Thrombocytopenia: a practial approach Dr. med. Jeroen Goede FMH Innere Medizin, Medizinische Onkologie, Hämatologie FAMH Hämatologie Chefarzt Hämatologie Kantonsspital Winterthur
Outline Introduction and Definitions Diagnostic steps differential diagnosis Thrombocytopenia during pregnancy Immune thrombocytopenia Conclusions 2
Introduction Thrombocytes are formed by fragmentation of the cytoplasm of megakaryocytes Under physiological circumstances thrombocytes then circulate in the blood for 7-10 days and play a critical role in haemostasis In case of significant quantitative or qualitative platelet dysfunction: Patients present typically with mucocutaneous bleeding Typically no soft tissue or joint bleeding Presence should raise suspicion of additional plasmatic coagulation problems 3
Introduction In most laboratories: normal platelet count between 150-450 G/l (+/- 2 standard deviations) By definition 2.5% of the normal range will be below 150 G/l NCI-definition of grading for thrombocytopenia (for cancer patients receiving treatment): Grade 1 : 75-150 G/l Grade 2 : 50-75 G/l Grade 3 : 25-50 G/l Grade 4 : <25 G/l 4
Introduction In otherwise healthy conditions Bleeding time is generally not prolonged until platelet count is below 100 G/l As long as platelet counts are above 20 G/l clinical manifestations are mild Below 10 G/l the risk for spontaneous bleeding increases rapidly Several factors such as functional defects modify the bleeding risk 5
Diagnostic steps Main laboratory questions in newly diagnosed thrombocytopenia: Exclude pre-analytic reasons for thrombocytopenia Concomitant anemia and/or neutropenia? Degree of thrombocytopenia? Tc 75-150 G/l vs. 50-75 G/l vs. 25-50 G/l vs. <25 G/l 6
Diagnostic steps Main clinical questions in newly diagnosed thrombocytopenia: Recent and actual medication? History of previous thrombocytopenia? Family history? Pregnancy? 7
Diagnostic steps Mr. S.O. 1971
Diagnostic steps 9
Diagnostic steps Mr. M.O. 1968
Diagnostic steps 11
Diagnostic steps Diagnosis: Bernhard-Soulier-Syndrome 12
Diagnostic steps Initial laboratory evaluation: Peripheral blood smear with reticulocytes Serum creatinine DIC panel LDH Total and direct bilirubin AST and ALT Ev. pregnancy testing This allows as initial determination whether thrombocytopenia is an isolated abnormality or part of a constellation of abnormalities 13
Diagnostic steps If thrombocytopenia is confirmed: Stepwise evaluation to assess the causes and the urgency of treatment
Diagnostic steps If thrombocytopenia is confirmed: Stepwise evaluation to assess the causes and the urgency of treatment: Thrombotic thrombocytopenic purpura (TTP) Heparin-induced thrombocytopenia (HIT) Immediate Intervention is required 15
Diagnostic steps Isolated thrombocytopenia without specific clues on the peripheral blood smear: Diagnosis of immune-thrombocytopenia (ITP) is probable Drug induced thrombocytopenia can t be excluded 16
Diagnostic steps The role of bone marrow exam: Differentiation between inadequate production versus excessive destruction/consumption as predominant cause of thrombocytopenia With age the incidence of primary marrow disorders is rising (lymphoma as condition that causes ITP) 17
Differential diagnosis Decreased production: Hematologic malignancies Aplastic anaemia Myelodysplasia Chemotherapy and alcohol Radiation HIV Vitamin D deficiencies Hereditary thrombocytopenia Metastatic cancer to bone marrow Increased destruction: Immune: ITP HIT Drug-induced antibodies HIV Post transfusion purpura Connective tissue diseases Nonimmune: DIC Sepsis Cardiac valves TTP-HUS Splenic sequestration
Sudhir S. et al. SMJ, 2006
Thrombocytopenia during pregnancy:
Thrombocytopenia during pregnancy 21
Immune thrombocytopenia (ITP) Immune thrombocytopenia of the adult: Outcome 5 years after diagnosis (Sailer, Haematologica 2006, McMillan, Blood 2004): 40% of the patients have a platelet count lower than 100 G/l 15% of the patients have a platelet count lower than 30 G/l 60% of the patients are in remission ITP is becoming more and more a disease of elderly people (median of age around 50 years) 22
Immune thrombocytopenia (ITP) Schoonen, BJH 2009 23
Immune thrombocytopenia (ITP) Therapeutic options: 1915 Splenectomy 1951 Steroids (Wintrobe) 1960ies Azathioprin 1970ies Vincristin Cyclophosphamid 1990ies Cyclosporin A Mycophenolat 1998 Rituximab 2009 Eltrombopag Romiplostim 1980ies Danazol IVIG anti-d 24
Definition of response to treatment Complete response: increase in platelet count above 100 G/l Clinically relevant response: platelet increase above 30 G/l with at least a twofold increase of the baseline count and the absence of bleeding 25
Phases of Immune thrombocytopenia Marc Michel: Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily Practice and Clinical Research? Seminars in Hematology Volume 50, Supplement 1 2013 S50 - S54 26
TPO agonists Very good clinical data with a high proporiton of responders Good tollerability Chronic treatment Chronic costs 27
Splenectomy Splenectomy is an option with a high rate of durable and complete remissions Mortality of the intervention: 0.5-1% Gonzalez-Porras JR et al. Eur J Haematol. 2013 Sep;91: Comparison of 57 patients 65 years of age with 162 patients below the age of 65 years with splenectomy due to ITP: Favorable response in 72% of elderly patients and 92% of younger patients (P=0.005) Probability of maintaining response for 14 years after splenectomy was 56% In elderly patients mortality is higher (1.8% vs. 0.6%)
Splenectomy 29
Rituximab First report at ASH 1998: Perotta, ASH Annual Meeting 1998 Since then many case reports and phase II studies, but only two phase III studies in first line treatment: Zaja, Blood 2010 Gudbrandsdottir, Blood 2013 With rituximab we can expect 21% of adult patients to be without ITP-treatment after 5 years Patel VL et al., Blood 2012 Jun 21 30
Rituximab Patel VL et al., Blood 2012 Jun 21 31
Which treatment in which phase of the disease? Marc Michel: Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily Practice and Clinical Research? Seminars in Hematology Volume 50, Supplement 1 2013 S50 - S54 32
My approach in ITP Newly diagnosed ITP (during the first 3 months): Be sure that steroids don t work Personally I prefer dexamethason (4 days every 14-28 days) In clinically severe cases I give IVIg and wait for the action of steroids (I don t give up to early) In general: I avoid second line treatment Persistent and chronic ITP (3 12 months and later) Now I know that steroids did not work! I start with a TPO receptor agonist the patient gets stabilized. After stabilization I discuss the option of rituximab Splenectomy can be discussed in chronic phase 33
Conclusion At first diagnosis of thrombocytopenia: Combined evaluation of laboratory and clinical data Laboratory and clinical data determine further investigations Diagnostic algorithms can be helpful Thrombocytopenia during pregnancy In most cases not therapy is indicated or very low doses of prednisone resolve the problem Immune thrombocytopenia Despite the number of treatment options: some cases still stay very challenging! 34
35