Efficacy and safety of half‐dose desmopressin for bleeding prophylaxis in bleeding disorder patients undergoing predominantly low to moderate risk invasive procedures
Authors: Fateeha Furqan, Ronald Sham, Peter Kouides
Journal: American Journal of Hematology (2020)

Desmopressin (DDAVP), an analogue of vasopressin, has a been used for management of coagulation disorders for about four decades. The standard intravenous dose of DDAVP is 0.3 µg/kg of body weight, which is interestingly based on a study in five healthy controls.1 This dose was found to produce a maximal response with no further increase in factor VIII activity (F VIII:C) levels at higher doses. The maximum dose in United States is often capped at 25 to 30 µg in obese patients.2 Though infrequent, desmopressin has been associated with undesirable side effects including hyponatremia, thrombosis, headache and flushing.3 Given the reported side effects as well as potentially higher risk of thrombosis in patients with normal or high von Willebrand factor (VWF) levels, the lower dose can theoretically have fewer side effects. Recently, a lower dose of DDAVP, that is, 0.15 µg/kg of body weight has been reported in children with similar efficacy as the full dose.4 However, there have been no studies reported in adults to the best of our knowledge. We carried out a retrospective review of adult patients with von Willebrand disease (VWD) with subsequent age-related normalization of their VWF levels.5 And, in those with a platelet function disorder (PFD) or bleeding of unknown cause (BUC) with an increased bleeding score who received half dose DDAVP (0.15 µg/kg of body weight). Patients were eligible for half dose DDAVP if they had a history of VWD with subsequently normal or elevated VWF levels or a PFD (Bernard Soulier and Glanzman's thrombasthenia excluded), or BUC which was defined as an increased bleeding score with normal laboratory findings, despite extensive hemostasis testing. The medical record was reviewed for demographic information, age, weight, sex, family history, International Society of Thrombosis and Hemostasis Bleeding Assessment Tool bleeding score (ISTH BAT), VWF levels, reason for desmopressin, reason for dose reduction, bleeding control and sodium levels. The study was approved by our Institutional Review Board and all patient data was de-identified. The efficacy of DDAVP was judged by bleeding control which was categorized as excellent, good, poor or no control. Excellent control was defined as hemostasis not clinically different from normal, good control as mildly abnormal hemostasis, for example slight oozing; poor control as moderate controllable bleeding, while no control was defined as severe hemorrhage that is difficult to control. The safety was assessed in terms of thrombosis, hypotension and hyponatremia; classified as mild, moderate and severe. Mild hyponatremia was defined as sodium levels of 130 to 134 mmol/L, moderate hyponatremia as Na of 125 to 129 mmol/L and severe hyponatremia as Na less than 125 mmol/L. We identified 17 patients at our treatment center who received half dose DDAVP for a total of 33 procedures (baseline characteristics in Table S1). Among them, 82% were female with mean age of 50 years (range 18-71 years) and mean ISTH BAT score of 8.2 ± 3.7 (median score 7, range 4-17). So, 41.2% had either history of mild VWD or history of low VWF levels, 29.4% patients had PFD, 23.5% had BUC and only one patient (5.9%) had low VWF. The dose was capped in two out of 17 patients at 12 µg for weight more than 80 kg. These patients underwent a variety of procedures including upper/lower endoscopies with biopsy or device placement (12.1%), therapeutic and diagnostic laparoscopies (9.1%); genitourinary (21.2%), orthopedic (24.2%), dental (15.2%), ENT (9.1%) and miscellaneous procedures (9.1%). Twelve percent of these procedures were considered high risk, which included tonsillectomy, hip replacement, shoulder repair and bilateral mastectomy. Five patients had post-DDAVP levels assayed; mean levels of factor VIII coagulant activity (FVIII:C) were 164.6 ± 39.6, VWF: ristocetin cofactor assay (VWF:RCo) 107.8 ± 28.8 and VWF Antigen (VWF:Ag) 108.7 ± 16.7. Twelve patients received pre-operative and post-operative prophylaxis with either tranexamic acid or aminocaproic acid if the procedure was mucosal based. Bleeding control was excellent in 87.9% and good in 12.1% of procedures (Table 1). Among non-bleeding complications, hyponatremia occurred in 15.2% of procedures-there were two cases of mild and three of moderate hyponatremia. None of them were symptomatic. One patient had an episode of pre-syncope which was attributed to DDAVP use. There were no thrombotic complications (Table 1). Given the usual robust response to the standard DDAVP dose in the setting of relatively normal levels of VWF, a lower dose of DDAVP intuitively would likely be clinically effective and safe. This was undertaken at our center due to the theoretical concern of hypercoagulability associated with extremely elevated VWF levels, as well as concern for hyponatremia. To the best of our knowledge, this is the first study to assess the clinical efficacy and safety profile of half dose DDAVP in patients with a standardized bleeding phenotype, with or without a prior history of VWD. Semi-empiric DDAVP at 0.3 µg/kg (maximum 28 µg) and/or tranexamic acid have been reported in patients with BUC undergoing invasive procedures (mostly minor) to be safe and effective.6 Our results suggest that in similar patients, half dose DDAVP can be clinically efficacious as well as safe in patients undergoing predominantly minor procedures. Previously, Akin et al. used a dose ranging from 0.12 to 0.2 µg/kg of body weight in children with VWD, the mean dose being 0.15 µg/kg.4 This dose was shown to produce a three to four times increase in the patients' VWF:RCo, VWF:Ag, and FVIII:C levels, which is similar to that of the standard dose. However, the study did not report the clinical efficacy and safety of the lower dose DDAVP. There are various limitations in our study. As our study is a retrospective review and the data was collected via review of post-operative notes, they could potentially have reporting bias. The number of patients was relatively small especially patients with PFD and BUC. Also, our study only reports clinical efficacy in terms of bleeding control; the levels of FVIII:C, VWF:RCo and VWF:Ag were not routinely checked post infusion of half dose DDAVP. However, the major objective of our study was to assess the clinical efficacy of the half dose. Interestingly, in the subset of five patients who had post-DDAVP VWF levels, none exceeded 250%. In conclusion, half dose DDAVP appears to be a relatively safe and effective option in terms of bleeding control and a relatively low incidence of hyponatremia for patients with a presumed bleeding disorder/phenotype based on an increased bleeding score, but with normal or increased VWF levels. However, larger prospective and comparative studies are needed to fully define the efficacy and safety of 0.15 µg/kg dose of DDAVP in patients with bleeding disorders, particularly those patients with a history of the laboratory diagnosis of VWD with subsequent normalization of VWF levels, which is recognized to occur in an expanding cohort of patients.5 Patients undergoing major surgeries were not excluded but over-all under-represented in our series. So, future studies will hopefully include a greater proportion of major surgeries, as well as study the role of withholding DDAVP completely with or without antifibrinolytic therapy for minor invasive procedures. The authors declare no conflicts of interest. F.F. data collection, manuscript writing, revision and editing of the manuscript; R.S.: revision and editing of the manuscript and P.K.: concept, revision and editing of the manuscript. Table S1 Baseline characteristics of patients Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.