Genetics in Thrombotic Microangiopathy

Introduction: The underlying molecular mechanisms in complement mediated Thrombotic Microangiopathy (C-TMA) tend to overlap but unify at the common end-point of endothelial injury. Literature has shown that complement activation is triggered at the endothelial surface. Some triggers like infection is the first presentation of TMA even in the genetically susceptible individuals. In this case, we discuss the unmasking of C-TMA after an infection. Case Description: A 30-year-old African American male presented with acute pancreatitis and acute kidney injury (AKI). Workup was significant for creatinine 5.4 mg/dl, hemoglobin 10.3g/dl, platelets 21x10*3/uL, 2+ Schistocytes, reticulocyte 1.7%, bilirubin 1, Fibrinogen 365mg/dL, D-dimer >20, PT 1.5, APTT 28, C3 102, C4 23, and direct Coombs test negative.The ADAMTS13 activity at 67%. A genetic panel for C-TMA was sent and decision was made to start the patient on complement inhibitor therapy until genetic study was pending. Unfortunately, the patient left hospital against medical advice and two days later presented at an outside hospital. There he was started on hemodialysis for worsening renal failure and underwent a kidney biopsy which showed chronic TMA. Genetic results were positive for C-TMA due to the presence of a splice variant in CFHR1 in combination with large CFHR1-3 deletion which makes the patient in effect CFHR1-null. Discussion: C-TMA is caused by the dysregulation of alternate pathway (AP), perpetuating the downstream effects of the complement pathway. Only 50-60% of cases of C-TMA are caused by genetic variants and the absence of the gene does not exclude the diagnosis. C-TMA is not a monogenic disease and familial forms are only reported in 20% of patients. More genetic variants are emerging as genetic testing is becoming frequent and patient registries continue to expand. Due to the variable penetrance in familial cases of C-TMA, most patients present at an advanced age and often require a second hit such as an infection, pregnancy, and vaccination to unmask the TMA. The studies done so far to compare the enrichment of the variant frequency have been geographically limited and the issue of race has not been addressed in the field of TMA genetics. The data on the incidence of C-TMA and complement genetics is lacking in black individuals. Further studies are needed to explore the frequency of genetic variants in the African American population.