62
Desmopressin (DDAVP) Marco Cattaneo* and Pier Mannuccio Mannucci†
* Unità di Medicina 2, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy, †Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
INTRODUCTION 1111 MANAGEMENT WITH DESMOPRESSIN OF MILD HEMOPHILIA A AND von WILLEBRAND DISEASE 1111 Congenital Hemophilia A and von Willebrand Disease 1111 Acquired Hemophilia and von Willebrand Syndrome 1112 DESMOPRESSIN AS A GENERAL HEMOSTATIC AGENT 1113 Congenital and Acquired Bleeding Diathesis Not Due to Defects of Factor VIII and von Willebrand Factor 1113 Desmopressin as a Blood-Saving Agent in Major Surgery 1114 SIDE-EFFECTS 1115 MECHANISMS OF ACTION OF DESMOPRESSIN 1115 Mechanisms of Desmopressin-Induced Increase in Plasma Factor VIII and VWF 1115 Mechanisms of Desmopressin Efficacy in Patients with Normal Factor VIII and von Willebrand Factor 1116 CONCLUSIONS 1116 REFERENCES 1117
INTRODUCTION Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of the antidiuretic hormone vasopressin. Like the natural antidiuretic hormone, desmopressin increases the plasma levels of factor VIII (FVII) and von Willebrand factor (VWF), with the advantage, compared to vasopressin, that it produces no vasoconstriction, nor any increase in blood pressure and contraction of the uterus or gastrointestinal tract, so that it is well tolerated when administered to humans.1,2 In 1977, desmopressin was used for the first time in patients with mild hemophilia A and von Willebrand disease (VWD) for the prevention and treatment of bleeding, first during dental extractions and then during major surgical procedures.3 Surgery was performed without blood products, demonstrating that autologous factor VIII and VWF raised in patient plasma by the intravenous infusion of desmopressin could effectively replace allogeneic factors derived from plasma.3 After the original clinical study performed in Italy, desmopressin was used in many other countries and the World Health Organization included it in its list of essential drugs. A drug that could be used for the prophylaxis and treatment in many cases of the two most common congenital bleeding disorders without the need of blood products was very attractive, in view of its safety (no risk of transmission of blood-borne viral diseases nor of onset of FVIII alloantibodies) and cost (desmopressin is relatively inexpensive, compared to other sources of FVIII and VWF). Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00062-X Copyright © 2019 Elsevier Inc. All rights reserved.
The original clinical indications for desmopressin subsequently expanded. The compound was used in bleeding disorders not involving a deficiency or dysfunction of FVIII or VWF, including congenital and acquired defects of platelet function and such frequent acquired abnormalities of hemostasis as those associated with chronic kidney and liver disease. Desmopressin has been also used prophylactically in patients undergoing surgical operations characterized by large blood losses and transfusion requirements (especially cardiac, joint replacement and spinal surgery). Some of these indications for desmopressin have been strengthened by the experience accumulated; others have not been supported by clinical trials or have been superseded by the advent of more efficacious treatments. This chapter reviews the spectrum of indications of desmopressin in the prevention and treatment of bleeding, with emphasis on its use in patients with congenital or acquired defects of primary hemostasis.
MANAGEMENT WITH DESMOPRESSIN OF MILD HEMOPHILIA A AND von WILLEBRAND DISEASE Congenital Hemophilia A and von Willebrand Disease Well-established indications of desmopressin are prophylaxis and treatment of spontaneous, posttraumatic and postsurgical bleeding in patients with mild hemophilia A and type 1 VWD. An intravenous dose of 0.3 μg/kg can be successfully used in patients with at least 10 U/dL of plasma levels of the deficient protein, because FVIII and VWF increase on average to approximately 2–4 times resting levels, with little intrapatient variability in responses.4 Patients with severe deficiencies do not respond at all, but it was recently shown in the frame of a large international cohort study4 that at least one third of patients with moderate hemophilia (defined by plasma FVIII levels between 1 and 5 U/dL), respond adequately to desmopressin.5 The biological half-lives of endogenous FVIII and VWF released by desmopressin infusion are slightly shorter than those of plasma-derived proteins when they are infused in the same patients.6 Release into plasma of tissue plasminogen activator (tPA) is another effect of desmopressin.6–8 Plasminogen activator does generate plasmin in vivo, but most of the plasmin is quickly complexed to α2-antiplasmin and does not produce fibrin(ogen)olysis in circulating blood.9 Accordingly, it is usually unnecessary to inhibit fibrinolysis pharmacologically when desmopressin is used for clinical purposes. In mild and moderate hemophilia A, the efficacy of desmopressin usually correlates with the postinfusion plasma levels of FVIII.3,10–12 Therefore, therapeutic indications are defined by the nature of the bleeding episode, the baseline FVIII levels and the levels that must be attained and maintained for hemostasis. Clinical failures of desmopressin can usually be explained by the attainment of FVIII levels in plasma that are insufficient to control bleeding.3,10–12 For example, a major surgical procedure in a patient with FVIII levels of 10 U/dL may not be successfully managed with desmopressin, because the expected posttreatment levels of 20–40 U/dL are not high
1111
1112
PART VI Therapy to Increase Platelet Numbers and/or Function
enough for normal hemostasis. On the other hand, these levels should be sufficient for the patient to undergo such minor procedures as dental extractions. The factors that underlie the magnitude of the biological response to desmopressin in mild hemophilia A are incompletely understood, even though baseline plasma levels of FVIII appear to predict the response.6 Most patients with VWD type 1, who have a functionally normal VWF, respond to desmopressin with relative increases in FVIII and VWF that are usually greater than those seen in patients with mild hemophilia A and corresponding FVIII levels.10,11,13–16 Hence, desmopressin should be the first choice for treatment of these patients. The plasma defects of patients with VWD type 3 and of those with dysfunctional molecules (VWD type 2) are usually not corrected by desmopressin, with some exceptions.13–15 General guidelines for the choice between desmopressin and plasma products in the different subtypes of VWD are given in Table 62.1. There is, however, some variability in the response to desmopressin among patients with type 1 VWD.14–16 Patients with mutations in the D0 -D3 domains of the VWF gene have the greatest relative increase, whereas the majority of partially responsive or nonresponsive patients have mutations in the A1–A3 domains.16 However, the practical predictive usefulness of genotyping is limited, and a test dose is the best way to differentiate responders from poor- or nonresponders.16 Table 62.2 shows the schedule of desmopressin administration and blood sampling recommended to evaluate the degree of laboratory response to a test dose. Based on the results, one can predict with some degree of accuracy whether or not the attained factor levels and the duration of their persistence in plasma allow the successful management of a given clinical situation (Table 62.3).
TABLE 62.1 Summary of Recommended Treatments in Different Types of von Willebrand Disease Type
Treatment of Choice
Alternative Therapy
1
Desmopressin
2A 2B 2M 2N
FVIII-VWF concentrates FVIII-VWF concentrates FVIII-VWF concentrates desmopressin
FVIII-VWF concentrates Desmopressin None Desmopressin FVIII-VWF concentrates
3 In patients without alloantibodies In patients with alloantibodies
FVIII-VWF concentrates Recombinant activated factor VII
Platelet concentrates Recombinant FVIII
Abbreviations: FVIII, factor VIII; VWF, von Willebrand factor.
TABLE 62.2 Schedule of the Test Dose of Desmopressin Given to Assess Responsiveness in Patients With von Willebrand Disease (and Mild/Moderate Hemophilia) Step 1
Step 2
Step 3
Infuse 0.3 μg/kg of desmopressin in 100 mL saline over 30 min in newly diagnosed patients or in those who must undergo an elective treatment Obtain citrated blood samples at 60 min after starting desmopressin (to assess the postinfusion peak) and at 4 h (to assess the rate of factor clearance) Measure FVIII coagulant activity and ristocetin cofactor activity
Note: If the subcutaneous or intranasal routes are preferred for desmopressin administration, the same schedule may be followed.
TABLE 62.3 Target Levels of Factor VIII and von Willebrand Factor Recommended in Patients With Mild/Moderate Hemophilia A and von Willebrand Disease for Different Clinical Situations Clinical Situation
Target
Major surgery
Peak factor levels of 100% and trough daily levels of at least 50% until healing is complete (usually 5–10 days) Peak factor levels of 60% and trough daily levels of at least 30% until healing is complete (usually 2–4 days) Peak factor levels of 50% (single dose) Peak factor levels higher than 50% until bleeding stops (usually 2–4 days) Peak factor levels higher than 80% and trough levels of at least 30%, usually for 3–4 days
Minor surgery
Dental extractions Spontaneous bleeding episodes Delivery and puerperium
In patients with von Willebrand disease, the same target levels of factor VIII and ristocetin cofactor activity are recommended.
Patients treated repeatedly with desmopressin may become less responsive, perhaps because stores of FVIII and VWF become exhausted.3,17 The average FVIII and VWF responses obtained when desmopressin is repeated at 24-h intervals are approximately 30% lower than those obtained after the initial dose.17 In general, treatment with this drug can be usefully repeated 2–4 times, but it is preferable to monitor FVIII and/ or VWF responses and tailor repeated treatments based on the plasma values obtained pre- and post-infusion. In the situations in which FVIII and VWF levels must be maintained at relatively high levels in plasma for a prolonged period of time, it may become necessary to use plasma-derived or recombinant factors, or to supplement desmopressin with them. Desmopressin is also available in formulations for subcutaneous injections (at a dose of 0.3 μg/kg) and nasal inhalation (at fixed doses of 300 μg in adults and 150 μg in children). These formulations are at least as efficacious as intravenous desmopressin and perhaps more clinically practical when they are self-administered at home to prevent or treat minor bleeding episodes or excessive bleeding at menstruation in women with VWD.18,19
Acquired Hemophilia and von Willebrand Syndrome Desmopressin is sometime clinically useful for treatment of patients with the acquired von Willebrand syndrome (AVWS), which occurs in association with in lymphoproliferative, cardiovascular and myeloproliferative disorders. Management of bleeding episodes in these patients is based on the choice between desmopressin, FVIII/VWF concentrates, and high-dose intravenous immunoglobulins, but no single drug is effective for all.20 In a large series of 186 cases treated with desmopressin to control bleeding episodes, this treatment was clinically effective in 38 cases (20%). The variability of the clinical response to desmopressin was related to the variably short half-life of endogenous FVIII and VWF released by the compound.21 In some patients with acquired hemophilia due to anti-FVIII autoantibodies, desmopressin elicits a rise in plasma FVIII levels that may be relatively long lasting and sufficient to attain hemostasis. It is difficult to predict the degree and duration of the response, but patients with low titer inhibitor and residual FVIII are more likely to respond and avoid the anamnestic rise of FVIII that can be seen when these patients are treated with allogeneic sources of FVIII. A test dose should be given to each candidate patient to establish the potential usefulness of desmopressin (see Table 62.2).
Desmopressin (DDAVP)
DESMOPRESSIN AS A GENERAL HEMOSTATIC AGENT Congenital and Acquired Bleeding Diathesis Not Due to Defects of Factor VIII and von Willebrand Factor Congenital Disorders of Primary Hemostasis Desmopressin shortens or normalizes the bleeding time and/or the platelet function test PFA-100 in most patients with congenital defects of platelet function (Refs. 22–52 in Table 62.4). There is usually a good response in patients with defects of the release reaction and in those with isolated and unexplained prolongations of the bleeding time. Most patients with storage pool deficiency respond to desmopressin but a few do not, in particular those with severe deficiencies of platelet δ-granules content. Most patients with Glanzmann thrombasthenia and afibrinogenemia are not responsive. The documented efficacy in patients with Bernard-Soulier syndrome, who lack GPIb-IX-V, the platelet receptor for VWF that is essential for platelet adhesion to the vessel wall at high shear forces, supports the views that the drug may shorten the prolonged bleeding time through mechanism (s) independent of released VWF (see below). Whether or not the effect on a laboratory test such as the bleeding time corresponds to hemostatic efficacy in case of bleeding remains to be established. Although there are anecdotal reports of desmopressin successfully stopping or preventing bleeding in these patients (Table 62.4), the clinical efficacy of desmopressin is not formally proven.
Acquired and Drug-induced Disorders of Hemostasis The hemostatic defect in uremia is characterized by a prolonged bleeding time, a laboratory abnormality that correlates strongly with the hemorrhagic symptoms of mucosal type of these patients, mainly epistaxis and bleeding from the gastrointestinal tract (see Chapter 49). Even though there is no definite evidence that the derangement of primary hemostasis in uremia is due to the deficiency or abnormality of FVIII and/or VWF, a preliminary report on the possible effectiveness of the infusion of cryoprecipitate56 suggested that the effects of desmopressin could also be tested in these patients.57 After the intravenous infusion of 0.3 μg/kg of this drug, the prolonged bleeding time became normal in about 75% of uremic patients.57 Similar
1113
results were subsequently obtained after administering desmopressin subcutaneously58 or intranasally.59 Uncontrolled clinical studies in uremic patients have suggested that desmopressin can be successfully used to prevent bleeding before invasive procedures (biopsies and major surgery) and to stop spontaneous bleeding;60–67 in contrast, a retrospective observational study showed that desmopressin was unable to control severe gastrointestinal severe bleeding in 76 patients with end-stage renal disease.68 Conjugated estrogens are a long-acting alternative to desmopressin in uremic patients, because they shorten the bleeding time with a more sustained effect lasting for 10–15 days.69 The two products can be given together, exploiting the different timings of their maximal effects. Currently, most patients with chronic renal insufficiency are regularly treated with erythropoietin, which leads to the sustained improvement not only of anemia but also of the hemostatic defect,70 so that compounds such as desmopressin and conjugated estrogens are now seldom needed. The bleeding time is prolonged in some patients with liver cirrhosis with mild or moderate thrombocytopenia and was shortened by both intravenous and subcutaneous desmopressin administrations.71–73 However, a more recent study failed to show any effect of desmopressin on in vitro platelet adhesion of patients with cirrhosis.74 Desmopressin is not useful in the management of acute variceal bleeding.75 The efficacy of desmopressin to shorten the prolonged bleeding time in patients with thrombocytopenia varies according to the baseline platelet count.76,77 A good response is usually obtained in patients with platelet counts higher than 50 109/L, while a variable degree of shortening can be observed for platelet counts lower than 50 109/L. In terms of clinical efficacy in preventing bleeding, there is insufficient evidence to recommend the use of desmopressin in patients with thrombocytopenia due to chronic bone failure,78 or undergoing intensive chemotherapy or stem cell transplantation for hematologic malignancies.79 Desmopressin counteracts the effects on hemostasis measurements of some antithrombotic drugs. It shortens the prolonged bleeding time or PFA-100 closure times of individuals taking aspirin and ticlopidine,21,23,80,81 but not of subjects taking ticagrelor.82 In addition, it shortens the prolonged bleeding time and activated partial thromboplastin time of patients receiving heparin,83 and the prolonged bleeding time of rabbits treated with aspirin and streptokinase84 or hirudin85 (without corresponding human data). Desmopressin also accelerates the normalization of the in vitro platelet dysfunction in patients receiving GPIIb-IIIa
TABLE 62.4 Reports on the Hemostatic Effect of Desmopressin in Patients With Congenital Disorders of Platelet Function Effect on the Prolonged Bleeding Timea or PFA-100 Condition δ-Storage pool deficiency Hemansky-Pudlak syndrome Gray platelet syndrome Other secretion defects Glanzmann thrombasthenia Bernard-Soulier syndrome Defect of P2Y12 receptors MYH9-related disorders Defective calcium ionophore-induced platelet aggregation Easy bruisability (aspirin intolerance) Unexplained prolonged bleeding time Afibrinogenemia
Case Reports of Clinical Efficacya
Shortening/ Normalization
No Effect
Prevention/Control of Bleeding
No Effect/Worsening
821,23,26,30,34,37,43,44 232,33 125 721,26,34,43,44,46,48 134 629,34,35,38,41,45 142 134 149
323,37,43 233,50 122 – 223,26 – – – –
126 147 – 226,43 – – 142 151 –
– 147 – – – – – – –
139 521,23,31,37,53 124
– 137 136
– 531,40,53–55 –
– – –
Number of studies, with reference numbers in superscript. Some studies reported high variability of responses among patients with the same abnormality of primary hemostasis.
a
62
1114
PART VI Therapy to Increase Platelet Numbers and/or Function
antagonists.86 A few small studies have shown that desmopressin controls postsurgical bleeding complications in patients treated with aspirin.87 Finally, desmopressin has been reported to be beneficial for bleeding episodes in patients with congenital or acquired bleeding diathesis not due to abnormalities of the hemostatic system, such as Ehlers-Danlos syndrome, Rendu-Osler telangiectasia, and sickle cell trait.88–91 In summary, in chronic renal disease desmopressin is seldom indicated, only for those patients with renal failure not treated or unresponsive to erythropoietin. Desmopressin is a possible treatment for patients with liver cirrhosis and prolonged bleeding time who need invasive diagnostic procedures. Notwithstanding the shortened bleeding times and improved PFA-100, there is as yet little clinical evidence that desmopressin prevents or stops bleeding complications that develop in association with the use of antithrombotic agents. However, the compound may provide an opportunity to control druginduced bleeding without stopping treatment and perhaps avoiding recurrence or progression of thrombosis. The data obtained from a few nonrandomized studies would indicate that desmopressin can be a useful alternative to blood products during or after surgery or delivery, assuring satisfactory hemostasis in patients with congenital or acquired defects of primary hemostasis (Tables 62.4 and 62.5).
Desmopressin as a Blood-Saving Agent in Major Surgery The broadening indications of desmopressin, since the first use in hemophilia and VWD in 1977, led to evaluate whether or not the compound was beneficial during surgical operations in which blood loss is large and for which multiple blood transfusions are needed. Open heart surgery with extracorporeal circulation is the epitome of operations that warrant the adoption of blood-saving measures. In addition to such techniques as presurgical removal of autologous blood for postsurgical retransfusion, returning all oxygenator and tubing contents to the patient, and autotransfusion of the mediastinal shed blood, prophylaxis with pharmacological agents might help reduce blood transfusion further. Since 1986, desmopressin has been evaluated for this purpose. In the first controlled randomized study carried out in patients undergoing complex cardiac operations
associated with large blood losses, results were impressive.97 Given at the time of chest closure, desmopressin reduced dramatically perioperative and early (12 h) postoperative blood loss and transfusion requirements by about 40%.97 On the other hand, in two subsequent large trials including patients undergoing less complex operations with lesser blood loss, there were no significant differences between desmopressin- and placebo-treated patients in terms of total blood loss or transfusion requirements.98,99 Other studies, mainly in patients undergoing relatively standard and uncomplicated operations such as coronary artery bypass grafting and valve replacement, gave conflicting results.100–117 The conflicting results of desmopressin in open-heart surgery might be due to the fact that most studies were of small size and had insufficient statistical power to detect differences in blood loss. A metaanalysis of 17 randomized, double-blind, placebo-controlled trials, which included 1171 patients undergoing open heart surgery, attempted to overcome this pitfall.118 Overall, desmopressin reduced postoperative blood loss by 9%, a value that was statistically significant but of little clinical impact. A subgroup analysis has shown that although desmopressin had no blood-saving effect when the 24-h postoperative total blood loss in placebo-treated patients was in the lower or middle third of distribution (687–1108 mL), the compound reduced blood losses by 34% in those trials in which the 24-h blood loss in the placebo-treated patients was in the upper third of distribution (>1108 mL),118 suggesting that the drug may be clinically efficacious only in patients at risk of excessive postoperative bleeding. These data were confirmed in a subsequent prospective, double-blind, placebo-controlled trial, in which the effects of desmopressin were compared to those of placebo in patients identified as being at high risk of postoperative bleeding by means of the point-of-care test hemoSTATUS.119 The average 24-h blood loss in desmopressin-treated, high-risk patients was 39% lower than that in placebo-treated-high risk patients (624 vs. 1028 mL, P ¼ 0.0004) and was comparable to that of low-risk, untreated patients (656 mL). The study also showed that transfusion requirements were significantly reduced by desmopressin (total donor exposures 1.6 in desmopressin-treated high-risk patients, vs. 5.2 in placebo-treated high-risk patients [P ¼ 0.0001] and 1.6 in untreated, low-risk patients). Two subsequent metaanalysis confirmed the mild clinical effect of desmopressin in reducing
TABLE 62.5 Reports on the Hemostatic Effects of Desmopressin in Patients With Acquired Defects of Primary Hemostasis and Other Conditions at Risk of Bleeding Not Related to Abnormalities of the Hemostatic System Effects on the Prolonged Bleeding Time or PFA-100 Condition Uremia Liver cirrhosis Thrombocytopeniaa Drug-induced: Aspirin Ticlopidine Clopidogrel Heparin Dextran GPIIb-IIIa antagonists Ticagrelor Sickle cell trait Ehlers-Danlos syndrome Hereditary telangectasia
Shortening/Normalization 56–64
No Effect
Case Reports of Clinical Efficacy Prevention/Control of Bleeding 62–67
No Effect/Worsening
9 523,34,71–73 323,75,76
– – 223,75
6 – 176
168 174 –
321,23,81 223,77 – 178 193 180 – – 196 –
126 – – – – – 182 – – –
282,83 – 192 – – – – 286,95 284,96 185
– – – 194 – – – – –
Number of studies, with reference numbers in superscript. Conditions associated with acquired VWD are not included in this table. Desmopressin is of proven clinical efficacy in patients with acquired VWD (see text). a Good responses are usually obtained in patients with platelet counts higher than 50 109/L (see text).
Desmopressin (DDAVP)
peri- and post-operative blood loss,120,121 but did not repeat the subgroup analysis of the effects of the drug as a function of the severity of blood losses in the placebo-treated patients. In these metaanalyses, no demonstrable effect of the drug was shown on transfusion requirements, need for rethoracotomy or mortality. A more recently published randomized, placebo-controlled clinical trial in 102 patients undergoing valvular heart surgery showed that desmopressin reduces blood loss within 6 h postoperatively and reduces the need for transfusion of fresh-frozen plasm.94 Desmopressin is not the only blood-saving agent used in cardiac surgery.122 The synthetic antifibrinolytic amino acid epsilon-aminocaproic acid (EACA), tranexamic acid and the broad-spectrum protease inhibitor aprotinin are also used. A few direct comparison studies and two metaanalyses120,121 have shown that the order of efficacy of these hemostatic agents (greatest to least) is aprotinin, tranexamic acid, EACA, and desmopressin. However, patients undergoing high-risk cardiac surgery using aprotinin have a higher mortality than those treated with the lysine analogues.123 Hence, the use of aprotinin in high-risk cardiac surgery should be abandoned, and tranexamic or aminocaproic acid preferred.123 In a more recent multicenter, randomized, double-blind, placebo-controlled, parallelgroup study desmopressin failed to decrease the need for red blood cell transfusion and postoperative blood loss in elective patients with excessive bleeding after cardiac surgery despite pretreatment with tranexamic acid.124 The efficacy of desmopressin has also been evaluated in noncardiac surgical operations characterized by large blood loss. In 1987, Kobrinsky et al. showed that, when administered to hemostatically normal children before spinal fusion for idiopathic scoliosis, desmopressin reduced their average operative blood loss by about one-third.125 However, these favorable results could not be confirmed in a subsequent study.126 Contrasting results were also reported by other small trials in total hip or knee arthroplasty.127–129 Preoperative desmopressin failed to reduce blood loss in patients undergoing debridement and grafting of burn wounds, a procedure in which extreme blood losses are a frequent occurrence,130 and in patients undergoing elective aortic operations.131 It must be considered, however, that most of these trials had insufficient statistical power to detect true differences in postsurgical blood loss. In 2015, a placebo-controlled randomized clinical trial of 90 patients undergoing endoscopic sinus surgery for chronic sinusitis showed that desmopressin decreased blood loss and the need for further administration of propofol and remifentanil.132 A metaanalysis was conducted in 38 randomized, placebocontrolled trials (including 2488 patients) that investigated desmopressin not only in cardiac but also in noncardiac surgery (mainly orthopedic) and provided data at least on preoperative blood loss and transfusion of blood products.133 Desmopressin slightly reduced blood loss (almost 80 ml per patients) and transfusion requirements (almost 0.3 unit per patients), with no reduction in the rate of patients who needed transfusion. These modest effects were more pronounced in the noncardiac surgery patients and occurred without a statistically significant increase in thromboembolic complications in these high risk, usually elderly patients (see section “Side-effects”). In summary, the efficacy of desmopressin as a blood-saving agent in cardiac and noncardiac surgical operations appears of modest clinical significance.
SIDE-EFFECTS Side-effects of desmopressin include mild facial flushing, transient headache, and 10%–20% increases in heart rate and diastolic blood pressure.1 Because of its potent antidiuretic effects
1115
and the large doses needed for hemostatic efficacy (15 times greater than for treatment of diabetes insipidus), there is a definite risk of water retention, which can lead to severe hyponatremia.134,135 Because several cases of water intoxication have been reported, fluid restriction, avoidance of hyponatremic solutions and monitoring of serum electrolytes and body weight during and for 24 h after treatment are warranted, especially when desmopressin is used in children under the age of 2 years. Desmopressin has been used with caution in the first two trimesters of pregnancy in women with bleeding disorders, because there is concern that the compound may cause placental insufficiency due to arterial vasoconstriction and increase the risks of miscarriage due to an oxytocic effect and of maternal and/or neonatal hyponatremia.136,137 The compound is however practically devoid of these biological activities, so that its potential for vasoconstriction and uterine contraction is negligible. Evidence of its safety during pregnancy in women with diabetes insipidus is available.138 Desmopressin was also used in 32 pregnant women with low factor VIII levels (27 obligatory carriers of hemophilia A and 5 with VWD type 1) in order to improve hemostasis at the time of such invasive procedures such as chorionic villus sampling or amniocentesis.139 There was no abnormal bleeding and 20 pregnancies went successfully to term with the delivery of healthy newborns. In the remaining 12 women, male fetuses found to be affected by hemophilia on genotyping were aborted under coverage with additional doses of desmopressin.139 There were no side-effects in the treated women other than mild facial flushing and headache and no significant increase in body weight. A metanalysis of published reports did not find high quality evidence on the effects of desmopressin for prevention of bleeding during pregnancy in women with congenital bleeding disorders.140 Several case reports indicate that desmopressin increases the risk of arterial thrombosis, especially stroke and myocardial infarction. A systemic review of 31 clinical trials of patients who had undergone cardiac surgery, orthopedic surgery and other high-risk surgical interventions showed that the risk of thrombosis in desmopressin-treated and placebo-treated patients was 3.4% and 2.7%, respectively: this difference was not statistically significant.141 Also the forementioned metaanalysis of Crescenzi et al.133 failed to find an increased risk of thrombosis in high-risk surgical patients. In contrast, a systematic review of 16 trials evaluating the efficacy of desmopressin to reduce blood loss after cardiac surgery, showed that desmopressin treatment was associated with an almost 2.4-fold increased risk of perioperative myocardial infarction compared with placebo (2.39, 95% confidence intervals 1.02–5.6).121 In consideration of the increased risk for arterial thrombosis, the use of desmopressin should be considered cautiously in the elderly and in patients with clinical overt atherosclerosis.
MECHANISMS OF ACTION OF DESMOPRESSIN Mechanisms of Desmopressin-Induced Increase in Plasma Factor VIII and VWF Because FVIII, VWF, and tPA raise rapidly and transiently after desmopressin administration, it is most likely that desmopressin causes them to be released from storage sites. The storage site for VWF is probably the Weibel-Palade bodies of the endothelial cells.1 This view is supported by the observation that, in rats, injections of desmopressin elicit biological responses that are clearly related to the activation of endothelial cells, including surface expression of P-selectin and subsequent margination of leukocytes.142 The addition of desmopressin to cultured human umbilical vein endothelial cells (HUVEC) in vitro does
62
1116
PART VI Therapy to Increase Platelet Numbers and/or Function
not release VWF.143 However, in endothelial cells obtained from human oral mucosa, there is a reduction in the amount of this protein and a change in its localization, which causes a tendency for the protein to move abluminally toward the cellular basement membrane.144 The apparent paradox was solved by the demonstration that the lack of direct effect of desmopressin addition to HUVEC is attributable to the fact that these cells do not express the V2 receptor (V2R).145 When desmopressin was added to cultured HUVEC that had been transfected to express V2R, or to lung microvascular endothelial cells (which express endogenous V2R), the compound did indeed elicit the release of VWF, which was mediated by an increase in intracellular cAMP.145,146 The interactions between released FVIII and concomitantly released VWF and tPA are not well established. The observation that patients with VWD type 3 treated with desmopressin not only fail to release VWF (which is not synthesized in these patients), but also FVIII and tPA (which are normally synthesized and stored in different tissues), supports the hypothesis that these effects are regulated by a single mechanism, which is probably defective in type 3 VWD.147 The site of cellular storage and release of FVIII is less well established than that of VWF.145 Desmopressin did elicit the expected VWF rise but no FVIII rise in dogs with hemophilia A after hepatocyte-driven neonatal gene therapy.148 This observation suggests that the increase of FVIII induced by desmopressin is due to its release from cells other than the hepatocyte, for example endothelial cells where FVIII is co-localized and complexed with VWF. That cellular co-localization of FVIII and VWF is required for the rise in FVIII after desmopressin is also demonstrated by the observation that, following liver transplantation, patients with hemophilia A infused with desmopressin showed the expected VWF rise but no change in plasma FVIII.149 Because FVIII is synthesized only in the transplanted liver, it appears that co-localization of FVIII and VWF in extrahepatic cells is necessary for in vivo release of FVIII after desmopressin.149
Mechanisms of Desmopressin Efficacy in Patients with Normal Factor VIII and von Willebrand Factor Released VWF: A Biologically Plausible, But as Yet Unproven Mediator A puzzling question is how desmopressin is efficacious in patients who have normal or even high levels of FVIII and VWF. The favorable effects of the compound may be mediated by increased platelet adhesion to the vessel wall150 due not only to the rise of plasma VWF but also to the abluminal secretion of the protein toward the subendothelium144 and by the fresh appearance in plasma of ultralarge VWF multimers.13 These are hemostatically very effective because they support platelet adhesion to the vascular subendothelium to higher degree than regular VWF multimers and induce platelet aggregation under conditions of high shear. Infusion of desmopressin improves the formation of platelet aggregates that form at the high shear rates found in the microcirculation. This effect of desmopressin can be observed not only in patients with VWD type 1,53,54 but also in those with normal VWF, whose impairment of platelet aggregation at high shear is due to congenital or drug-induced abnormalities of the secretory mechanisms or of the interaction of released ADP with its platelet receptors. The improvement of platelet aggregation at high shear after desmopressin administration to these patients correlated with the shortening of the bleeding time and the increase in the plasma levels of VWF with ultralarge multimers, suggesting that these changes in VWF may indeed be responsible, at least in part, for the observed effects of desmopressin on primary hemostasis.
Mechanisms Independent of Released VWF: Proven, But as Yet Uncharacterized There is no direct evidence that the potentiation of platelet adhesion is mediated by desmopressin-induced release of VWF is responsible for the effects of the drug observed in vivo. In contrast, clear evidence exists that other, yet unknown mechanisms are operating in vivo. Desmopressin infusion in patients with VWD type 3 further shortened their prolonged bleeding times, which had been partially corrected by the administration of cryoprecipitate.55 Since type 3 VWD patients lack VWF in tissue stores even after replacement therapy with VWF-containing products, the beneficial effect of desmopressin on their bleeding times was not associated with an increase in plasma VWF levels, nor with the appearance of ultralarge VWF multimers. These results unequivocally indicated that the drug can affect primary hemostasis independently of released VWF. Subsequent studies in rabbits, who do not respond to desmopressin infusion with an increase in the plasma levels of factor VIII and VWF, gave further support to the demonstration that the drug can affect primary hemostasis independently of released VWF.79 In rabbits whose bleeding times had been prolonged by the combined treatment with aspirin and the thrombolytic agent streptokinase, desmopressin infusion shortened the prolonged bleeding times without increasing the plasma levels of VWF.79 As mentioned before, another indirect demonstration of a VWF-independent mechanism comes from the observation that desmopressin shortens the prolonged bleeding times of patients with Bernard-Soulier syndrome (Table 62.4), who lack GPIb, the platelet receptor for VWF that is essential for platelet adhesion and activation at high shear. In addition, it has been shown that the enhancement of platelet interaction with the subendothelium, which was observed after desmopressin infusion in some studies, could not be mimicked by the addition of VWF in vitro in amounts designed to match the postinfusion concentrations of the protein attained in vivo.144 Effects of desmopressin on the platelet count and on agonist-induced platelet aggregation have been ruled out by many studies.43,93,96 Several putative mechanisms or mediators other than VWF have been proposed. For example, the compound has been shown to induce the adhesion of erythrocytes to the endothelium,92 decrease the endothelial production of 13-hydroxyoctadecadienoic acid, a derivative of linoleic acid that powerfully inhibits platelet adhesion to the vessel wall,151 increase the expression of tissue factor by cultured endothelial cells152 and the platelet procoagulant activity.153 The role of these mechanisms is uncertain and the search for additional or alternative mechanisms of action has not been fruitful so far.
CONCLUSIONS Desmopressin is efficacious in mild hemophilia and VWD type 1 and often permits the avoidance of FVIII/VWF concentrates, with significant reductions in costs. Recent data indicate that a number of patients with moderate hemophilia A may also respond adequately to desmopressin, thus avoiding the risk of anti-FVIII alloantibodies formation. The benefits of this nontransfusional hemostatic agent are not limited to cost savings. Desmopressin may be needed to meet religious requests, such as the avoidance of blood products in Jehovah’s Witnesses. Desmopressin is likely to have spared many patients from infection with the human immunodeficiency virus type 1 (HIV). In Italy, where desmopressin was used earlier and more extensively than in other parts of the world, the prevalence of HIV infection in patients with mild hemophilia A (2.1%) is much lower than in the USA154 and in Italian patients with mild hemophilia B who, being unresponsive to desmopressin, could only be treated with plasma-derived factor IX at the time of the HIV epidemic.154
Desmopressin (DDAVP)
In patients with congenital defects of platelet function, desmopressin has been used to prevent or stop bleeding.28,155–157 However, there is still no well-designed clinical trial that truly shows the hemostatic efficacy of the compound in these conditions. Currently, the widespread use of erythropoietin and the resulting sustained correction of the hemostatic defect make the use of desmopressin unnecessary in the majority of patients with chronic renal insufficiency. Antifibrinolytic amino acids should be preferred to desmopressin in reducing blood loss and transfusion requirements during cardiac surgery with extracorporeal circulation. The use of desmopressin in surgical operations other than cardiac surgery is not warranted at this time. REFERENCES 1. Mannucci PM. Desmopressin: a non transfusional agent. Annu Rev Med 1990;41:55–64. 2. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90:2515–21. 3. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrand’s diseases. Lancet 1977;1:869–72. 4. Mannucci PM. Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prog Hemost Thromb 1986;8:19–45. 5. Loomans JI, Kruip MJHA, Carcao M, Jackson S, van Velzen AS, Peters M, Santagostino E, Platokouki H, Beckers E, Voorberg J, van der Bom JG, Fijnvandraat K. RISE consortium. Desmopressin in moderate hemophilia A patients: a treatment worth considering. Haematologica 2018;103(3):550–7. 6. Mannucci PM, Canciani MT, Rota L, Donovan BS. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with hemophilia A and von Willebrand’s disease. Br J Haematol 1981;47:283–93. 7. Cash JD, Gader AMA, de Costa J. The release of plasminogen activator and factor VIII by LVP, AVP and DDAVP, ATIII, and OT in man. Br J Haematol 1974;27:363–4. 8. Mannucci PM, Aberg M, Nilsson IM, Robertson B. Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. Br J Haematol 1975;30:81–93. 9. Levi M, de Boer JP, Roem D, ten Cate JH, Hack CE. Plasminogen activation in vivo upon intravenous infusion of DDAVP. Quantitative assessment of plasmin-alpha2-antiplasmin complex with a novel monoclonal antibody based radioimmunoassay. Thromb Haemost 1992;67:111–6. 10. Mariani G, Ciavarella N, Mazzucconi MG, Antoncecchi S, Solinas S, Ranieri P, Pettini P, Agrestini F, Mandelli F. Evaluation of the effectiveness of DDAVP in surgery and bleeding episodes in hemophilia and von Willebrand’s disease. A study of 43 patients. Clin Lab Hematol 1984;6:229–38. 11. de la Fuente B, Kasper CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate hemophilia A and von Willebrand disease to treatment with desmopressin. Ann Intern Med 1985;103:6–14. 12. Castaman G, Mancuso ME, Giacomelli SH, Tosetto A, Santagostino E, Mannucci PM, Rodeghiero F. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost 2009;7:1824–31. 13. Ruggeri ZM, Mannucci PM, Lombardi R, Federici AB, Zimmerman TS. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood 1982;58:1272–8. 14. Revel-Vilk S, Schmugge M, Carcao MD, Blanchette P, Rand ML, Blanchette VS. Desmopressin (DDAVP) responsiveness in children with von Willebrand disease. J Pediatr Hematol Oncol 2003;25:874–9. 15. Federici AB, Mazurier C, Berntorp E, Lee CA, Scharrer I, Goudemand J, Lethagen S, Nitu I, Ludwig G, Hilbert L, Mannucci PM. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004;103:2032–8.
1117
16. Castaman G, Lethagen S, Federici AB, Tosetto A, Goodeve A, Budde U, Batlle J, Meyer D, Mazurier C, Fressinaud E, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Pasi J, Hill F, Peake I, Rodeghiero F. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008;111:3531–9. 17. Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992;82:87–93. 18. Lethagen S, Ragnarson U, Tennvall G. Self-treatment with desmopressin intranasal spray in patients with bleeding disorders: effect on bleeding symptoms and socioeconomic factors. Ann Hematol 1993;66:257–60. 19. Rodeghiero F, Castaman G, Mannucci PM. Prospective multicenter study of subcutaneous concentrated desmopressin for home treatment of patients with von Willebrand disease and mild or moderate hemophilia A. Thromb Haemost 1996;76:692–6. 20. Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H, Meyer D, Rodeghiero F, Sadler JE. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000;84:345–9. 21. Federici AB, Stabile F, Castaman G, Canciani MT, Mannucci PM. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches. Blood 1998; 92:2707–11. 22. Kobrinsky NL, Israels ED, Gerrard JM, Cheang MS, Watson CM, Bishop AJ, Schroeder ML. Shortening of bleeding time by 1-deamino-8-D-arginine vasopressin in various bleeding disorders. Lancet 1984;1:1145–8. 23. Kohler M, Hellstern P, Morgenstern E, Mueller-Eckhardt C, Berberich R, Meiser RJ, Scheffler P, Wenzel E. Gray platelet syndrome: selective alpha-granule deficiency and thrombocytopenia due to increased platelet turnover. Blut 1985;50:331–40. 24. Mannucci PM, Vicente V, Vianello L, Cattaneo M, Alberca I, Coccato MP, Faioni E, Mari D. Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time. Blood 1986;67:1148–53. 25. De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986;77:1272–7. 26. Pfueller SL, Howard MA, White JG, Menon C, Berry EW. Shortening of bleeding time by 1-deamino-8-arginine vasopressin (DDAVP) in the absence of platelet von Willebrand factor in Gray platelet syndrome. Thromb Haemost 1987;58:1060–3. 27. Schulman S, Johnsson H, Egberg N, Blomback M. DDAVPinduced correction of prolonged bleeding time in patients with congenital platelet function defects. Thromb Res 1987; 45:165–74. 28. Kentro TB, Lottenberg R, Kitchens CS. Clinical efficacy of desmopressin acetate for hemostatic control in patients with primary platelet disorders undergoing surgery. Am J Hematol 1987;24:215–9. 29. Sieber PR, Belis JA, Jarowenko MV, Rohner Jr TJ. Desmopressin control of surgical hemorrhage secondary to prolonged bleeding time. J Urol 1988;139:1066–7. 30. Cuthbert RJ, Watson HH, Handa SI, Abbott I, Ludlam CA. DDAVP shortens the bleeding time in Bernard-Soulier syndrome. Thromb Res 1988;49:649–50. 31. Nieuwenhuis HK, Sixma JJ. 1-Desamino-8-D-arginine vasopressin (desmopressin) shortens the bleeding time in storage pool deficiency. Ann Intern Med 1988;108:65–7. 32. Kim HC, Salva K, Fallot PL, Karp GI, Eisele J, Matts L, Heller I, Saidi P. Patients with prolonged bleeding time of undefined etiology, and their response to desmopressin. Thromb Haemost 1988;59:221–4. 33. Wijermans PW, van Dorp DB. Hermansky-Pudlak syndrome: correction of bleeding time by 1-desamino-8-D-arginine vasopressin. Am J Hematol 1989;30:154–7. 34. Van Dorp DB, Wijermans PW, Meire F, Vrensen G. The Hermansky-Pudlak syndrome. Variable reaction to 1-desamino-
62
1118
35. 36. 37. 38.
39.
40. 41. 42. 43.
44.
45.
46.
47.
48.
49. 50.
51.
52. 53.
54.
55.
PART VI Therapy to Increase Platelet Numbers and/or Function
8-D-arginine vasopressin for correction of the bleeding time. Ophthalmic Paediatr Genet 1990;11:237–44. Di Michele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunctions. Am J Hematol 1990;33:39–45. Waldenstrom E, Holmberg L, Axelsson U, Winqvist I, Nilsson IM. Bernard-Soulier syndrome in two Swedish families: effect of DDAVP on bleeding time. Eur J Haematol 1991;46:182–7. Castaman G, Rodeghiero F. Failure of DDAVP to shorten the prolonged bleeding time of two patients with congenital afibrinogenemia. Thromb Res 1992;68:309–15. Castaman G, Rodeghiero F. Consistency of responses to separate desmopressin infusions in patients with storage pool disease and isolated prolonged bleeding time. Thromb Res 1993;69:407–12. Greinacher A, Potzsch B, Kiefel V, White JG, Muller-Berghaus G, Mueller-Eckhardt C. Evidence that DDAVP transiently improves hemostasis in Bernard-Soulier syndrome independent of von Willebrand-factor. Ann Hematol 1993;67:149–50. Lekas MD, Crowley JP. Easy bruisability, aspirin intolerance, and response to DDAVP. Laryngoscope 1993;103:156–9. Prinsley P, Wood M, Lee CA. Adenotonsillectomy in patients with inherited bleeding disorders. Clin Otolaryngol 1993;18:206–8. Kemahli S, Canatan D, Uysal Z, Akar N, Cin S, Arcasoy A. DDAVP shortens the bleeding time in Bernard-Soulier syndrome. Thromb Haemost 1994;71:675. Cattaneo M, Zighetti ML, Lombardi R, Mannucci PM. Role of ADP in platelet aggregation at high shear: studies in a patient with congenital defect of platelet responses to ADP. Br J Haematol 1994;88:826–9. Rao AK, Ghosh S, Sun L, Yang X, Disa J, Pickens P, Polansky M. Mechanisms of platelet dysfunction and response to DDAVP in patients with congenital platelet function defects. A double-blind placebo-controlled trial. Thromb Haemost 1995;74:1071–8. Cattaneo M, Pareti FI, Zighetti M, Lecchi A, Lombardi R, Mannucci PM. Platelet aggregation at high shear is impaired in patients with congenital defects of platelet secretion and is corrected by DDAVP: correlation with the bleeding time. J Lab Clin Med 1995;125:540–7. Noris P, Arbustini E, Spedini P, Belletti S, Balduini CL. A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. Br J Haematol 1998;103:1004–13. Cattaneo M, Lecchi A, Agati B, Lombardi R, Zighetti ML. Evaluation of platelet function with the PFA-100 system in patients with congenital defects of platelet secretion. Thromb Res 1999; 96:213–7. Zatik J, Poka R, Borsos A, Pfliegler G. Variable response of Hermansky-Pudlak syndrome to prophylactic administration of 1-desamino 8-D-arginine in subsequent pregnancies. Eur J Obstet Gynecol Reprod Biol 2002;104:165–6. Fuse I, Higuchi W, Mito M, Aizawa Y. DDAVP normalized the bleeding time in patients with congenital platelet TxA2 receptor abnormality. Transfusion 2003;43:563–7. Fuse I, Higuchi W, Aizawa Y. 1-Deamino-8-D-arginine vasopressin (DDAVP) normalized the bleeding time in patients with platelet disorder characterized by defective calcium ionophore-induced platelet aggregation. Br J Haematol 2003;122:870–1. Cordova A, Barrios NJ, Ortiz I, Rivera E, Cadilla C, SantiagoBorrero PJ. Poor response to desmopressin acetate (DDAVP) in children with Hermansky-Pudlak syndrome. Pediatr Blood Cancer 2005;44:51–4. Sehbai AS, Abraham J, Brown VK. Perioperative management of a patient with May-Hegglin anomaly requiring craniotomy. Am J Hematol 2005;79:303–8. Pareti FI, Cattaneo M, Carpinelli L, Zighetti ML, Bressi C, Mannucci PM, Ruggeri ZM. Evaluation of the abnormal platelet function in von Willebrand disease by the blood filtration test. Thromb Haemost 1996;76:460–8. Cattaneo M, Federici AB, Lecchi A, Agati B, Lombardi R, Stabile F, Bucciarelli P. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999;82:35–9. Cattaneo M, Moia M, Delle Valle P, Castellana P, Mannucci PM. DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate.
56. 57.
58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
71. 72.
73.
74.
75.
76.
77.
Evidence for a mechanism of action independent of released von Willebrand factor. Blood 1989;74:1972–5. Janson PA, Jubelirer SJ, Weinstein MS, Deykin D. Treatment of bleeding tendency in uremia with cryoprecipitate. N Engl J Med 1980;303:1318–21. Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, Zimmerman TS. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308:8–12. Viganò GL, Mannucci PM, Lattuada A, Harris A, Remuzzi G. Subcutaneous desmopressin (DDAVP) shortens the bleeding time in uremia. Am J Hematol 1989;31:32–5. Shapiro, M.D., Kelleher, S,P. (1984). Intranasal deamino-8-Darginine vasopressin shortens the bleeding time in uremia. Am J Nephrol 4:260–261. Canavese C, Salomone M, Pacitti A, Mangiarotti G, Calitri V. Reduced response of uraemic bleeding time to repeated doses of desmopressin. Lancet 1985;1:867–8. Gotti E, Mecca G, Valentino C, Cortinovis E, Bertani T, Remuzzi G. Renal biopsy in patients with acute renal failure and prolonged bleeding time. Lancet 1984;2:978–9. Watson AJ, Keogh JA. Effect of 1-deamino-8-D-arginine vasopressin on the prolonged bleeding time in chronic renal failure. Nephron 1982;32:49–52. Gotti E, Mecca G, Valentino C, Cortinovis E, Bertani T, Remuzzi G. Renal biopsy in patients with acute renal failure and prolonged bleeding time: a preliminary report. Am J Kidney Dis 1985;6:397–9. Buckley DJ, Barrett AP, Koutts J, Stewart JH. Control of bleeding in severely uremic patients undergoing oral surgery. Oral Surg Oral Med Oral Pathol 1986;61:546–9. Juhl A, Jorgensen F. DDAVP and life-threatening diffuse gastric bleeding in uraemia. Case report. Acta Chir Scand 1987;153:75–7. Donovan KL, Moore RH, Mulkerrin E, Mumar-Bashi W, Williams JD. An audit of appropriate tests in renal biopsy coagulation screens. Am J Kidney Dis 1992;19:335–8. Sateriale M, Cronan JJ, Savadler LD. A 5-year experience with 307 CT-guided renal biopsies: results and complications. J Vasc Interv Radiol 1991;2:40–407. McCartney C, Santosh S, Patolia S, Santosh S. Transfusion requirements in ESRD patients admitted with GI hemorrhage undergoing inpatient endoscopy. South Med J 2016;109(12):785–91. Livio M, Mannucci PM, Viganò G, Mingardi G, Lombardi R, Mecca G, Remuzzi G. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986;315:731–5. Moia M, Mannucci PM, Vizzotto L, Casati S, Cattaneo M, Ponticelli C. Improvement in the hemostatic defect of uremia after treatment with recombinant human erythropoietin. Lancet 1987;2:1227–9. Burroughs AK, Matthews K, Qadiri M, Thomas N, Kernoff PBS, Tuddenham EGD, McIntyre N. Desmopressin and bleeding time in patients with cirrhosis. Br J Med 1985;291:1377–81. Lopez P, Otaso JC, Alvarez D, Rojter S, Podesta A, Albornoz L, Terg R, Romero G, Mastai R. Hemostatic and hemodynamic effects of vasopressin analogue DDAVP in patients with cirrhosis. Acta Gastroenterol Latinoam 1997;27:59–62. Cattaneo M, Tenconi PM, Alberca I, Vicente Garcia V, Mannucci PM. Subcutaneous desmopressin (DDAVP) shortens the prolonged bleeding time in patients with liver cirrhosis. Thromb Haemost 1990;64:358–60. Arshad F, Stoof SC, Leebeek FW, Ruitenbeek K, Adelmeijer J, Blokzijl H, van den Berg AP, Porte RJ, Kruip MJ, Lisman T. Infusion of DDAVP does not improve primary hemostasis in patients with cirrhosis. Liver Int 2015;35(7):1809–15. de Franchis F, Arcidiacono PG, Carpinelli PG, Andreoni B, Cestari L, Brunati S, Zambelli A, Battaglia G, Mannucci PM. Randomized controlled trial of desmopressin plus terlipressin and terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double blind study. Hepatology 1993;18:1102–7. Parker RI, Grewal RP, McKeown LP, Barton NW. Effect of platelet count on the DDAVP-induced shortening of the bleeding time in thrombocytopenic Gaucher’s patients. Am J Pediatr Hematol Oncol 1992;14:39–43. Castaman G, Bona ED, Schiavotto C, Trentin L, D’Emilio A, Rodeghiero F. Pilot study on the safety and efficacy of
Desmopressin (DDAVP)
78.
79.
80.
81.
82. 83. 84.
85. 86.
87. 88. 89.
90. 91. 92.
93.
94. 95.
96.
97.
desmopressin for the treatment or prevention of bleeding in patients with hematologic malignancies. Haematologica 1997;82:584–7. Desborough M, Hadjinicolaou AV, Chaimani A, Trivella M, Vyas P, Doree C, Hopewell S, Stanworth SJ, Estcourt LJ. Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review. Cochrane Database Syst Rev 2016;10:CD012055. Desborough M, Estcourt LJ, Doree C, Trivella M, Hopewell S, Stanworth SJ, Murphy MF. Alternatives, and adjuncts, to prophylactic platelet transfusion for people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation. Cochrane Database Syst Rev 2016;8:CD010982. Cattaneo M, Lombardi R, Bettega D, Lecchi A, Mannucci PM. Shear-induced platelet aggregation is potentiated by desmopressin and inhibited by ticlopidine. Arterioscler Thromb 1993; 13:393–7. Tsui PY, Cheung CW, Lee Y, Leung SW, Ng KF. The effectiveness of low-dose desmopressin in improving hypothermia-induced impairment of primary haemostasis under influence of aspirin—a randomized controlled trial. BMC Anesthesiol 2015;15:80. Teng R, Mitchell PD, Butler K. The effect of desmopressin on bleeding time and platelet aggregation in healthy volunteers administered ticagrelor. J Clin Pharm Ther 2014;39(2):186–91. Schulman S, Johnsson H. Heparin, DDAVP and the bleeding time. Thromb Hemost 1991;65:242–4. Johnstone MT, Andrews T, Ware JA, Rudd MA, George D, Weinstein M, Loscalzo J. Bleeding time prolongation with streptokinase and its reduction with 1-deamino-8-D-arginine vasopressin. Circulation 1990;82:2142–51. Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 1996;75:471–5. Reiter RA, Mayr F, Blazicek H, Galehr E, Jilma-Stohlawetz P, Domanovits H, Jilma B. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003;102:4594–9. Kam PC. Use of desmopressin (DDAVP) in controlling aspirininduced coagulopathy after cardiac surgery. Heart Lung 1994; 23:333–6. Stine KC, Becton DL. DDAVP therapy controls bleeding in EhlersDanlos syndrome. J Pediatr Hematol Oncol 1997;19:156–8. Quitt M, Froom P, Veisler A, Falber V, Sova J, Aghai E. The effect of desmopressin on massive gastrointestinal bleeding in hereditary telangiectasia unresponsive to treatment with cryoprecipitate. Arch Intern Med 1990;150:1744–6. Baldree LA, Ault BH, Chesney CM, Stapleton FB. Intravenous desmopressin acetate in children with sickle trait and persistent macroscopic hematuria. Pediatrics 1990;86:238–43. Moudgil A, Kamil ES. Protracted, gross hematuria in sickle cell trait: response to multiple doses of 1-desamino-8-D-arginine vasopressin. Pediatr Nephrol 1996;10:210–2. Tsai J-M, Sussman II, Nagel RL, Kaul DK. Desmopressin induces adhesion of normal human erythrocytes to the endothelial surface of a perfused microvascular preparation. Blood 1990; 75:261–5. Escolar G, Cases A, Monteagudo J, Garrido M, Lopez J, Ordinas A, Revert L, Castillo R. Uremic plasma after infusion of desmopressin (DDAVP) improves the interaction of normal platelets with vessel subendothelium. J Lab Clin Med 1989;114:36–42. Jin L, Ji HW. Effect of desmopressin on platelet aggregation and blood loss in patients undergoing valvular heart surgery. Chin Med J 2015;128(5):644–7. Chard RB, Kam CA, Nunn GR, Johnson DC, Meldrum-Hanna W. Use of desmopressin in the management of aspirin-related and intractable haemorrhage after cardiopulmonary bypass. Aust N Z J Surg 1990;60:125–8. Lethagen S, Nilssonm IM. DDAVP-induced enhancement of platelet retention: its dependence on platelet-von Willebrand factor and the platelet receptor GP IIb/IIIa. Eur J Haematol 1992;49:7–13. Salzman EW, Weinstein MJ, Weintraub RM, Ware JA, Thurer RL, Robertson L, Donovan A, Gaffney T, Bertele V, Troll J, Smith M, Chute LE. Treatment with desmopressin acetate to reduce blood
98.
99.
100.
101.
102.
103.
104.
105. 106.
107.
108.
109.
110.
111.
112.
113.
114.
1119
loss after cardiac surgery. A double-blind randomized trial. N Engl J Med 1986;314:1402–6. Rocha E, Llorens R, Paramo JA, Arcas R, Cuesta B, Trenor AM. Does desmopressin acetate reduce blood loss after surgery in patients on cardiopulmonary bypass? Circulation 1988;77: 1319–23. Hackmann T, Gascoyne RD, Naiman SC, Growe GH, Burchill LD, Jamieson WR, Sheps SB, Schechter MT, Townsend GE. A trial of desmopressin (1-desamino-8-D-arginine vasopressin) to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med 1989;321:1437–43. Seear MD, Wadsworth LD, Rogers PC, Sheps S, Ashmore PG. The effect of desmopressin acetate (DDAVP) on postoperative blood loss after cardiac operations in children. J Thorac Cardiovasc Surg 1989;98:217–9. Lazenby WD, Russo I, Zadeh BJ, Zelano JA, Ko W, Lynch CC, Isom OW, Krieger KH. Treatment with desmopressin acetate in routine coronary artery bypass surgery to improve postoperative hemostasis. Circulation 1990;82:IV413–9. Andersson TL, Solem JO, Tengborn L, Vinge E. Effects of desmopressin acetate on platelet aggregation, von Willebrand factor, and blood loss after cardiac surgery with extracorporeal circulation. Circulation 1990;81:872–8. Hedderich GS, Petsikas DJ, Cooper BA, Leznoff M, Guerraty AJ, Poirier NL, Symes JF, Morin JE. Desmopressin acetate in uncomplicated coronary artery bypass surgery: a prospective randomized clinical trial. Can J Surg 1990;33:33–6. Reich DL, Hammerschlag BC, Rand JH, Weiss-Bloom L, Perucho H, Galla J, Thys DM. Desmopressin acetate is a mild vasodilator that does not reduce blood loss in uncomplicated cardiac surgical procedures. J Cardiothorac Vasc Anesth 1991;5:142–5. Horrow JC, van Riper DF, Strong MD, Brodsky I, Parmet JL. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991;84:2063–70. Gratz I, Koehler J, Olsen D, Afshar M, DeCastro N, Spagna PM, Ablaza SG, Larijani GE. The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 1992;104:1417–22. de Prost D, Barbier-Boehm G, Hazebroucq J, Ibrahim H, Bielsky MC, Hvass U, Lacombe C, Francais JL, Desmonts JM. Desmopressin has no beneficial effect on excessive postoperative bleeding or blood product requirements associated with cardiopulmonary bypass. Thromb Haemost 1992;68: 106–10. Ansell J, Klassen V, Lew R, Ball S, Weinstein M, VanderSalm T, Okike N, Gratz I, Leslie J, Roberts A. Does desmopressin acetate prophylaxis reduce blood loss after valvular heart operations? A randomized, double-blind study. J Thorac Cardiovasc Surg 1992;104:117–23. Mongan PD, Hosking MP. The role of desmopressin acetate in patients undergoing coronary artery bypass surgery. A controlled clinical trial with thromboelastographic risk stratification. Anesthesiology 1992;77:38–46. Marquez J, Koehler S, Strelec SR, Benckart DH, Spero JA, Cottington EM, Torpey Jr DJ. Repeated dose administration of desmopressin acetate in uncomplicated cardiac surgery: a prospective, blinded, randomized study. J Cardiothorac Vasc Anesth 1992;6:674–6. Dilthey G, Dietrich W, Spannagl M, Richter JA. Influence of desmopressin acetate on homologous blood requirements in cardiac surgical patients pretreated with aspirin. J Cardiothorac Vasc Anesth 1993;7:425–30. Reynolds LM, Nicolson SC, Jobes DR, Steven JM, Norwood WI, McGonigle ME, Manno CS. Desmopressin does not decrease bleeding after cardiac operation in young children. J Thorac Cardiovasc Surg 1993;106:954–8. Rocha E, Hidalgo F, Llorens R, Melero JM, Arroyo JL, Paramo JA. Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery. Circulation 1994;90:921–7. Sheridan DP, Card RT, Pinilla JC, Harding SM, Thomson DJ, Gauthier L, Drotar D. Use of desmopressin acetate to reduce blood transfusion requirements during cardiac surgery in patients with acetylsalicylic-acid-induced platelet dysfunction. Can J Surg 1994;37:33–6.
62
1120
PART VI Therapy to Increase Platelet Numbers and/or Function
115. Temeck BK, Bachenheimer LC, Katz NM, Coughlin SS, Wallace RB. Desmopressin acetate in cardiac surgery: a doubleblind, randomized study. South Med J 1994;87:611–5. 116. Casas JI, Zuazu-Jausoro I, Mateo J, Oliver A, Litvan H, MunizDiaz E, Aris A, Caralps JM, Fontcuberta J. Aprotinin versus desmopressin for patients undergoing operations with cardiopulmonary bypass. A double-blind placebo-controlled study. J Thorac Cardiovasc Surg 1995;110:1107–17. 117. Oliver Jr WC, Santrach PJ, Danielson GK, Nuttall GA, Schroeder DR, Ereth MH. Desmopressin does not reduce bleeding and transfusion requirements in congenital heart operations. Ann Thorac Surg 2000;70:1923–30. 118. Cattaneo M, Harris AS, Stromberg U, Mannucci PM. The effect of desmopressin on reducing blood loss in cardiac surgery—a metaanalysis of double-blind, placebo-controlled trials. Thromb Haemost 1995;74:1064–70. 119. Despotis GJ, Levine V, Saleem R, Spitznagel E, Joist JH. Use of point-of-care test in identification of patients who can benefit from desmopressin during cardiac surgery: a randomised controlled trial. Lancet 1999;354:106–10. 120. Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, McLean RF, Goldman BS, Naylor CD. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994;58:1580–8. 121. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940–7. 122. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007;356:2301–11. 123. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, C^ ote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, Investigators BART. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319–31. 124. Bignami E, Cattaneo M, Crescenzi G, Ranucci M, Guarracino F, Cariello C, Baldassarri R, Isgrò G, Baryshnikova E, Fano G, Franco A, Gerli C, Crivellari M, Zangrillo A, Landoni G. Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial. Acta Anaesthesiol Scand 2016;60(7):892–900. 125. Kobrinsky NL, Letts RM, Patel LR, Israels ED, Monson RC, Schwetz N, Cheang MS. 1-Desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery. A randomized, double-blinded, controlled trial. Ann Intern Med 1987;107:446–50. 126. Theroux MC, Corddry DH, Tietz AE, Miller F, Peoples JD, Kettrick RG. A study of desmopressin and blood loss during spinal fusion for neuromuscular scoliosis: a randomized, controlled, double-blinded study. Anesthesiology 1997;87:260–7. 127. Flordal PA, Ljungstrom KG, Ekman B, Neander G. Effects of desmopressin on blood loss in hip arthroplasty. Controlled study in 50 patients. Acta Orthop Scand 1992;63:381–5. 128. Schott U, Sollen C, Axelsson K, Rugarn P, Allvin I. Desmopressin acetate does not reduce blood loss during total hip replacement in patients receiving dextran. Acta Anaesthesiol Scand 1995;39:592–8. 129. Karnezis TA, Stulberg SD, Wixson RL, Reilly P. The hemostatic effects of desmopressin on patients who had total joint arthroplasty. A double-blind randomized trial. J Bone Joint Surg Am 1994;76:1545–50. 130. Haith LR, Patton ML, Goldman WT, McCutchan KM. Diminishing blood loss after operation for burns. Surg Gynaecol Obstet 1993;176:119–23. 131. Lethagen S, Rugarn P, Bergqvist D. Blood loss and safety with desmopressin or placebo during aorto-iliac graft surgery. Eur J Vasc Surg 1991;5:173–8. 132. Shao H, Kuang LT, Hou WJ, Zhang T. Effect of desmopressin administration on intraoperative blood loss and quality of the surgical field during functional endoscopic sinus surgery: a randomized, clinical trial. BMC Anesthesiol 2015;15:53. 133. Crescenzi G, Landoni G, Biondi-Zoccai G, Pappalardo F, Nuzzi M, Bignami E, Fochi O, Maj G, Calabrò MG, Ranucci M, Zangrillo A. Desmopressin reduces transfusion needs after surgery: a metaanalysis of randomized clinical trials. Anesthesiology 2008;109: 1063–76. 134. Smith TJ, Gill JC, Ambruso DR, Hathaway WE. Hyponatremia and seizures in young children given DDAVP. Am J Hematol 1989;31:199–202.
135. Bertholini DM, Butler CS. Severe hyponatraemia secondary to desmopressin therapy in von Willebrand’s disease. Anaesth Intensive Care 2000;28:199–201. 136. Cohen AJ, Kessler CM, Ewenstein BM. Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America. Haemophilia 2001; 7:235–41. 137. Kujovich JL. Von Willebrand disese and pregnancy. J Thromb Haemost 2005;3:246–53. 138. Ray JG. DDAVP use during pregnancy: an analysis of its safety for mother and child. Obstet Gynecol Surv 1998;53:450–5. 139. Mannucci PM. Use of desmopressin (DDAVP) during early pregnancy in factor VIII-deficient women. Blood 2005;105:3382. 140. Karanth L, Barua A, Kanagasabai S, Nair S. Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. Cochrane Database Syst Rev 2015;9:CD009824. 141. Mannucci PM, Carlsson S, Harris AS. Desmopressin, surgery and thrombosis. Thromb Haemost 1994;71:154–5. 142. Kanwar S, Woodman RC, Poon MC, Murohara T, Lefer AM, Davenpeck KL, Kubes P. Desmopressin induces endothelial Pselectin expression and leukocyte rolling in postcapillary venules. Blood 1995;86:2760–6. 143. Booyse EM, Osikowicz G, Fedr S. Effects of various agents on ristocetin-Willebrand factor activity in long-term cultures of von Willebrand and normal human umbilical vein endothelial cells. Thromb Haemost 1981;46:668. 144. Takeuchi M, Naguza H, Kanedu T. DDAVP and epinephrine induce changes in the localization of von Willebrand factor antigen in endothelial cells of human oral mucosa. Blood 1988;72:850–4. 145. Kaufmann JE, Oksche A, Wollheim CB, Gunther G, Rosenthal W, Vischer UM. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000;106:107–16. 146. Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003;1:682–9. 147. Cattaneo M, Simoni L, Gringeri A, Mannucci PM. Patients with severe von Willebrand disease are insensitive to the releasing effect of DDAVP: evidence that the DDAVP-induced increase in plasma factor VIII is not secondary to the increase in plasma von Willebrand factor. Br J Haematol 1994;86:333–7. 148. Xu L, Nichols TC, Sarkar R, McCorquodale S, Bellinger DA, Ponder KP. Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl Acad Sci U S A 2005;102:6080–5. 149. Lamont PA, Ragni MV. Lack of desmopressin (DDAVP) response in men with hemophilia A following liver transplantation. J Thromb Haemost 2005;3:2259–63. 150. Sakariassen KS, Cattaneo M, van den Berg A, Ruggeri ZM, Mannucci PM, Sixma JJ. DDAVP enhances platelet adherence and platelet aggregate growth on human artery subendothelium. Blood 1984;64:229–36. 151. Setty BN, Dampier CD, Stuart MJ. 1-Deamino-8-D-arginine vasopressin decreases the production of 13-hydroxyoctadecadienoic acid by endothelial cells. Thromb Res 1992;67:545–58. 152. Galvez A, Gomez-Ortiz G, Diaz-Ricart M, Escolar G, GonzalezSarmiento R, Zurbano MJ, Ordinas A, Castillo R. Desmopressin (DDAVP) enhances platelet adhesion to the extracellular matrix of cultured human endothelial cells through increased expression of tissue factor. Thromb Haemost 1997;77:975–80. 153. Colucci G, Stutz M, Rochat S, Conte T, Pavicic M, Reusser M, Giabbani E, Huynh A, Th€ urlemann C, Keller P, Alberio L. The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects. Blood 2014;123:1905–16. 154. Mannucci PM, Ghirardini A. Desmopressin: twenty years after. Thromb Haemost 1997;78:958. 155. Edlund M, Blomback M, Fried G. Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time. Blood Coagul Fibrinolysis 2002;13:225–31. 156. Mast KJ, Nunes ME, Ruymann FB, Kerlin BA. Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms. Br J Haematol 2009;144:230–3. 157. Dunn AL, Cox GJ. Adenotonsillectomy in patients with desmopressin responsive mild bleeding disorders: a review of the literature. Haemophilia 2010;16:711–6.