Tolvaptan inhibition of desmopressin effects on coagulation factors in a patient with decreased von Willebrand factor and polycystic kidney disease

To the editor:

Desmopressin (dDAVP) is a synthetic analog of vasopressin that stimulates release of von Willebrand factor (VWF). This effect is attenuated in vitro by a type 2 vasopressin receptor (V2R) antagonist.¹  dDAVP is administered for prophylaxis and treatment of bleeding in von Willebrand disease (VWD), mild hemophilia, and chronic kidney disease (CKD).

In autosomal dominant polycystic kidney disease (ADPKD), cyclic AMP promotes abnormal growth and proliferation of renal epithelium that results in cyst formation and CKD.^2,3  V2R inhibition attenuates progression of CKD in rodent orthologs of ADPKD.⁴  Tolvaptan, a V2R antagonist, is effective treatment for hyponatremia and is being evaluated in clinical trials as treatment for ADPKD.^4,5 

Tolvaptan's effects on dDAVP stimulation of VWF have not been reported. We evaluated a 42-year-old man with ADPKD found to have low VWF levels during screening for a study of tolvaptan treatment for ADPKD. A comprehensive bleeding history, using a standardized instrument,⁶  found no excessive bleeding with several minor procedures, but revealed one episode of hematuria from renal cyst hemorrhage and one episode of hemoptysis during an upper respiratory infection. Laboratory tests (Table 1) were compatible with type 1 VWD or decreased VWF in the context of blood type O.^7,8  Mild thrombocytopenia and leukopenia were attributed to splenomegaly, considered a consequence of his ADPKD-associated polycystic liver disease. Thrombocytopenia may have contributed to the prolonged platelet function analyzer closure times (PFA).

dDAVP infusion, before treatment with tolvaptan (Table 1), caused 2- to 3-fold increases in VWF antigen, ristocetin cofactor activity, and factor VIII coagulant levels, and normalization of PFA and the activated PTT (aPTT). A dDAVP infusion was repeated after 12 weeks of protocol treatment with tolvaptan (60 mg orally every morning/30 mg orally every evening; Table 1). Comparing pretolvaptan and posttolvaptan laboratory values before dDAVP was administered showed no effect of tolvaptan on VWF antigen, ristocetin cofactor activity, or factor VIII coagulant activity. In contrast, tolvaptan inhibited the previously observed dDAVP-induced increases in VWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity, and attenuated correction of the aPTT and PFA. These effects were most likely related to inhibition of V2R by tolvaptan. Epinephrine infusion can stimulate VWF secretion even in the absence of V2R activation.⁹  However, this alternative mechanism was not assessed in our patient.

In conclusion, during treatment with tolvaptan, dDAVP may not be sufficient for bleeding prophylaxis or treatment. This is a concern in ADPKD, a major cause of CKD, where bleeding from cysts and aneurysms has significant morbidity. Consequently, VWF replacement may be required. Because the prevalence of individuals with levels of VWF below the conventional lower limit of normal is estimated to be as high as 1%, and because tolvaptan is prescribed for hyponatremia in patients with heart failure, cirrhosis, and cancer and is potentially a treatment⁵  to slow the progression of CKD in patients with ADPKD, our findings may be of general importance.^4,5,10  Evaluation of the responses to dDAVP is warranted in patients with low VWF levels and these other conditions during treatment with V2R antagonists.