Development of Spontaneous Subdural Hematoma and Bone Marrow Depression after Hydroxyethyl Starch Administration DANIEL CHAPPELL, MD,* WALTRAUD BRUCHELT, MD,* WILFRIED SCHENK, MD, MATTHIAS JACOB, MD, KLAUS HOFMANN-KIEFER, MD, PETER CONZEN, MD, UWE KREIMEIER, MD, AND MARKUS REHM, MD lthough hydroxyethyl starch (HES) solutions are known to interfere with hemostasis, the various available HES preparations are frequently used in clinical practice for volume therapy and to improve blood rheology.1 We report a serious hemostatic disturbance in a 17-month-old toddler after the infusion of 6% HES 450/0.72 over 10 days, resulting in cutaneous bleeding and subdural hematoma necessitating surgical intervention. In addition, severe pruritis occurred, and histiocytes with hydroxyethyl starch–associated vacuoles were found in aspirated bone marrow, combined with severe hyporegenerative anemia and thrombopenia. A CASE REPORT A 17-month-old, previously healthy boy (89 cm, 12.1 kg) was treated with intravenous cefotaxime and dexamethasone for pneumococcal meningitis. At the end of therapy, acute deafness occurred and was treated according to the Stennert-scheme (dextran 40, cortisone, and pentoxifylline),2 but modified to 6% HES 450 kDa/0.72 (Plasmasteril; Fresenius, Bad Homburg, Germany) instead of dextran to benefit from the prolonged drug effect. The cumulative amount of HES administered over 10 days was 2500 mL (1.2 g/kg/d). Two days after completion of therapy, several hematomas appeared on the boy’s head, back, and lower extremities. Results of laboratory tests performed on day 2 after HES administration showed profound anemia, which was treated by red blood cell transfusion. Results of coagulation tests were severely abnormal (Table). Three days after the last HES administration, the patient became somnolent and had development of anisocoria. A magnetic resonance imaging scan showed a subacute, right-sided subdural hematoma (⬎2.5 cm, temporoparietal, Figure 1), which was immediately evacuated. Repeated bleeding was detected in a postoperative scan, necessitating revision surgery on the same night. Despite perioperative substitution of red blood cells, platelet concentrate, and fresh frozen plasma, the coagulation disturbance persisted (Table). The observed factor VIII deficiency was treated for 24 days after surgery with a continuous infusion of up to 15 IU/kg/h of factor VIII:C and von Willebrand factor (vWF):RCoF (Haemate; CLS Bering, Marburg, Germany) until laboratory measures of factor VIII activity normalized. Development of unexplained hepatosplenomegaly, hyporegenerative anemia, and thrombocytopenia led to bone marrow aspiration. This showed no evidence of malignancy, although numerous storage cells with vacuoles, a maturation-arrest of granulopoiesis, an increased number of megakaryocytes, and a dysplastic erythropoiesis were present (Figure 2; available at www.jpeds.com). Highly elevated HES concentrations were measured in From the Clinic of Anesthesiology, LudwigMaximilians University Munich (D.C., W.B., the plasma throughout treatment. HES was detectable in the boy’s plasma 6 months after M.J., K.H., P.C., U.K., M.R.), Munich, and the treatment (Table), indicating highly prolonged accumulation. Severe pruritis, a characDepartment of Pediatrics, Central Clinic of 3 teristic side effect of HES, occurred 25 days after the last HES application and was Augsburg (W.S.), Augsburg, Germany. *Drs. Chappell and Bruchelt contributed successfully treated with intravenously and topically applied diphenhydramine. There equally to this work. were no signs of impaired renal function. The boy was discharged in good general This study was performed using departcondition. Labyrinthine deafness persisted, but there were no other neurologic deficits. mental money from the Ludwig-Maximil- DISCUSSION Serious hemostatic complications and bone marrow depression developed in a 17-month-old boy after a 10-day infusion of 6% HES 450/0.72 administered at recommended doses. Our findings of severe factor VIII deficiency, decreased activity of vWF: RiCO (ristocetin cofactor) after HES administration, and the fact that bleeding persisted until the specific therapy with factor VIII/vWF concentrate (Haemate) was initiated HES vWF Hydroxyethyl starch Von Willebrand factor vWS Von Willebrand syndrome ians University of Munich, Germany. Submitted for publication Feb 5, 2008; last revision received Mar 27, 2008; accepted Apr 30, 2008. Reprint requests: Dr. Daniel Chappell, Clinic of Anesthesiology, Ludwig-Maximilians University Munich, Nussbaumstrasse 20, 80336 Munich, Germany. E-mail: daniel. chappell@med.uni-muenchen.de. J Pediatr 2008;153:579-81 0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.04.073 579 Table. Laboratory parameters Days after administration of HES White blood cells [⫻109/L] Red blood cells [⫻1012/L] Hematocrit [%] HES [g/dL] Quick [%] PTT [sec] Factor VIII:C [%] Factor IX [%] Factor XI [%] vWF:RiCO [%] Bleeding time [sec] Platelets [⫻109/L] Hemoglobin [g/dL] Reticulocytes [%] Fibrinogen [mg/dL] ATIII [%] D-Dimer [ng/mL] Admission 2 3 7.8 4.35 36 109 32 41 90 47 79 322 8.1 5.9 60 4 10 18 27 68 6.1 3.45 28 2.16 66 136 38 49 34 26 ⬎300 174 9.7 0 108 61 819 8.6 2.44 22 8.8 3.24 26 72 46 54 80 40 67 106 196 128 112 169 119 6.9 3.66 33 1.83 95 38 85 86 71 110 176 93 6.1 2.57 165 83 430 6.8 3.89 36 0.74 92 36 97 102 82 102 155 341 10.3 4.75 210 97 322 186 0.29 Normal values 6-15 3.7-5.3 35-43 0 70-100 20-38 70-200 70-110 70-120 50-150 ⬍180 150-350 10.7-13.1 1-13 150-350 80-120 ⬍500 PTT, Partial thromboplastin time; vWF:RiCO, von Willebrand ristocetin cofactor; ATIII, antithrombin III. Admission day was before starting the HES application. On day 2 after HES administration, a cutaneous hematoma occurred. In the evening of day 3, anisocoria was noticed and MRT scanning revealed subdural bleeding, which resulted in emergency craniotomy. Laboratory measurements on day 4 were obtained after revision surgery, during which transfusion of platelets, red blood cells, and fresh frozen plasma was performed. Haemate therapy was started on day 4 and discontinued on day 28. Figure 1. Magnetic resonance imaging scan of the head demonstrates a subacute, right-sided subdural temporoparietal hematoma (⬎2.5 cm). strongly suggests a HES-associated von Willebrand-like syndrome as the underlying reason for development of subdural hematoma and cutaneous bleeding. HES exerts pleiotropic effects on coagulation, including reductions in factors, decreased number and function of platelets, and increased fibrinolysis.4 Various HES solutions spe580 Chappell et al cifically impair fibrinogen/fibrin polymerization.5 In addition, HES solutions impair platelet reactivity by reducing the availability of the platelet fibrinogen receptor glycoprotein IIb/IIIa and by decreasing platelet-linking properties of vWF.1,6,7 It has been reported before that the decline of vWF after HES infusion is greater than can be explained by simple hemodilution and a decrease of coagulation factor VIII and vWF by up to 80% in healthy volunteers6 and in patients,7 even when used below the recommended daily amounts.6 At admission our patient showed normal routine coagulation test results, especially activated partial thromboplastin time results within the normal range (Table), and specific laboratory workup after recovery excluded possibly unknown von Willebrand syndrome (vWS) Type 1, which would have been aggravated by the administration of HES. Because meningitis was the underlying cause, the observed bleeding could also have been provoked by an infection-associated acquired vWS. Acquired vWS is a rare bleeding disorder and describes a very complex syndrome usually occurring in patients with myeloproliferative and cardiocirculatory disease and mostly classified as von Willebrand disease type IIa.8 The ultimate diagnosis is made by the lack of multimers of the vWF because frequently vWF:Ag and sometimes also vWF:RiCo can be reduced or even normal.9 In our patient, bleeding occurred in the late course of meningitis during appropriate therapy, thus an underlying infection-related acquired vWS seems very unlikely. The indication for the HES infusion reported on here was acute deafness occurring after pneumococcal meningitis. The Stennert scheme has proved to be safe and effective2 but The Journal of Pediatrics • October 2008 in this case was modified from dextran 40% to 6% HES 450/0.72. This high molecular colloid with a high substitution degree was administered in expectation of greater and longer enduring plasma persistence. However, the daily amount of 1.2 g/kg corresponded to the recommended daily maximum dose. Dextran is rarely used because of its pronounced effects on hemostasis and considerable high incidence of anaphylactic reactions.10 HES is well known to persist in a minimal remaining quantity for several months11 and is by no means restricted to high molecular–weight colloids. Serum concentrations were measured by the hexokinase method as previously described.12 However, serum concentrations of HES detected here were higher than measured after an acute normovolemic hemodilution performed before surgery in young children by applying 1469 ⫾ 246 mL of HES 200/0.5:2.16 versus 1.95 ⫾ 0.5 g/dL.13 Elimination of HES is known to be impaired with increasing molecular weight, grade of substitution, C2/C6 ratio, and concentration and it can, therefore, accumulate.14 Repeated application of HES has been shown to impede macromolecule elimination, causing an accumulation of molecules and leading to an increase of the serum concentration.15 This evidently occurred, because much higher HES concentrations were measured in the patient’s plasma than previously reported.14 Even after 6 months significant HES values were still detectable in plasma. Accumulation of HES is believed to increase complex formation and clearance of factor VIII and vWF.16 After infusion of HES, previous studies have shown vacuolation in perivascular histiocytes of the skin and in other mononuclear cells17 and a nearby accumulation of radioactively labeled HES. However, this is the first report of vacuolation in the bone marrow in combination with prolonged accumulation of HES in blood plasma, severe hyporegenerative anemia, and thrombocytopenia. HES tissue deposition has been shown to lead to major organ dysfunction, for example, in the liver.18 The HES storage in the bone marrow might have caused myelosuppression; however, platelets were not reduced to levels associated with spontaneous bleeding, platelet function was not assessed, and FVIII/vWF synthesis is not related to the bone marrow. Our case report shows several severe hemostatic complications after infusion of high molecular–weight hydroxyethyl starch. 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Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorrheology, coagulation and elimination kinetics. Thromb Haemost 1995;74:1452-6. 16. Jonville-Bera AP, Utret-Leca E, Gruel Y. Acquired type I von Willebrand’s disease associated with highly substituted hydroxyethyl starch. N Engl J Med 2001; 345:622-3. 17. Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related. Br J Anaesth 1999; 82:510-15. 18. Christidis C, Mal F, Ramos J, Senejoux A, Callard P, Navarro R, et al. Worsening of hepatic dysfunction as a consequence of repeated hydroxyethylstarch infusions. J Hepatol 2001;35:726-32. Development of Spontaneous Subdural Hematoma and Bone Marrow Depression after Hydroxyethyl Starch Administration 581 Figure 2. Bone marrow smear reveals numerous storage cells with vacuoles, a maturation-arrest of granulopoiesis, an increased number of megakaryocytes, and dysplastic erythropoiesis. 581.e1 Chappell et al The Journal of Pediatrics • October 2008