1. (*or, how I learned to stop worrying and love the peripheral blood smear) R. Campbell Garland, PGY-2

2. Overview Review of normal platelet life cycle Definition of thrombocytopenia Mechanisms of thrombocytopenia Production, destruction, sequestration Outpatient approach to the patient with thrombocytopenia H&P Lab studies “When should I place a hematology consult?”

3. Real Life Problems: Exhibit A A 68-year-old man is transferred by helicopter from a small regional hospital to a large urban medical center due to refractory epistaxis, multiple blood blisters in his mouth, multiple bruises and tiny red dots all over his body. His platelet count at the time was found to be 2,000. He carries a history of ITP after a similar episode 7 years prior which responded exceptionally well to steroids and splenectomy. He has had no bleeding problems in the seven-year interim, including no issues during or after a CABG procedure approximately 9 months prior. He’s started on IVIg at the accepting facility with a presumptive diagnosis of relapsed ITP. However, after two days of hospitalization with IVIg, his platelet count has failed to respond appropriately.

4. Real Life Problems: Exhibit B A 26-year-old G3P3 female with no significant medical or family history is referred by her primary care physician to a hematologist after a routine CBC for her annual wellness exam revealed a platelet count of 110,000. A repeat CBC performed approximately 3 weeks later reveals a platelet count of 119,000. WBC and Hgb counts on both studies were within normal limits, including differential & indices. She takes no medications, OTC or otherwise. On review of systems, the patient denies any issues with bleeding or bruising, feels she is in her normal state of health, and she reports she really has no idea why she’s here. Physical exam is performed and is unremarkable.

5. Review of Normal Platelets

6. A Platelet Is Born

7. Normal Bone Marrow

8. Peripheral Blood Smear

9. Peripheral Blood Smear (cont.)

10. Platelet Function

11. Defining Thrombocytopenia What you might – (but shouldn’t) – feel like right about now

12. Textbook definitions are okay… “…defined as a platelet count below the 2.5 th lower percentile of the normal platelet count distribution.” NHANES III supports a traditional value of 150,000 as the lower limit of normal

13. …but they’re not real life Platelet counts between 100 and 150 that have been stable for more than 6 months may be normal Many non-Western countries have lowered the threshold of the normal platelet count <150. Blood, 2009; 113(11):2386-2393 Hematology, 2012:191-197

14. Mechanisms of Thrombocytopenia because things get very confusing when you don’t understand how they happened (not a real doctor)

15. Mechanisms of Thrombocytopenia Increased destruction Decreased production Sequestration

16. Increased destruction TTP/HUS DIC ITP, DITP Evans syndrome

17. Decreased production Bone marrow disorder PMF Malignancies Infiltrative disorders Ineffective hematopoiesis

18. Sequestration 1/3 rd of platelet population sequestered in the spleen Hypersplenism (up to 90% sequestered) Extramedullary hematopoiesis (e.g., PMF) Myeloproliferative diseases (e.g., PCV, ET) Liver disease, portal hypertension

19. Outpatient Approach to the Patient with Thrombocytopenia History Family history Correlation between timing of low platelet counts and episodes of bleeding Recent medications, vaccinations Travel history, social history Transfusions, organ transplantation Risk factors for viral hepatitis or retroviral infections Physical Organomegaly Skeletal abnormalities Limb necrosis

20. Peripheral Blood Smear Platelets Platelet clumping Size and granularity

21. Peripheral Blood Smear WBC’s Leukemic cells Leukocyte inclusions, Pelger-Huet anomaly, Dohle bodies, toxic granulations

22. Peripheral Blood Smear RBC’s Schistocytes Microspherocytes Macrocytosis Dacryocytes nRBC’s Parasites

23. Algorithm for workup of thrombocytopenia based on observation of the peripheral blood film. Roberto Stasi Hematology 2012;2012:191-197 ©2012 by American Society of Hematology

24. Additional Investigation Liver, renal function tests Clotting screen with D-dimer LDH Is a bone marrow investigation warranted? Reticulated platelets Increased platelet destruction Immature Platelet Fraction Low percentages: BM failure High percentages: increased platelet destruction

25. Isolated Thrombocytopenia

26. ITP Most common cause of isolated thrombocytopenia Strictly a diagnosis of exclusion International Consensus Report (ICR) +/- RUQ U/S +/- CXR Antiplatelet antibodies (poor sensitivity, specificity ~90%)

27. ITP (cont.) Primary ITP Secondary ITP HIV, HCV, SLE, CLL Severity  Timing Newly-diagnosed Persistent Chronic Response to treatment (refractory vs non-refractory) Response vs complete response

28. ITP When to refer to a hematologist 1 New ITP diagnosis Severe or clinically important bleeding Inadequate platelet count response to therapy Upcoming hemostatic challenge (e.g., surgery, pregnancy) Platelet counts stable above 30K without significant bleeding problems rarely require the attention of a hematologist 1 adapted from UpToDate

29. DITP Frequency in critically ill patients appr. 20% Accelerated platelet destruction Drug-specific antibodies due to either GP conformational change from drug binding or due to molecular mimicry Decreased platelet production Clinically, the thrombocytopenia is isolated and severe Median time to development of thrombocytopenia from drug exposure = 6 days [1-10]

31. DITP (cont.) Withdrawal of the suspected offending drug No lab studies required for establishment of diagnosis Platelet transfusion if necessary +/- oral prednisone 1mg/kg daily often employed due to clinical possibility of ITP IVIg has no established role

32. HIT Occurs in 0.5 – 5% of exposed subjects n.b., rare in ICU setting (<1%) 1 >50% decrease in platelet count compared to baseline or total platelet count <100K with normal baseline levels Degree of TCP is moderate (50-80K), rarely <20K 4T’s to assess likelihood Anti-platelet factor 4 assay: an activating antibody Gold standard: serotonin release assay 1 Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Crit Care Clin. 2011;27(4):805-823

33. Thrombocytopenia in Pregnancy Gestational thrombocytopenia (70%) Pre-eclampsia (21%) ITP (3%)

34. Real Life Problems: Exhibit A A 68-year-old man is transferred by helicopter from a small regional hospital to a large urban medical center due to refractory epistaxis, multiple blood blisters in his mouth, multiple bruises and tiny red dots all over his body. His platelet count at the time was found to be 2,000. He carries a history of ITP after a similar episode 7 years prior which responded exceptionally well to steroids and splenectomy. He has had no bleeding problems in the seven-year interim, including no issues during or after a CABG procedure approximately 9 months prior. He’s started on IVIg at the accepting facility with a presumptive diagnosis of relapsed ITP. However, after two days of hospitalization with IVIg, his platelet count has failed to respond appropriately.

35. Real Life Problems: Exhibit B A 26-year-old G3P3 female with no significant medical or family history is referred by her primary care physician to a hematologist after a routine CBC for her annual wellness exam revealed a platelet count of 110,000. A repeat CBC performed approximately 3 weeks later reveals a platelet count of 119,000. WBC and Hgb counts on both studies were within normal limits, including differential & indices. She takes no medications, OTC or otherwise. On review of systems, the patient denies any issues with bleeding or bruising, feels she is in her normal state of health, and she reports she really has no idea why she’s here. Physical exam is performed and is unremarkable.

36. References Stasi, R. “How to approach thrombocytopenia”, Hematology 2012;2012(1):191-7. Hoffman, R. Hematology : basic principles and practice, 6 th ed. Saunders/Elsevier, 2013. UpToDate