Acquired Factor IX (fIX) Deficiency Associated with a Multiple Myeloma.

Abstract

Multiple myeloma is associated with bleeding disorders in about 15 % of patients. The pathophysiology is multifactorial and may be related to the paraprotein level. The bleeding tendency has been reported to be caused by thrombocytopenia, paraprotein-induced qualitative platelet dysfunction, inhibition of polymerization of fibrin monomers, monoclonal thrombin inhibitor, factor X deficiency, acquired von Willebrand syndrome and local tissue fragility secondary to amyloidosis. Here, we report the first case of acquired fIX deficiency associated with a multiple myeloma (MM) in a 54 year-old Caucasian man.The patient presented with a Monoclonal Gammapathy of Undetermined Significance (MGUS) (IgA lambda 15 g/L). His laboratory evaluation then revealed an activated prothrombin time (aPTT) of 37 s (normal 29–36 seconds) without any bleeding disorder. Three years later, the MGUS evolved into a stage III multiple myeloma (IgA lambda 55 g/L) and the patient presented a hemorrhage after a bone marrow biopsy. At this time, the coagulation tests showed an aPTT of 54 s, a thrombin time of 27 s (normal 20–25 seconds), a normal platelet count without any other abnormalities. Clotting factors assay revealed a fIX deficiency of 10 %. No inhibitor was found using the Bethesda method and no fIX mutation was detected in the patient DNA as well as in his sister's. After receiving chemotherapy (VAD-type chemotherapy and high-dose of Melphalan with autologous stem cells transplantation), the paraprotein concentration decreased to 9 g/L and the coagulation results returned to normal. Sixteen months later, the MM recurred (IgA lambda 78 g/L) and the patient presented hemorrhagic manifestations associated with an aPTT of 70 s and a fIX deficiency at 11 %. Factor IX deficiency and bleeding diathesis were detected in every MM relapses. He died during a severe bleeding event (epistaxis, hematuria and rectorrhagia) despite fIX concentrate treatments.The etiology of this acquired fIX deficiency is not clear. The simultaneous evolution of MM and fIX deficiency, and the absence of congenital hemophilia mutation confirm that it is an acquired deficiency. Nevertheless there is no fIX inhibitor. Until now no case of acquired fIX deficiency is described in the literature apart from Gaucher disease. Our hypothesis is that fIX can be adsorbed by the malignant plasma cells. We are currently performing immunostaining of fIX in the bone marrow of this patient to assess whether fIX is adsorbed by the medullar malignant cells.