Spontaneous acute subdural hematoma due to fondaparinux: Report of two cases
Karsten Fryburg1, Ha Son Nguyen2, Aaron A Cohen-Gadol2
1 St. Francis Hospital, Division of Neurological Surgery, Department of Neurological Surgery, Indiana University, Indianapolis, IN, USA
2 Goodman Campbell Brain and Spine, Department of Neurological Surgery, Indiana University, Indianapolis, IN, USA
|Date of Submission||17-Mar-2011|
|Date of Acceptance||22-Mar-2011|
|Date of Web Publication||19-Apr-2011|
Aaron A Cohen-Gadol
Goodman Campbell Brain and Spine, Department of Neurological Surgery, Indiana University, Indianapolis, IN
| Abstract|| |
Background : Spontaneous acute subdural hematomas (SDHs) are rare. Risk factors for development of these hematomas include conditions such as hypertension, vascular abnormalities such as aneurysm or arteriovenous malformation, or consumption of anticoagulants.
Case Description : Here, the authors report two patients who suffered from spontaneous acute SDH while taking fondaparinux for venous thromboembolism prophylaxis. One patient suffered from a remote episode of traumatic brain injury and underwent a decompressive craniectomy 3 weeks prior to presentation, whereas the other patient had been self-medicating with aspirin.
Conclusion : To our knowledge, these two patients illustrate the first cases of spontaneous acute SDH formation most likely attributed to consumption of fondaparinux.
Keywords: Acute subdural hematoma, decompressive craniectomy, fondaparinux, venous thromboembolism prophylaxis
|How to cite this article:|
Fryburg K, Nguyen HS, Cohen-Gadol AA. Spontaneous acute subdural hematoma due to fondaparinux: Report of two cases. Surg Neurol Int 2011;2:44
| Introduction|| |
Acute subdural hematomas (SDHs) are frequently due to injury to cerebral bridging veins secondary to head trauma. , Spontaneous acute SDH is rare. The reported incidences of spontaneous acute SDHs relative to total acute SDHs have ranged from 2 to 6.7%. ,,, Conditions associated with development of spontaneous acute SDH include hypertension,  aneurysms, , arterio-venous malformations,  and cocaine usage. ,, Pharmacologic therapy linked with the development of spontaneous acute SDH includes aspirin, , heparin,  and warfarin. ,,, Other reports of spontaneous acute SDH mention risk factors such as coagulopathies related to coagulation factor deficiencies ,, and immune thrombocytopenic purpura. 
Here, we report two patients who suffered from spontaneous acute SDH while taking fondaparinux for venous thromboembolism (VTE) prophylaxis. One patient suffered from a remote episode of traumatic brain injury and underwent decompressive craniectomy 3 weeks prior to presentation, whereas the other patient had been self-medicating with aspirin. A literature review will underscore these two cases, with a focus on the risk of fondaparinux for causing spontaneous intracranial hemorrhage during VTE prophylaxis.
| Case Reports|| |
A 33-year-old male suffered a severe traumatic brain injury after a motorcycle accident. He underwent evacuation of a left epidural hematoma and subsequently a decompressive craniectomy. He improved to a Glascow Coma Scale (GCS) 11 (E4M5V2) and was transferred to rehabilitation 3 weeks after the accident. During his rehabilitation, the patient was started on fondaparinux for VTE prophylaxis. Several days into the course of his rehabilitation, the patient developed a sudden decrease in his mental status without any trauma. An emergent head computed tomography (CT) showed a new acute SDH with a midline shift [[Figure 1]a, b] The patient was immediately taken to the operating room, a ventriculostomy catheter was placed, and the subgaleal and the subdural hematomas were evacuated [[Figure 1]c, d].The patient returned to his baseline neurologic status within days and continued his rehabilitation.
|Figure 1: Several days into the course of his rehabilitation, patient 1 developed a sudden decrease in his mental status without any trauma. An emergent head CT showed a new acute SDH with a midline shift (a and b). The patient was immediately taken to the operating room, a ventriculostomy catheter was placed, and the subgaleal and the subdural hematomas were evacuated (c and d)|
Click here to view
A 34-year-old Burmese male presented to the Emergency Room with intractable headaches. The patient had a history of polycythemia vera and had been recently started on fondaparinux for thromboembolism prophylaxis. On the day of admission, he also took aspirin to relieve his headaches. His neurologic examination was non-focal. A head CT showed a 2.2-cm left frontal acute SDH [[Figure 2]a]. He received platelet transfusion and underwent an urgent hematoma evacuation [[Figure 2]b]. His use of fondaparinux medication was not made known to us until the following day. On the follow-up CT scan [[Figure 2]c], he developed a recurrent subdural hemorrhage and required a repeat evacuation within 24 hours of the initial surgery. He received fresh frozen plasma and platelets preoperatively; intraoperative hemostasis was obtained using Gel foam powder and thrombin. He recovered gradually and was discharged neurologically intact after a short course of rehabilitation.
|Figure 2: For patient 2, on admission, a head CT showed a 2.2-cm left frontal acute SDH (a) He received platelet transfusion and underwent an urgent hematoma evacuation (b) His use of fondaparinux medication was not made known to us until the following day. A follow-up CT scan (c) showed that he had developed a recurrent subdural hemorrhage, and he required a repeat evacuation within 24 hours of the initial surgery|
Click here to view
| Discussion|| |
Spontaneous acute SDH is a rare but serious condition. Mortality rate has been reported to be between 60 and 76.5%. , Early surgical intervention is often imperative for hematomas with significant mass effect. The survival rate for surgery within 4 hours of acute onset compared to surgery after 4 hours is 50 to 0%, respectively.  Other favorable variables include a high GCS score upon admission, appropriate pupillary reactivity, and young age. 
The term "spontaneous acute SDH" has been used rather indiscriminately in the literature. Some authors , use the term strictly to refer to subdural hematomas caused by the rupture of a cortical vessel that does not involve a cerebral aneurysm, arterio-venous malformation, tumor, metastasis, or blood dyscrasias. Other authors ,,,,, have used the term based simply on the absence of a traumatic history. We prefer to use the term according to the latter definition. Head trauma was not an immediate factor in the development of SDH in either of the authors' patients. Patient 1 was recovering from a decompressive craniectomy that had occurred 3 weeks earlier. There was no history of any trauma for the second patient. Aggravating cofactors existing in these two patients included self-medication with a platelet inhibitor in the second patient. No cerebrovascular abnormality was observed in either case during surgery.
Both the patients experienced a spontaneous acute SDH after recently taking fondaparinux for VTE prophylaxis. There has been one report of an SDH resulting from a fall while a patient was taking fondaparinux.  Another report linked a large spontaneous retroperitoneal hematoma to this pharmacologic agent.  To our knowledge, our report presents the first instances of spontaneous acute SDH most likely attributed to fondaparinux. The second patient had also been taking aspirin, but the influence of this on the development of spontaneous hemorrhage cannot be fully assessed. However, the recent introduction of fondaparinux in this patient's drug regimen suggested that this drug was the trigger, either as an independent factor or in a combined mechanism with aspirin.
Fondaparinux acts as a selective AT-III dependent inhibitor of activated factor Xa.  The drug is approved by the Food and Drug Administration for VTE prophylaxis after hip fracture surgery, total hip replacement, total knee replacement, and major abdominal surgery.  Moreover, it is approved for the initial management of deep venous thrombosis (DVT) and pulmonary embolism.  However, the drug is contraindicated in patients with renal failure (creatinine clearance <30 ml/min), body weight <50 kg, active major bleeding, and bacterial endocarditis.
Although its safety has been shown in previous studies when compared to low-molecular-weight heparin (LMWH), a black box warning has been issued for its use near the neural axis, describing the potential for development of epidural hematomas. During the Phase III trials of fondaparinux, the patients who underwent surgical procedures involving brain and spine in the last 3 months were excluded from the study. There is no specific antidote available to counteract the effects of fondaparinux. However, in cases of severe bleeding, the anticoagulant effect can be reversed with fresh frozen plasma or recombinant factor VIIa.
The occurrences of spontaneous hematomas and the subsequent re-hemorrhage in our second patient echo the potential risks of major bleeding while taking medications for pharmacologic VTE prophylaxis. Unfortunately, no controlled trials have focused on VTE prophylaxis for the neurosurgical population. Established in 2004, the present guidelines for neurosurgical procedures were extrapolated from data for general surgery and orthopedic surgery; the recommendations embraced multimodal prophylaxis with mechanical methods, which could be enhanced by either LMWH or unfractionated heparin (UFH). , There are no guidelines for the use of fondaparinux in neurosurgery. Since that time, several articles , have emerged stressing the increased risk of intracranial hemorrhage for patients receiving LMWH prophylaxis compared with the patients receiving mechanical modalities. Surprisingly, a meta-analysis by Collen et al.  suggested that mechanical modalities (i.e., intermittent compression devices) may be as effective as heparin therapy in the neurosurgical population without the hemorrhagic risks. This is contrary to popular belief that pharmacologic therapy is considered superior for prevention of thromboembolism. 
The selectivity and long half-life of fondaparinux made the drug an appealing possibility for VTE prophylaxis.  A meta-analysis  of four multicenter, prospective, randomized controlled trials ,,, involving orthopedic procedures showed that fondaparinux had a lower incidence of VTE compared with enoxaparin, but had more episodes of bleeding leading to re-operation and/or bleeding with high index (a measure of blood transfusions required). No episodes of major intraspinal or intracranial bleeding occurred during these trials. However, the studies excluded patients with a hemorrhagic stroke within the previous 3 months; patients with a brain, spinal, or ophthalmologic surgery within the previous 3 months; patients whose surgery required an indwelling, intrathecal, or epidural catheter during the study; and patients with difficulty achieving epidural or spinal anesthesia.
| Conclusions|| |
Fondaparinux may be associated with an increased rate of intracranial hemorrhage. Its use for neurosurgical patients should be exercised with caution.
| References|| |
|1.||Abdulhamid MM, Li YM, Hall WA. Spontaneous acute subdural hematoma as the initial manifestation of chronic myeloid leukemia. J Neurooncol 2011;101:513-6. |
|2.||Agnelli G. Prevention of venous thromboembolism in surgical patients. Circulation 2004;110:IV4-12. |
|3.||Agrawal D, Mahapatra AK. Spontaneous subdural hematoma in a young adult with hemophilia. Neurol India 2003;51:114-5. |
|4.||Ahn ER, Lander G, Bidot CJ, Jy W, Ahn YS. Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy. Am J Hematol 2005;78:127-9. |
|5.||Alves OL, Gomes O. Cocaine-related acute subdural hematoma: an emergent cause of cerebrovascular accident. Acta Neurochir (Wien) 2000;142:819-21. |
|6.||Arienta C, Ceretti L, Caroli M, Villani R. Acute spontaneous subdural hematomas. J Neurosurg Sci 1986;30:197-204. |
|7.||Balak N, Silav G, Kilic Y, Timur C, Elmaci I. Successful surgical treatment of a hemophiliac infant with nontraumatic acute subdural hematoma. Surg Neurol 2007;68:537-40; discussion 540. |
|8.||Bauer KA. New anticoagulants. Curr Opin Hematol 2008;15:509-15. |
|9.||Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-10. |
|10.||Bordes J, Asencio Y, Kenane N, Fesselet J, Meaudre E, Goutorbe P. Recombinant activated factor VII for acute subdural haematoma in an elderly patient taking fondaparinux. Br J Anaesth 2008;101:575-6. |
|11.||Collen JF, Jackson JL, Shorr AF, Moores LK. Prevention of venous thromboembolism in neurosurgery. Chest 2008;134:237-49. |
|12.||Danish SF, Burnett MG, Ong JG, Sonnad SS, Maloney-Wilensky E, Stein SC. Prophylaxis for deep venous thrombosis in craniotomy patients: A decision analysis. Neurosurgery 2005;56:1286-92; discussion 1292-4. |
|13.||Depreitere B, Van Calenbergh F, van Loon J. A clinical comparison of non-traumatic acute subdural haematomas either related to coagulopathy or of arterial origin without coagulopathy. Acta Neurochir (Wien) 2003;145:541-6; discussion 546. |
|14.||Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345:1298-304. |
|15.||Fortina M, Carta S, Del Vecchio EO, Crainz E, Urgelli S, Ferrata P. Retroperitoneal hematoma due to spontaneous lumbar artery rupture during fondaparinux treatment. Case report and review of the literature. Acta Biomed 2007;78:46-50. |
|16.||Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al. Prevention of venous thromboembolism. Chest 2004;126:338S-400. |
|17.||Gilad R, Fatterpekar GM, Johnson DM, Patel AB. Migrating subdural hematoma without subarachnoid hemorrhage in the case of a patient with a ruptured aneurysm in the intrasellar anterior communicating artery. AJNR Am J Neuroradiol 2007;28:2014-6. |
|18.||Keller TM, Chappell ET. Spontaneous acute subdural hematoma precipitated by cocaine abuse: Case report. Surg Neurol 1997;47:12-4; discussion 14-5. |
|19.||Kocak A, Ates O, Durak A, Alkan A, Cayli S, Sarac K. Acute subdural hematomas caused by ruptured aneurysms: Experience from a single Turkish center. Turk Neurosurg 2009;19:333-7. |
|20.||Komatsu Y, Uemura K, Yasuda S, Shibata T, Kobayashi E, Maki Y, et al. Acute subdural hemorrhage of arterial origin: Report of three cases. No Shinkei Geka 1997;25:841-5. |
|21.||Lassen MR, Bauer KA, Eriksson BI, Turpie AG; European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomised double-blind comparison. Lancet 2002;359:1715-20. |
|22.||Missori P, Fenga L, Maraglino C, Rocchi G, Nardacci B, Calderaro G, et al. Spontaneous acute subdural hematomas. A clinical comparison with traumatic acute subdural hematomas. Acta Neurochir (Wien) 2000;142:697-701. |
|23.||Naama O, Belhachmi A, Ziadi T, Boulahroud O, Abad Elasri C, Elmostarchid B, et al. Acute spontaneous subdural hematoma: An unusual form of cerebrovacular accident. J Neurosurg Sci 2009;53:157-9. |
|24.||O'Brien DF, Basu S, O'Donnell JR, Roberts GA, Phillips J. The impact of aspirin therapy and anticoagulation on the prevalence of spontaneous subdural haematoma. Ir Med J 2000;93:244-6. |
|25.||Oikawa A, Aoki N, Sakai T. Arteriovenous malformation presenting as acute subdural haematoma. Neurol Res 1993;15:353-5. |
|26.||Pal D, Gnanalingham K, Peterson D. A case of spontaneous acute subdural haematoma in the posterior fossa following anticoagulation. Br J Neurosurg 2004;18:68-9. |
|27.||Saito K, Sakurai Y, Uenohara H, Seki K, Imaizumi S, Katakura R, et al. A case of acute subdural hematoma in the posterior fossa with idiopathic thrombocytopenic purpura. No To Shinkei 1992;44:377-81. |
|28.||Saleh T, Badshah A, Afzal K. Spontaneous acute subdural hematoma secondary to cocaine abuse. South Med J 2010;103:714-5. |
|29.||Scott M. Spontaneous nontraumatic subdural hematomas. J Am Med Assoc 1949;141:596-602. |
|30.||Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: A randomised double-blind trial. Lancet 2002;359:1721-6. |
|31.||Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs Enoxaparin for the Prevention of Venous Thromboembolism in Major Orthopedic Surgery: A meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833-40. |
|32.||Veshchev I, Elran H, Salame K. Recombinant coagulation factor VIIa for rapid preoperative correction of warfarin-related coagulopathy in patients with acute subdural hematoma. Med Sci Monit 2002;8:CS98-100. |
|33.||Vural M, Yarar C, Durmaz R, Atasoy MA. Spontaneous acute subdural hematoma and chronic epidural hematoma in a child with F XIII deficiency. J Emerg Med 2010;38:25-9. |
|34.||Westermaier T, Eriskat J, Kunze E, Gunthner-Lengsfeld T, Vince GH, Roosen K. Clinical features, treatment, and prognosis of patients with acute subdural hematomas presenting in critical condition. Neurosurgery 2007;61:482-7; discussion 487-8. |
|35.||Yagi T, Suzuki T, Nagata Y, Naruse H, Nakagawa O. The cases of acute spontaneous subdural hematoma. No Shinkei Geka 1996;24:665-9. |
[Figure 1], [Figure 2]