Successful use of lenalidomide to treat refractory acquired von Willebrand disease associated with monoclonal gammopathy.

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.

Protective effect of pharmacologic preconditioning with pioglitazone on random-pattern skin flap in rat is mediated by nitric oxide system.

BACKGROUND: Pioglitazone, a thiazolidinedione, is primarily used as an antidiabetic agent. In addition, recent reports have identified anti-ischemic and anti-inflammatory properties of pioglitazone through nitric oxide (NO) pathways. OBJECTIVE: To determine the protective effects of pioglitazone on random-pattern skin flaps in a rat model. METHODS: Forty-eight male Rats were randomly assigned to eight groups. Bipedicled dorsal skin flaps (2 × 8 cm) were elevated at the midline. In pharmacologic preconditioning groups, three different doses of pioglitazone (25, 40, 80, mg/kg; doses were selected according to our pilot study) gavaged 4 h before elevating flaps. Seven days after operation, the survival of skin flap was measured. For investigating the role of NO system, in other groups the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg) was administered alone or with an effective dose of pioglitazone. Finally, in another group, subeffective dose of nitric oxide precursor L-arginine (100 mg/kg) was coadministered with subeffective pioglitazone. RESULTS: Significant increase in flap survival was seen with pioglitazone (40 mg/kg). This protective effect was abolished by systemic administration of L-NAME (10 mg/kg). Coadministration of subeffective doses of pioglitazone with subeffetcive L-arginine significantly improved flap survival. CONCLUSION: Pharmacologic preconditioning with pioglitazone improves survival of random-pattern skin flaps in rats through NO dependent mechanisms.

Co-administration of FVIII with IVIG reduces immune response to FVIII in hemophilia A mice.

Hemophilia A is an X-linked recessive congenital bleeding disorder. Exogenous infusion of FVIII is the treatment of choice, and the development of immunoglobulins against FVIII (inhibitors) remains the major challenge in clinical management of the disease. Here, we investigated the effect of co-administration of FVIII with intravenous immunoglobulin (IVIG) on the development of inhibitors in previously untreated hemophilia A mice. A group of hemophilia A mice (C57BL/6FVIII-/-) received weekly injections of recombinant human FVIII (rFVIII) for twelve consecutive weeks while a second group received co-injections of rFVIII + IVIG. An in-house enzyme-linked immunosorbent assay (ELISA) was designed to detect antibodies to rFVIII. Every mouse in the first group developed antibodies to rFVIII. In contrast, mice treated with rFVIII + IVIG showed significantly lower antibody titers. Interestingly, when co-administration of IVIG was discontinued after 12 weeks in some mice (rFVIII continued), these mice experienced an increase in antibody titer. In contrast, mice that continued to receive rFVIII + IVIG retained significantly lower titers. In conclusion, prophylactic rFVIII co-administration with IVIG modulated the immune response to FVIII and resulted in decreased anti-FVIII antibody titer. These findings suggest that co-injection therapy with IVIG could potentially be effective in the management of hemophilia A patients at risk of inhibitor development.

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1.

The occurrence of neutralizing anti-FVIII antibodies is a major complication in the treatment of patients affected by hemophilia A. The immune response to FVIII is a complex, multi-factorial process that has been extensively studied for the past two decades. The reasons why only a proportion of hemophilic patients treated with FVIII concentrates develop a clinically significant immune response is incompletely understood. The "danger theory" has been proposed as a possible explanation to interpret the findings of some observational clinical studies highlighting the possible detrimental impact of inflammatory stimuli at the time of replacement therapy on inhibitor development. The host immune system is often challenged to react to FVIII under steady state or inflammatory conditions (e.g., bleeding, infections) although fine tuning of mechanisms of immune tolerance can control this reactivity and promote long-term unresponsiveness to the therapeutically administered factor. Recent studies have provided evidence that multiple interactions involving central and peripheral mechanisms of tolerance are integrated by the host immune system with the environmental conditions at the time of FVIII exposure and influence the balance between immunity and tolerance to FVIII. Here we review evidences showing the involvement of two key immunoregulatory oxygenase enzymes (IDO1, HO-1) that have been studied in hemophilia patients and pre-clinical models, showing that the ability of the host immune system to induce such regulatory proteins under inflammatory conditions can play important roles in the balance between immunity and tolerance to exogenous FVIII.