6 difetto coagulativo Cause congenite Malattia di von Willebrand; Emofilia A (deficit fattore VIII);Emofilia B (deficit fattore IX);Deficit qualitativi o quantitativi del fibrinogeno;Emofilia C (deficit fattore XI);Deficit di fattore VII;Deficit di fattore XII, V, XIII, X e II;Deficit combinati di fattori V + VIII, VII + VIII, VIII + IX.
7 difetto coagulativo Cause acquisite Deficit vitamina K Insufficienza epaticaCoagulazione intravascolare disseminata (CID)Deficit di fibrinogeno1. terapia con L-asparaginasi2. morso di serpenteAnticorpi anticoagulanti circolanti (anti-fattore VIII)1. tumori2. LES3. idiopatici4. post-partum
8 fattore di von Willebrand Factor (vWF) sintetizzato nei megacariociti e nelle cellule endoteliali(MW kD)formazione di multimeri a livello plasmatico(MW 1x x106 kD).carrier del fattore VIII a livello plasmaticomultimeri ad alto peso molecolaremolto efficaci nel mediare l’adesione piastrinicapreponderanti nelle cellule endoteliali e nel subendotelio;
13 vonWillebrand Disease vonWillebrand Disease (VWD) is the most common inherited bleeding disorder, with anestimated incidence as high as 1 in 100 to 1000.Classification: There are three main types of VWD.1. Type I - by far the most common form. Inheritance is autosomaldominant. Most patients are heterozygotes.Mild to moderate decrease in plasma VWF concentrations.Most patients have mild disease with excessive bleeding aftersurgery or trauma.2. Type II - Rare, patients have normal levels but dysfunctional VWF,leading to decreased VWF activity.IIa - deficiency in high and medium molecular weight VWF due toeither inability to secrete them from the megakaryocyte or endothelialcell or due to proteolysis as soon as they enter the circulation.IIb - also a deficiency in high molecular weight VWF, but due toinappropriate binding of VWF to platelets.3. Type III - Severe decrease in plasma VWF levels. Most individuals are theoffspring of two Type I patients and therefore homozygous.
14 2. DDAVP (desmopressina) Options for therapy:1. Cryoprecipitate (which is rich in VWF) or Factor VIII concentrates (whichcontain some high molecular weight VWF)For minor bleeding such as epistaxis, a single dose may suffice.Perioperatively, either must be given twice a day until hourspost-op2. DDAVP (desmopressina)Triples the plasma VWF in normal patients and in those with mildVWD.Not effective in Type III, because there is no VWF to begin with.Should do trial to ensure that patient will respond before actuallyusing DDAVP for treatment.Effects last 2-3 days before tachyphylaxis can occur3. Note: Aspirin is totally contraindicated in patients with VWD becauseof inhibitory effect on platelet aggegration. This would exacerbate VWD.There is an acquired form of VWD, which occurs when antibodies inhibit VWF or whentumors (such as lymphoid tumors) that adsorb VWF on to their surface are present.
15 Malattia di von Willebrandt I.EpidemiologyA .Most common inherited bleeding disorderB.Mild bleeding disorder (often undiagnosed)C.Autosomal dominant disorderII.PathophysiologyA.Von Willebrand factor mediates platelet adhesionB.vWF Deficiency results in mucocutaneous bleedingIII.Symptoms and SignsA.Severe Menorrhagia (common presentation in women)B.Postpartum Hemorrhage several days after deliveryIV.LabsA.Lab Results vary over time in each patientB.Partial Thromboplastin Time (PTT) prolongedC.Bleeding Time prolongedV.ManagementA.Synthetic hormone arginine vasopressin (DDAAVP)1.Indicated for surgery or traumaB.Cryoprecipitate
16 I. Review - Factor VIII(FVIII): Factor VIII is the precursor to Factor VIIIa, which catalyzes the activation of Factor IX toIXa. Protein C and Protein S function to inactivate Factor VIIIa.FVIII normally circulates in the plasma bound to vonWillebrand Factor. This associationhas several functions including protecting FVIII from proteolysis, enhancing FVIIIsynthesis, and concentrating FVIII at the site of active hemostasis.FVIII is a dimer with A,B,and C domains on each monomer. When activated, it becomes atrimer which has lost most of the B domain.II. Hemophilia AA. Inheritance is X-linked recessive.B. Incidence is 1 in 5000 live male births.C. Mechanism - quantitative deficiency in the synthesis of FVIII
17 D. Clinical features1. Suspect hemophilia in any male who has history of extensive bleeding aftertrauma or spontaneous bleeding into joints and muscles.2. Excessive bleeding at time of circumcision3. Severity of bleeding depends on level of FVIIISevere hemophilia - FVIII < 1% - at risk for spontaneous hemorrhages and softtissue bleeds.Moderate hemophilia - FVIII 1-5%Mild hemophilia - FVIII > 5% - little risk for spontaneous bleeds but may bleedexcessively following surgery or trauma.E. Lab abnormalities1. Prolongation of aPTT (variable with degree of hemophilia)2. Decreased FVIII acitvity3. Normal vonWillebrand Factor and Ristocetin cofactor4. Normal bleeding time
18 4. The amount of FVIII to give depends on the severity of the bleed. F. Management1. Avoid aspirin2. Mild hemophilia - prophylaxis with desmopressin (DDAVP) before dentalprocedures or minor surgery. Desmopressin induces release of stored FVIII andvonWillebrand Factor. If the increase in FVIII activity is not sufficient, administerFVIII concentrates. Antifibrinolytics such as aminocaproic acid may be helpful. Formajor surgery, give FVIII concentrates perioperatively.3. Moderate and Severe hemophilia - give FVIII concentrate at the earliest signof bleeding. Desmopressin will not be helpful because these patients do not haveenough stored FVIII.4. The amount of FVIII to give depends on the severity of the bleed.Major bleeding or surgery % replacementHemarthroses - 25% replacementFor major bleeding, treat for 10 days.To prevent hemarthosis induced joint destruction, some propose prophylactic FVIIIconcentrates three times a week to maintain trough levels of FVIII activity between1-3%.
21 Il fattore VIII ricombinante è disponibile per Prima priorità - Pazienti mai precedentemente trattatiSeconda priorità - Pazienti HCV e HIV negativiTerza priorità - Pazienti con infezione da HIVQuarta priorità - Pazienti con infezione da HCV
22 5. Available forms of FVIII Fresh frozen plasmaCryoprecipitate - contains FVIII, vonWillebrand factor, and fibrinogenConcentratesIntermediate purity with specific activity of FVIII < than 10units/mg.High purity with specific activity of FVIII ~ 150 units/mg.Ultra-high purity with specific activity of FVIII ~ 3000 units/mgRecombinant FVIII with specific activity of FVIII units/mg.Porcine FVIII - high degree of homology with human FVIII, but much greaterpotency. There is about 25% cross-reactivity between porcine and human FVIII.
23 III. Factor VIII Inhibitors A. Acquired, not inherited B. They are antibodies that neutralize FVIII and can either be alloantibodiesagainst exogenous FVIII or autoantibodies.C. They are a serious complication of FVIII treatment in the severe hemophiliacpopulation where the incidence of developing an inhibitor is 15-20%..D. Inhibitors can also occur in non-hemophiliac patients in the setting of:1. Idiopathic conditions - i.e. otherwise normal elderly individuals.2. Autoimmune disorders such as systemic lupus erythematosus, rheumatoidarthritis, etc.3. Malignancies such as lymphoproliferative disorders, lymphomas, and solidtumors.4. Drug reactions to penicillin, chloramphenicol, phenytoin, etc.5. Pregnancy and the postpartum state
24 E. Risk factors for development of antibodies 1. Severity of hemophilia: Patients with severe hemophilia are at much higher riskbecause they are exposed to more FVIII therapy.2. Age of the patient and degree of FVIII exposure: % of heavily treatedhemophiliac children develop antibodies by the age of 20.3. Genetic defect that results in the absence of synthesis of FVIII protein: Thesepatients are at greater risk for developing antibodies after treatment with FVIIIconcentrates.F. Characteristics of FVIII antibodies1. The majority of FVIII inhibitors are IgG antibodies, more specifically of the IgG4subclass.2. There are two main types of antibodiesType I antibodies - seen in classic hemophiliacs. Their inhibition of FVIII followslinear kinetics.Type II antibodies - these are the autoantibodies and they exhibit a more complexpattern of inhibition.3. Antibodies are identified by their ability to neutralize FVIII at 37 degrees Celciusafter incubation for 2-3 hours.
25 2. Laboratory information G. Diagnosis1. Clinical suspiciona. Whenever classic hemophiliacs show a decreased response to FVIIIreplacement therapy, screen for FVIII inhibitor.b. Acquired inhibitors should be suspected when non-hemophiliac patientspresent with spontaneous hematomas with sudden, life-threatening bleeds.2. Laboratory informationa. aPTT - will be prolonged and will not correct upon mixing patient's plasmawith normal plasma.b. However, the presence of FVIII inhibitor can be confirmed by addinginhibitor plasma with normal plasma and then assaying all the residualclotting factors in the normal plasma.c. Quantification of the inhibitor can be done with the Bethesda Assay
26 H. Characteristics of patients - Grouped as low responders or high responders 1. Low responders are patients who usually have low titers of inhibitor (less than 10BU), which does not increase after challenge with FVIII. Therefore, these patientsdo not show significant anamnestic response with subsequent FVIII treatments.2. High responders are mostly hemophiliacs who develop a high titer of inhibitorwhen challenged with FVIII.
27 a. Mild bleeding episodes - options include: I. ManagementLow respondersa. Mild bleeding episodes - options include:Prothrombin complexes - contain all Vitamin K-dependent clottingfactors (II, VII, IX, X, and thrombin)Activated prothrombin complexes - contain activated clotting factorsRecombinant FVIIIThe first two are bypass agents because they do not contain FVIII.Other bypass agents include Factor VIIa and Factor IXa, whichbypass the necessity for FVIII mediated activation of FIX. However,these two are under clinical trials currently and may be associatedwith increased risk of thrombosis.b. Severe bleeding - options include:High dose human Factor VIIIPorcine Factor VIII (see above)Factor VIIa or another by pass agent
28 High responders a. Mild bleeding episodes - considerations include: Avoiding FVIII products to prevent an anamnestic response, whichwould preclude this treatment from being a treatment option in theevent of future bleeding episodes.b. Severe bleeding episodesUse human or porcine FVIII until an anamnestic response occurs,after which a bypass agent must be used instead.5. Alternative therapiesa. Immunosuppressive agents to control antibody productionCorticosteroidsCyclophosphamideAzithoprineb. Intravenous gamma globulin - in the hope that some antibodies in thispooled sample may be directed against the inhibitorc. Induction of immune tolerance to suppress inhibitor formation byadministration of FVIII on a continuous basis.
29 Factor IX Deficiency I. Review - Factor IX(FIX): Factor IX is the precursor to Factor IXa, which is a Vitamin K-dependent serine proteasethat catalyzes the activation of Factor X to XaFIX normally circulates in the plasma in an inactive form. Factor VIIIa plays a role in theenzymatic activation of FIX to FIXa.FIX can also be activated directly by Tissue Factor - Factor VIIa complex in the extrinsicpathway.FIXa is a serine protease.II. Hemophilia B (Christmas Disease)A. Inheritance is X-linked recessive.B. Incidence is 1 in 30,000 live male births.C. Mechanism - quantitative deficiency in the synthesis of FIX
30 D. Clinical features - identical to Hemophilia A 1. Suspect hemophilia in any male who has history of extensive bleeding aftertrauma or spontaneous bleeding into joints or muscles.2. Bleeding at time of circumcision3. Severity of bleeding depends on level of FIXSevere hemophilia - FIX < 1% - at risk for spontaneous hemorrhages and softtissue bleeds.Moderate hemophilia - FIX 1-5%Mild hemophilia - FIX > 5% - little risk for spontaneous bleeds but may bleedexcessively following surgery or trauma.E. Lab abnormalities1. Prolongation of aPTT (variable with degree of hemophilia)2. Decreased FIX acitvity3. Normal bleeding time and thrombin time.
33 F. Management 1. Avoid aspirin 2. Mild hemophilia - Antifibrinolytics such as aminocaproic acid may be helpful. Formajor surgery, give FIX concentrates perioperatively. For surgery, the FIX activityshould be maintained between 30-60%. Higher levels may lead to thrombosis (seebelow).3. Moderate and Severe hemophilia - give FIX concentrate at the earliest sign ofbleeding.4. Available forms of FIXFIX concentratesProthrombin complex - contains the inactive Vitamin K-dependent clotting factorsActivated prothrombin complex - contains the active Vitamin K-dependent clottingfactors.Fresh frozen plasma - contains FIX. Limited by the fact that unless exchangetransfusion is done, sufficient FFP cannot be given to patients with severehemophilia to raise FIX levels sufficiently in order to prevent or control bleedingepisodes.
36 esami di laboratorio della CID: PT allungatoaPTT allungatod-dimero aumentatofibrinogeno ridottopiastrine ridotteterapia della CID:rimuovere la causaAT-IIIplasmaeparinaanti-fibrinolitici
37 difetto parete vascolare aumentata fragilita’ vascolareporpora non-trombocitopenicacause:A. Eta’ (porpora senile)B. FarmaciC. Deficit vitamina CD. InfezioniD. Malattie del collagene (vasculiti)E. Paraproteinemia (amiloidosi, crioglobulinemia)F. Telangectasia emorragica ereditariaG. deposizione da immunocomplessimalattia da sieroporpora di Henoch-Schonlein
38 Causes of thrombocytosis Secondary or reactive thrombocytosisInfection (acute and chronic)Inflammatory disorders (eg Kawasaki's disease)Chronic iron deficiencyAcute or chronic blood lossTissue damage from trauma or surgeryMedicines (steroids)SplenectomyMalignancy (Hodgkin's disease, solid tumours)Rebound from chemotherapyPrimary thrombocytosisEssential thrombocytosisChronic myeloid leukaemiaPolycythaemia veraMyelofibrosisMyelodysplastic syndromes
46 Stato trombofilico trombosi in eta’ giovanile (< 50 anni) familiarita’ per trombositrombosi ricorrentitrombosi in sedi insolitegravidanze ripetutamente complicate da aborti
47 Factor V Leiden Deficiency (APCR) Prothrombin 20210Hyperhomocysteinemiacause frequenticause meno frequentiprimari (ereditari)Antithrombin III deficiencyProtein C DeficiencyProtein S DeficiencyFactor VIII IncreasedFibrinolysisDysfibrinogenemiaPregnancyEstrogensSurgeryTraumaInfection or SepsisMalignancyMyeloproliferative disorderHyperlipidemiaHomocystinuriaLupus Inhibitor (LAC)Antiphospholipid Antibodies (ACL)Nephrotic SyndromeOral ContraceptivesEstrogen Replacement therapytamoxifensecondari
48 Activated Protein C Resistance (Factor V Leiden) A. Inheritance - autosomal dominantB. Epidemiology1. Estimated to occur in 25-40% of patients with family history of thrombosis.2. It also occurs in 3-5% of apparently normal individuals.C. Mechanism: the arginine at position 506 is substituted with glutamine.This renders FVa resistant to cleavage by APC.D. Clinical Features1. Mean onset of DVT: 44 in heterozygotes, 31 in homozygotes;2. Increased risk of venous thrombosis and pulmonary embolism. Venous thrombosisoccurs most frequently in the deep veins of the lower extremities.3.Thrombosis may be precipitated by surgery, trauma, pregnancy, OCP use, or infection.4. Arterial thrombosis is not increased.
49 Thrombophilic Status Relative Risk of DVT NormalOral contraceptive (OCP) use 4Factor V Leiden, heterozygous 5 to 7Factor V Leiden, heterozygous + OCP 30 to 35Factor V Leiden, homozygous 80Factor V Leiden, homozygous + OCP >100Prothrombin Gene Mutation, heterozygous 3Prothrombin Gene Mutation, homozygous ???Prothrombin Gene Mutation, heterozygous + OCP 16Protein C deficiency, heterozygous 7Protein C deficiency, homozygous Severe DVT at birthProtein S deficiency, heterozygous 6Protein S deficiency, homozygous Severe DVT at birthAntithrombin deficiency, heterozygous 5Antithrombin deficiency, homozygous lethal prior to birthHyperhomocysteinemia to 4Hyperhomocyst + Factor V Leiden, heterozygous 20
51 Management A.High Risk Indications for life-long Anticoagulation 1.Two or more spontaneous thrombotic events2.One spontaneous life-threatening event (PE)3.One spontaneous event with high risk causea. Antiphospholipid Syndromeb. Antithrombin III deficiencyc. More than one inherited abnormalityB.Moderate Risk Indications for event-based prophylaxis1.One event with known provocative stimulus
52 Farmaci per il controllo dell’emostasi piastrineplasmaderivati del plasmafattori ricombinantiinibitori della fibrinolisivitamina Kprocoagulantieparinadicumaroliciattivatori del plaminogenoanti-aggreganti piastrinicianticoagulanti