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Emostasi, trombosi e piastrine Anna Falanga, MD Immunohematologia e Medicina Transfusionale E Centro Emostasi e Trombosi Dipar=mento Onco-‐ematologico Ospedali Riuni= di Bergamo Quesi( Quali limi( all’uso dei TPO mime(ci Profilassi primaria nel paziente internis(co Monitoraggio delle terapie an(aggregan(/an(coagulan( ImmuneThrombocytoPenia George, Am J Hematol 2012 George, Am J Hematol 2012 • Romiplos(m: Warning/poten(al serious adverse effects TGF class-‐specific toxici(es: – Bone marrow re4culin fiber deposi4on (new forma4on or progression) – Thrombosis (due to excessive platelet increases) – Tumorogenicity, increased risk for hematologic malignancy or progression of underlying myelodysplas(c syndrome – Rebound thrombocytopenia • Romiplos(m-‐specific toxici(es: – Neutralizing an(body forma(on • Common adverse events: – – – – – – – – Headache (mild to moderate) Fa(gue Arthralgia/myalgia Dizziness Insomnia Limb pain/back pain/shoulder pain Diarrhea Nausea/vomi(ng7abdominal pain/dyspepsia Serious Toxici(es in Trials of Romiplos(m NR= not reported; NA: not available aIncludes a pooled analysis of the 6-‐week phase II trials and the 24-‐week phase III trials of Romiplos(m cRou(ne bone marrow biopsies were not performed. Therefore, the number of iden(fied cases may underes(mate the true incidence of bone marrow fibrosis fTwo pa(ents developed neutralizing an(-‐romiplos(m an(bodies. These an(bodies did not cross-‐react with endogenous thrombopoie(n Cuker A, Seminars in Hematology 2010 SAFETY ANALYSIS OF LONG-‐TERM ROMIPLOSTIM USE IN PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA (ITP) • Data from 13 clinical studies of romiplostim in patients with ITP were analyzed, including patients treated from October 2003 to the data cutoff of June 2009. • Patients received romiplostim, placebo, or standard of care (SOC). • Data from patients given placebo/SOC were pooled. Rodeghiero F, et al EHA 2010 Bone Marrow Fibrosis • Re(culin can be a normal component of bone marrow – Increased re(culin (re(culin fibrosis, detected by silver stain) is associated with both benign condi(ons and malignant diseases; usually not associated with abnormal blood cell counts, o`en reversible • Collagen is less commonly found in bone marrow – Increased collagen (collagen fibrosis, detected by trichrome stain) is characteris(c of myeloprolifera(ve disorders and metasta(c tumors; frequently associated with abnormal blood cell counts, less likely to be reversible9 • Re(culin deposi(on in bone marrow sec(ons graded on a scale of 0 to 4 – Grade 1 to 2 re(culin found in bone marrow from 69 to 76% of healthy individuals; 4 to 5% grade 2; none were grade 3 or 4 – Grades 1 to 2 re(culin found in bone marrow from 63% of ITP pa(ents not exposed to TPO receptor agonists; 3% grade 2; none were grade 3 to 4 • Increased re*culin detected in ITP pa*ents treated with TPO receptor agonists Discussione e Conclusioni Non ci sono evidenze per raccomandare i TPO mimetici in prima linea al posto dello steroide + Ig Nella seconda linea di trattamento, non ci sono evidenze sufficienti per raccomandare i TPO mimetici come prima scelta. La splenectomia è efficace nell’80% dei casi, ma può essere anche rifiutata dal paziente. Altri immunospressivi possono essere scelti prima della splenectomia e prima dei TPO mimetici. Riferita esperienza negativa con rituximab dopo la splenectomia (mortalità da infezioni). Primary preven4on of venous thromboembolism (VTE) in medical pa4ents Surgical and medical diagnoses associated with VTE Risk factors for VTE The Padua Predic(on Score Barbar et al, 2010 Contraindica(ons to an(coagulant use Ac(ve bleeding within 3 months Intracranial bleeding within one year Known poten(al bleeding site, pep(c ulcera(on, bronchiectasis Thrombocytopenia ( platelets < 75 x10^9/L) Coagulopathy Significant liver disease (INR > 1.4) Effec(ve an(coagulant therapy (i.e. warfarin with an INR >2 or therapeu(c heparin) obvia(ng the need for thromboprophylaxis Lumbar puncture/epidural/spinal anesthesia within the previous 4 hours or expected within the next 12 hours Trials of VTE prophylaxis in Medicine 1999 2004 1102 pa(ents age> 40 years H> 6 days 3706 pa(ents age> 40 years 14 days 2006 849 pa(ents age> 40 years 6-‐14 days An(thrombo(c prophylaxis in the non surgical pa(ent Venous thromboembolic disease in cancer • Thromboembolism is the second leading cause of death in cancer pa(ents1 • In ambulatory cancer pa(ents receiving chemotherapy – thromboembolism is the # 1 cause of death2 • VTE occurs in over 20% of cancer pa(ents through their life(me3 • VTE may be present in as much a 50% of pa(ents at the (me of death4 1. Lyman GH, et al. J Clin Oncol. 2009;27:4821-46. 2. Khorana AA, et al. J Thromb Haemost. 2007;5:632-4. 3. Lyman GH, et al. J Clin Oncol. 2007;25:5490-505. 4. Gao S, et al. Expert Rev Anticancer Ther. 2004;4:303-20. Risk factors for VTE in cancer pa(ents Demographics Cancer • Older age • Gender: higher in females • Race: ↗ in African-Americans and ↘ in Asians • Site: brain, pancreas, kidney, stomach, lung, bladder, gynecologic, hematologic malignancies • Stage: advanced stage and initial period after diagnosis Cancer Treatments Biomarkers • • • • • • • • • • • Hospitalization Surgery Chemo- and hormonal therapy Anti-angiogenic therapy Erythropoiesis stimulating agents Blood transfusions Platelet count >350,000/µl Leukocyte count > 11,000/µl D-dimer Procoagulant Microparticles Soluble P-selectin THROMBOPROPHYLAXIS IN MEDICAL PATIENTS HOSPITALIZED CANCER PATIENTS No studies designed ad hoc for cancer pa*ents are available Evidence comes from Hospitalized General Medical Pa*ents -‐ A number of large-‐scale, well-‐designed clinical trials have examined thromboprophylaxis in hospitalized general medical pa*ents -‐ Pa*ents with cancer cons*tute only a small propor*on of the pa*ents enrolled in these trials 20 MEDICAL CANCER PATIENTS Recommenda4ons for VTE Prophylaxis in Hospitalized Pa4ents with Cancer • Hospitalized pa*ents with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindica*ons to an*coagula*on Recommenda(ons for Primary VTE Prophylaxis in Ambulatory Pa(ents with Cancer • Current guidelines do not recommend: – Rou(ne prophylaxis with an an(thrombo(c agent in ambulatory cancer pa(ents LMWH prophylaxis during chemotherapy: new evidence Study PROTECHT Agnelli et al, Lancet Oncology 2009 SAVE-‐ONCO Agnelli et al, ASCO 2011 Pa*ent (n=) Tumor Agent & Regimen 1150 Lung, Breast, Gastrointes*nal, Ovarian, Head/ Neck cancer Nadroparin vs placebo 3,800 an*Xa units sc OD for dura*on of chemotherapy (up to 4 months) 3200 Lung, bladder, GI, ovary -‐Metasta*c or locally advanced Semuloparin 20 mg od vs placebo, un*l change of chemotherapy (up to 4 months) New strategies • The risk of VTE is increased , but is highly variable (wide range -‐ 1% to 20%, influenced by tumor burden, and tumor stage) § New studies are evalua*ng the benefit of thromboprophylaxis in cancer outpa*ents by using different approaches: • Target specific cancer site or histology • Target high-‐risk pa*ents selected by using risk-‐model and/or biomarker-‐ based interven*ons Monitoring An4platelets/An4coagulant Drugs Evolu(on of an(thrombo(c therapy An*coagulant An*platelet • Need for laboratory monitoring • Need for laboratory monitoring • No need for laboratory monitoring • No need for laboratory monitoring Old e new P2Y12 inhibitors Some platelets test func(on that have been used to monitor an(platelet agent Laboratory monitoring of an(thrombo(c therapy -‐ CONS • • • • • Costs Workload Inaccuracy Pa(ents’ discomfort Pa(ents’ nonadherence (Baroles S, Dell'Orfano H. Medica(on adherence in cardiovascular disease. Circula4on 2010; 121:1455-‐1458) Which one is right? Paniccia et al, T&H 2010 Ticagrelor New An(coagulants (NOACs) Prothrombinase FONDAPARINUX DESIRUDIN ARGATROBAN BIVALIRUDIN (XIMELAGATRAN) Xa, Va lipid RIVAROXABAN APIXABAN EDOXABAN Prothrombin Platelet activation Thrombin Fibrin formation DABIGATRAN Fibrinolysis inhibition Cellular effects Why monitoring drugs? • Drug monitoring aims to op(mize dosage regimens in order to increase efficacy and/or safety • If the plasma concentra(on of a drug can be accurately an(cipated from the dose applied and the pa(ent’s body weight, it does not usually require monitoring, even if its therapeu(c window is narrow. “Monitoring” vs “measuring” the an*coagulant effects of the NOACs monitoring measuring Measurement of the anticoagulant activity after a therapeutic dose of rivaroxaban or dabigatran etexilate may be informative in cases of: - Patients with low body weights or obese patients - Pediatric Patients - Renal or hepatic impairment - Accidental or deliberate overdose - To measure adherence - To evaluate patients with hemorrhagic or thrombotic complication - Before surgery However, in the absence of specific antidotes, a measured high activity merely allows us to approximate after which time the drug activity will vanish, according to its pharmacokinetic properties, which could have been calculated if the timing of administration and the exact dose are known. Effects of NOACs on Coagula=on Assays NOACs cause a significant prolonga(on of coagula(on reac(ons producing misleading results in rou(ne closng assays Direct Thrombin Inhibitors Direct FXa Inhibitors PT in sec and INR ↑ ↑ APTT ↑ ↑ ↑↑ No Thrombin Time (TT) Fibrinogen (Clauss) No/↓ No D-‐dimers No No These altera(ons do not correlate with the clinical effect, therefore these tests are not to be performed to determine the drug ac(vity. Effect of Dabigatran on APTT Current problems with measuring these drugs • No validated assays • Each drug has unique effect • Drug effect on cloing factors is transient • Therapeu*c ranges are uncertain WHICH TEST? • APTT • Thrombin Time (TT) • PT-INR • Ecarin clotting time (ECT) • Anti-Xa • Thrombin Generation What the users of the new oral anticoagulants need to know • The new direct Factor Xa- and IIa-inhibitors affect conventional clotting tests • These effects are reagent-dependent • Do not routinely measure aPTT or prothrombin time to detect over- or underdose • Use specific tests recommended (if available) to detect over- or underdose, in particular in special patient populations • However there is no need for routine monitoring.
