIESAcquired & Associated Conditions with increased C4BP:

    Pregnancy, OCP, Diabetes, Inflammation, SLE, AIDS, Nephrosis Conditions with increased synthesis:

    Pre-term infants, liver disease, vit K defects, OAT, CT for breast cancer Conditions with increased cell binding:

    PV, ET, Sickle Cell disease

  • FACTOR V LEIDENDefinitions In 1993, Dahlback first described families with

    thrombosis whose plasma was resistant to the effects of activated protein C (APC) --Arg506-- APC --------I ---Arg562-- FV Leiden: a specific mutation: Arg-Gln506 FVIIIa F VaFV InactFVIII Inact

  • FACTOR V LEIDEN Epidemiology and Clinic 3-8% of Caucasians are heterozygous for the

    FV Leiden defect, 1/1000 are homozygous

    >90% of subjects who are APC resistant show

    the FV Leiden defect

    Many clinical studies have shown that the

    odds ratio (OR) for VTE in subjects with FV506 is 2-8 fold and is frequently (20%) in VTE

  • Main characteristics of congenitalAPC resistance (FV Leiden)

  • PROTHROMBIN G20210ADefinitions In 1996, a genetic defect (nt G20210A) was

    discovered in the 3 untranslated region of the prothrombin gene that was linked to an increased risk of VTE. The mutation is associated with elevated levels of Factor II

    The increased concentrations of Factor II could

    contribute to enhanced risk of VTE by promoting enhanced thrombin generation

  • PROTHROMBIN G20210A Epidemiology and Clinic 2-3% of Caucasians are heterozygous for the

    II G20210A. Rare homozygous have been reported

    Many clinical studies have shown that the

    odds ratio (OR) for thrombosis in subjects with Factor II G20210A is 2-6 fold, and has been identified in 4-8% of subjects with VTE

  • HOMOCYSTEINEMIADefinitions Elevated levels of homocysteine in the blood

    are strongly associated with premature vascular disease as well as arterial and VTE 2 enzymes and 3 vitamins play key roles in the regulation of homocysteine: Cystationine-beta-synthase (CBS) MethylenTetra-HydroFolate-Reductase (MTHFR)

  • HOMOCYSTEINEMIA Epidemiology and Clinic Data from a large number of studies strongly

    suggest that elevated levels of Homocys are associated with an elevated risk of arterial (OR 2-4) and venous (OD 2-7) occlusions

    End-stage renal disease, renal transplantation,

    and cyclosporin therapy are associated with high levels of Homocysteinemia

  • ANTIPHOSPHOLIPID SYNDROMEDefinitions Antiphospholipid antibodies (APA) are IgG, IgM

    or IgA allo-antibodies that occur as a results of autoimmune disease or as a reaction to infections or drugs.

    APA can be divided into two broad categories:

    - anticardiolipin antibodies (ACA) - lupus like anticoagulant (LLAC)

  • ANTIPHOSPHOLIPID SYNDROMEPathogenesis of Thrombosis Autoimmune APA are associated with

    thrombosis and vascular disease, whereas APA secondary to infections or drugs are usually asymptomatic

    APA may promote thrombosis by inhibiting the

    action of APC or by stimulating increased binding of prothrombin to PL surfaces: the result is excessive thrombin generation

  • ANTIPHOSPHOLIPID SYNDROME Diagnosis Two different types of assays can be used to determine the APA: 1) Assays in fluid phase: Lupus Anticoagulant

    APTT, DRVVT Dilute PT 2) Assays in solid phase: ACA

    anti-B2-GPI anti-II anti-ox-LDL

  • Patients with history of thrombosisFamily membersNo general screening of the population for APC resistance.Is prophylactic APC resistance testing beneficial in association with risk situation?

    Who should be testedLab diagnosis of thrombophilia

  • Laboratory diagnosis of thrombophiliaAfter (and far from) a thrombotic episodeAfter discontinuation of oral anticoagulationIs prophylactic APC resistance testing beneficial in association with risk s