Correspondence

Acquired Type I von Willebrand's Disease Associated with Highly Substituted Hydroxyethyl Starch

N Engl J Med 2001; 345:622-623August 23, 2001

Article

To the Editor:

High-molecular-weight hydroxyethyl starches (hetastarches) can cause acquired type I von Willebrand's disease.1 A case has also occurred after treatment with medium-molecular-weight hydroxyethyl starches (pentastarches).2 We analyzed all patients with hemostatic disorders that occurred during treatment with pentastarch (Elohes and Hesteril, Fresenius, Paris; and Lomol, Dupont, Wilmington, Del.) and that were spontaneously reported to the 31 French regional drug-monitoring centers.

Nine cases of hemostatic disorders were reported between 1990 and 1997 (Table 1Table 1Characteristics of Patients with a Hemostatic Disorder.). All patients were treated with Elohes as hemodilution therapy (for vasospasm secondary to subarachnoid hemorrhage).

Of the nine patients, six had a diagnosis of acquired type I von Willebrand's disease. Before the abnormalities in coagulation were discovered, patients had received a mean dose of 121±52 ml of pentastarch per kilogram of body weight. The cumulative dose was higher in the three patients (Patients 1, 5, and 6) with hemorrhage (mean, 144 ml per kilogram) than in those without bleeding (mean, 87.5 ml per kilogram). Five patients received concentrates of von Willebrand factor (Patients 2, 3, 4, and 5) or desmopressin (Patient 6). The abnormalities resolved each time treatment with pentastarch was stopped. Of the nine patients with a hemostatic abnormality, four had cerebral hemorrhage (Patients 3, 4, 5, and 6), three of whom died (Patients 4, 5, and 6).

In three patients, the only reported abnormality was a prolonged activated partial-thromboplastin time (Patients 7, 8, and 9). In Patient 8, an extradural hematoma developed three days after pentastarch was withdrawn, even though the activated partial-thromboplastin time returned to normal. Acquired type I von Willebrand's disease was suspected in these three patients but not proved, since factor VIIIc and von Willebrand factor antigen levels were not measured.

In these patients, pentastarch probably induced acquired type I von Willebrand's disease, because blood-coagulation results were normal before treatment with pentastarch was initiated, and all abnormalities disappeared in patients who survived after pentastarch was withdrawn.

Accumulation of starch probably led to quantitative defects of the complex of factor VIII and von Willebrand factor by accelerated elimination from the circulation of complexes attached to starch molecules.3 Because Elohes is highly substituted and has a higher C2/C6 ratio, it is difficult to break down and therefore is eliminated more slowly and has a longer-lasting effect on plasma volume than other pentastarches. The accumulation of Elohes after repeated administration can explain why its adverse effects on coagulation resemble those of hetastarch.4 However, pentastarches other than Elohes affect the coagulation system much less, because their effect on plasma volume is transient.5

As a result of this study, the following guidelines for the use of Elohes were defined in France. The infusion should be limited to 33 ml per kilogram per day, and the cumulative dose to 80 ml per kilogram. Treatment should be given for no more than three days. Elohes is contraindicated in patients with coagulation disorders. Patients should be monitored with blood tests (activated partial-thromboplastin time and, if necessary, factor VIIIc and von Willebrand factor levels).

Annie-Pierre Jonville-Béra, M.D.
Elisabeth Autret-Leca, M.D.
Yves Gruel, M.D.
University Hospital of Tours, 37044 Tours, France
jonville-bera@chu-tours.fr

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