Hemolysis and Septic Shock with Encapsulated Bacteria in Eculizumab Management of Paroxysmal Nocturnal Hemoglobinuria

Special Article - Clinical Cases and Images

Ann Hematol Oncol. 2015;2(2): 1024.

Hemolysis and Septic Shock with Encapsulated Bacteria in Eculizumab Management of Paroxysmal Nocturnal Hemoglobinuria

Shi J1, Yellu M2* and Medlin SC2

1University of Cincinnati College of Medicine, USA

2Division of Hematology/Oncology, University of Cincinnati, USA

*Corresponding author: Yellu M, Department of Hematology/ Oncology and Stem Cell Transplantation, University of Cincinnati, 3130 Highland Avenue, Cincinnati, OH 45219, USA

Received: November 18, 2014; Accepted: January 27, 2015; Published: January 29,2015


Diagnosis and management of severe hemolysis in patients taking eculizumab is rather challenging and may indicate an onset of life-threatening conditions such as septic shock or drug resistance. Eculizumab-related sepsis due to Neisseria meningitides has been reported in the literature but report of severe infections secondary to other encapsulated organisms is lacking. Vaccinating patients against these bacterial pathogens may help prevent such devastating infections, but the bacterial organisms without vaccinations still pose a problem. Hemolysis related to eculizumab resistance has also been reported, and various hypotheses have been put forward. We present a young patient with paroxysmal nocturnal Hemoglobinuria treated with eculizumab, who subsequently developed severe sepsis, preceded by hemolysis and complicated by IgG-related extra vascular hemolysis.

Keywords: AIHA; PNH; Eculizumab; Resistance


PNH: Paroxysmal Nocturnal Hemoglobinuria; PIG-A: Phosphatidylinositol N-Acetylglucosaminyltransferase Subunit A; GPI: Glycosyl Phosphatidylinositol; AA-PNH: Aplastic Anemia- Paroxysmal Nocturnal Hemoglobinuria; AA: Aplastic Anemia; CDR: Complementarity-Determining Regions; IgG: Immunoglobulin G; ATG: Anti-Thymocyte Globulin; FACS: Fluorescence-Activated Cell Sorting; FLAER: Fluorescent Aerolysin; CBC: Complete Blood Count; ANC: Absolute Neutrophil Count; TRIUMPH: Randomized, Placebo-Controlled, Phase 3 Study; DAT: Direct Antiglobulin Test; AIHA: Autoimmune Hemolytic Anemia; FcγRs: Fc-Gamma Receptors; RBC: Red Blood Cell; ADCC: Antibody-Dependent Cellular Cytotoxin


Paroxysmal Nocturnal Hemoglobinuria (PNH) is a hematopoietic stem cell disease characterized by complement-induced intravascular lysis of erythrocytes. These cells are abnormally vulnerable to attacks by complement due to the clonal expansion of stem cells with the PIG-A gene mutation, resulting in the deficiency of the endogenous Glycosyl Phosphatidylinositol (GPI)-anchored complement inhibitor protein CD59 on the surface of blood cells [1]. AA-PNH syndrome was first reported in 1967 as a case of AA presenting with PNH-like characteristics of hemolysis, bone marrow failure and thrombosis [2]. The only curative therapy for PNH is hematopoietic stem cell transplantation, but because of severe morbidity and mortality associated with this procedure, patients have been traditionally managed with blood transfusions, steroids, and warfarin.

Eculizumab is a humanized monoclonal antibody directed against the complement protein C5, inhibiting C5 cleavage to C5a and C5b, preventing the generation of the terminal complement complex C5b- 9 and thus blocking complement-mediated cell lysis and activation. The antibody is an IgG2/4 kappa immunoglobulin comprised of human constant regions and murine Complementarity-Determining Regions (CDRs) grafted onto human framework light- and heavychain variable regions. Eculizumab has been shown to inhibit intravascular hemolysis, but may lead to extra vascular hemolysis by inhibiting C5 long enough for C3d fragments to accumulate on the surface of erythrocytes [3].

The most life threatening complication associated with the use of eculizumab is sepsis related to encapsulate bacterial organisms [4]. Phase III clinical trials have shown that patients treated with eculizumab may rarely develop sepsis with Neisseria meningitides [5]. The increased risk of meningococcal infection seems to be due to the critical action of the terminal complement in prevention of such infections. Complications related to the use of eculizumab including sepsis are rare but can be preceded by hemolysis. Therefore vigorous search for underlying infection should be considered in the setting of worsening hemolysis.

Case Report

A 25 year-old African American female with a nine-year history of a plastic anemia and two-year history of PNH was admitted for sepsis and severe hemolysis.

She initially presented at age 16 with severe anemia and was diagnosed with aplastic anemia. She did not have a matched sibling donor and her bone marrow function was adequate enough that she was managed for a long time with supportive care measures including cyclosporine, pentamidine, Anti-Thymocyte Globulin (ATG), mycophenolatemofetil and red cell transfusions. She was found to have normal CD59 expression at her initial presentation. However, the disease evolved and she developed a hemorrhagic stroke associated with a cerebral venous sinus thrombosis that led to the diagnosis of PNH based on reduced expression of CD55 and CD59 with Fluorescence-Activated Cell Sorting (FACS) and Fluorescent Aerolysin (FLAER). She was then initiated on eculizumab and maintained on 1200mg every 14 days. Complete inhibition of complement activity was seen in vitro per Alexion testing.

Upon admission at age 25, she presented with complaints of abdominal pain, fatigue, and diarrhea. Complete Blood Count (CBC) revealed hemoglobin 7.2 g/dL (normal 11.7-15.7 gm/dl), Absolute Neutrophil Count (ANC) 3268 cells/mm3, lactate dehydrogenase (LDH) 2144 U/L (normal 313-618 U/L), total bilirubin 1.3 mg/dL (normal 0.1-1.1 mg/dl), platelets 81 (150-450 /mcl), creatinine 1.80 (0.5-1.1 mg/dL)and haptoglobin not detectable. Blood culture grew Klebsiellaoxytoca and Escheriahermannii. Her sepsis has resolved with fluid resuscitation and intravenous cefepime, vancomycin, and metronidazole. The patient was seen in the outpatient clinic and her labs demonstrated initial improvement followed by a spike in hemolytic markers including LDH 2229 U/L, total bilirubin 1.6 mg/ dL, and hemoglobin 8.0 g/dL. Platelets remained stable at 201 /mcl and creatinine stayed at baseline 1.70 mg/dL. A direct antiglobulin test detected warm anti-IgG auto antibodies along with schistocytes on peripheral smear. The patient was treated with prednisone and showed rapid improvement in her hemolysis.



Eculizumab is the first and only targeted therapy introduced for the treatment of PNH. Based on the clinical trials, eculizumab has been found to be effective, well tolerated, and relatively safe [4-7]. The efficacy of eculizumab was first demonstrated by the TRIUMPH study in 2006, a double-blinded, randomized, placebo-controlled, phase III trial involving 87 patients, with 86% reduction in intravascular hemolysis [7]. Our patient experienced similar efficacy with decrease in LDH at 16 weeks and further improvement at 26 weeks (Figure 1). However, she developed severe hemolysis during the episode of sepsis.

Citation: Shi J, Yellu M and Medlin SC. Hemolysis and Septic Shock with Encapsulated Bacteria in Eculizumab Management of Paroxysmal Nocturnal Hemoglobinuria. Ann Hematol Oncol. 2015;2(2): 1024. ISSN:2375-7965