When to suspect a diagnosis of congenital inherited thrombocytopenia (CTP) ? Or when low platelet level does not mean immune thrombocytopenic purpura (ITP).

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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

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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

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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?

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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)

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Reasons to suspect CTP family history

• Especially gt 2 family members
• Especially parent-child or maternal uncle-nephew
• Non-specific criteria
• Cases of familial ITP (autoimmune diseases)

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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
• gt 30,000/µl increase from baseline ITP
• lt 10,000/µl increase is compatible with CTP, but
  "refractory" ITP is possible.

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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.

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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

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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).

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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 hypogammaglobulinem
  ia!

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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)
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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

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

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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

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ACKNOWLEDGEMENTS

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