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Diagnosi dei Difetti dellEmostasi Primaria Marco Cattaneo Unità di Ematologia e Trombosi Ospedale San Paolo DMCO, Università di Milano.

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Presentazione sul tema: "Diagnosi dei Difetti dellEmostasi Primaria Marco Cattaneo Unità di Ematologia e Trombosi Ospedale San Paolo DMCO, Università di Milano."— Transcript della presentazione:

1 Diagnosi dei Difetti dellEmostasi Primaria Marco Cattaneo Unità di Ematologia e Trombosi Ospedale San Paolo DMCO, Università di Milano

2 EMOSTASI Fase vasopiastrinica (Emostasi Primaria) Fase della coagulazione Fase della fibrinolisi

3 EMOSTASI Fase vasopiastrinica (Emostasi Primaria) Fase della coagulazione Fase della fibrinolisi

4 EMOSTASI TROMBOSI Meccanismo di difesa che arresta il sanguinamento da soluzioni di continuo dellalbero vascolare Dipende da una complessa interazione tra flusso ematico, parete vascolare e sangue (cellule e proteine del plasma) Forma malregolata o inappropriata di emostasi

5 Tutti i test di laboratorio che esplorano lemostasi primaria sono utili solamente per la diagnosi dei difetti dellemostasi Nessuno di essi e utile per la definizione del rischio trombotico o per il monitoraggio della terapia antitrombotica

6 vaso Lesione di continuo sottoendotelio w ww w w FASE VASO-PIASTRINICA sottoendotelio

7 w ww w w www FASE VASO-PIASTRINICA

8 Difetti dellEmostasi Primaria Piastrinopenie Piastrinopatie Difetti di proteine adesive (afibrinogenemia, malattia di von Willebrand) Anemia (es: uremia)

9 Difetti dellEmostasi Primaria Piastrinopenie Piastrinopatie Difetti di proteine adesive (afibrinogenemia, malattia di von Willebrand) Anemia (es: uremia)

10 PIASTRINOPENIA Classificazione PIASTRINOPENIE EREDITARIE PIASTRINOPENIE ACQUISITE: - Da ridotta o difettosa produzione midollare - Da aumentata distruzione/consumo periferico su base immune su base non immune - Da sequestro od anomalo pooling - Da emodiluizione PSEUDOPIASTRINOPENIA (riduzione in vitro della conta piastrinica, per agglutinazione EDTA-dipendente)

11 PIASTRINOPENIA Pseudopiastrinopenia?

12 PIASTRINOPENIA Pseudopiastrinopenia? Striscio di sangue periferico in EDTA

13 Normale – Sangue in EDTA

14 Pseudopiastrinopenia – Sangue in EDTA

15 Satellitismo piastrinico

16 STOP Ereditaria o Acquisita? Conta piastrinica normale in passato? Familiarità? Anomalie morfologiche e/o funzionali? EreditariaAcquisita Sì No PIASTRINOPENIA Pseudopiastrinopenia? Striscio di sangue periferico in EDTA

17 Inherited Thrombocytopenias: a Proposed Diagnostic Algorithm from the Italian Gruppo di Studio delle Piastrine CL Balduini, M Cattaneo, F Fabris, P Gresele, A Iolascon, FM Pulcinelli, A Savoia, on behalf of the Italian Gruppo di Studio delle Piastrine Haematologica 2003, 88:

18 PIASTRINOPENIA ACQUISITA [Emocromo, MPV] [Striscio di sangue periferico] Anamnesi farmacologica e trasfusionale Valutazione splenomegalia Markers virus epatite, Herpes, HIV Elettroforesi sieroproteica Analisi aspirato midollare (obbligatorio se >60 anni e se anomalie sangue periferico) Ricerca ANA Ridotta/difettosa Produzione di MK/plts Aumetata distruzione/consumo Sequestro o pooling anomalo

19 Difetti dellEmostasi Primaria Piastrinopenie Piastrinopatie Difetti di proteine adesive (afibrinogenemia, malattia di von Willebrand) Anemia (es: uremia)

20 Patients with bleeding diathesis, no thrombocytopenia:

21 Screening tests: PT, aPTT, BT (or PFA-100)

22 Punteggio normali (03) basso (47) intermedio (811) alto (1219) p Numero TE (min) 5.3 (3,0-10,0) 5.0 ( ) 5.0 ( ) 4.8 ( ) PCE (s) 130 (85-244) 142 (88-300) 152 (74-300) 153 (95-300) PCA (s) 85 (67-179) 91 (57-182) 89 (59-300) 95 (73-207) Valori mediani (range) Kruskall-Wallis test

23 P Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

24 P N Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

25 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT N aPTT, BT PT, BT BT - aPTT Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

26 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT N aPTT, BT PT, BT BT - aPTT Work-up for hemophilia Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

27 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT N aPTT, BT PT, BT BT - aPTT Work-up for hemophilia FVII FXI, FIX FV, FX, FII FV FVII FVIII Fibrinogen Fibrinogen Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

28 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophilia FVII FXI, FIX FV, FX, FII FV FVII FVIII Fibrinogen Fibrinogen Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

29 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophiliaWork-up for vWD FVII FXI, FIX FV, FX, FII FV FVII FVIII Fibrinogen Fibrinogen Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

30 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophiliaWork-up for vWD FVII FXI, FIX FV, FX, FII FV FVII vWD FVIII Fibrinogen Fibrinogen Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

31 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophiliaWork-up for vWD FVII FXI, FIX FV, FX, FII FV FVII vWD negative FVIII Fibrinogen Fibrinogen Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

32 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophiliaWork-up for vWD FVII FXI, FIX FV, FX, FII FV FVII vWD negative FVIII Fibrinogen Fibrinogen Work-up for Platelet Function Disorders Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

33 Diagnosi di malattia di von Willebrand

34 Adapted from Castaman et al, 2003 plasma VWF:Ag Absent Present Diagnostic Flow Chart of VWD Types

35 Adapted from Castaman et al, 2003 plasma VWF:Ag Absent Present Type 3 Diagnostic Flow Chart of VWD Types

36 Adapted from Castaman et al, 2003 plasma VWF:Ag Absent Present Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCo

37 Adapted from Castaman et al, 2003 plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) Type 2 Type 1 Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

38 Adapted from Castaman et al, 2003 plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) R.I.P.A (mg/mL) Increased ( ) Decreased (>1.2) Type 2 Type 1 Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

39 Adapted from Castaman et al, 2003 Type 2B plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) R.I.P.A (mg/mL) Increased ( ) Decreased (>1.2) Type 2 Type 1 Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

40 Adapted from Castaman et al, 2003 Type 2B plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) R.I.P.A (mg/mL) Increased ( ) Decreased (>1.2) Plasma High Multimers Type 2 Type 1 Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

41 Adapted from Castaman et al, 2003 Type 2B Type 2M Type 2A plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) R.I.P.A (mg/mL) Increased ( ) Decreased (>1.2) Plasma High Multimers Absent Present Type 2 Type 1 Type 3 Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

42 Adapted from Castaman et al, 2003 Type 2B Type 2M Type 2A plasma VWF:Ag Absent Present Proportionate (0.7 – 1.2) Discrepant (<0.7) R.I.P.A (mg/mL) Increased ( ) Decreased (>1.2) Plasma High Multimers Absent Present Type 2 Type 1 Type 3 Proportionate Discrepant Type 2N Platelet VWF Plasma FVIII:C/vWF:Ag FVIII binding assay Diagnostic Flow Chart of VWD Types plasma VWF:RCoRco:Ag

43 P PT aPTT PT, aPTT PT, aPTT, BT PT, BT PTT, BT BT - N aPTT, BT PT, BT BT - aPTT PT PT, aPTT PT, aPTT, BT Work-up for hemophiliaWork-up for vWD FVII FXI, FIX FV, FX, FII FV FVII vWD negative FVIII Fibrinogen Fibrinogen Work-up for Platelet Function Disorders Patients with bleeding diathesis, no thrombocytopenia: Screening tests: PT, aPTT, BT (or PFA-100)

44 Aggregazione piastrinica

45 OUT IN

46 GPIIb/IIIa OUT IN OUT IN

47 Epinephrine Thrombin TxA2 ADP 5HT Shear GPIIb/IIIa OUT IN OUT IN

48 GPIIb/IIIa OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

49 GPIIb/IIIa OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

50 Adesive protein GPIIb/IIIa OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

51 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

52 Platelet 1 Platelet 2 Platelet Aggregation

53 Strong agonists Aggregation TxA 2 Synthesis Secretion ADP Low [Ca 2 ] o Weak agonists

54 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

55 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

56 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

57 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

58 Adesive protein GPIIb/IIIa OUT IN OUT IN OUT IN Epinephrine Thrombin TxA2 ADP 5HT Shear OUT IN

59 Strong agonists Aggregation TxA 2 Synthesis Secretion ADP Low [Ca 2 ] o Weak agonists

60 Diagnosi di difetti funzionali piastrinici

61 1.Whom? Patients with positive history for abnormal bleedings (particularly if mucocutaneous and/or associated with prolonged BT or PFA-100 CT), in whom the following conditions were excluded: Thrombocytopenia vWD Afibrinogenemia Drugs known to affect platelet function Patients with positive history for abnormal bleedings (any type), in whom other hemostatic abnormalities were ruled out Inherited Platelet Function Disorders Laboratory Diagnosis - 1

62 Inherited Platelet Function Disorders Laboratory Diagnosis - 2 Where? –Specialized institutions (importance of pre- analytical variables!) First-step screening tests: –Simple –Rapid –Cost-effective –Sensitive to the most common disorders

63 1.Light microscopy of whole-blood smear: platelet size and morphology Inherited Platelet Function Disorders First-step screening tests

64 Bernard-Soulier syndrome Pseudo-vWD Bolin-Jamieson syndrome Glanzmann thrombasthenia GPIa/IIa deficiency GPVI deficiency P2Y 12 defects TxA 2 receptor defects α 2 -receptor defect δ-Storage Pool Deficiency α,δ -Storage Pool Deficiency Grey-Platelet Syndrome Quebec Platelet disorder Paris-Trousseau- Jacobsens Syndrome Defects of signal transduction Scott syndrome Stormorken syndrome Primary Secretion Defects Macrothrombocytopenia with glycophorin expression Wiskott-Aldrich syndrome Montreal Platelet syndrome Inherited Platelet Function Disorders that can be suspected by inspection of the blood smear

65 Inherited Platelet Function Disorders Laboratory Diagnosis - 2 Where: –Specialized laboratories (importance of pre-analytical variables!) First-step screening tests: –Simple –Rapid –Cost-effective –Sensitive to the most common disorders

66 Patients screened for Platelet Function Disorders at the A. Bianchi Bonomi Hemophilia and Thrombosis Ctr, University of Milano - From 1990 to 2002 Total number of screened patients:318 Diagnosis: No abnormalities187 (59%) Primary Secretion Defects 63 (20%) δ-Storage Pool Deficiency 38 (12%) Glanzmann Thrombasthenia 5 (2%) Aspirin-like Defects 4 (1.3%) Bernard-Soulier syndrome 3 (1%) P2Y 12 defect 2 (0.6%) Incomplete 15 (5%)

67 Patients screened for Platelet Function Disorders at the A. Bianchi Bonomi Hemophilia and Thrombosis Ctr, University of Milano - From 1990 to 2002 Total number of screened patients:318 Diagnosis: No abnormalities187 (59%) Primary Secretion Defects 63 (20%) δ-Storage Pool Deficiency 38 (12%) Glanzmann Thrombasthenia 5 (2%) Aspirin-like Defects 4 (1.3%) Bernard-Soulier syndrome 3 (1%) P2Y 12 defect 2 (0.6%) Incomplete 15 (5%)

68 Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies in one hundred six patients HK Nieuwenhuis, JW Akkerman, JJ Sixma Blood 1987; 70:

69 1.Light microscopy of whole-blood smear: platelet size and morphology 2.Lumiaggregometry on citrated PRP: explores platelet aggregation and secretion simultaneously: ADP 2 μM (if abnormal, ADP 10 μM) Collagen 2 μg/mL (if abnormal, 10 μg/mL) U μM Adrenaline 5 μM Ristocetin 1.2 mg/mL (if normal, 0.6 mg/mL) Arachidonic acid 1 mM No agonists (SPA) Inherited Platelet Function Disorders First-step screening tests

70 NormalII-7 Normal + ASA II-4II-6III Platelet aggregation (upper tracings) and secretion (lower tracings) induced by ADP at the indicated concentrations (μM), obtained with the lumiaggregometer

71 Bernard-Soulier syndrome Pseudo-vWD Bolin-Jamieson syndrome Glanzmann thrombasthenia GPIa/IIa deficiency GPVI deficiency P2Y 12 defects TxA 2 receptor defects α 2 -receptor defect δ-Storage Pool Deficiency α,δ -Storage Pool Deficiency Grey-Platelet Syndrome Quebec Platelet disorder Paris-Trousseau- Jacobsens Syndrome Defects of signal transduction Scott syndrome Stormorken syndrome Primary Secretion Defects Macrothrombocytopenia with glycophorin expression Wiskott-Aldrich syndrome Montreal Platelet syndrome Inherited Platelet Function Disorders that can be identified by the first screening step

72 1.Light microscopy of whole-blood smear: platelet size and morphology 2.Lumiaggregometry on citrated PRP: explores platelet aggregation and secretion simultaneously ADP 2 μM (if abnormal, ADP 10 μM) Collagen 2 μg/mL (if abnormal, 10 μg/mL) U μM Adrenaline 5 μM Ristocetin 1.2 mg/mL (if normal, 0.6 mg/mL) Artachidonic acid 1 mM No agonists (SPA) 3.Clot retraction (save serum for TxB 2 assay, to confirm abnormalities of AA pathway or rule out NSAID) Inherited Platelet Function Disorders First-step screening tests

73 Raccomandazioni Test dellemostasi primaria: no per trombosi Sospettare pseudopiastrinopenia (striscio!) Anticorpi antipiastrine: inutili Escludere VWD e farmaci prima di indagare difetti funzionali piastrinci Diagnosi di difetti funzionali piastrinici: lumiaggregometria Diagnosi di difetti funzionali piastrinici: solo in Centri specializzati


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