The use of haemostatic drugs in haemophilia:desmopressin and antifibrinolytic agents

A. VILLAR, V. JIMENEZ-YUSTE, M. QUINTANA and F. HERNANDEZ-NAVARRO

Hematology Department, Hospital Universitario La Paz, Madrid, Spain

Summary. Over the last 4 decades, there have beenvery significant advances in the treatment of haemo-philia. Plasma products first became available in the1960s, beginning with cryoprecipitate and thenintermediate-purity plasma concentrates, for thetreatment of haemophilia A and B. The disasters ofviral infections amongst people with haemophilia inthe 1980s served to stimulate both the developmentof techniques of viral inactivation of concentratesand the manufacture of purer products. We thereforenow have safe plasma products that are also pure inthat they are concentrates of only the deficientprotein responsible for the congenital coagulopathy.Preparations of specific coagulation proteinsobtained using recombinant biotechnology tech-niques have been available since 1995.

By contrast, pharmacological options for thetreatment of the haemophilia remain very limited.The only therapeutic alternatives of real practicalvalue which have been available in the last 30 yearsfor the treatment of haemophilic patients are des-mopressin, antifibrinolytic agents, aprotinin, concen-trated oestrogens, and local haemostatic agents suchas topical thrombin or fibrin glue.

This article aims to assess the pharmacologicalbasis and accumulated experience relating to thesedrugs when used for the prevention and treatment ofbleeding in patients with haemorrhagic disorders.

Keywords: anti-fibrinolytic agents, desmopressin,haemophilia, haemostatic drugs.

Introduction

In 1957, Marcinak [1] described an acceleration ofclot formation after adrenaline (epinephrine) infu-sion, as well as a transitory increase in coagulation offactor VIII (FVIII) after adrenaline injection inrabbits. Subsequent independent studies confirmedthat this also occurred in humans. In patients withmild haemophilia, the magnitude of the response ofFVIII induced by adrenaline is similar to thatobserved in healthy subjects [2].

These findings stimulated the search for an agentthat would increase the FVIII level, but was free fromthe risk of significant side-effects. The infusion ofvasopressin (antidiuretic hormone; ADH) and insulinalso induces an increase in the level of FVIII, buttheir use is associated with significant adverse reac-tions that prevent them from being used in routineclinical practice. A chemical analogue of ADH,

arginine–vasopressin (AVP), was developed in1956. This hormone was found to exert two actions,an antidiuretic activity associated with a vasoactiveeffect. A synthetic analogue of this vasopressin,desmopressin, was first produced in 1967, and wasobserved to increase the plasma levels of both FVIIIand von Willebrand factor (vWF) in healthy individ-uals [3].

Desmopressin

Desmopressin has a similar structure to that ofvasopressin, retaining its antidiuretic effect. How-ever, it has minimal stimulatory action on smoothmuscle so that infusion is not associated with anincrease in blood pressure, or with contractions ofsmooth muscle in the uterus or gastrointestinaltract. It is thus much better tolerated when admin-istered to humans. This new molecule (1-d-amino-8-d-arginine-vasopressin, also known as DDAVP) wasadopted as the treatment of choice in insipiddiabetes.

In 1977, this agent was used for the first time inmild haemophilia A and vWD for the prevention and

Correspondence: A. Villar, Hematology Department, HospitalUniversitario La Paz, Madrid, Spain.E-mail: avillar@hulp.insalud.es

Accepted 13 March 2002

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treatment of bleeding episodes, as well as for surgeryand dental extractions [5]. This represented a verysignificant clinical advance, showing that desmopres-sin could boost the levels of both FVIII and vWF inthe plasma very significantly and avoiding the needfor factor concentrates. These early results wereconfirmed in subsequent clinical studies [6–8].

Mechanism of action of desmopressin

Even after more than 20 years of clinical use, theprecise mode of action of desmopressin remainsobscure. The increase in the plasma levels of FVIIIand vWF is not limited only to patients withdeficiencies in these factors, but is also observed inhealthy individuals.

Desmopressin also interacts directly with platelets,facilitating activation by other agonists such asadenine diphosphate and collagen [9]. It has beendemonstrated that desmopressin stimulates plateletadhesion and shortens the bleeding time in patientstreated with either aspirin or placebo. This effectlasts approximately 3 hours, although the plateletscan be stimulated again. The effect on plateletadhesion seems to be independent of the increase inthe plasma vWF levels [10]. Desmopressin alsoshortens the activated partial thromboplastin time(APTT) and the bleeding time [11]. It induces releaseof large quantities of tissue-type plasminogen activ-ator in plasma, generating plasmin in vivo. Most ofthis is eliminated from the circulation throughformation of complexes with a2-antiplasmin, avoid-ing stimulation of fibrinolysis in the circulation [12].It is therefore not necessary to inhibit fibrinolysis(e.g. by using tranexamic acid) when desmopressin isused for clinical purposes.

The rapid and transitory increases in FVIII andvWF after infusion of desmopressin seem to be due totheir release from their storage sites rather than to anincrease in the rate of synthesis of these products.The vascular endothelium is presumably the greatestsource of vWF, although FVIII is not stored inendothelial cells and is primarily synthesized in theliver. The rises in the plasma FVIII and vWF levelsafter infusion of desmopressin are not affected byprior administration of propanolol, acetylsalicylicacid or naloxone, implying that beta-adrenergicmechanisms, prostaglandins, or mediators such asthe endorphins, are not involved [13]. The hypothesisthat desmopressin increases the levels of FVIII andvWF through V2 receptors is based on the fact thatpatients with congenital nephrogenic diabetes, whodo not have V2 receptors, do not respond to aninfusion of desmopressin [14]. This has also been

confirmed in an animal model, in which a specificantagonist for the V2 receptor was administeredafter infusion of desmopressin, and this prevented therelease of FVIII and vWF [15].

Desmopressin infusion in rats causes an increase inP-selectin expression in endothelial cells [16]. It isknown that P-selectin is important in promotingleucocyte adhesion to the subendothelium, whichcould be relevant in primary haemostasis. desmo-pressin also increases expression of tissue factor (TF)in the subendothelium and in the endothelial cells[17].

The conclusion is that desmopressin exerts aneffect in several ways, including: (1) boosting thelevels of plasma FVIII and vWF; (2) increasingplatelet adhesion through the secretion of P-selectin;and (3) increasing expression of tissue factor. Allthese mechanisms act in synergy to accelerate therate of fibrin formation.

Desmopressin in the treatment of haemophilia

Extensive clinical data have been accumulated andpublished since 1977, when Mannucci [1] first pub-lished his experience on the use of desmopressin inpatients with mild haemophilia A and vWD. Des-mopressin is the drug of choice in the prophylaxisand treatment of haemorrhagic episodes in patientswith moderate and mild haemophilia A.

Patients with measurable baseline levels of circu-lating FVIII may be predicted to respond best todesmopressin [1–7], while those with undetectablelevels will not respond. In haemophilia A, theefficacy of desmopressin is correlated with thepostinfusion plasma levels of FVIII.

The therapeutic indications are defined by thenature of the haemorrhagic episode, the baselinelevel of FVIII and the desired target level to achievehaemostasis. Most of the failures in the use ofdesmopressin can be explained because the level ofFVIII in plasma is too low to control the bleeding[1–7]. For major surgical procedures, haemophilicpatients with FVIII levels of 10 U dL)1 should not betreated with desmopressin because the postinfusionlevels will not be greater than 30–50 U dL)1, and theuse of FVIII concentrates should be considered. Incontrast, these levels can be sufficient for patientswho are about to undergo minor surgical procedures,such as dental extractions.

Because desmopressin induces a transient increasein plasma fibrinolytic activity, it might be imaginedthat concomitant antifibrinolytic therapy couldenhance efficacy. However, there is no clinicalevidence of haemostatic improvement when both

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drugs are used in combination, and there are no datato suggest that the postinfusion half-lives of FVIIIand vWF are enhanced. However, combined therapyoffers a clear benefit in the treatment of mucosalbleeds and during dental surgery.

Other uses for desmopressin have been reported inthe literature. In patients with acquired haemophiliaand an inhibitor titre less than 2 Bethesda units,bleeding episodes may be controlled with desmo-pressin, because these patients continue to produce,store and release FVIII. If the inhibitor level is low,the quantity of FVIII released after the desmopressininfusion can be sufficient to neutralize the circulatinginhibitor and to produce haemostatic levels of FVIII[18].

Improved pharmacokinetic properties of high-purity and recombinant FVIII concentrates adminis-tered to patients with severe haemophilia A havebeen observed following administration of a 300-lgdose of desmopressin acetate (StimateTM, AventisBehring), as the stability of circulating FVIII isenhanced by association with vWF [19].

It has recently been suggested that desmopressinmay also be of some value in patients with severe/moderate haemophilia B undergoing dental extrac-tion, when used together with tranexamic acid[20,21].

Desmopressin is now universally accepted ashaving a role in the treatment of cases of mildhaemophilia A and the World Health Organizationhas included desmopressin in its list of essential drugssince 1992. It is unfortunate that the value of thisdrug was not as widely appreciated in the first half ofthe 1980s, a period in which the use of plasmaconcentrates of FVIII subjected to viral inactivationprocedures was not routine and therefore manypatients were exposed to hepatitis B and C, and tohuman immunodeficiency virus.

Administration routes and desmopressin controls

The optimal dose of desmopressin to obtain maxi-mum response of FVIII and vWF is 0.3 lg kg)1,giving an increase in FVIII of 3–5 times that ofbaseline 1 hour after completion of the infusion; theincrease in vWF is somewhat less. The intensity ofthe response is similar in both moderate and mildhaemophilia. The half-life of the circulating FVIIIvaries from 2–5 h, and that of vWF is 6–9 h. Thelevel of tissue plasminogen activator (tPA) alsoincreases transiently [6].

Desmopressin is usually administered by intraven-ous infusion at a dose of 0.3 lg kg)1. However, it isalso effective after intranasal and subcutaneous

administration [22]. A subcutaneous injection of0.3 lg kg)1 produces a similar response to that seenwith intravenous infusion, although the maximumresponse is slower. By contrast, intranasal insuffla-tion inhalation of 250 lg of desmopressin elicits aslower and less marked response, with a maximumFVIII level of approximately 2.5 times the baselinevalue. When a maximum response is desired, thesubcutaneous or intravenous routes of administra-tion should therefore be chosen.

Repeated doses of desmopressin over short inter-vals of time are associated with progressively lowerrises in the FVIII and vWF levels, a phenomenonknown as tachyphylaxis [23]. This is a disadvantagethat must be borne in mind when planning atreatment regimen for prolonged periods of time,e.g. for surgery, when treatment may need to beextended for up to 7 days. For this reason, the FVIIIlevel should be checked daily, with blood samplestaken daily 1 hour after completion of the infusion.The preferred route for home treatment is intranasal.

The recommended dose in very young haemophilicpatients is similar to that of adults, 0.3 lg kg)1, andshould be diluted in saline solution and slowlyinfused, over approximately 30 min. When thebodyweight is greater than 10 kg, the drug shouldbe diluted in 50 mL of fluid. In patients weighing lessthan 10 kg, the volume of fluid should be 10 mL andit is particularly important in such cases to monitorthe plasma sodium level.

Contraindications and adverse effectsof desmopressin administration

The use of desmopressin is contraindicated in chil-dren under 3 months of age, patients with type 2BvWD and where there is evidence of hypersensitivityto the components of desmopressin acetate.

Transient facial and conjunctival reddening iscommonly observed, and this can sometimes beaccompanied by haemodynamic changes such as adecrease in blood pressure (10% of the patients) anda mild increase in heart rate (10%–20% of thepatients) [6].

Isolated cases of myocardial infarction and cere-brovascular accidents have been reported in patientstreated with desmopressin, although the precise riskof thromboembolic complications associated withthe administration of desmopressin reamain uncer-tain [24]. However, desmopressin should not be usedin patients known to have arterial disease.

Desmopressin is an antidiuretic hormone, alsoused in the treatment of diabetes insipidus, and mayinduce significant water retention in isolated cases.

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Transient headache is another common side-effect inpatients treated with desmopressin. When the head-aches are persistent, the possibility of hyponatraemiashould be considered and excluded by checking thesodium levels, as there is at least one published casereport of a patient with cerebral oedema associatedwith severe hyponatraemia induced by desmopressin[25]. This phenomenon is more marked in children,who have a greater risk of fluid retention, andrepeated doses should be avoided if at all possible inchildren under the age of 2 years. The plasmasodium level should be checked 24 h after the lastdose of desmopressin, and the intake of fluids shouldbe restricted to 75% of the normal volume [26].

Antifibrinolytic agents

Mechanism of action

Antifibrinolytic agents are useful in various clinicalconditions. The two main drugs available are tran-examic acid and epsilon-aminocaproic acid (EACA),both of which are lysine derivatives.

The mechanism of action of both drugs is based ontheir capacity to bind to the lysine-binding site ofplasminogen, responsible for binding to fibrin,resulting in inhibition of fibrinolysis.

Tranexamic acid is 10 times more potent thanEACA and also has a longer half-life. Both drugsreadily diffuse into the extravascular space, whichfacilitates their action. Both these drugs may beadministered either orally or intravenously.

Antifibrinolytic agents in the treatmentof haemophilia

Clinical experience indicates that these drugs are veryhelpful in controlling blood loss following dentalextractions in patients with haemophilia. When car-ried out by an experienced dental surgeon, it has evenbeen suggested that it is possible to completely avoidthe need for FVIII and FIX concentrates [27] bycombining the use of antifibrinolytic agents withsustained local pressure. A typical dose regime fortranexamic acid is 3 g (orally) every 6 hours, while theequivalent dose of EACA is 5 g every 6 hours, alsoorally. In spite of the accumulated clinical experience,there are few references in the literature to prospectiveand controlled studies that confirm this evidence, withthe exception of one study performed on 77 haemo-philiac patient compared to a control group. Thehaemophilic patients received 20 mg kg)1 of tranex-amic acid and a single dose of FVIII/FIX to reach alevel of 30 U dL)1 of FVIII/FIX in vivo prior to dental

extraction. In the haemophilic patients, two haemor-rhagic complications were observed (one late haemor-rhage and one haematoma in the site of the anaesthesiainjection), while in the control group, a late haemor-rhage occurred. There was no statistically significantdifference in the incidence of haemorrhagic compli-cations between the two groups [28].

Adverse effects

In general, antifibrinolytics are well tolerated,although gastrointestinal disturbances (e.g. cramps,diarrhoea) may be experienced when used at highdoses.

Antifibrinolytic drugs are contraindicated in casesof haematuria as their use in such cases couldpromote the formation of fibrin clots in the renalpelvis and/or ureters and cause clot colic.

They are also contraindicated forcentral nervoussystem haemorrhage as they can induce arterialvasospasm, with the risk of precipitating a secondaryischaemic event.

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