Upshaw-Schulman Syndrome (USS)

Upshaw-Schulman syndrome is a rare, inherited form of thrombotic thrombocytopenic purpura (congenital TTP) characterized by severe deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.

Key Points

• Inheritance: Autosomal recessive pattern
• Gene: ADAMTS13 mutations
• Prevalence: Approximately 1 in 1 million individuals
• Age of Onset: Can present from neonatal period to adulthood
• Gender Distribution: Affects males and females equally

Molecular and Cellular Mechanisms

• ADAMTS13 Function:
  • Normal role in cleaving ultra-large von Willebrand factor multimers
  • Regulation of platelet adhesion and aggregation
  • Prevention of spontaneous microvascular thrombosis
• Disease Mechanism:
  • Mutations in ADAMTS13 gene leading to enzyme deficiency
  • Accumulation of ultra-large vWF multimers
  • Formation of platelet-rich microthrombi
  • Subsequent tissue ischemia and organ damage
• Trigger Factors:
  • Infections
  • Pregnancy
  • Physical stress
  • Surgery or trauma
  • Inflammatory conditions

Clinical Manifestations

• Early Presentation:
  • Neonatal hyperbilirubinemia
  • Thrombocytopenia in early infancy
  • Unexplained hemolytic anemia
  • Petechiae and purpura
• Classic Pentad:
  • Microangiopathic hemolytic anemia
  • Thrombocytopenia
  • Neurological symptoms
  • Renal dysfunction
  • Fever
• Organ-Specific Manifestations:
  • Neurological:
    • Headaches
    • Confusion
    • Seizures
    • Focal neurological deficits
  • Renal:
    • Proteinuria
    • Hematuria
    • Acute kidney injury
    • Chronic kidney disease
  • Gastrointestinal:
    • Abdominal pain
    • Nausea and vomiting
    • Diarrhea

Diagnostic Approach

• Laboratory Studies:
  • Complete blood count:
    • Thrombocytopenia
    • Schistocytes on peripheral smear
    • Elevated LDH
    • Decreased haptoglobin
  • Specific Tests:
    • ADAMTS13 activity level (severe deficiency <10%)
    • ADAMTS13 antigen level
    • Genetic testing for ADAMTS13 mutations
• Additional Investigations:
  • Renal function tests
  • Liver function tests
  • Coagulation profile
  • Urinalysis
  • Brain imaging when indicated
• Family Studies:
  • Genetic counseling
  • Family member screening
  • Carrier testing

Treatment Strategy

• Acute Episode Management:
  • Plasma therapy:
    • Fresh frozen plasma infusion
    • Plasma exchange in severe cases
    • Frequency based on clinical response
  • Supportive care:
    • Blood product support
    • Management of complications
    • Monitoring of organ function
• Prophylactic Treatment:
  • Regular plasma infusions
  • Individualized schedule based on:
    • Clinical symptoms
    • Laboratory parameters
    • Patient response
• Novel Therapies:
  • Recombinant ADAMTS13
  • Gene therapy (experimental)
  • Other emerging treatments

Special Patient Populations

• Pregnancy Management:
  • Increased monitoring frequency
  • Prophylactic plasma therapy
  • Close collaboration with obstetrics
  • Special delivery planning
• Surgical Procedures:
  • Pre-operative plasma therapy
  • Perioperative monitoring
  • Post-operative prophylaxis
• Pediatric Considerations:
  • Growth and development monitoring
  • Vaccination schedule adjustments
  • School and activity modifications

Disease Complications

• Acute Complications:
  • Neurological:
    • Stroke
    • Seizures
    • Coma
  • Renal:
    • Acute kidney injury
    • End-stage renal disease
  • Cardiac:
    • Myocardial infarction
    • Heart failure
• Chronic Complications:
  • Cognitive impairment
  • Chronic kidney disease
  • Developmental delays
  • Quality of life impact
• Treatment-Related Complications:
  • Catheter-related infections
  • Transfusion reactions
  • Venous access issues

Long-term Outcomes

• Prognostic Factors:
  • Age at diagnosis
  • Severity of initial presentation
  • Frequency of episodes
  • Compliance with prophylactic therapy
  • Development of complications
• Quality of Life:
  • Impact on education and employment
  • Psychological aspects
  • Social support needs
  • Long-term medical care requirements
• Monitoring Requirements:
  • Regular clinical follow-up
  • Laboratory monitoring
  • Organ function assessment
  • Quality of life evaluation