DDAVP and EACA used for minor oral surgery in von Willebrand disease Raymond Williamson, BDS, FRACDS* Deryck J. Eggleston, M B BS, FDSRCSt

Key words: bleeding disorder, medical condition, oral surgery.

Abstract A therapeutic approach to the management of mild von Willebrand disease in four patients requiring minor oral surgery is reported, using a combination of 1 -deamino-8 d-arginine vasopressin (DDAVP) and epsilon-aminocaproic acid (EACA).

(Received for publication March 1986. Accepted May 1986.)

Introduction Von Willebrand disease is a bleeding disorder

characterized by a complex haemostatic defect. In 1926' von Willebrand described a familial disorder of both sexes characterized by excessive mucous membrane bleeding and prolonged bleeding times. Initially the defect was suspected to be of the platelets and capillaries but a relationship to factor VIII was established in 1953.*

In von Willebrand disease there are defects in both platelet-mediated and plasma-clotting aspects of haemostasis. It has only recently3 been appreciated that normal factor VIII is a protein complex containing both plasma coagulant activity and an activity for platelet haemostasis. The two portions are under separate genetic control and have distinct properties.

The portion of factor VIII complex necessary for coagulant activity is known as factor VIII procoagulant protein (VIII C ) and classical haemophilia is characterized by a reduction in this protein. The portion of the factor VIII complex necessary for platelet function is called the von Willebrand factor (VIII R:WF). The primary defect

*Formerly Oral Surgery Department, Perth Dental Hospital. ?Oral Surgery Department, Perth Dental Hospital.

in von Willebrand disease is due to an absolute decrease in VIII R:WF (quantitative defect) or its presence in a dysfunctional form (qualitative defect). The bulk of normal factor VIII complex consists of von Willebrand factor with a ratio of 100 to 1 to procoagulant protein but the two closely interact to form a plasma complex. The VIII R:WF protein is composed of a population of multimers of different molecular masses. The haemostatic efficiency of the different multimers is directly proportional to their size and the larger multimers must be present to correct the bleeding abnormality in von Willebrand's disease.

The von Willebrand factor is present in plasma, platelets, megakaryocytes and endothelial cells and is synthesized by the latter two types of cells. It plays a central role in normal platelet function and platelet adhesion to the vessel wall. A specific receptor for VIII R:WF has been demonstrated on the surface of platelets by using the antibiotic r i~ toce t in .~

There are no specific tests for measuring VIII R:WF activity in virro but it was observed5 in von Willebrand disease that platelets did not aggregate normally in the presence of ristocetin. Ristocetin- induced platelet aggregation (RIPA) and ristocetin co-factor activity (VIII R:Co) are techniques devised to reflect von Willebrand factor activity. Although the former has been generally abandoned, there is a good correlation between ristocetin co-factor activity in vitro and von Willebrand activity in vivo in most cases. However, it is not completely reliable in conditions such as pregnancy or following the administration of the vasopressin analogue DDAVP.6 This test measures the proportion of the von Willebrand factor which has biological activity, and this may be different from the total VIII R:WF. The factor VIII-related antigen (VIII R:Ag)' has been isolated using specific antisera to von

32 Australian Dental Journal 1988;33(1):32-6.

Table 1. Classification. of von Willebrand disease? Type I Type IIA Type IIB Type IIC Type I11

Genetic transmission Needing time VIII c VIII Ag

VIII R:Co

RIPA

Multimeric structure

Autosomal dominant Prolonged Decreased

Decreased

Decreased

Decreased or normal Normal in plasma and platelets

Autosomal dominant Prolonged Decreased or normal Decreased or normal Markedly decreased Absent or decreased Absence of large and intermediate multimers from plasma and

Autosomal dominant Prolonged Decreased or normal Decreased or normal Decreased or normal Increased

Absence of only larger multimers from plasma; normal in platelets

Autosomal recessive Prolonged Normal

Normal

Decreased

Decreased

Absence of large multimers from plasma and platelets; triplet

Autosomal recessive Prolonged Markedly decreased

Minute amounts or absent Absent

Absent

Variable

platelets structure is aberrant.

*After Zimmerman and Ruggeri." tClossary

van Willebrand disease. It is known as the von Willebrand factor.

A plasma.

VIIl R:WF = T h e portion of factor VIII complex necessary for the platelet plug and which corrects the bleeding abnormality in

VIII C = The portion of the factor VIII complex necessary for coagulation activity which corrects the clotting abnormality in haemophilia

VIII Ag = Factor VIII related antigen. The antigenic expression of the von Willebrand factor. VIII R:Co = Ristocetin Co-factor. A property of von Willebrand factor which promotes platelet agglutination in the presence of

RIPA = Ristocetin induced platelet aggregation. An inaccurate biochemical test used to estimate von Willebrand factor activity. the antibiotic ristocetin.

Willebrand factor, and this is regarded as the expression of the total VIII R:WF in the factor VIII complex.

Most cases of von Willebrand disease present as a mild to moderate bleeding disorder transmitted as an autosomal dominant, associated with prolonged bleeding time and reduced factor VIII complex activity. Zimmerman and Ruggeris have proposed an extensive classification of the disorder and this is shown in Table 1 together with a glossary of terms. In addition, a rare acquired form of von Willebrand disease has been de~cribed.'.'~

T h e substance 1-deamino-8 d-arginine Vasopressin (DDAVP) is a synthetic analogue of the posterior pituitary hormone vasopressin (ADH). Manucci and his colleagues" showed that intravenous infusion of DDAVP raised factor VIII complex activity in cases of mild haemophilia and von Willebrand disease. The effect is not seen in severe cases of the disorders.

The precise mechanism by which factor VIII complex is released is not known, but release from endothelial storage cells has been suggested and the drug may have direct effect on vessel walls with increased platelet spreading and adhesion at injury sites."

A separate effect of DDAVP infusion is an increased fibrinolysis due to the release of the fibrinolytic enzyme, plasminogen ac t iva t~r . '~ Plasminogen activator converts plasminogen to plasmin which degrades fibrin and leads to increased bleeding. The synthetic amino acid, Epsilon amino caproic acid (EACA) is known to have an antifibrinolytic effect1 due to its action as a competitive inhibitor of plasminogen activator, and therefore serves to stabilize the blood clot and minimize bleeding.I4

Four cases of mild von Willebrand disease requiring dental extraction are described in which bleeding was controlled by DDAVP and EACA. Three patients were Type I according to the classifi- cation shown in Table 1 and one was Type IIA.

Method Four patients requiring dentoalveloar surgery

were hospitalized for assessment of their von Willebrand disease with a view to suitability for treatment with DDAVP.

iOkamatos S, Okamata U. 22nd Inr Cong Physiological Science, 1962: Abstr.

Australian Dental Journal 1988:33:1 33

Table 2. Factor Vlll C coagulant levels at pre- and post-infusion times using DDAVP Infusion of DDAVP Patient A (per cent) Patient B (per cent) Patient C (per cent) Patient D (per cent)

Pre DDAVP 54 30 rnin post DDAVP 170 24 h post DDAVP 64

45 146 90

22 95 47

58 100 68

Table 3. Typical profile of patient with mild von Willebrand disease Patient A

Normal value Pre-DDAVP

Activated partial thrornboplastin time 43.5 s (35.5 s) Factor VIII C 54% (50-200%) Factor VIII R:WF 39% (50-200%) Factor VIII R:Ag 25% (50-17070) 30 rnin post-DDAVP Activated partial thrornboplastin time

Factor VIII R:Ag 100%

Activated partial thrornboplastin time 44 s Factor VIII:C 64% Factor VIII R:WF 53% Factor VIII R:Ag 45%

35 s Factor VIII C 170% Factor VIII R:WF 142%

24 h post-DDAVP

Administration of DDAVP, (0.4 pg/kg) was given intravenously in 50 m L of saline over 15 minutes. Blood samples were assayed before DDAVP was given and 30 minutes and 24 hours post-infusion for the following factors: - Activated partial thromboplastin time - VIII R:WF - VIII c - VIII R:Ag

As the factor VIII C levels were only mildly depressed and there was a favourable response to the DDAVP, the patients were considered suitable for therapy using DDAVP with a systemic antifibrinolytic drug (EACA).

At a later date the patients were hospitalized for surgery under general anaesthesia. Two hours before operation each patient was given an intravenous infusion of DDAVP (0.4 pglkg body mass) in 50 mL of saline over 15 minutes. One hour pre-operatively, antifibrinolytic cover of 4 mg of EACA was given intravenously. Mucoperiosteal flaps were raised for the unerupted and impacted teeth, and bone removal was carried out with a bur. The surgical sites were closed with interrupted silk sutures. In the case of erupted teeth, absorbable gelatin sponge was also inserted into the sockets and catgut mattress sutures placed.

The three type I von Willebrand patients each had four wisdom teeth removed, while the Type IIA patient had an upper clearance of eleven teeth, with four being removed surgically. No untoward bleeding occurred and blood loss was less than 50 mL per patient. The patients continued post- operatively with oral EACA therapy for five days using 4 mg every 8 hours. The post-operative course was uncomplicated in each case and the black silk sutures were removed after one week.

The factor VIII C levels at pre- and post-infusion times following injection of DDAVP were measured and the results shown in Table 2. An example of a patient's typical coagulation profile is shown in Table 3.

Discussion Von Willebrand's disease is the most common

congenital bleeding disorder to affect man. In many cases it remains undiagnosed until an episode of prolonged post-traumatic or post-operative bleeding occurs. Once a diagnosis has been established tradi- tional management has been by factor VIII replacement, using factor VIII concentrate or cryoprecipitate.

In 1977 Mannucci and his colleagues" suggested an alternative pharmacological approach for milder

34 Australian Dental Journal 1988;33:1.

cases of the disease utilizing DDAVP and a synthetic antifibrinolytic drug. In light of recent reports of hepatitis and acquired immune deficiency syndrome (AIDS) associated with factor VIII replacement it is essential that full use is made of these pharmacological alternatives. Minor oral surgery, including dental extractions, in mildly affected von Willebrand patients is a particularly appropriate indication for this approach.

This report confirms that following intravenous infusion of DDAVP, VIII C plasma levels can rise sufficiently high in patients with mild or moderate von Willebrand disease to enable minor oral surgery to be carried out without the use of blood products (Table 2, 3). All the patients would normally have been expected to bleed but with DDAVP the average blood loss at operation was 50 mL. The quality of the clot formed and the rate of healing both appeared clinically within the limits expected of the normal patient.

The three- to four-fold rise in VII1:C levels observed after the administration of DDAVP intravenously has previously been reported." This rapid and large increase in VII1:C following DDAVP inhsion suggests endogenous release from storage sites rather than protein synthesis. In keeping with the concept of storage-site release, a reduced response to more DDAVP over a short period has been reported," and at least 48 hours must elapse between doses in order to reproduce the full response.

Consistent with observations made by Mannucci and it was observed in our cases that the response to DDAVP is apparently determined by baseline VIII C levels. This has led Mannucci and co-workersL8 to suggest that DDAVP is only useful in patients whose baseline level of VIII C exceeds 10 per cent. As can be seen from Table 3, the range of response is wide, but a particular patient is likely to respond similarly on different occasions.18 For this reason patients can be assessed before operation to determine suitability of treatment using DDAVP.

The therapeutic usefulness of DDAVP is limited in severe von Willebrand disease as there is an inadequate rise of VIII C after infusion. It should also be noted that DDAVP is contraindicated in the rare Type IIB form of the disease, which is charact- erized by an increase in platelet aggregation with ristocetin. When DDAVP is given to these patients there is platelet aggregation which may result in thrombo~ytopenia, '~ and the presence of platelet aggregates in the circulation may be harmful. These patients should be treated with cryoprecipitate. Thus the severity of the disease and the different-

iation of the variants of the disease (Table 1) are of considerable clinical importance.

Table 3 illustrates a typical profile of a patient with subclinical von Willebrand disease (patient A). The individually measured factors of activated partial thromboplastin time, factor VIII C, factor VIII R:WF, and factor VIII R:Ag, are raised within 30 minutes of infusion of DDAVP to an acceptable therapeutic level. However, after 24 hours all the factors had returned to almost pre-DDAVP levels. Repeat infusion of DDAVP within 48 hours will result in a diminished response, and should persistent bleeding occur within the first 48 hours after surgery other methods to control bleeding should be considered.

Both silk and catgut sutures were used in these patients, 310 black silk sutures being used where it was considered important to ensure surgical flaps remained repositioned long enough for adequate healing to minimize the chance of wound breakdown. Where simple extractions were carried out, 3/0 catgut sutures were placed and sometimes absorbable gelatin sponge was used to assist local haemostasis. Although each patient's coagulation levels had returned to pre-DDAVP levels after one week, the removal of the black silk sutures was uneventful. In these cases of von Willebrand disease, it seems the choice of silk or catgut can be left to the surgeon's preference.

Vasopressin (DDAVP) is frequently given for medical purposes by the nasal ('sniffing') route, but Mannucci and co-workers'8 showed the intravenous route is more efficient than nasal administration. Eastman and colleagueszo confirmed this, showing that patients with a basal factor VIII C level of 12 per cent or more revealed a higher maximal level of factor VIII C when DDAVP was given intra- venously.

It is suggested that a synthetic antifibrinolytic agent should be used in conjunction with the DDAVP therapy. The normal balance between clot formation and fibrinolysis is shifted towards clot dissolution as the patient's factor VIII C declines to basal levels. The antifibrinolytic agent (EACA) will stabilize the blood clot preventing premature breakdown of the clot. DDAVP has also been shown to independently increase blood levels of plasminogen activator which initiates the process of fibrinolysis.21.22 EACA is an antifibrinolytic agent which acts as a competitive inhibitor of the plasminogen activators and so prevents rapid clot dissolution and recurrent bleeding.

DDAVP and EACA in combination represent a successful therapeutic approach to bleeding in minor oral surgery in patients with mild von

Australian Dental Journal 1988;33:1 35

Willebrand disease; the protocol is unsuitable for severe cases of the disease. Since this treatment decreases the need for factor VIII replacement therapy, it reduces the risk from viral hepatitis, acquired immune deficiency syndrome, haemolytic anaemia and other blood-borne diseases and disorders. It is the method of choice in the management of suitable patients with mild von Willebrand disease undergoing minor oral surgery.

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Requests for reprints: D. J. Eggleston,

Oral Surgery Department, Perth Dental Hospital,

196 Goderich Street, East Perth, WA, 6001.

36 Australian Dental Journal 1988;33:1