Thrombocytopenia: a practial approach

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1 Thrombocytopenia: a practial approach Dr. med. Jeroen Goede FMH Innere Medizin, Medizinische Onkologie, Hämatologie FAMH Hämatologie Chefarzt Hämatologie Kantonsspital Winterthur

2 Outline Introduction and Definitions Diagnostic steps differential diagnosis Thrombocytopenia during pregnancy Immune thrombocytopenia Conclusions 2

3 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

4 Introduction In most laboratories: normal platelet count between 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 : G/l Grade 2 : G/l Grade 3 : G/l Grade 4 : <25 G/l 4

5 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

6 Diagnostic steps Main laboratory questions in newly diagnosed thrombocytopenia: Exclude pre-analytic reasons for thrombocytopenia Concomitant anemia and/or neutropenia? Degree of thrombocytopenia? Tc G/l vs G/l vs G/l vs. <25 G/l 6

7 Diagnostic steps Main clinical questions in newly diagnosed thrombocytopenia: Recent and actual medication? History of previous thrombocytopenia? Family history? Pregnancy? 7

8 Diagnostic steps Mr. S.O. 1971

9 Diagnostic steps 9

10 Diagnostic steps Mr. M.O. 1968

11 Diagnostic steps 11

12 Diagnostic steps Diagnosis: Bernhard-Soulier-Syndrome 12

13 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

14 Diagnostic steps If thrombocytopenia is confirmed: Stepwise evaluation to assess the causes and the urgency of treatment

15 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

16 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

17 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

18 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

19 Sudhir S. et al. SMJ, 2006

20 Thrombocytopenia during pregnancy:

21 Thrombocytopenia during pregnancy 21

22 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

23 Immune thrombocytopenia (ITP) Schoonen, BJH

24 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

25 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

26 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 S50 - S54 26

27 TPO agonists Very good clinical data with a high proporiton of responders Good tollerability Chronic treatment Chronic costs 27

28 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 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%)

29 Splenectomy 29

30 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

31 Rituximab Patel VL et al., Blood 2012 Jun 21 31

32 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 S50 - S54 32

33 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 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

34 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 35

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