Definition/General
Introduction:
X-linked thrombocytopenia (XLT) is a milder variant of Wiskott-Aldrich syndrome characterized by microthrombocytopenia without the full clinical triad
It results from missense mutations in the WAS gene that preserve some WASP protein function
Patients have bleeding tendency but typically no severe immunodeficiency.
Origin:
Results from missense mutations in WAS gene (Xp11.23) that allow residual WASP protein function
Unlike classical WAS with null mutations, XLT mutations preserve partial protein activity
The mutations affect actin cytoskeleton regulation in platelets primarily
Immunological function relatively preserved.
Classification:
Classified as WAS spectrum disorder: Classical WAS (complete triad, null mutations)
XLT (isolated thrombocytopenia, missense mutations)
Intermittent XLT (mild, fluctuating)
XLT with mild immunodeficiency
Based on WASP expression levels.
Epidemiology:
Rare disorder, subset of WAS spectrum
X-linked inheritance affects males
Carrier females may have mild symptoms
Better prognosis than classical WAS
Variable family history.
Clinical Features
Presentation:
Microthrombocytopenia (small platelets, low count)
Bleeding tendency (bruising, epistaxis)
No severe eczema (unlike WAS)
No severe immunodeficiency
Normal growth and development
Occasional mild infections.
Symptoms:
Easy bruising from childhood
Frequent nosebleeds
Prolonged bleeding after trauma
Normal infection rate (unlike WAS)
No significant eczema
Normal intellectual development.
Risk Factors:
X-linked inheritance (maternal transmission)
Family history of bleeding disorders
Male gender
Carrier mother
Previous affected male relatives
No environmental factors.
Screening:
Complete blood count (microthrombocytopenia)
Platelet size analysis (small platelets)
Bleeding time (prolonged)
WASP protein expression
Genetic testing for WAS mutations
Family screening.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity
Normal or increased megakaryocytes
Small megakaryocytes may be present
Normal erythropoiesis and granulopoiesis
No abnormal infiltrates.
Characteristics:
Normocellular bone marrow
Adequate megakaryocyte numbers
Possible small megakaryocytes
Normal other lineages
No dysplastic changes
No inflammatory infiltrates.
Size Location:
Normal bone marrow distribution
No organomegaly typically
Normal lymph nodes
No systemic involvement
Isolated platelet defect.
Multifocality:
Uniform bone marrow pattern
Consistent findings across sites
Stable over time
No progression to aplasia
Isolated platelet dysfunction.
Microscopic Description
Histological Features:
Normal bone marrow cellularity
Normal or increased megakaryocytes
Small megakaryocytes with reduced cytoplasm
Normal nuclear morphology
Normal other lineages.
Cellular Characteristics:
Micromegakaryocytes (smaller than normal)
Reduced platelet production
Normal nuclear segmentation
Decreased cytoplasm
Normal other cell morphology.
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
Appropriate megakaryocyte location
Normal sinusoidal pattern
No fibrosis.
Grading Criteria:
Severity by platelet count: Mild (50,000-100,000/μL)
Moderate (20,000-50,000/μL)
Severe (<20,000/μL)
Platelet size consistently small
WASP expression reduced but present.
Immunohistochemistry
Positive Markers:
CD61 and CD41 highlight megakaryocytes
WASP protein reduced but detectable
MPO shows normal granulopoiesis
Glycophorin A shows normal erythropoiesis
CD3/CD20 show lymphoid cells.
Negative Markers:
Abnormal infiltrate markers negative
Viral markers typically negative
Blast markers negative
Dysplastic markers negative.
Diagnostic Utility:
Demonstrates reduced WASP expression
Confirms megakaryocyte presence
Shows small megakaryocyte morphology
Distinguishes from classical WAS
Guides genetic testing.
Molecular Subtypes:
Missense mutation XLT
Mild deletion XLT
Splice site XLT
Variable WASP expression
Genotype-phenotype correlation.
Molecular/Genetic
Genetic Mutations:
WAS gene missense mutations (Xp11.23)
Mutations preserving WASP function
Specific mutation hotspots
Different from null mutations (classical WAS)
Variable protein expression.
Molecular Markers:
Reduced but present WASP protein
Partial actin polymerization defect
Mild platelet dysfunction
Preserved immune function
Normal lymphocyte function.
Prognostic Significance:
Better prognosis than classical WAS
No severe immunodeficiency
Lower malignancy risk
Normal life expectancy often
Manageable bleeding tendency.
Therapeutic Targets:
Platelet transfusions (severe bleeding)
Antifibrinolytic agents
Desmopressin (DDAVP)
Avoidance of antiplatelet drugs
Bleeding precautions
Gene therapy (experimental).
Differential Diagnosis
Similar Entities:
Classical Wiskott-Aldrich syndrome
Immune thrombocytopenic purpura
Bernard-Soulier syndrome
May-Hegglin anomaly
Other inherited thrombocytopenias.
Distinguishing Features:
XLT: Small platelets
XLT: Reduced WASP
XLT: No severe immunodeficiency
WAS: Complete triad
WAS: Absent WASP
ITP: Normal platelet size
BSS: Giant platelets
May-Hegglin: Döhle bodies.
Diagnostic Challenges:
Distinguishing from classical WAS
Confirming WASP expression levels
Genetic testing interpretation
Family screening
Carrier detection.
Rare Variants:
Intermittent XLT
XLT with mild immunodeficiency
Late-onset XLT
Atypical presentations
Female XLT (X-inactivation).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
X-Linked Thrombocytopenia
Classification
Classification: WAS spectrum disorder with isolated thrombocytopenia
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with small megakaryocytes
Lineage Assessment
Megakaryopoiesis: adequate numbers, small size. Erythropoiesis: normal. Granulopoiesis: normal
Morphological Features
Shows small megakaryocytes with reduced cytoplasm and normal nuclear morphology
Special Studies
WASP protein: reduced but present
Genetic testing: recommend WAS gene analysis
Platelet studies: microthrombocytopenia
Clinical Correlation
Findings consistent with X-linked thrombocytopenia. Recommend genetic counseling
Final Diagnosis
Bone marrow showing changes consistent with X-linked thrombocytopenia