Response to low-dose desmopressin by a subcutaneous route in children with type 1 von Willebrand disease

Abstract

Objective

The primary objective of this study was to determine responses to low-dose desmopressin (DDAVP) by a subcutaneous route in children with type 1 VWD.

Methods

This study analyzed responses to low doses of DDAVP administered by a subcutaneous route to 14 children between the ages of 3 and 16 with type 1 VWD and a personal and familial history of bleeding. At 0 (baseline) and 1 hour (initial response) after the subcutaneous injection of DDAVP, the vital signs were assessed and blood samples were obtained for VWD panel determinations (VWF:Ag, VWF:RCo, FVIII:C levels, and Col/Epi, Col/ADP). At 4 hours (sustained response), only Col/Epi and Col/ADP were assessed.

Results

The DDAVP mean (min–max range, μg/kg) based on the patient's weight was 0.15 (0.12–0.18). Laboratory values mean (min–max range in U/dl) baseline for VWF:RCo, VWF:Ag, and FVIII:C were 28 (20–36), 34 (25–42), and 40 (29–48), respectively. After a subcutaneous administration, the laboratory values mean (min–max range in U/dl⁻¹) achieved for 1 hour for VWF:RCo, VWF:Ag, and FVIII:C were 109 (72–144), 132 (88–166), and 151 (96–198), respectively.

PFA 100^® CT (Col/Epi <134 seconds and Col/ADP <110 seconds) returned to normal values at 1 and 4 hours after a subcutaneous administration.

Conclusion

Subcutaneous low-dose DDAVP therapy is at least effective as 0.3 µg/kg intravenous therapy for children with type 1 VWD. This study shows that a wider use of DDAVP should be promoted, especially in developing countries.

Keywords:

• VWD
• Desmopressin
• Children
• Low dose

Introduction

Desmopressin (DDAVP) is the treatment of choice for the majority of patients with type 1 von Willebrand disease (VWD).

DDAVP (1-desamino-8-d-arginine vasopressin), a synthetic vasopressin analog, increases endogenous von Willebrand factor (VWF) by secreting it from the vascular endothelial cell, its natural site of synthesis and storage.¹ DDAVP can be administered intravenously, subcutaneously or intranasally.^2,3 In addition, DDAVP stabilizes circulating factor VIII (FVIII), stimulates platelet adhesiveness, restores thrombin generation in responders to normal and shortens bleeding time.

DDAVP is usually effective in patients with type 1 and baseline VWF and FVIII levels higher than 10 IU/dl; therefore, it is usually used in minor bleeding episodes. The response to DDAVP can change because of the poor release of VWF from storage sites or accelerated clearance of mutant VWF; thus, administering a DDAVP challenge testing is recommended to assess each patient's response to DDAVP therapy. The intravenous or subcutaneous dose is 0.3 µg/kg. Treatment can be repeated every 12 to 24 hours depending on the type and severity of the bleeding.^4–6 The main limitation of using DDAVP intravenously in children younger than 5 is the development of tachyphylaxis, hyponatremia, and seizures.^7,8

Although DDAVP has been recommended for the treatment of VWD since 1977, research into the responses of children with type 1 VWD to low doses of this agent has not been conducted. Therefore, the primary objective of this study was to determine responses to low doses of DDAVP delivered through a subcutaneous route in children with type 1 VWD.

Patients and methods

This study analyzed responses to low doses of DDAVP administered by a subcutaneous route to 14 children between the ages of 3 and 16 with type 1 VWD and a personal and familial history of bleeding (Table 1).

Table 1. Baseline characteristics of investigated subjects

	Group 1 (n:4) (<6 years old)	Group 2 (n:7) (6–10 years old)	Group 3 (n:3) (10–16 years old)
Male/female	2/2	4/3	0/3
Mean age (year)*	4.8 (3–5.9)	7.9 (6.2–9.8)	13.7 (11–16)
Blood group O (%)	50%	60%	66%
Bleeding symptoms	Bleeding from cuts, epistaxsis	Bleeding after dental operation, epistaxsis	Bruising, menorrhagia
DDAVP (μg/kg)*	0.14 (0.12–0.18)	0.15 (0.15–0.17)	0.15 (0.12–0.17)
FVIII:C, (IU/dl)*	45.5 (39–48)	38.8 (29–47)	38.6 (32–43)
VWF:Ag, (IU/dl)*	31 (26–36)	28 (20–36)	26.6 (22–30)
VWF:RCo, (IU/dl)*	36.7 (31–40)	33.8 (25–42)	33 (25–38)
Col/Epi s*	204 (192–227)	223 (194–256)	224 (194–268)
Col/ADP s*	126 (120–138)	134 (118–168)	124 (119–129)

*Mean (min–max).

Abbreviations: VWF: von Willebrand factor; RCo: Ristocetin Cofactor activity; Ag: Antigen; FVIII:C: Factor VIII coagulant activity; Col/Epi s; collagen/epinephrine second, Col/ADP s; collagen/adenosine diphosphate second.

Criteria for the diagnosis of low VWF level or mild, moderate type 1 VWD included 4 moderate type 1 (VWF levels within 15–31 IU/dl); 10 mild type 1 or low VWF level (VWF levels within 31–49 IU/dl); laboratory data consistent with the diagnosis, including the VWF antigen (VWF:Ag) <50 dl⁻¹, VWF:ristocetin cofactor (VWF:RCo) <50 U/dl and/or disproportionately low ratio of VWF:RCo to VWF:Ag (VWF:RCo/VWF:Ag <0.7); and at least one bleeding symptom.⁹

Laboratory tests for VWD included VWF:Ag, VWF:RCo, FVIII activity assay (FVIII:C), and the platelet function analyzer closure-time (PFA-100^® CT, Siemens, Marburg, German) analysis.

Subcutaneous DDAVP challenge test

The subcutaneous preparation of DDAVP (4 µg/ml; Minirin^® Ferring, Kiel, Germany) was utilized. Under medical supervision, patients subcutaneously received less than 0.2 µg/kg DDAVP based on their weight.

At 0 (baseline) and 1 hour (initial response) after the subcutaneous injection of DDAVP the vital signs were assessed and blood samples were obtained for VWD panel determinations (VWF:Ag, VWF:RCo, FVIII:C levels, and Col/Epi, Col/ADP).

At 4 hours (sustained response), only Col/Epi and Col/ADP were assessed.

The initial response criteria were: (i) at least a threefold increase from baseline in the plasma VWF:RCo level and (ii) a minimum VWF:RCo activity of greater than 40% at 1 hour. The sustained response criterion for subcutaneous administration was the maintenance of normal PFA-100 values for 4 hours throughout the testing period. Blood samples were drawn from each participant's antecubital vein using the BD Vacutainer System (Becton-Dickinson, Plymouth, UK). Tests for blood group, complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (aPTT) were conducted on each sample. The requirements for VWF assays were fasting, the lack of an acute or chronic inflammation and menses, and the absence of struggling, crying, and exercise within the previous 30 minutes.

For all tests 8 ml of whole-blood specimens were drawn into 0.109 mol/l (3.2% weight/volume (w/v)) buffered, sodium-citrate collection tubes and kept at room temperature. Hemolyzed or clotted samples were not used. Plasma was separated from blood cells at room temperature. PFA-100^® analysis was performed.

Immediately, the plasma sample was stored at −80°C for a maximum of 2 weeks to detect VWF:RCo and VWF:Ag levels. Both PT and aPTT were assayed by automatic coagulation machines (Sysmex, CA-1500, Kobe, Japan). The VWF:RCo levels were detected using aggregometry (Bio/Data Corporation, Horsham, PA, USA) and the VWF:Ag levels were determined through a latex immunoassay using the STACompact analyzer (Diagnostica Stago, Asnié res, France).

Normal closure-time reference mean (ranges) values for PFA-100^® were 92 seconds (71–118 seconds) for Col/ADP cartridge and 132 seconds (85–165 seconds) for Col/Epi cartridge. Closure time was assessed using the platelet function analyzer (PFA-100^® Dade-Behring, Marburg, Germany).

Results

This study included 14 children aged 3–16 with type 1 VWD, weighing 22–65 kg.

Of the patients, 57% were in the O-blood group and 43% in non-O blood groups. A summary of the biological response parameters is displayed in Table 2.

Table 2. Results of low-dose DDAVP challenge test with subcutaneous administration

ID	DDAVP dose (μg/kg)	Baseline WVD parameters					1-h post-DDAVP response					4-h post-DDAVP response
		FVIII:C	VWF:Ag	VWF:RCo	C/Epi	C/ADP	FVIII:C	VWF:Ag	VWF:RCo	C/Epi	C/ADP	C/Epi	C/ADP
1	0.17	32	25	22	212	124	112	88	82	112	80	134	86
2	0.15	34	30	24	198	120	134	126	98	132	92	138	94
3	0.15	46	38	32	194	119	168	158	112	124	96	128	100
4	0.16	29	25	20	256	136	122	102	72	138	100	136	108
5	0.13	39	31	26	227	138	148	152	128	122	86	140	104
6	0.18	48	39	31	195	124	168	144	110	118	92	122	110
7	0.12	47	40	36	192	122	198	142	112	98	80	132	92
8	0.16	43	38	30	194	119	158	144	128	90	72	108	88
9	0.13	48	37	32	202	120	178	162	130	88	70	126	94
10	0.17	46	42	31	198	118	198	166	144	92	68	132	98
11	0.16	32	26	22	250	168	96	88	72	100	86	123	75
12	0.15	47	40	36	231	128	156	146	132	95	66	131	111
13	0.12	41	36	28	268	129	150	124	108	86	71	121	92
14	0.15	38	36	31	234	152	132	119	110	89	72	125	100

Abbreviations: VWF: von Willebrand factor; RCo: Ristocetin Cofactor activity; Ag: Antigen; FVIII:C: Factor VIII coagulant activity; C/Epi; collagen/epinephrine, C/ADP; collagen/adenosine diphosphate.

All 14 patients met the criteria for initial response to subcutaneous DDAVP and for sustained response.

Subcutaneous injections of Minirin during DDAVP efficacy tests were well tolerated, except for two patients (9.8 and 14.3 years old) who experienced the side effect of flushing.

The DDAVP mean (min–max range, μg/kg) based on the patient's weight was 0.15 (0.12–0.18). Laboratory values mean (min–max range in U/dl) baseline for VWF:RCo, VWF:Ag, and FVIII:C were 28 (20–36), 34 (25–42), and 40 (29–48), respectively. After a subcutaneous administration, the laboratory values mean (min–max range in U/dl) achieved for 1 hour for VWF:RCo, VWF:Ag, and FVIII:C were 109 (72–144), 132 (88–166), and 151 (96–198), respectively.

The mean (min–max) fold increase in the plasma VWF:RCo, VWF:Ag, and FVIII:C levels compared to baseline levels after a single administration of DDAVP were 3.8 (3.2–4.9), 3.8 (3.3–4.9), and 3.6 (3–4.3), respectively.

After subcutaneous administration, there was a 3.6-, 4-, and 4.2-fold increase in the patients' VWF:Rco, VWF:Ag, and FVIII:C levels with the lowest levels at the baseline, respectively.

PFA 100^® CT (Col/Epi <134 seconds and Col/ADP <110 seconds) returned to normal values at 1 and 4 hours after a subcutaneous administration.

Discussion

In this report, subcutaneous low doses of DDAVP were effective in children with type 1 VWD and levels of VWF:Ag and VWF:RCo were between 22 and 46 U/dl.

The aim was to prove the effectiveness of a dose lower than 0.2 µg/kg whether it is 0.18 µg/kg or another amount. As we have demonstrated, the lowest dose used was 0.12 µg/kg, and it was effective.

The complete response to low-dose subcutaneous DDAVP was evaluated according to the FVIII:C, VWF:Ag, and VWF:RCo levels pre-infusion and 1 hours post-infusion.

The response of prolonged baseline PFA-100 CT to DDAVP was normalized at 1 and 4 hours.

A DDAVP therapy of is 0.3 µg/kg/dose was administered intravenously in 25–50 ml of saline over 20–30 minutes. Alternatively, subcutaneous injections of DDAVP of approximately the same dose have been used effectively.^10,11

A retrospective review of DDAVP administration to 194 children with non-severe type 1 VWD found a 93% response rate.¹²

The result of earlier studies observed a response to DDAVP in 56 (80%) of 70 children with type 1 VWD.¹³ Previous studies demonstrated that one dose of DDAVP was effective and safe for pediatric patients with mild or moderate type 1 VWD and a history of bleeding history.^14,15

Castaman et al.¹⁶ showed that the response to DDAVP in patients with type 1 VWD was associated with the location of the causative mutation.

This study showed that low doses of DDAVP consistently increased plasma VWF and FVIII from threefold to more than four-and-a-half fold over baseline levels.

Sustained hemostatic levels of VWF:RCo are critical to achieving adequate homeostasis. The adequate or sustained response criteria for the Federici et al.¹⁷ study included VWF:Ag and VWF:RCo activity of more than 40% at 1 and 4 hours after intravenous DDAVP administration.

Most researchers have also commented on the strong correlation between PFA-100 CT results and various VWF parameters, including VWF:Ag and VWF:RCo.^18,19

In addition, the PFA-100 is sensitive to homeostatic changes induced by DDAVP therapy in appropriately responding individuals.^20–22

In this study, all the type 1 VWD patients, except for those with severe type 1 VWD, achieved initial and sustained response (VWF:RCo levels >40% for a minimum of 1 hour and normal PFA-100 CT for 4 hours) to low doses of DDAVP delivered by a subcutaneous route.

In conclusion, subcutaneous low-dose DDAVP therapy is at least effective as 0.3 µg/kg intravenous therapy for children with type 1 VWD.

This study shows that a wider use of DDAVP should be promoted, especially in developing countries.

The PFA-100 system might be useful for routine evaluations of responses to DDAVP therapy because of its accuracy and rapid turnaround for results.