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).

Table 1

Laboratory test responses to dDAVP before and during treatment with tolvaptan

ScreeningBefore tolvaptan
During tolvaptan
Before dDAVPAfter dDAVPBefore dDAVPAfter dDAVP
VWF antigen, % (50%-150%) 43 57 116 51 47 
PFA-100 collagen/epinephrine, s (74-186 s) 225 245 111 244 211 
PFA-100 collagen/ADP, s (56-128 s) 148 160 93 158 150 
VWF ristocetin cofactor activity, % (50%-125%) 40 46 131 53 51 
Factor VIII coagulant activity, % (56%-172%) 53 52 120 57 56 
Activated PTT, s (25-35 s) 33.7 35.5 29.4 35.0 34.3 
VWF multimer Normal Normal Larger than normal Normal Normal 
Factor XI coagulant activity, % (69%-155%) 89     
Factor IX coagulant activity, % (69%-176%) 79     
Prothrombin time INR 1.0     
WBC, ×103/μL 3.9     
Hemoglobin, g/dL 13.6     
Platelet count, ×103/μL 121     
Serum LDH, IU/L 172     
BUN, mg/dL 23     
Serum creatinine, mg/dL 1.3     
eGFR, mL/min/1.73 m2 64.3     
MRI results      
    Left kidney length, cm 21.3     
    Right kidney length, cm 20.2     
Total kidney volume, mL 1960     
Liver length, cm 22     
Spleen length, cm 13.6     
ScreeningBefore tolvaptan
During tolvaptan
Before dDAVPAfter dDAVPBefore dDAVPAfter dDAVP
VWF antigen, % (50%-150%) 43 57 116 51 47 
PFA-100 collagen/epinephrine, s (74-186 s) 225 245 111 244 211 
PFA-100 collagen/ADP, s (56-128 s) 148 160 93 158 150 
VWF ristocetin cofactor activity, % (50%-125%) 40 46 131 53 51 
Factor VIII coagulant activity, % (56%-172%) 53 52 120 57 56 
Activated PTT, s (25-35 s) 33.7 35.5 29.4 35.0 34.3 
VWF multimer Normal Normal Larger than normal Normal Normal 
Factor XI coagulant activity, % (69%-155%) 89     
Factor IX coagulant activity, % (69%-176%) 79     
Prothrombin time INR 1.0     
WBC, ×103/μL 3.9     
Hemoglobin, g/dL 13.6     
Platelet count, ×103/μL 121     
Serum LDH, IU/L 172     
BUN, mg/dL 23     
Serum creatinine, mg/dL 1.3     
eGFR, mL/min/1.73 m2 64.3     
MRI results      
    Left kidney length, cm 21.3     
    Right kidney length, cm 20.2     
Total kidney volume, mL 1960     
Liver length, cm 22     
Spleen length, cm 13.6     

dDAVP dose (0.3 μg/kg): blood samples obtained 30 minutes after dDAVP infusion. “During tolvaptan” blood samples obtained 2 hours after the morning dose of tolvaptan.

VWF indicates von Willebrand factor; PFA, platelet function analyzer; INR, international normalized ratio; WBC, white blood cell count; LDH, lactate dehydrogenase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate by Modification of Diet in Renal Disease formula; and MRI, magnetic resonance imaging.

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.

Authorship

Acknowledgments: Stephanie Donahue and Ines Chicos participated in coordination of the study.

At the time of this clinical evaluation, the patient was participating in ClinicalTrials.gov identifier NCT01214421, sponsored by Otsuka Pharmaceutical Development and Commercialization Inc. Oversight for this study is provided by Western Institutional Review Board; the IRB determined that additional informed consent for the clinical evaluation reported in this manuscript was not required. This study was supported in part by research funding from Otsuka Pharmaceutical Development and Commercialization Inc (J.D.B.).

The project described was supported by grant award no. UL1RR024143 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

Contribution: J.D.B. designed research and performed research, collected, analyzed, and interpreted data, and wrote the manuscript; J.T. and A.M. performed research, collected, analyzed, and interpreted data, and wrote the manuscript; B.C. analyzed and interpreted data and wrote the manuscript; D.G.B. participated in the design of the research protocol; and B.S. wrote the manuscript.

Conflict-of-interest disclosure: J.D.B. is a co-Executive Editor of the American Journal of Hypertension, for which he receives compensation by American Journal of Hypertension, Ltd. He is participating in ongoing clinical trials of tolvaptan for the treatment of autosomal dominant polycystic kidney disease sponsored by Otsuka Pharmaceutical Development and Commercialization Inc, and is a consultant to Forest Research Institute Inc and Primrose Therapeutics Inc. A.M. has received honoraria from CSL Behring. B.C. is an inventor of abciximab (Centocor) and, in accord with Federal law and the policies of the Research Foundation of the State University of New York, receives royalties based on the sales of abciximab; is an inventor of the VerifyNow assays (Accumetrics) and, in accord with Federal law and the policies of the Mount Sinai School of Medicine, receives royalties based on the sales of the VerifyNow assays; is an inventor of small molecule αIIbβ3 antagonists (RUC-1 and RUC-2) and Rockefeller University has applied for patents on these molecules. D.G.B. has received grant/research support from Otsuka Pharmaceuticals for treatment of polycystic kidney disease with tolvaptan, a vasopressin V2 receptor antagonist. The remaining authors declare no competing financial interests.

Correspondence: Jon Blumenfeld, MD, 505 East 70th St, New York, NY 10021; e-mail: jdblume@nyp.org.

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