Desmopressin as a hemostatic and blood sparing agent in bleeding disorders

Abstract

Intranasal, subcutaneous, or intravenous desmopressin can be utilized to release von Willebrand Factor and Factor VIII into circulation, enhance platelet adhesion and shorten bleeding time. Due to these properties, desmopressin can be effective in controlling bleeding in mild hemophilia A, certain subtypes of von Willebrand disease and in acute bleeding from uremia, end stage renal disease, and liver disease. Its use, however, can be complicated by hyponatremia and rarely arterial thrombotic events. While desmopressin has also been used as a prophylactic blood sparing agent in orthopedic, renal, and hepatic procedures, clinical studies have shown limited benefit in these settings. The purpose of this article is to review the evidence for desmopressin in primary hematologic disorders, discuss its mechanism of action and evaluate its utility as a hemostatic and blood sparing product in various bleeding conditions.

1 |. INTRODUCTION

Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) is a synthetic analog of vasopressin (commonly known as anti-diuretic hormone). It has been used in several diseases including nocturnal enuresis, diabetes insipidus and hematologic bleeding disorders including hemophilia and von Willebrand disease (vWD). Desmopressin was first introduced into the market in 1977 and initially used in patients with mild hemophilia A and vWD.¹ After the inadvertent transmission of human immunodeficiency virus (HIV) via pooled and unscreened clotting factor concentrates to many patients with congenital hemophilia,² researchers looked to desmopressin as a nontransfusion option and investigators would go on to evaluate its use in a number of clinical scenarios.³ The primary purpose of this review is to outline the current literature underlying the indications for desmopressin in patients with hemophilia or vWD and patients at increased risk of bleeding due to acute blood loss (from surgery or trauma) or from secondary causes like liver dysfunction due to cirrhosis or end stage renal disease/uremia. Finally, the paper will discuss use of desmopressin as a blood sparing product in transfusion medicine.

2 |. MECHANISM OF ACTION

Desmopressin increases the levels of Factor VIII (FVIII) and von Willebrand Factor (vWF) in the plasma in both healthy and deficient individuals. Desmopressin acts primarily on V2 receptors, thus eliminating the alpha 1 constriction (and related pressor activity and uterotonic properties) seen with vasopressin (Figure 1). Binding of desmopressin with the V2 receptor releases cyclic adenosine monophosphate and stimulates the secretion of vWF (major product) and tissue plasminogen activator (minor product) from storage sites including Weibel-Palade bodies in vascular endothelial cells and alpha granules within platelets (Figure 1). The release of multimeric vWF has a hemostatic effect by mediating adhesion between exposed subendothelial collagen and platelets, initiating primary hemostasis.^4–6 Additionally, desmopressin augments platelet adhesion to the vessel wall^7,8 by increasing the expression of glycoprotein 1b/IX and CD62 (P-selectin) receptors on platelet surfaces.^9,10 Desmopressin has no thrombopoietic properties and thus has no effect on total platelet mass. In summary, desmopressin releases pro-thrombotic factors (vWF and FVIII) from storage sites and promotes platelet-vessel wall adhesion. Diminished efficacy (tachyphylaxis) can occur with repeated desmopressin doses, as storage pools are depleted with repeated administration.¹¹

FIGURE 1.

Schematic displaying the mechanism of action of desmopressin in hemostasis. Created with BioRender.com. (A) Desmopressin binds to the V2 receptor present on endothelial cells. This triggers cyclic adenosine monophosphate (cAMP) mediated release of the contents of the Weibel-Palade bodies into the vasculature. This includes von Willebrand Factor (vWF) multimers, Factor VIII and t-PA. The effects of t-PA are outweighed by the release of vWF. (B) The V2 receptor is also on the surface of platelets and the binding by desmopressin leads to the transport of alpha granules to the surface of platelets. This results in the release of vWF and the translocation of the receptors Gp1b/IX and P-selecting to the surface of platelets. (C) vWF binds with circulating Factor VIII and factor released from the Weibel-Palade bodies, preserving the factor from rapid degradation. (D) Factor VIII becomes more readily available in the coagulation cascade and forming a fibrin clot. (E) vWF will bind to exposed sub-endothelial collagen on damaged vasculature and bind to Gp1b/IX on platelets. P-selectin that has now been upregulated on the surface of platelets will bind to its receptor on white blood cells and endothelial cells.

3 |. PHARMACOLOGY

Desmopressin can be administered intravenously, subcutaneously or via intranasal spray.¹² Its half-life is 3.5 h but can be as long as 9 h in patients with acute or chronic kidney injury as it is renally cleared.⁵ A dissolvable sublingual formulation is now available and primarily used in the pediatric population for nocturnal enuresis at a lower dose (0.12/0.24 mg) compared to the standard tablet (0.2/0.4 mg), with greater response and fewer bedwetting nights.^13,14 The intravenous formulation has a quicker onset of action achieving a peak level within 60 min of administration while the subcutaneous and intranasal formulations attain peak efficacy around 90–120 min.^4,15 The subcutaneous, intranasal and sublingual formulations can be self-administered by patients at home if fluid restriction can be maintained. Notably, the sublingual/intranasal formulations are well tolerated by children. The dose for the intravenous and subcutaneous routes is 0.3 μg/kg; the intranasal dose (one puff per nostril) is weight-dependent at 150 μg for patients weighing <50 kg and 300 μg for those weighing >50 kg.

4 |. ADVERSE EFFECTS

The most common adverse effects of desmopressin include flushing, headaches, and compensatory tachycardia, while the most serious reported adverse effect is hyponatremia. There is no known antidote for desmopressin currently available, and absolute contraindications include hypersensitivity reaction to desmopressin acetate.⁶ Recent studies have shown that desmopressin is well-tolerated with rare adverse events; a study by Stoof et al. observed only 1 out of over 100 patients with significant side effects after infusion of desmopressin. Most side effects seen during the administration of desmopressin were minor and resolved within 24 h.¹⁶

The anti-diuretic properties of desmopressin promote free water absorption from the kidneys and the generation of concentrated urine. A black box warning has thus been issued warning of possible hyponatremia with desmopressin use. A normal serum sodium level is recommended prior to administration, with serial monitoring of sodium levels for several days thereafter. Fluid restrictions should be ordered to reduce the risk of hyponatremia, though evidence is lacking to determine specific patient populations in which this practice is critical. A study showed a discrepancy in the risk of hyponatremia based on biologic sex with women having a 2.7-fold increased sensitivity to desmopressin compared to men.¹⁷

Hyponatremia can be severe, potentially necessitating intensive care unit management, with sequela including seizures, respiratory depression, and death. A retrospective chart review of 107 children with bleeding disorders between the ages of 2–19 years demonstrated a statistically significant mean decrease in serum sodium levels of 4.9 mEq/L following administration, with 11 patients developing sodium levels <130 mEq/L.¹⁸

Management of desmopressin induced hyponatremia can be challenging.¹⁹ Case reports have described strategies including discontinuation of desmopressin with concomitant administration of hypertonic saline, though this risks rapid overcorrection leading to osmotic demyelination.^20,21 In light of these risks, desmopressin is currently on the Beers List of medications to avoid in the geriatric population.²² High risk populations identified as highly susceptible to hyponatremia include patients >65 years of age, patients taking loop diuretics, and patients who are otherwise at risk of severe fluid/electrolyte imbalances due to comorbid illnesses. Fluid restriction and avoidance of hypo-osmolar fluids for several days after desmopressin administration should be considered in these populations and caution should be taken when using desmopressin in the geriatric population.^18,23,24

Rare but reported serious adverse effects of desmopressin are arterial thromboembolic events including myocardial infarction and stroke. In the meta-analysis by Levi et al., patients undergoing cardiac surgery who received peri-operative desmopressin had a twofold higher risk of myocardial infarction compared to placebo.²⁵ Older case reports describe thromboembolic events in patients with coronary artery disease following desmopressin infusion even in patients with hemophilia and uremic dysfunction, respectively.^26,27 This is in contrast to a review of 1833 patients undergoing various cardiac, orthopedic and vascular surgeries which showed no significant difference between desmopressin and placebo (3.4% vs. 2.7% respectively) in terms of the frequency of thromboembolic events.²⁸ Newer case reports in the literature have also seen desmopressin related myocardial infarction, specifically in the setting of Wegner’s granulomatosis.²⁹ The hypothesized etiology of thrombosis in these scenarios is the relative abundance of high-molecular weight vWF multimers leading to excessive platelet aggregation.²⁷ The incidence of thromboembolic events in patients with a higher bleeding risk is unknown.

Review of literature would suggest that desmopressin is safe to use during pregnancy. A systematic review showed no postpartum complications in 97% of pregnancies when desmopressin was used for bleeding prophylaxis in the first and second trimesters.³⁰ Unlike vasopressin (its synthetic counterpart), desmopressin does not bind to the vasopressin receptors found in the uterus³¹ and thus will not induce premature contractions of the myometrium. Case reports have suggested desmopressin can be transmitted via breastmilk to nursing infants, though the oral absorption by the infant from the intranasal formulation is reportedly minimal.^32,33 There is literature with evidence of premature delivery and increased uterine activity with administration of desmopressin in pregnancy. In the absence of randomized control trials, safe use of desmopressin in pregnancy remains debated and clinicians will need to use clinical judgment and available evidence to decide if administration of desmopressin during pregnancy is indicated.³⁴

5 |. HEMOPHILIA A

Hemophilia A is an X-linked recessive inherited bleeding disorder due to a deficiency or complete absence of FVIII, a coagulation protein involved in the intrinsic coagulation pathway. Hemophilia A can be either congenital or acquired (through development of an autoantibody), though the latter scenario is much less common. In either case, patients can be at risk for both traumatic and spontaneous bleeding complications, depending on the severity of deficiency.

Hemophilia A is categorized into mild, moderate, or severe disease based on the amount of measured FVIII activity: Mild >5% to <40%, moderate 1%–5%, and severe <1%.³⁵

5.1 |. Congenital hemophilia A

The first reported study of desmopressin as a hemostatic agent for hemophilia A was in 1977, when Mannucci et al. reported that 8 out of 10 patients bleeding patients who received desmopressin achieved good hemostasis while the other two patients required an infusion of plasma concentrates to control bleeding.¹ Several papers have subsequently confirmed these initial results about desmopressin’s utility in mild hemophilia A.^36–42

Since its development, various formulations have been produced and the intranasal formulation has been shown to be equally as effective in achieving hemostasis compared to the intravenous formulation. The largest study published was a multicenter trial to evaluate the efficacy of the intranasal formulation in 333 patients with mild hemophilia A (124 patients with mild hemophilia A) and vWD. The trial that showed intranasal desmopressin attained hemostatic efficacy in 95% (743/784) of bleeding episodes, 93% (384/413) as prophylaxis and 100% (8/8) of dental and surgical procedures in patients with mild hemophilia A and vWD paving the way for a convenient in-home use of desmopressin.⁴³

Prior to administering desmopressin, a test dose should be given when the individual is healthy. This involves obtaining a baseline measurement of Factor VIII, administration of desmopressin and post-test Factor VIII levels 1 h after administration. An appropriate response would be a 2- to 4-fold increase in Factor VIII activity 1–2 h following the test dose, with the response lasting 6–12 h.⁴⁴

5.2 |. Acquired hemophilia

The prevalence of acquired hemophilia A (AHA) is extremely low in the general population, typically encountered in older populations. While most often idiopathic in nature, AHA can be associated with autoimmune disorders, pregnancy, or malignancy. AHA is usually detected in a bleeding patient with prolonged activated partial thromboplastin time (APTT) that fails to correct to normal when mixing patient plasma with normal pooled plasma. The inhibitor is an autoantibody that binds and neutralizes to FVIII. Treatment of bleeding thus requires the use of a bypassing agent such as recombinant Factor VIIa or activated prothrombin complex concentrates (e.g., FEIBA).^45–47 The second critical component of treatment is eradication of the inhibitor with immune suppressing therapy, typically a combination of corticosteroids, rituximab and/or cyclophosphamide.⁴⁷

Desmopressin has a role in the treatment of minor bleeding in patients with AHA and low inhibitor titers (measured in Bethesda units) and measurable levels of FVIII activity (Table 1).⁴⁸ These conclusions stem largely from a study by Mudad et al. from 1993 which found that 11 of 22 patients with AHA treated with desmopressin demonstrated increased FVIII activity (between 15% and 140%) following IV administration.⁴⁹

TABLE 1.

Summary of indications for treatment with desmopressin in primary hematological disorders.

Bleeding disorder	Indications	Utility
Mild congenital hemophilia A	Surgical prophylaxis and acute bleeding	Evidence to support use36–43
Mild acquired hemophilia A	Acute bleeding episodes	Evidence to support use if inhibitor titers are low42,45,48,49
Hemophilia B	Acute bleeding episodes	No Evidence to support use Factor IX not in storage pools50
FXI deficiency	Surgical prophylaxis	Systematic review with 16 case reports and no adverse bleeding51–54
FXI deficiency	Acute bleeding episodes	More research needed-case reports in patients with dual coagulopathies and improvement from vWF release54,55
Type 1 vWDa	Surgical prophylaxis and acute bleeding episode	Evidence to support use56–58
Type 2A vWDa	Acute bleeding episodes	Generally avoided due to defective multimer formation and release59
Type 2B vWD	Acute bleeding episodes	Contraindicated due to bleeding and thrombocytopenia60
Type 2M vWDa	Acute bleeding episodes	Generally avoided due to defective multimer formation and release59,61
Type 2N vWDa	Acute bleeding episodes	Case report level evidence to suggest some benefit61

^aIt is recommended that all patients undergo a desmopressin trial to determine whether this agent can be used to treat bleeding.

A systematic review on the use of desmopressin in AHA showed that desmopressin was most commonly used in acute, minor, non-life threatening bleeding and achieved a hemostatic effect in 75% of cases.⁴⁸ However, the gold standard for the treatment of AHA are bypass agents so desmopressin can be considered in resource-limited settings (where bypass agents are not readily available), and where inhibitor titers are low (<2–5 Bethesda units/ml) and FVIII activity is >5 IU as seen in some clinical trials.^42,45

In summary, desmopressin can be used to treat mild to moderate cases of acquired hemophilia A if titers are low and FVIII activity is >5 IU but would require close monitoring of their serum sodium levels. Activated prothrombin complex concentrate and activated recombinant FVII are first line agents in acquired hemophilia.

6 |. HEMOPHILIA B

Hemophilia B is an inherited, congenital lifelong hematologic bleeding disorder caused by a deficiency in Factor IX. Unlike hemophilia A and C (see below), there is no evidence to support the role of desmopressin in Hemophilia B because factor IX is not present in the released storage pools.⁵⁰

7 |. HEREDITARY HEMORRHAGIC TELANGIECTASIA

Hereditary hemorrhagic telangiectasia (HHT) is a common autosomal dominant disorder that causes abnormal blood vessel formation. Clinically, HHT is associated with mucocutaneous telangiectasias, arteriovenous malformations (AVMs), and bleeding. Management of HHT usually includes supportive measures such as iron supplementation, transfusions, and ablation of AVMs. Since HHT is not a disease of coagulation factor deficiency, there is no evidence to support the use of desmopressin in the management of HHT.⁶²

8 |. FXI DEFICIENCY

Factor XI deficiency is a congenital bleeding disorder caused by a deficiency in Factor XI (FXI). In a systematic review by Franchini et al., there appeared to be a statistically significant increase in FXI levels (basal level 34.5 vs. 47.9 U/dL) 1 h following desmopressin infusion in 16 patients, though the mechanism for this remains unclear.⁵¹ Most case reports^52–54 from the systematic review have discussed patients with mild FXI deficiency with detectable FXI levels where desmopressin was used as pre-surgical prophylaxis, so it remains unclear if desmopressin was actually indicated. Importantly, no adverse effects were seen in this study. The most likely mechanism of action for the observed effect is increased secretion of FXI from stored sites rather than an increase in synthesis of FXI. Fresh frozen plasma, FXI concentrate, or anti-fibrinolytic agents are otherwise the mainstays of treatment for hemodynamically significant bleeding.⁶³

A review of 16 individuals with dual coagulopathies (vWD and coagulation factor deficiencies), showed no improvement in FXI levels in the 3 patients with dual FXI deficiency and Type 1 vWD when desmopressin was administered, but notable improvement in bleeding in 2/3 cases, from increase in vWF levels rather than FXI.⁵⁵ Castaman et al. reported two patients with prior bleeding history with a genotypically-determined, heterozygous FXI deficiency who underwent uncomplicated carpal tunnel surgery with desmopressin as bleeding prophylaxis with mild increases in FXI (15–20 U/dL from baseline 34 and 39 U/dL) levels post-operatively.⁵⁴ FXI concentrate is indicated in procedures with a high risk of bleeding in patients with FXI deficiency but there is a risk of thrombosis, notably in older populations.^55,64

9 |. von WILLEBRAND DISEASE

von Willebrand disease is the most common inherited autosomal dominant blood disorder in the world. The inherent defect is either a qualitative or quantitative deficiency of vWF. vWF is synthesized in endothelial cells and megakaryocytes, stored in Weibel-Palade bodies of endothelial cells and alpha granules of platelets and secreted upon vascular injury to initiate platelet adhesion to subendothelial collagen.

vWD is broken down into Subtypes 1, 2 and 3, with 1 being the most common. Types 1 and 3 are quantitative deficiencies of vWF (with three characterized by completely absent stores), while Type 2 includes several subtypes characterized by qualitative vWF defects. Clinically, bleeding from vWD tends to be less significant than hemophilia. vWD manifests in young women with menorrhagia, or individuals with recurrent mucocutaneous bleeding, and easy bruising following simple procedures. The exception is patients with Type 3 who can present with hemarthrosis similar to hemophilia. The vWD subtypes are clinically relevant because of the differences in response to desmopressin.

ASH ISH NHF WFH 2021 guidelines on the management of von Willebrand disease provide guidance on the use of desmopressin in VWD.⁶⁵ Specifically, for Type 1 vWD, which comprises roughly 60% of detected cases, desmopressin is effective in the management of bleeding as it increases the release of stored vWF into the circulation.^4,66 Studies have shown a 2- to 4-fold increase in vWF levels following desmopressin administration so it is commonly used in dental extractions, epistaxis and menstrual bleeding.⁵⁶ A desmopressin “responder” will demonstrate at least a twofold increase in baseline vWF and FVIII levels, which remain >50 IU/dL for 4 h after administration.^57,61 Revel-Vilk et al. showed 80% of children had a twofold increase in vWF levels with posttreatment FVIII activity and vWF ristocetin cofactor activity >30 U/dL following desmopressin administration⁵⁷ while Castaman et al. revealed an 83% complete response with desmopressin administration and threefold increase in basal levels in patients with Type 1 vWD.⁵⁸ However, patients with lower baseline vWF levels (<10 IU/dL) may not respond to desmopressin as well.^67,68 Response to treatment has also been noted to correlate with the specific VWF mutation; partial and non-responders have been found to have a mutation in the A1–A3 domain of the protein.⁵⁸

Special note should be made of the vWD Type 1 variant called 1C, which is characterized by intact synthesis and secretion of vWF, but increased clearance. Thus, while desmopressin may increase vWF levels in these patients, the response is limited to a short duration and can render desmopressin sub-optimal for bleeding treatment.^66,69

The qualitative deficiencies are classified as Type 2, and include the Subtypes 2A, 2B, 2M and 2N. Response to desmopressin is highly variable among the subgroups.⁷⁰

Type 2A is the most common and represents a dysfunctional vWF due to reduced high molecular weight multimers or increased susceptibility to ADAMTS13 cleavage. Desmopressin is generally less effective in Type 2A disease, but can be considered in those with mild reduction in vWF levels.⁵⁹

Type 2B is characterized by a gain of function mutation in vWF that enhances its binding affinity to platelets. While this may suggest a hemostatic effect, in reality the vWF-platelet aggregates are cleared from circulation leading to a decrease in vWF levels and loss of the high molecular weight multimers. Desmopressin should be avoided in Type 2B as it can precipitate thrombocytopenia and increased risk of bleeding.⁶⁰

Type 2M occurs due to a loss of function mutation on the A1 Domain of vWF which decreases its affinity for platelets. Desmopressin has not been shown to be effective in Type 2M as it releases defective vWF into circulation with increased clearance of the defective multimers.⁵⁹ Federici et al. reported an 18% (7 of 40 patients) response rate with desmopressin in patients with Type 2 vWD with higher response in the 2N subtype (3/4) and 2M subtype (3/21) with almost no response in Type 2A (1/15).⁶¹

In summary, the treatment strategy for bleeding in vWD is to increase or replace the circulating volume of vWF. The use of desmopressin in vWD is useful because of the inherent mechanism of desmopressin that promotes release of vWF that is stored in endothelial cells. It is most useful in vWD Subtype 1, contraindicated in 2B, of no use in Type 3, and has limited role in Subtypes 2M and 2N (Table 1).

10 |. TRANSFUSION MEDICINE

Desmopressin has been hypothesized as a possible blood-sparing product due to its hemostatic properties. Interest in this was amplified after a double-blind, prospective, randomized trial revealed desmopressin decreased intra-operative and early post-operative bleeding and transfusion requirements in patients undergoing cardiopulmonary bypass by approximately 30%.⁷¹ Unfortunately, subsequent studies have failed to replicate these findings. In a meta-analysis of 17 double-blinded, placebo-controlled trials with a total of 1171 patients, desmopressin reduced post-operative blood loss by 9% (and up to 34% in patients undergoing complex cardiac surgery), but failed to show a statistically significant difference in transfusion requirements.⁷² A systematic review and meta-analysis suggested possible use for desmopressin in reducing bleeding and transfusion requirements in patients on antiplatelet therapy.⁷³ The 10 trials Desborough et al.⁷³ reviewed were limited to cardiac surgery, however, and so further research is warranted in patients on antiplatelet therapy undergoing noncardiac surgeries.

Desborough et al. explored the intra-operative use of desmopressin which resulted in a 0.5-unit average reduction in transfusion of packed red blood cells during cardiac surgery but no difference during orthopedic surgery.⁷⁴ A similar review of the literature revealed there was no evidence for intra-operative desmopressin use in reducing blood transfusions in patients without congenital bleeding disorders.⁷⁵ Kidney biopsies are associated with a high risk of bleeding due to the rich vascular anatomy; a systematic review that investigated the routine use of desmopressin prior to percutaneous kidney biopsies found insufficient evidence to warrant routine use of this hemostatic agent but with a higher risk of hyponatremia.^76,77 Wong et al. performed a randomized controlled trial with a double blinded study on 59 patients undergoing hepatectomy and showed desmopressin did not reduce intra-operative blood loss or transfusion requirements even though it raised clotting factor levels.⁷⁸ Thus, desmopressin should not be used as a blood sparing product peri-operatively (Table 2) though further research is needed to clarify its role in complex cardiac surgeries.

TABLE 2.

Summary of indications for desmopressin in secondary hematological disorders.

Secondary hematologic disorders	Indications	Utility
Transfusion medicine	Intra-operative use as a blood sparing product	Evidence argues against its use72–77
Uremia	Acute bleeding episodes	Could be beneficial in patients with acute renal failure or CKD14,79,80
Cirrhosis	Acute bleeding episodes	No evidence to support its use81–84—more research needed
Intracerebral hemorrhage	Acute bleeding episodes	Not indicated85,86

11 |. INTRACEREBRAL HEMORRHAGE

Desmopressin has been investigated as a hemostatic agent in patients with intracerebral hemorrhage (ICH). A recent meta-analysis demonstrated a lack of efficacy of desmopressin in preventing hematoma expansion after antiplatelet-associated ICH.⁸⁵ Three retrospective controlled studies were included in the meta-analysis which also showed similar rates of thrombotic events regardless of desmopressin use.⁸⁵ These results were further supported in a multicenter retrospective cohort study in patients with spontaneous antiplatelet-associated intracerebral hemorrhage where desmopressin was not associated with a reduction in hematoma expansion or poor outcomes.⁸⁶ In conclusion, desmopressin should not be used to control ICH (Table 2).

12 |. UREMIC BLEEDING

The hemorrhagic manifestations of uremia are clinically seen as bleeding diathesis from puncture sites, mucocutaneous bleeds, subdural hematomas and generalized prolonged bleeding. The broad clinical manifestations are multifactorial ranging from dysfunctions in platelet adhesions, accumulation of uremic toxins, to end-stage renal disease (ESRD) induced anemia. Conversely, ESRD can also cause a pro-thrombotic state in patients through a variety of means including increased platelet-erythrocyte aggregates.⁸⁷

A recent systematic review and meta-analysis determined that prolonged bleeding time, impaired platelet/platelet and platelet/vessel adhesion are the most common abnormalities affected in the coagulation cascade in patients with chronic kidney disease (CKD).⁸⁸ Other notable factors include fluctuating platelet counts/platelet volume and variable granular contents with impaired secretion.⁸⁸ Additionally, when the kidneys are unable to clear toxins, the metabolites accumulate in high concentrations and the cross interaction with other toxins increased the risk of cardiovascular, fibrinogenic and proinflammatory complications which independently increased patients’ risk of morbidity and mortality.⁸⁹ Bleeding time is one potential index in assessment of bleeding risk rather than blood urea nitrogen (BUN) or the creatinine in patients with CKD.

Treatment is directed at targeting the uremic-induced hemostatic dysfunction; erythropoietin corrects the underlying anemia while dialysis clears metabolic toxins and reduces the pro-thrombotic effect but dialysis can worsen bleeding from puncture sites.⁹⁰ Desmopressin has been used in patients with uremia as it shortens bleeding time⁷⁹ from acute or chronic renal failure by increasing platelet interaction with the vessel subendothelial wall.^91,92 Mannucci et al. identified desmopressin administration as a possible hemostatic agent in uremia where 12 patients with uremia and an additional 9 patients with acute or chronic renal failure received a desmopressin infusion and were noted to have shorter bleeding times. While rarely used in clinical practice, the bleeding time has been shown to shorten in uremic patients receiving desmopressin.

Interestingly, larger vWF multimers were seen in these patients which resulted in normal hemostasis suggesting its use as a temporary hemostatic agent in renal disease.¹⁵ Intravenous and subcutaneous routes of administration are effective in acute uremic bleeding.^15,80 In summary, desmopressin can be used as a hemostatic agent in acute or chronic uremia to control acute bleeding (Table 2).

13 |. CIRRHOTIC BLEEDING

Patients with end stage liver disease demonstrate a precarious imbalance in coagulation manifesting as either hyper- or hypocoagulability. Bleeding in these patients is most often related to portal hypertension, hypersplenism-associated thrombocytopenia, and coagulopathies from synthetic dysfunction. Aside from FVIII and vWF, all other clotting factors are synthesized in the liver. Cirrhotic patients are known to have higher levels of vWF and FVIII, so the use of desmopressin is not indicated and evidence is less established.^81,82 A study comparing terlipressin versus terlipressin with desmopressin in variceal hemorrhage was discontinued early due to higher rates of bleeding in the desmopressin group (54.2% vs. 27.3%).⁸³ Other studies have shown that desmopressin did not induce any significant effect in attaining primary hemostasis.⁸⁴

Conversely, desmopressin was shown to induce a statistically significant decrease in bleeding time from 9 to 6 min with a corresponding decrease in aPTT an hour after infusion in a double blind, placebo-controlled crossover study in nine patients with cirrhosis.⁹³ Another study revealed the use of intranasal desmopressin as an effective agent in attaining hemostasis compared to a blood transfusion (FFP and/or platelets) in cirrhotic patients with moderate coagulopathy (defined by platelet count between 30 000 and 50 000 and an INR between 2 and 3) undergoing dental extraction while being a more cost-effective option.⁹⁴

Ultimately, the use of desmopressin as a hemostatic agent in cirrhosis remains controversial and lacks an evidence-based foundation so its use must be determined on a case-by-case basis (Table 2).

14 |. CONCLUSION

Bleeding is one of the most commonly encountered problems in medicine. It can be caused by primary hematologic disorders (quantitative or qualitative disorders in primary hemostasis) or by non-hematologic causes including cirrhosis and uremia. Assessing the underlying cause of bleeding is vital to prevent life threatening hemorrhage.

Desmopressin was first introduced 45 years ago and has consistently proven to be a safe and cost-effective agent for achieving hemostasis in mild hemophilia A and certain subtypes of vWD. By releasing stored vWF and FVIII, desmopressin allows for rapid control in bleeding due to quantitative deficiencies in these hemostatic components. Its utility is limited, however, by the potential for hyponatremia in vulnerable populations, and its long-term use is limited by tachyphylaxis as storage vesicles containing pro-thrombotic factors are eventually depleted.

In terms of peri-operative bleeding risk, there appears to be limited evidence favoring desmopressin’s use as an intra-operative prophylaxis agent in renal, hepatic and orthopedic procedures without notable reduction in blood transfusion requirements. There is room for growth in assessing its use as intra-operative prophylaxis in high-risk cardiac surgeries including bypass where there is a higher estimated average blood loss.

Interestingly, desmopressin facilitates platelet adherence to the subendothelial collagen of blood vessel walls and plays a role in controlling uremic bleeding. An area of growth and research is investigating the use of desmopressin to achieve hemostasis in patients with acute bleeding events on life sustaining support including extracorporeal membrane oxygenation and dialysis circuits. There may be a role for the drug to control acute bleeding events without the need to discontinue anticoagulation through the circuit, though further research is needed.

Novelty statements.

• This article reviews the prior, current and most updated literature of the indications for desmopressin in various bleeding and hemostatic disorders.

• Desmopressin has a tole in hemostasis in patients with mild hemophilia A and C, certain types on von Willebrand disease.

• Hematologists and surgeons can use this article to review evidence for desmopressin as a hemostatic and blood sparing agent.

DATA AVAILABILITY STATEMENT

The authors confirm that the data supporting the findings of this study are available within the article.