Emostasi, trombosi e piastrine

Emostasi, trombosi e piastrine Marco Ca2aneo Medicina 3, Ospedale San Paolo, Milano. Dipar;mento di Scienze della Salute, Università degli Studi di Milano. Sessioni educazionali •  Bleeding disorders –  Regula;on of the coagula;on by the fibrinoly;c system – K.A. Haijar –  How to assess the bleeding phenotype – F. Rodeghiero –  Acquired hemophilia A – P.D. Collins •  Coagula/on problems in intensive care –  Coagulopathy in trauma and massive preopera;ve bleeding – D. Bolliger –  Mission impossible: DIC protocol – J. Thachil –  Heparin-­‐induce thrombocytopenia – A. Greinacher •  Platelets –  Recent advances in platelet signalling – A. Poole –  Inherited platelet func;on disorders – C. Van Geets –  P2Y12 inhibitors: any role for laboratory monitoring? – M. Ca2aneo •  Thrombosis –  Blood coagula;on ac;vity and atherosclerosis – H. ten Cate –  Detec;on and role of circula;ng micropar;cles in thrombosis – M.J. Mooberry –  Primary preven;on of venous thromboembolism – A. T. Cohen Sessioni educazionali •  Bleeding disorders –  Regula;on of the coagula;on by the fibrinoly;c system – K.A. Haijar –  How to assess the bleeding phenotype – F. Rodeghiero –  Acquired hemophilia A – P.D. Collins •  Coagula/on problems in intensive care –  Coagulopathy in trauma and massive preopera;ve bleeding – D. Bolliger –  Mission impossible: DIC protocol – J. Thachil –  Heparin-­‐induce thrombocytopenia – A. Greinacher •  Platelets –  Recent advances in platelet signalling – A. Poole –  Inherited platelet func;on disorders – C. Van Geets –  P2Y12 inhibitors: any role for laboratory monitoring? – M. CaCaneo •  Thrombosis –  Blood coagula;on ac;vity and atherosclerosis – H. ten Cate –  Detec;on and role of circula;ng micropar;cles in thrombosis – M.J. Mooberry –  Primary preven/on of venous thromboembolism – A. T. Cohen George, Am J Hematol 2012
George, Am J Hematol 2012
Afdhal et al, NEJM 2012
ANALYSIS OF BASELINE BONE MARROW CHARACTERISTICS IN A LONGITUDINAL 2-­‐YEAR BONE MARROW STUDY OF ELTROMBOPAG IN PREVIOUSLY TREATED PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA -­‐ R Brynes et al •  TPO-­‐RAs have been associated with varying degrees of increases in re;culin fibers [Brynes 2011, Ghanima 2011], but the lack of prospec;vely collected and consistently stained and analyzed pre-­‐treatment bone marrow specimens has limited the robustness of the conclusion. •  This study was designed to prospec;vely inves;gate poten;al effects of eltrombopag on the bone marrow. ANALYSIS OF BASELINE BONE MARROW CHARACTERISTICS IN A LONGITUDINAL 2-­‐YEAR BONE MARROW STUDY OF ELTROMBOPAG IN PREVIOUSLY TREATED PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA -­‐ R Brynes et al •  Re;culin fibers were graded as MF-­‐0 in 139 (90%) and MF-­‐1 in 16 (10%) pa;ents. •  Re;culin fibers were graded as MF-­‐0 for all 12 pa;ents who had received prior TPO-­‐RA treatment. •  No pa;ents demonstrated collagen deposi;on. RESULTS FROM A PHASE IV OPEN-­‐LABEL STUDY EVALUATING CHANGES IN BONE MARROW MORPHOLOGY IN ADULT IMMUNE THROMBOCYTOPENIA (ITP) PATIENTS RECEIVING ROMIPLOSTIM: ANALYSIS OF THE 1-­‐YEAR ROMIPLOSTIM COHORT. F Rodeghiero et al •  The study of adult ITP pa;ents treated with romiplos;m was designed to prospec;vely evaluate bone marrow biopsies for collagen and re;culin levels. •  Changes in cytokine levels (TGF-­‐ß, PDGF, bFGF, and osteoprotegerin) rela;ve to bone marrow changes were also assessed. RESULTS FROM A PHASE IV OPEN-­‐LABEL STUDY EVALUATING CHANGES IN BONE MARROW MORPHOLOGY IN ADULT IMMUNE THROMBOCYTOPENIA (ITP) PATIENTS RECEIVING ROMIPLOSTIM: ANALYSIS OF THE 1-­‐YEAR ROMIPLOSTIM COHORT. F Rodeghiero et al •  Of the 50 pa;ents enrolled in the 1-­‐year romiplos;m cohort, 37 (74%) had grade 0 re;culin, 13 (26%) had grade 1 re;culin, and none had collagen in baseline biopsies. •  Examina;on of the 38 available biopsies from the 1-­‐year cohort showed that none had collagen and 2 had an increase in re;culin grade from 0 to 2. •  Overall, cytokine levels remained within normal levels. Primo quesito Quali limi; all’uso dei TPO mime;ci? Absolute risk of DVT in hospitalized pa;ents not receiving prophylaxis Pa/ent group DVT Prevalence, % Medical pa;ents 10-­‐20 General surgery 15-­‐40 Major gynecologic surgery 15-­‐40 Major urologic surgery 15-­‐40 Neurosurgery 15-­‐40 Stroke 20-­‐50 Hip or knee arthroplasty, hip fracture surgery 40-­‐60 Major trauma 40-­‐80 Spinal cord injury 60-­‐80 Cri;cal care pa;ents 10-­‐80 ACCP, 2004
Metanalysis of DVT prophylaxis Dentali, F. et. al. Ann Intern Med 2007;146:278-288
Metanalysis of PE prophylaxis Dentali, F. et. al. Ann Intern Med 2007;146:278-288
Metanalysis of bleeding risk Dentali, F. et. al. Ann Intern Med 2007;146:278-288
Extended thromboprophylaxis •  Extended thromboprophylaxis for about 30 days (enoxaparin, rivaroxaban, apixaban) vs about 10 days enoxaparin were associated with higher incidence of bleeding •  Higher efficacy for extended enoxaparin or rivaroxaban, no effect of apixaban •  In general, risk-­‐to-­‐benefit ra;o unclear An;thrombo;c prophylaxis in the non surgical pa;ent Acutely ill Età > 65 anni Scompenso cardiaco conges;zio Insufficienza respiratoria grave Condizioni acute infepve, reuma;che o infiammatorie •  Immobilizzazione + altro fdr (età >40, cancro, VTE pregressa, infezione grave) • 
• 
• 
• 
Predic;on of TEV •  There are a few predic;on diagrams available, which have been validated in limited and/or selected popula;ons. •  The main limita;on of each is that weight of interac;on of different risk factors has been arbitrarily a2ributed, and so has a score value. •  Another important limit is that these prediciton rules do not take into account bleeding risk. The Padua Predic;on Score Barbar et al, 2010
PROSPECTIVE TWELVE MONTH STUDY COMPARING RISK FACTORS FOR HOSPITAL ACQUIRED THROMBOSIS WITH COMMUNITY ACQUIRED THROMBOSIS. J. Nokes et al •  In 2011 there were 801 VTE events (331 DVT & 470 PE) of which 241 (30%) met the HAT criteria (165 PE & 76 DVT). •  There was a significantly increased associa;on of HAT with PE compared to DVT •  Age is the most common risk factor showing a greater rela;onship with HAT compared to CAT events. •  Cancer is significantly more associated with PE than DVT in both HAT & CAT groups. PROSPECTIVE TWELVE MONTH STUDY COMPARING RISK FACTORS FOR HOSPITAL ACQUIRED THROMBOSIS WITH COMMUNITY ACQUIRED THROMBOSIS. J. Nokes et al •  Personal and family history of VTE are more associated with CAT than HAT events and finally, not surprisingly, intravenous drug users are more associated with CAT and DVT. •  16% of CAT events had no risk factors whereas only 1% of HAT events fell in this category. Compliance to prophylaxis guidelines Endorse Study, Lancet 2008
Scatter plot and correlation between underuse and overuse
of thromboprophylaxis in the different Swiss hospitals
Chopard et al, J Int Med, 2005
Secondo quesito Come opmizzare l’uso della tromboprofilassi nel paziente non chirurgico nella pra;ca clinica? agonist
ADP
ADP
specific
receptor
P2Y12
Gq
+
δ
prostacyclin
IP receptor
Gi
Gs
PI3K
AC
cAMP
+
stabilization
Platelet aggregation
THIENOPYRIDINES
N
S
ACTIVE METABOLITES
HOOC
HS
Cl
N
Cl
Ticlopidine
O
CH3
N
S
Cl
Clopidogrel
O
HOOC
HS
CH3
N
Cl
O
N
HOOC
SADP Cl
agonist
CH3
S
specific
receptor
P2Y12
Gq
Gi
δ
prostacyclin
IP receptor
Gs
AC
cAMP
Platelet aggregation
Problems with Clopidogrel (and Ticlopidine) • 
• 
• 
• 
Toxicity (Ticlopidine >> Clopidogrel) Slow onset of ac;on Slow reversal (irreversible P2Y12 inhibi;on) High inter-­‐individual variability of response Incidence of MACE for Normal and High On-Treatment Platelet Reactivity:
Meta-analysis of Studies of ACS Patients on Treatment with Clopidogrel
PRU ≥230
PRU<230
Brar et al, JACC 2011:58:1945–54
Mega, J. L. et al. Circulation 2009;119:2553-2560
Schematic representation of the metabolism
of clopidogrel
A
Increased Risk
in Noncarriers
Increased Risk
in Carriers
CV Death
CLARITY-TIMI 28
EXCELSIOR
TRITON-TIMI 38
AFIJI
FAST-MI
RECLOSE
ISAR
CLEAR-PLATELETS
Intermountain
Overall
Carriers of 1 or 2 CYP2C19
Reduced-Function Alleles
vs Noncarriers
P=0.006
0.1 0.2
Cardiovascular Death, Myocardial Infarc;on, or Ischemic Stroke by CYP2C19 Genotype 0.5
1
2
5
10
HR (95% CI)
B
CLARITY-TIMI 28
EXCELSIOR
TRITON-TIMI 38
AFIJI
FAST-MI
RECLOSE
ISAR
CLEAR-PLATELETS
Intermountain
Overall
AMI
Carriers of 1 CYP2C19
Reduced-Function Alleles
vs Noncarriers
P=0.01
0.1 0.2
0.5
1
2
5
10
HR (95% CI)
C
AMI, acute myocardial infarction; CI, confidence
interval; CV, cardiovascular; HR, hazard ratio.
Mega JL, et al. JAMA. 2010;304:1821-30.
Stroke
TRITON-TIMI 38
AFIJI
FAST-MI
RECLOSE
ISAR
CLEAR-PLATELETS
Intermountain
Overall
Carriers of 2 CYP2C19
Reduced-Function Alleles
vs Noncarriers
P=0.002
0.1 0.2
0.5
1
2
HR (95% CI)
5
10
Response variability (“resistance”) to Clopidogrel The solu;on? “Tailored treatment”: increase the dose of Clopidogrel in poor responders (based on the results of platelet func;on tests) Is it the right approach? Two ques;ons about «tailored» clopidogrel treatment, based on platelet func;on monitoring 1.  Is it a desirable solu;on to the problem of the wide inter-­‐individual variability of response? Laboratory monitoring of an;thrombo;c therapy -­‐ CONS • 
• 
• 
• 
• 
Costs Workload Inaccuracy Pa;ents’ discomfort Pa;ents’ nonadherence (Barolep S, Dell'Orfano H. Medica;on adherence in cardiovascular disease. Circula-on 2010; 121:1455-­‐1458) «Evolu;on» of an;thrombo;c therapy ANTICOAGULANT
Need for laboratory
monitoring
No Need for laboratory
monitoring
«Evolu;on» of an;thrombo;c therapy ANTICOAGULANT
ANTIPLATELET
Need for laboratory
monitoring
No
needforforlaboratory
laboratory
Need
monitoring
monitoring
No Need for laboratory
monitoring
No Need for laboratory
monitoring
Two ques;ons about «tailored» clopidogrel treatment, based on platelet func;on monitoring 1.  Is it a desirable solu;on to the problem of the wide inter-­‐individual variability of response? 2.  Supposing that it is the only solu;on to the problem of inter-­‐individual variability of response to clopidogrel, are we ready for it? (should we implement it in the clinical prac;ce, today?) Valida;on of laboratory monitoring of clopidogrel treatment 1.  Iden;fica;on of the most accurate laboratory test [??] 2.  Standardiza;on of pre-­‐analy;cal and analy;cal variables [??] 3.  Iden;fica;on of universal cut-­‐off values [??] 4.  Clinical valida;on [??] Which one is right?
Paniccia et al, T&H 2010
Cumulative Kaplan-Meier Estimates of the Time to the First
Adjudicated Occurrence of the Primary Efficacy End Point
Price, M. J. et al. JAMA 2011;305:1097-1105
RECLOSE 2-­‐ACS Study •  Iden;fica;on of pa;ents with «high residual platelet reac;vity» (HRPR) 12-­‐18 h a|er 600 mg clopidogrel (≥70% [10 µM]ADP-­‐induced platelet aggrega;on) •  Treat pa;ents with HRPR with high-­‐dose clopidogrel (up to 300 mg qd) or ;clopidine (250-­‐500 mg bid) •  End point: cardiac death, myocardial infarc;on, any urgent coronary revasculariza;on, and stroke at 2-­‐
year followup Parodi et al, JAMA 2011;306:1215-23
Incidence of Primary End Point Events at 2y F.U. in ACS patients
on DAPT undergoing PCI, according to their platelet reactivity at
baseline and F.U. RECLOSE 2-ACS
HRPR
LRPR
P
14.6%
8.7%
0.003
therapy adjustment
HRPR
at F.U.
LRPR
at F.U.
14.9%
14.4%
0.91
Parodi et al, JAMA 2011;306:1215-23
Response variability to Clopidogrel Another solu;on? Personalized treatment, based on CYP geneotype CYP2C19*2 carrier status and
the clinical variables
could explain 11.5% of the variability
of on-clopidogrel RPA
Hochholzer et al, JACC 2010
Response variability to Clopidogrel Another solu;on? Change the drug! Mega, J. L. et al. Circulation 2009;119:2553-2560
Schematic representation of the metabolism
of clopidogrel and prasugrel
TICAGRELOR •  direct-­‐ac;ng, reversible P2Y12 antagonist •  pIC50 of 7.9 with 30 µM ADP –induced platelet aggrega;on (PRP) •  Highly selec;ve for P2Y12 (apparently, does not inhibit P2Y1 or other purinergic receptors) •  T1/2 7-­‐8.5h (BID drug) •  Tmax 2 h Use of the new P2Y12 inhibitors: concerns •  Safety: both prasugrel and ;cagrelor caused a higher incidence of major bleeding, compared to clopidogrel (but the net clinical benefit was in favour of new drugs) Incidence of TIMI-­‐major non-­‐CABG bleeding in studies comparing drugs inhibi;ng P2Y12 Comparison
N. of pa/ents
Increase in TIMI-­‐
major bleeding
P
Study
Prasugrel vs clopidogrel
13,457
32%
0.03 TRITON-­‐TIMI38, NEJM 2007;357:2001-­‐15
Ticagrelor vs clopidogrel
18,421
25%
0.03 PLATO, NEJM 2009;361:1045-­‐57
Clopidogrel responders vs clopidogrel non-­‐responders
1,608
85%
0.25 Sibbing et al, JACC 2009;53:849-­‐56
Use of the new P2Y12 inhibitors: concerns •  Cost: the new drugs are more expensive than generic clopidogrel, BUT: –  COST OF MONITORING?(1 VerifyNow cartridge ~75 € x how many tests per pa;ent? –  COST of 2x, 3x DOSE CLOPIDOGREL OR of NEW INHIBITORS FOR «POOR RESPONDERS» (about 30% of pa;ents)? Conclusion
•  Resistance to aspirin or clopidogrel should be evaluated for inves/ga/onal purposes only •  At present, aspirin and clopidogrel resistance should not be looked for in the clinical se]ng Cattaneo M, SSC ISTH Meeting, Venice 2004
Terzo quesito Terapia con clopidogrel: monitorare o non monitorare? uso alterna;vo dei nuovi inibitori del P2Y12? [uso di nuovi an;coagulan; vs VKA?]