Pr JF Viallard Hôpital Haut-Lévêque, CHU BORDEAUX FRANCE

1. When to suspect a diagnosis of congenital inherited thrombocytopenia (CTP)? Or when low platelet level does not mean immune thrombocytopenic purpura (ITP). Pr JF Viallard Hôpital Haut-Lévêque, CHU BORDEAUX FRANCE

2. Chronic thrombocytopenia in adult diagnostic procedure • Pseudothrombocytopenia • Bone marrow examination • HIV, B- or C-hepatitis • Antinuclear antibodies, antiphospholipid antibodies,… • Coagulation tests • Schistocytes • hypogammaglobulinemia • Spleen echography

3. ITP or CTP? • ITP: diagnosis of exclusion • A number of CTP had been misdiagnosed as ITP and the patients subjected to spleenectomy and/or cyclophosphamide, amongst other unappropriate therapies • Which patients must be explored?

4. FOUR POINTS OF TRIAGE TO SUSPECT CONGENITAL THROMBOCYTOPENIA (CTP) • A family history of "ITP" • Absence of an increase in the platelet count in response to ITP treatments (refractory ITP) • Presence of certain "associated features" suggesting very specific diagnoses, for example thrombocytopenia with absent radii • Platelet size estimated on smear (blood smears are universally available)

5. Reasons to suspect CTP: family history • Especially > 2 family members • Especially parent-child or maternal uncle-nephew • Non-specific criteria • Cases of familial ITP (autoimmune diseases)

6. Reasons to suspect CTP: non-response to ITP treatment • Lack of platelet response to classical autoimmune thrombocytopenia therapies including IVIG, steroids, and spleenectomy • Non-specific criteria: refractory ITP • No exact definition of lack of response; no well-defined response thresholds • Arbitrarily: • > 30,000/µl increase from baseline: ITP • < 10,000/µl increase is compatible with CTP, but "refractory" ITP is possible.

7. Reasons to suspect CTP: non-response to ITP treatment • Possible immunological component to the CTP • Impeding the clearance mechanism for aberrant platelets helps to offset impaired platelet production. • Since "spontaneous" fluctuation in the platelet count may occur (for example as a result of a viral infection), the assessment of two treatment responses is probably more helpful as a diagnostic criterion.

8. Reasons to suspect CTP: associated features • In the patient or in a family member • Absence of radii (± other orthopaedic malformations) is suggestive of a TAR syndrome, • Severe thrombocytopenia in the first year of life with reduced megakaryocytes • Severe bleedings • their platelet counts increase with time • the platelets may fall again during adulthood • Signaling via the TPO receptor is abnormal

9. Reasons to suspect CTP: associated features • Features of velocardiofacial (VCF) syndrome and DiGeorge syndrome : • T-cell defect (but variable clinical immunodeficiency) • Rightsided heart disease • Neonatal hypocalcemia • Cleft palate or bifid uvula • Neuro-psychologic issues • Acronym "CATCH22" (cardiac abnormality, T-cell deficit, cleft palate, hypocalcemia due to Chr22 deletion).

10. Reasons to suspect CTP: associated features • Patients with either Wiskott-Aldrich syndrome (WAS) or the XLT form of WAS: • Marked or severe thrombocytopenia and smaller than normal platelets. • Severe infections (predilection to pneumococcal sepsis) • Eczema is common • Very young infants: milk allergy, and hematochezia • Frequent infections may overlap with immune thrombocytopenias secondary to hypogammaglobulinemia!

11. Thrombocytopenia + large/giant platelets bleeding +/- Fechtner Syndrome (1985) : +leuko. Inclusions, nephritis, deafness, cataract Epstein Syndrome (1972): + nephritis, deafness Sebastian Syndrome (1990) : + leuko. inclusions May-Hegglin Anomaly : (1909; 1945) + leuko. inclusions Alport-like syndrome (1986): + nephritis, deafness, cataract Molecular basis : MYH9 mutations (Kelley 2000, Heath 2001, Seri 2002)

12. Reasons to suspect CTP: review of the smear • Visual inspection of the smear remains the "gold standard" for platelet size in clinical practice • Large platelets: Bernard-Soulier syndrome or MYH9 defects. • Very small platelets: consistent with Wiskott-Aldrich • Platelet clumping may suggest von Willebrand type IIb

13. Mutations MYH9 Döhle-like bodies (light-blue leukocytes inclusions) MHA FTNS FTNS MGG IC

14. Other reasons to suspect hereditary thrombocytopenia • Bleeding out of proportion to the platelet count • Onset at birth • Persistence of a stable level of thrombocytopenia for years • Normal life span of platelets determined by isotopic platelet life span study despite low platelet level

15. PERSPECTIVES • Certain patients do not fit into any of the known disorders • Refer to a specialist in inherited platelet disorders: • Number and morphology of megakaryocytes • MK colonies assays • MK cultures • Platelet function and aggregation studies with high platelet concentrations • Plasma TPO, glycocalicin levels • New therapies: TPO

16. ACKNOWLEDGEMENTS • A Nurden and P Nurden, Centre de Référence des pathologies plaquettaires rares, Hôpital Haut-Lévêque, BORDEAUX