Hydroxyethyl starch (HES) is a synthetic polysaccharide colloid, which is relatively cheap, free from hepatitis contamination and has oncotic advantages over electrolyte solutions widely used for plasma volume expansion. HES has been approved for adjunctive use for increasing granulocyte yields during centrifugation leukophoresis [1-3]. When used in moderate amounts in human and animals, HES produces relatively minor changes in coagulation tests, and bleeding rarely occurs . The exact mechanism of these changes is unclear, but it has been ascribed, at least in part, to haemodilution . However, questions arise regarding the interaction of HES with blood coagulation factors, as interactions in excess of simple haemodilution have been established for other polysaccharide colloids (e.g. dextran) [6,7]. In addition, abnormalities in platelet function, alterations in coagulation factor levels and fibrin clot formation have been related to significant bleeding in animals receiving very large volumes of HES (more than 25% of blood volume) . Therefore, to determine the effects of HES on the coagulation system, we have studied coagulation parameters over a time span of 1 h after its infusion.
Materials and methods
Twenty patients (12 men and eight women), aged 22-30 years, scheduled for elective abdominal surgery were included in the study. Operation under general anaesthesia with propofol has been shown to have no effect on platelet function . Criteria for the selection of those to be tested were: no history of hypersensitivity to any substance; no alcohol, no drug or substance abuse and no type of bleeding disorder; no known anticoagulant medication; perioperative blood loss expected to be slight (less than 100 mL); normal physical findings. Informed and written consent was obtained from the patients in accordance with the institution's guidelines. If the screening coagulation tests were within normal limits, the subject was entered into the study. All patients received 500 mL of 6% HES by preoperative infusion over 1 h. The blood samples were collected immediately before and after the HES infusion before the operation. Blood platelet counts were determined by standard laboratory technique using an Abbott Cell-Dyn 1600 cell counter device (Abbott Park, IL, USA). Prothrombin time and fibrinogen levels were assessed using a commercial kit (Diagnostica Stago, Asnieres-Sur-Seine, France; Coag-a-mate, Organon-Technica, NM, USA). Activated partial thromboplastin time was determined using the recalcification of plasma in the presence of a standardized amount of cephalin (platelet substitute) and a factor XII activator (kaolin) (Diagnostica Stago). Factor VIII activities were determined according to the Sigma Diagnostics procedure no. F8D (St Louis, MO, USA). Platelet aggregation induced by adenosine diphosphate (ADP) (20 mmol of collagen) (0.2 mg mL−1) and two different concentrations of ristocetin (1.2 mg mL−1 and 0.5 mg mL−1) were performed at 37°C using a Lumi-Dual Aggro-Meter (Crono-log Corporation, Havertown, PA, USA) according to the protocol of Sigma Diagnostics, procedure no. 885. The results are expressed as mean values±standard error. Significance was assessed using a paired Student's t-test. A value of P<0.05 was considered significant.
The results of the coagulation tests are shown in Table 1. There was no (P> 0.05) change in platelet count, and prothrombin time after the infusion of HES remained within the normal range. A decrease in fibrinogen concentration was noted after the infusion of HES (P<0.001). Partial thromboplastin time after the infusion of HES increased from a mean value of 36.5±0.731 to 42.05±0.913 s (P<0.001) in association with a decrease in factor VIII activity from 102.4±0.98 to 99.85±0.88% (P<0.01). The mean maximum platelet aggregations induced by all aggregating agents were decreased significantly.
The effect of HES on haemostasis has always been studied in terms of leukophoresis, traumatic shock and volume replacement [5,9,10]. Its effects on blood coagulation are important for donors undergoing leukaphoresis, for injured patients who may be at risk of bleeding as a result of trauma, surgery, dilution of clotting factors during plasma volume replacement and for surgical patients who need prophylaxis for deep vein thrombosis and exposure to drugs with adverse haemostatic effects [11-13]. Dextran is known to affect blood coagulation  and, because dextran and HES share some common chemical similarities, we undertook this study.
The results of this study demonstrate that hydroxyethyl starch has some effects on blood coagulation parameters. No significant effect of HES infusion was observed on platelet count, confirming the observations of others [4,5,7]. Decreases were expected in some instances because HES infusions have been associated with plateletphoresis . Despite some decrease, the platelet counts remained above the levels required for normal haemostasis. Slight alterations in clotting proteins were detected after moderate HES infusion [4,5,13]. In our study, after the infusion of HES, fibrinogen concentration decreased significantly from the preinfusion baseline value; a fall expected as a consequence of plasma volume expansion. Even when decreased, clotting factors were present in sufficient amounts to ensure effective haemostasis, and these usually returned to preinfusion levels within a few hours. The concentration of FVIII:C were decreased slightly but significantly after combined platelet and leukaphoresis using HES . Other studies have shown either no change or increased levels of FVIII:C after a 60- to 120-g infusion of HES . Our results demonstrate a significant decrease in factor VIII activities with prolongation of PTT. The mechanisms involved remain undefined. The effects of HES on factor VIII appeared to be independent of haemodilution. In contrast with fibrinogen and antithrombin III, factor VIII activities remained decreased, despite correction for plasma volume expansion [5,12]. Furthermore, the effects could not be correlated directly with plasma HES levels. Strauss et al. reported a case of mild von Willebrand's disease, which became severe after HES infusion.
No significant difference was noted in prothrombin time after the infusion of HES. This is in agreement with the small effect of HES on vitamin K-dependent coagulation properties. Attempts, to prevent deep venous thrombosis, which remains a serious cause of post-operative morbidity and mortality, have used many approaches including therapeutic intervention with heparin, acetylsalicylic acid and dextran [15-17].
Primary haemostasis (platelet aggregation activity) plays an important role in the initiation of thrombus formation. Our findings of the inhibition of platelet aggregation may explain one facet of the thromboprophylactic effect of HES. The inhibition of platelet function by HES may play a role in reducing the incidence of venous thromboembolic complications in patients undergoing major hip surgery (M. Schwarz, personal communications, 1985).
It may be, however, that the inhibition of platelet aggregation could (in some circumstances) increase the risk of intra- or post-operative haemorrhage. This may be more likely in patients who have an increased risk of haemorrhage because of pre-existing platelet dysfunction. HES has an excellent safety record when infused into healthy subjects during centrifugation leukophoresis or in patients requiring fluid resuscitation, usually at a dose of 500 mL of HES 6% solution.
The effects of HES that have been described do not accurately predict the risk of clinical bleeding, nor do they guarantee therapeutic anticoagulant effects. Bleeding has not been a problem when HES is used in recommended doses, or even when administered in fairly large volumes, as described in one study . None of the subjects in the present study had abnormal bleeding. However, caution should be taken when using larger doses of HES, particularly for patients requiring either massive fluid resuscitation or repeated therapeutic leukophoresis, until the haemostatic effects of large doses are completely defined. HES could increase the risk of bleeding in surgical patients who have underlying coagulation abnormalities resulting from either the effect of injury or treatment with drugs that adversely affect haemostasis.
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