Ann Janssens, MD, PhD. Department of Hematology, UZ Leuven BHS course 8 november 2014
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1 Ann Janssens, MD, PhD Department of Hematology, UZ Leuven BHS course 8 november 2014
2 The history of platelets, megakaryocytes and thrombopoietin
3 Platelet homeostasis etpo Production Platelet Pool Normal platelet lifespan 9-10d Normal Splenic Destruction Platelet production: /d Platelet count: /µl Platelet Production Platelets/megakaryocyte Endogenous thrombopoietin (etpo) Megakaryocyte precursor Megakaryocyte Platelet 1 Kuter et al PNAS 91:11104, 1994; 2 Stoffel et al Blood 87:567, 1996; 3 Gurney et al Science 265:1445, 1994; 4 de Sauvage et al JEM 183:651, 1996
4 Thrombopoietin signaling and megakaryocyte maturation Thrombopoietin Pluripotent Progenitor Megakaryocyte Progenitor Mitotic Expansion TPO-R (Mpl) JAK2 JAK2 Nuclear Maturation (End mitosis) Cell membrane S T A T 5 P P P Cytoplasmic Maturation (Platelet Specific Granules) Platelets Bone Marrow Proplatelet Formations Peripheral Blood
5 Thrombopoietin production: constitutive or regulated?
6 Izak et al. F1000Prime reports, 2014
7 Peripheral destruction Autoimmune Primary ITP Secondary ITP Drug induced: HIT, Alloimmune: posttransfusion, neonatal Pregnancy induced TTP-HUS DIC Hemangiomas Insufficient production AA MDS Myelofibrosis Bone marrow invasion Bone marrow toxicity Megaloblastic anemia Hereditary disorders others Platelet sequestration due to hypersplenism Portal hypertension (cardiac, cirrhosis, V. Porta or V. Cava thrombosis Gaucher Myelofibrosis Viral infections Dilution due to massive transfusion
8 In vitro agglutination of platelets when blood is collected in EDTA tubes ( 2% of all thrombocytopenias detected on EDTA blood) Measure platelets on blood collected in citrate or heparine tubes Look for agregates on the peripheral blood smear
9
10 Personal and familial history Recent infections Vaccinations ( >MMR, < H. Influenzae, pneumococci, Hep B,..) Malignancies Pregnancy Recent travels Recent transfusions Alcohol abuse Dietary habits, beverages, herbal preparations Risk factors for HIV and viral hepatitis Medication: especially those started 1 to 2 weeks before the onset of thrombocytopenia, recent exposure to heparine
11 Clinical examination with special attention to: Bleeding symptoms: pecheciae, purpura, ecchymoses Lymphadenopathy Spleno-, hepatomegaly Skeletal abnormalities Dysmorphy Skin abnormalities
12 Complete blood count Isolated vs pancytopenia With neutrophilia or lymphocytosis Blood smear True vs pseudo Platelet morphology: giant platelets, vs microthrombocytes Toxic granulation in the neutrophils Pelger Huet, blasts Atypical lymphocytes Fragmentocytes Tear drops, nucleated red blood cells Additional investigations LDH Coombs, hapto, bilirubin Renal function Coagulation Liver function Virus serology, Bone marrow examination
13 Lacey et al, Semin Thromb Hemost, 1977
14 fatal haemorrhage if platelets < 30000/ l persistently age < 40y: 0,4%/y age 40-60y: 1,2%/y age > 60y: 13% /y Cohen et al, Arch Intern Med, 2000
15 Petechiae Purpura Bruises
16 Mucous membrane bleeding Epistaxis Gingival UG-GI tract Intracerebral bleeding
17
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19 Dentistry: 10 à 20 x 10 9 /L Extractions: 30 x 10 9 /L Regional dental block: 30 x 10 9 /L Lumbar puncture: 50 x 10 9 /L GI endoscopy with biopsy: 20 x 10 9 /L Bronchoscopy: 20 x 10 9 /L ( 50 if also biopsy) Organ biopsy: 50 x 10 9 /L (lower for bone biopsy) Minor surgery: 50 x 10 9 /L Major surgery: 80 x 10 9 /L Epidural: 80 x 10 9 /L British Committee for Standards in Haematology General Haematology Task Force. Br J Haematol. 2003;120: Webert KE, et al. Blood. 2003;102:
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21 A. Janssens, C. Lambert, G. Bries, A. Bosly, D. Selleslag, Y. Beguin Belgian Journal of Hematology. 2013;4(1) (March 2013)
22 Isolated thrombocytopenia Threshold platelets for ITP-diagnosis /µl instead of /µl Normal complete blood count and peripheral smear Avoid Purpura: bleeding symptoms frequently absent or minimal at the onset of disease Rodeghiero et al, Blood 2009;113:
23 Basic evaluation Potential utility Unproven benefit Personal and family history Clinical examination Full blood count with reticulocytes and Coombs Peripheral blood film!!! Immunoglobulins Blood group? HIV, hep C, H pylori? Bone marrow in selected patients Antiplatelet antibodies Antiphospholipid antibodies Thyroid function and antithyroid antibodies pregnancy test Antinuclear antibodies PCR for CMV and parvovirus Hep B Chest radiograph Abdominal ultrasound Biological fitness Thrombopoitin Reticulated platelets Bleeding time Platelet survival time Serum complement MANDATORY!!!
24 Primary: no obvious initiating and/or underlying cause Avoid idiopathic SLE 5% APS 2% CVID 1% Primary 80% Cines DB, et al. Blood. 2009;113: CLL 2% Evan s 2% ALPS, post-tx 1% HIV 1% Hep C 2% H. pylori 1% Postvaccine 1% Misc systemic infection 2%
25 25% develop thrombocytopenia 15-25% of ITP pat are pos for ANF Bleeding risk? Activity of SLE? Vasculitis? Severe thr-penia with active SLE: treat SLE Severe thr-cytopenia without active SLE: treat as primary ITP; rituximab; splenectomy if refractory thrombopenia with thrombotic events and poor outcome of pregnancy Lupus anticoagulans and anticardiolipin AB pos +/- 40 (10-70)% of pat with ITP has APLAs treat as primary ITP, also good outcome with rituximab Aspirin? (hypothyroidism,thyrotoxicosis) 25-50% ITP patients has antithyroid AB Control of the underlying thyroid disease 10% develop ITP with or without AIHA Treat as primary ITP Avoid immunosuppressive agents rituximab
26 thrombocytopenia 1 to 4 weeks after an acute infection with mumps, rubella, EBV, CMV, appears sudden and can be severe remits mostly in 2 to 4w HIV, hep C, H. Pylori insidious onset, no tendency to remit spontaneously Stasi, Sem Hematol, 2009
27 US: prevalence of anti-hcv AB: 2% Platelets <150000/μl: 41% chronic Hep C (19% in chronic hep B) Platelets <50000/μl: +/- 9% chronic hep C Associated with cryoglobulins and anticardiolipin AB Bleeding symptoms at higher platelet counts Treatment Interferon-α with antiviral treatment Corticosteroids ( try to avoid) Cavé: increase in viral load, elevation in transaminases IGIV Splenectomy TPO-R agonists Nagamine et al. J Hepatol 1996 Rajan et al. Br J Haematol 2005 Stasi, Sem Hematol, 2009
28 Before HAART: 5 to 30% of HIV + patients develop thrombocytopenia (<150000/μl) Incidence of thrombocytopenia higher with an increase in immunosuppression If diagnosed before the stage of AIDS: thrombocytopenia mostly mild (can have additional bleeding problems: hemophilia, hep C, liver disease in drug addicts, ) Treatment Antiretroviral therapy ( can take weeks) Corticosteroids, IGIV Splenectomy TPO-R agonists Stasi, Sem Hematol, 2009
29 Prevelance depends on socio-economic conditions Prevalence in adult ITP: 20-80% (Japan 70%, Italy 50%, US 22%) Diagnostic methods: urea breath test and stool Ag test: highest sensitivity and specificity Association with dyspepsia???? Older than ITP without H. Pylori Eradication therapy: ORR 50 (14-100) % ( higher ORR in Japan), persistent response 70% Higher ORR in ITP with a short duration and a higher platelet count >30000 Platelet responses after 3d to 24 w (2 weeks in Italian trial) No responses to eradication therapy in pat H. Pylori neg Stasi, Sem Hematol, 2009
30 AITP can occur in all lymphoproliferative disorders However more frequent with (1-5%) (can occur at any time in the course of CLL), remission) 20%(mild)) (0,2-1%) (can occur at any time in the course of Ho, also in 1(severe)- Liebman, Sem Hematol,2009
31 Corticosteroids, IGIV, splenectomy Rituximab monotherapy or in combination with cyclophosphamide-dexamethasone Alemtuzumab Cyclosporine, Cellcept TPO-R agonists Ho treatment if active disease Corticosteroids, IGIV, splenectomy azathioprine Cytotoxic treatment against the LGL-clone Cyclosporine Alemtuzumab Corticosteroids, IGIV Rituximab,cellcept, SCT Liebman, Sem Hematol,2009
32 Eliminate the trombocytopenia inducing drug Heparin Quinine, tonic water Valproic acid Non steroidal inflammatory agents
33 HAT: 10-30%: binding of heparin to platelets with platelet aggregation (non-immune) ( first days of treatment, > 80000/ l, no bleeding or thrombosis, resolves even with continuing heparin) HIT: 5% if IV, <1% with LMWH, thrombocytopenia moderate to severe, 30-75% has a thrombotic event, venous predominance (2.5/1), late onset till 20d after stop heparin
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35 Discontinue all heparin products Alternative non heparin anticoagulants Direct thrombin inhibitors Argatroban Lepirudin Bivalirudin Factor X inhibitors (Arixtra) Vit K antagonists: NO Novel anticoagulants (Pradaxa, Xarelto, Eliquis) Heparinoids Danaparoid ( antix and anti-ii activity) (Orgaran)
36 Non immune: directly toxic to megakaryocytes Linezolid ( >10D 32%) Immune: after 1 to 2 weeks, severe bleeding 5 different mechanisms
37 Drug-induced ITP Mechanisms: 1 auto-antibodies 2 neo-epitope 3 hapteen gold 1 2 penicillins abciximab 4 drug specific 5 quinine type 6 Immune complex 6 Kinine, NSAIM, AB, anticonvulsiva heparin FAB FC :immuunglobuline :(glyco)proteïne :drug(metaboliet) :PF-4 :neo-epitope Aster et al., NEJM 2007
38 Autologeous Allogeneic Post liver transplantation
39 Active bleeding OR platelets <10000/ l treatment is obligatory No or mild bleeding AND platelets / l treatment is a potential option ( evaluation of pat characteristics) No bleeding AND platelets >30000/ l no need for treatment unless special circumstances Stasi, Eur J Haematol, 2009
40 Platelet count Previous major bleeding Age Life style: sedendary (office workers) vs active ( physical jobs), contact sports Additional risk factors for bleeding Platelet dysfunction or hemostatic defect (clopidogrel, ASA, po anticoagulantia) Uremia Untreated or poorly controled hypertension, Aneurysms Fever or Infections Chronic liver disease or alcoholism History of peptic ulcer Tolerance of expected adverse events of treatment Medical interventions that may cause bleeding Accessibily of care Patient s preferences ( anxiety, )
41 Minimize bleeding symptoms or risk of bleeding Decrease activity restrictions and improve QOL Minimize exposure to potentially toxic therapy
42 Newly diagnosed ITP (<3m) (retrospective diagnosis) Persistent ITP (3 à12m) ( time in which spontaneous remission can occur) Chronic ITP (>12m) Rodeghiero et al, Blood 2009:113;
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44 Table 2: Corticosteroids
45 : vomiting 3x/d since 1week; blood exam solitary thrombocytopenia: 12000/µl; not pregnant Some petechiae legs, 1 bruise, last period more explicit; no mucosal bleeding Corticosteroids IV because of the vomiting with a rapid rise of platelets, exacerbation of migraine ( gastroscopy neg, CT brain neg)
46 : petechiae arms, legs and face and also epistaxis; solitary thrombocytopenia 2000/µl Nasal cautery, corticosteroids IV and platelet transfusion Hospital discharge at d 4 with platelets of 3000/µl, nobleeding symptoms anymore and with Medrol 64mg/d d18
47 Iron deficiency anemia, depression : diagnosis of ITP, Medrol 64mg/d with rapid platelet increase Tapering corticosteroids very slowly ( stop ) No sustained response but safe platelet count
48 Table 3: Immunoglobulins (IGIV)
49 : diagnosis of ITP : platelets 16000/µl : Medrol 64 mg/d (corticorefractory) : IGIV monthly (4x) with tapering of corticosteroids
50 Relapse after a long treatment-free interval can be managed by restarting first line treatment. Long term steroid use (> 5mg prednisone or equivalent) must be avoided.
51 Azathioprine Cyclosporine Cyclophosphamide Danazol dapsone Mycophenolate mofetil Rituximab Splenectomy TPO-mimetica Vinca alkaloiden
52 Splenectomy (IB) TPO-R agonists after splenectomy TPO-R agonists if a contraindication for splenectomy (IB) TPO-R agonists after failure to corticosteroids or IgIV (2C) Rituximab after failure to corticosteroids,igiv or splenectomy (2C)
53 For adult ITP patients who are intolerant or unresponsive to or relapse after initial corticosteroid treatment and have a risk of bleeding (platelets < /µl OR bleeding symptoms), the BHS guideline panel on adult ITP : BHS recommendations Splenectomy as it is the only treatment with a curative potential and has an acceptable safety profile. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur TPO-R agonists for patients who are refractory to or relapse after splenectomy or who have a contra-indication to splenectomy irrespective of the duration of ITP BHS suggestion in TPO-R agonist refractory patients Rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options
54 Vaccination strategy 11/2013: *Prevenar 13 with/or without Pneumo 23/8w; boost with Pneumo 23/5y (rationale?) *Nimenrix
55 *
56 For adult ITP patients who are intolerant or unresponsive to or relapse after initial corticosteroid treatment and have a risk of bleeding (platelets < /µl OR bleeding symptoms), the BHS guideline panel on adult ITP : BHS recommendations Splenectomy as it is the only treatment with a curative potential and has an acceptable safety profile. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur TPO-R agonists for patients who are refractory to or relapse after splenectomy or who have a contra-indication to splenectomy irrespective of the duration of ITP BHS suggestion in TPO-R agonist refractory patients Rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options
57 Characteristics of treatment with TPO-R agonists : general
58 TPO-R agonists are very well tolerated: 5% of patients discontinue therapy because of side effects Experience in the clinic does not exceed seven years, suspicion for possible risks of long-term use is warranted
59 Characteristics of treatment with TPO-R agonists : dosing Response as long as therapy is maintained. Cavé compliance and adherence!!! +/- 15% can stop TPO-R agonists with long-term remission
60 For adult ITP patients who are intolerant or unresponsive to or relapse after initial corticosteroid treatment and have a risk of bleeding (platelets < /µl OR bleeding symptoms), the BHS guideline panel on adult ITP : BHS recommendations Splenectomy as it is the only treatment with a curative potential and has an acceptable safety profile. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur TPO-R agonists for patients who are refractory to or relapse after splenectomy or who have a contra-indication to splenectomy irrespective of the duration of ITP BHS suggestion in TPO-R agonist refractory patients Rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options
61 Most patients: concomitant therapy Dose: most frequently used 375 mg/m²/w x4 ORR 62,5%, CR 46,3% (all) ORR 57%, CR 41% (non-splenectomized: n=368)) ORR 68%, CR 39% (children: n= 323 pat) Time to response 1 to 6,34 w Cavé: Late onset neutropenia Hypogammaglobulinemia Hep B reactivation PML Duration of response : PR <6m, CR 12m Long-term response: 5y ( 21% of adults, 26% of children) Arnold et al, Ann Intern Med, 2007;146:25-33 Auger et al, B J Hematol 2012 epub Liang et al, PLoS ONE 2012;5: Patel et al, Blood, 2012;119:
62 Azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine have been used after treatment failure for decades. Variable individual responses Long-term side effects such as immune suppression
63 Antifibrinolytic agents (tranexamic acid : 3 g/day per os) Oral iron supplements if iron deficient Local application of adrenalin soaked nose pads Nasal cautery Hormone substitutes to prevent menorrhagia Control of blood pressure Stop ASA, antiplatelet agents, anticoagulation if appropriate : except case of recent stent, ischemic heart disease, several peripheral arterial occlusive disease Avoid nonsteroidal anti-inflammatory drugs or ASA
64 1. ITP patients with platelet counts higher than 30000/µl and absence of bleeding signs do not need treatment. 2. Corticosteroids with or without intravenous IVIg are the preferred treatment options for patients with ITP newly diagnosed or relapsing after a long-term treatment-free period. 3. Splenectomy is recommended as second-line treatment as it is the treatment with the highest curative potential and an acceptable safety profile. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur. 4. TPO-R agonists are recommended for patients who are refractory to or relapse after splenectomy or who are unfit for splenectomy, irrespective of the duration of ITP. 5. Rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options, especially for patients refractory to TPO-R agonists.
65 Megakaryocyte differentiation Congenital amegakaryocytic T T with absent radii T with radio-ulnar synostosis Megakaryocyte maturation Familial platelet disorder /AML Paris-Trousseau & Jacobsen syndrome GATA-1 related T GFI 1B- related T ANKRD26- related T Gray platelet syndrome Pecci et al, Br J Hematol 2014 Proplatelet formation and platelet release MYH9-related disease ACTN1-related T FLNA-related T Wiskott-Aldrich syndrome & X-linked T Bernard Soulier S
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