A 29-year-old woman, G1P1, is evaluated in the intensive care unit on postpartum day 4 for worsening fatigue, confusion, and significantly decreased urine output. She had an uncomplicated spontaneous vaginal delivery at term.
Temperature is 37.6°C (99.7°F), blood pressure is 168/102 mm Hg, heart rate is 108/min, and respiratory rate is 18/min. Physical examination reveals scleral icterus and scattered petechiae over her lower extremities.
Laboratory studies show:
| Test | Result | Reference Range |
|---|---|---|
| Hemoglobin | 7.1 g/dL | 12.0-16.0 g/dL |
| Platelet count | 32,000/mm³ | 150,000-400,000/mm³ |
| Leukocyte count | 9,400/mm³ | 4,500-11,000/mm³ |
| Creatinine | 3.9 mg/dL | 0.6-1.1 mg/dL |
| Aspartate aminotransferase (AST) | 22 U/L | 10-40 U/L |
| Alanine aminotransferase (ALT) | 28 U/L | 7-56 U/L |
| Lactate dehydrogenase (LDH) | 1,450 U/L | 140-280 U/L |
| Haptoglobin | < 10 mg/dL | 41-165 mg/dL |
| Prothrombin time (PT) | 12 sec | 11-15 sec |
| Partial thromboplastin time (PTT) | 28 sec | 25-40 sec |
| ADAMTS13 activity | 68% | > 60% |
| Direct antiglobulin (Coombs) | Negative | Negative |
Peripheral blood smear shows numerous schistocytes.
Which of the following best describes the precise mechanism of the most appropriate targeted pharmacotherapy for this patient's underlying condition?
- Binding to complement component C5 to prevent its cleavage and subsequent formation of the terminal membrane attack complexAnswer
- BInhibition of the interaction between ultra-large von Willebrand factor multimers and platelet glycoprotein Ib-IX-V
- CDirect enhancement of antithrombin III-mediated neutralization of thrombin and coagulation factor Xa
- DSaturation of reticuloendothelial macrophage Fc receptors to suppress IgG autoantibody-mediated cellular clearance
- ESupplementation of a plasma serine protease inhibitor to prevent uninhibited classical pathway and contact system activation
Answer
The correct targeted pharmacotherapy is eculizumab, which functions by binding to complement component C5 to prevent its cleavage and the subsequent formation of the terminal membrane attack complex.
The patient's presentation of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury in the postpartum setting, combined with normal ADAMTS13 activity, normal coagulation studies, and normal liver enzymes, confirms a diagnosis of atypical hemolytic uremic syndrome (aHUS). aHUS is caused by dysregulation of the alternative complement pathway. The standard targeted pharmacotherapy is eculizumab (or ravulizumab), a monoclonal antibody that binds directly to complement protein C5. This binding prevents the cleavage of C5 into C5a (a potent anaphylatoxin) and C5b, thereby halting the formation of the C5b-9 terminal membrane attack complex (MAC) that causes the hallmark endothelial damage in this disease.
Step-by-Step Solution
Key Concept
Diagnosis of atypical hemolytic uremic syndrome (aHUS) via exclusion of other TMAs, and management with C5 inhibitors (eculizumab) to block the terminal complement cascade.