DDAVP and interleukin-11: a boosting combination

Desmopressin (DDAVP) has found widespread clinical application in the management of hemophilia A and von Willebrand disease since its description by Mannucci et al in 1977 (Lancet. 1977;1:869-872). DDAVP is attractive because of the absence of risk for the transmission of infections, its lack of serious side effects, and its simple administration by nasal spray, which allows convenient home use. But patients become progressively less responsive upon repeated administration over several days, due to the depletion of storage pools. Furthermore, treatment is limited to patients with only moderately decreased levels of factor VIII (FVIII) or von Willebrand factor (VWF). Thus, new agents improving the application of DDAVP would be of great benefit. One potential candidate is recombinant human interleukin-11 (Neumega), a thrombopoietic growth factor that has been approved for treatment of thrombocytopenia following high-dose chemotherapy. Denis et al have previously shown that administration of interleukin-11 in mice produces a sustained increase of plasma levels of FVIII and VWF (Blood. 2001;97:465-472).

In this issue, Olsen and colleagues (page 436) show that interleukin-11 treatment of heterozygous VWF-deficient and normal dogs results in increased VWF mRNA levels. This may explain why interleukin-11 administration is associated with elevated VWF plasma levels, and it indicates that interleukin-11 and DDAVP modulate VWF plasma levels in a mechanistically distinct manner. Interleukin-11-pretreated dogs indeed still exhibit the characteristic response to DDAVP. Moreover, this response is now much stronger and perhaps not as easily exhausted. Apparently, interleukin-11 treatment not only results in elevated VWF plasma levels but probably also increases the amount of VWF available from DDAVP-responsive storage pools. This raises the question of how this extra VWF is stored: are there more Weibel-Palade bodies per cell, or do more cells contain them?

The promising data justify the initiation of clinical studies of the use of interleukin-11, alone or in combination with DDAVP, and point to new avenues for the exploration of fundamental aspects of VWF and FVIII biosynthesis. Several issues regarding efficacy and safety obviously need to be addressed, and special attention should be given to fluid retention in patients, since both DDAVP and interleukin-11 possess antidiuretic properties.