Possible high risk of thrombotic events in patients with paroxysmal nocturnal haemoglobinuria after discontinuation of eculizumab

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic intravascular haemolysis and a high risk of thrombosis, on a background of variable pancytopenia. The disease is caused by an acquired mutation of the PIGA gene in the haematopoietic stem cell, resulting in deficiency of glycosyl phosphatidyl inositol (GPI) anchors. The lack of GPIanchored complement inhibitors on erythrocytes renders them susceptible to complement-mediated haemolysis. Thrombosis frequently complicates PNH with high morbidity and mortality (de Latour et al, 2008). Thrombotic risk is correlated to the size of the PNH clone (Hall et al, 2003). Prophylaxis with coumarins does not offer full protection, particularly in patients with prior thrombosis (de Latour et al, 2008). Proposed mechanisms include shedding of procoagulant microparticles by complement-damaged platelets and deficiencies of GPI-anchored urokinase plasminogen activator receptor (uPAR) and tissue factor pathway inhibitor (TFPI) (reviewed in van Bijnen et al, 2011). Additionally, depletion of nitric oxide by free haemoglobin may promote platelet activation (Rother et al, 2005). Eculizumab, a monoclonal antibody to complement factor C5, effectively blocks intravascular haemolysis, improves anemia and reduces thrombotic risk (Hillmen et al, 2006, 2007; Schubert et al, 2008). Treatment must be continued lifelong to maintain terminal complement inhibition. During treatment, prolonged survival of GPI-deficient PNH erythrocytes increases their number (Hillmen et al, 2006). Consequently, in the first weeks after stopping eculizumab, significant haemolysis may be anticipated. Thrombotic risk is expected to return to pre-treatment levels; rebound thrombosis however has not been described. Here, we report a patient with a first thrombotic event shortly after stopping eculizumab. While on anticoagulant prophylaxis, this female patient suffered from a fatal arteriovenous thrombosis of the small bowel 3 weeks after her last eculizumab dose. The patient was diagnosed with classic PNH (granulocyte clone size 70%) at the age of 32 years. Initial treatment included erythrocyte transfusions (1–2 units/month) and anticoagulant prophylaxis with fenprocoumon. She never suffered from thrombosis. Three years after diagnosis, the PNH clone size had increased to 92%. She started eculizumab treatment, which normalized lactate dehydrogenase (LDH) levels, rendered her transfusion-independent and improved her quality of life. In 2007, 1 year after starting eculizumab, she developed progressive pancytopenia and transfusion dependency. LDH levels remained normal, and PNH clone size was still 98%. Underdosing of eculizumab was excluded. Bone marrow histology suggested the development of aplastic anaemia. At that time, the high transfusion requirements masked the clinical benefit of eculizumab. Though unlikely, a role for eculizumab in developing aplastic anaemia could not be excluded and eculizumab was stopped. PNH erythrocytes were undetectable at that time and significant haemolysis did not occur. Three weeks after her last eculizumab dose, while on therapeutically dosed fenprocoumon and severely thrombocytopenic, she reported abdominal pain and feculent vomiting. Explorative surgery revealed segmental necrosis of the small bowel. Histology showed extensive arteriovenous thrombosis (Fig 1). Anticoagulant treatment was switched to argatroban. Nine weeks later, she again developed abdominal pain and