A 19 year old female with systemic lupus erythematosus presented to a community hospital with hemoptysis. Bronchoscopy showed diffuse alveolar hemorrhage. She developed tachycardia and hypoxemic respiratory failure requiring ICU transfer, intubation and vasopressors. Labs revealed consumptive coagulopathy and thrombotic thrombocytopenic purpura (TTP), as ADAMTS-13 activity level revealed severe deficiency at less than 10%. Yet she only had partial response to pulse dose steroids, Rituximab, and plasma exchange. Hematology felt the partial response indicated an atypical, complement mediated thrombotic microangiopathy. She received one dose of Eculizumab, yet developed worsening coagulopathy with hemorrhagic stroke, diffuse GI bleeding, and recurrent alveolar hemorrhage leading to respiratory arrest. She developed asystole and died in spite of attempts at resuscitation.
Complement mediated thrombotic microangiopathy (TMA) describes various genetic mutations leading to uncontrolled activation of the alternative complement pathway. Dysregulation results in increased formation of the c5b-c9 membrane attack complex, causing platelet surface injury and malfunction. Complement mutations can lead to loss of function in a regulator gene or gain of function in an effector gene. The CFH mutation is most highly associated with disease recurrence, end stage renal disease (ESRD), and death. Most mutations are heterozygous.
Current diagnostic criteria for complement-mediated TMA are: serum creatinine level at or above the upper limit of normal, microangiopathic hemolytic anemia, thrombocytopenia, ADAMTS13 activity of 5% or more, and negative stool tests for Shiga toxin. One may see a partial response at best to plasma exchange. Diagnosis is difficult as criteria are non-specific and can be seen in other types of TMA. Genetic complement studies are more specific for diagnosis, but our patient decompensated too quickly to have them done.
Anti-complement therapy is recommended, with Eculizumab the only available anti-complement agent. Eculizumab is a monoclonal antibody binding to the C5 complement protein, inhibiting generation of C5a-C5b-9 and the final step of the complement cascade. In phase 2 trails, Eculizumab decreased the need for plasma exchange, improved platelet count, reversed organ damage, and improved survival in patients with complemented mediated TMA. It is difficult to decide when to initiate Eculizumab due to non-specific diagnostic criteria, and patients with no known mutation have had good responses to the drug. Recommendation is to consider treating atypical HUS patients with Eculizumab without testing for complement mutations. Optimal therapy duration is unknown.
Complement mediated TMA is a life threatening condition that can be confused with other coagulopathies. High index of suspicion is needed for diagnosis, with low threshold to initiate Eculizumab in patients who do not respond to plasma exchange.
To cite this abstract:Curtiss JS II, Farmer ZL. 19 Year Old Female with Diffuse Alveolar Hemorrhage. Abstract published at Hospital Medicine 2016, March 6-9, San Diego, Calif. Abstract 482. Journal of Hospital Medicine. 2016; 11 (suppl 1). https://www.shmabstracts.com/abstract/19-year-old-female-with-diffuse-alveolar-hemorrhage/. Accessed April 3, 2020.