How are complement-related thrombophilias, such as atypical Hemolytic Uremic Syndrome (aHUS), diagnosed and managed, including treatment with medications like eculizumab (eculizumab is a monoclonal antibody that inhibits the complement system)?

Diagnosis and Management of Complement-Related Thrombophilias (aHUS)

Eculizumab is the first-line treatment for atypical Hemolytic Uremic Syndrome (aHUS) and should be initiated immediately upon diagnosis to prevent life-threatening complications and reduce mortality.

Diagnostic Approach for aHUS

Initial Laboratory Evaluation

• Complete blood count with peripheral blood smear (critical to identify schistocytes) 1
• Comprehensive metabolic panel with serum creatinine 1
• Lactate dehydrogenase (LDH) and haptoglobin to assess hemolysis 1
• ADAMTS13 activity level (to rule out TTP) 1
• Complement testing: C3, C4, and CH50 1

Additional Testing

• Evaluation for infectious causes including shiga toxin and E. coli O157 (to rule out STEC-HUS) 1
• Homocysteine or methylmalonic acid levels 1
• Direct antibody test (Coombs test) 1
• Genetic testing for complement mutations (important for prognosis and treatment decisions) 2
• Evaluation for complement inhibitory antibodies for suspected familial cases 1

Grading and Management of aHUS

Grade 1-2 (Evidence of RBC destruction without significant clinical consequences)

• Close clinical follow-up and laboratory evaluation 1
• Consider initiating eculizumab if there are signs of progression 1

Grade 3 (Laboratory findings with clinical consequences such as renal insufficiency)

• Consult hematology immediately 1
• Initiate eculizumab therapy 1, 3

Grade 4 (Life-threatening consequences such as CNS thrombosis or renal failure)

• Begin therapy with eculizumab 900 mg weekly for 3-4 doses, then 1,200 mg at week 5, followed by 1,200 mg every 2 weeks 1, 3
• Provide red blood cell transfusions according to existing guidelines 1

Eculizumab Therapy for aHUS

Mechanism of Action

• Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with high affinity 3
• It inhibits cleavage of C5 to C5a and C5b, preventing generation of the terminal complement complex C5b-9 3
• This action blocks complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS 3

Dosing Protocol

• Initial phase: 900 mg weekly for 4 weeks 3
• Maintenance phase: 1,200 mg at week 5, then 1,200 mg every 2 weeks 3
• Dosing may need adjustment based on patient response and complement activity monitoring 4

Monitoring Therapy

• Monitor classical complement pathway (CCP) activity, targeting <30% for prevention of relapses 4
• Measure trough levels of free eculizumab using immunoenzymatic methods when available 4
• Regular laboratory monitoring should include CBC, LDH, creatinine, and urinalysis 2
• Significant decreases in LDH and creatinine are expected when on effective treatment 2

Special Considerations

Vaccination Requirements

• Complete meningococcal vaccination at least 2 weeks prior to the first dose of eculizumab 3
• Comply with current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination 3
• For pediatric patients, administer vaccinations for Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b 3

Treatment Duration and Monitoring

• Long-term treatment is typically required, with a median duration of treatment around 246.5 days in some studies 2
• Monitor patients monthly during the first six months, then every 2-3 months up to 12 months 1
• Some patients may benefit from individualized dosing intervals based on complement activity monitoring 4

Treatment Challenges

• Some patients may experience relapses despite eculizumab treatment, particularly those with specific genetic mutations 5
• In cases of frequent relapses, consider increasing dosing frequency or exploring alternative treatment options 5, 6
• Plasma exchange may be considered in refractory cases or as a bridge to eculizumab therapy 7

Pitfalls and Caveats

• Eculizumab increases the risk of serious meningococcal infections; monitor patients for early signs of infection 3
• Eculizumab is available only through a restricted program (ULTOMIRIS and SOLIRIS REMS) 3
• Not indicated for treatment of Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS) 3
• Infusion-related reactions may occur; monitor patients during infusion and be prepared to interrupt treatment if necessary 3
• Treatment is expensive and access may be limited; early engagement with insurance providers is recommended 7