Hemolytic Diseases with Negative Coombs Test

Introduction to Wilson's Disease

Wilson's disease is the most critical hemolytic disease with a negative Coombs test to identify, particularly when presenting as acute liver failure with Coombs-negative hemolytic anemia, as it requires urgent liver transplantation and carries 95% mortality if untreated 1, 2, 3
The American Association for the Study of Liver Diseases recommends suspecting Wilson's disease in any patient presenting with acute liver failure combined with Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, and low serum alkaline phosphatase with an alkaline phosphatase to bilirubin ratio <2 2, 3

Wilson's disease predominantly affects young females (female:male ratio 4:1 in acute presentations) 1
The disease is characterized by rapid progression to hepatic and renal failure 1, 3
Coagulopathy unresponsive to parenteral vitamin K is a common feature 3
Serum copper is typically ≥200 μg/dL (31.5 μmol/L) 2
Kayser-Fleischer rings may be absent in 50% of patients with acute liver failure 2

Wilson's disease can present as single acute episode, recurrent episodes, or chronic low-grade hemolysis 1, 4
Hemolysis was the presenting feature in 12% of cases in one series (25 of 220 patients) 1
Hemolysis may occur during delivery, mimicking HELLP syndrome 1

The diagnostic algorithm for Coombs-negative hemolysis involves confirming hemolysis, examining the peripheral blood smear, assessing for Wilson's disease, evaluating for thrombotic microangiopathy, considering hereditary causes, and evaluating for PNH and other causes 2, 4, 5
The American Association for the Study of Liver Diseases recommends measuring serum ceruloplasmin, serum copper, and 24-hour urinary copper, as well as performing a slit-lamp examination for Kayser-Fleischer rings, to assess for Wilson's disease 2, 4
The European Hematology Association suggests checking platelet count and renal function to evaluate for thrombotic microangiopathy 5