A 64-year-old female receiving clopidogrel and aspirin antiaggregation therapy after percutaneous coronary intervention for non-STEMI myocardial infarction developed nontraumatic bilateral subdural hematoma with dizziness, vertigo and headache. Craniotomy had to be postponed because of reduced ADP platelet aggregability. Four days after clopidogrel withdrawal and transfusion of 12 platelet concentrate units, ADP aggregation transiently normalized and bilateral trepanation with hematoma evacuation was performed. The procedure was followed by excellent neurologic and clinical recovery; however, decreased platelet aggregability was recorded by postoperative day 12 despite strict clopidogrel and other platelet inhibitor withdrawal. Suspicion of Glanzmann thrombastenia was excluded by flow cytometry. Two weeks after neurosurgery, the right femoral vein thrombosis was detected by color doppler ultrasonography and therapy with fractionated heparin was initiated, followed by warfarin. The risk and incidence of hemorrhagic complications of antiaggregation and anticoagulation therapy are discussed. Caution is warranted on prescribing this potentially harmful therapy to older patients, generally burdened with other chronic comorbidities.U 64-godišnje bolesnice koja je zbog ne-STEMI srčanog infarkta dobivala aspirin i klopidogrel razvio se netraumatski obostrani subduralni hematom praćen smušenošću, vrtoglavicom i glavoboljom. Kod prijma je utvrđena smanjena agregacija trombocita u ADP testu pa je kraniotomija i dekompresija odgođena za 4 dana. Četiri dana nakon prestanka uzimanja klopidogrela i aspirina te uz transfuziju od 12 doza trombocita prolazno se normalizirala agregabilnost trombocita pa je učinjena obostrana trepanacija i uklonjeni su hematomi. Slijedio je odličan neurološki oporavak. Smanjena agregabilnost trombocita bila je prisutna do 12. poslijeoperacijskog dana. Sumnja na Glanzmannovu trombasteniju isključena je protočnom citometrijom. Četrnaestoga poslijeoperacijskog dana nastala je tromboza desne femoralne vene koja je liječena smanjenim dozama heparina i varfarina. Uz prikaz bolesnice analizira se rizik od krvarenja i tromboze u bolesnika koji uzimaju antitrombocitne lijekove. Preporuča se oprez u starijih bolesnika kod kojih su prisutne i druge teške bolesti, što povećava rizik od krvarenja

Antonija Vuk

Goran Rinčić

Ljiljana Grbac

Mario Ledinsky

Nevenka Stančić

Vladimir Stančić

English

Hrčak - Portal of scientific journals of Croatia

Acta Clin Croat,  Vol. 48,  No. 3,  2009 163Acta Clin Croat 2010; 49:163-168 Case ReportNONTRAUMATIC BILATERAL SUBDURAL HEMATOMA CAUSED BY ANTIAGGREGATION THERAPY: CASE REPORT AND REVIEW OF THE LITERATUREAntonija Vuk1, Vladimir Stančić1, Goran Rinčić1, Mario Ledinsky2, Ljiljana Grbac3, and Nevenka Stančić41Department of Hematology, University Department of Medicine, 2University Department of Surgery, Sestre milosrdnice University Hospital, Zagreb; 3Department of Pediatrics, Požega General Hospital, Požega, Croatia; 4Nursing College, Sestre milosrdnice University Hospital, Zagreb, Croatia   SUMMARY – A 64-year-old female receiving clopidogrel and aspirin antiaggregation therapy after percutaneous coronary intervention for non-STEMI myocardial infarction developed nontrau-matic bilateral subdural hematoma with dizziness, vertigo and headache. Craniotomy had to be po-stponed because of reduced ADP platelet aggregability. Four days after clopidogrel withdrawal and transfusion of 12 platelet concentrate units, ADP aggregation transiently normalized and bilateral trepanation with hematoma evacuation was performed. Th e procedure was followed by excellent neurologic and clinical recovery; however, decreased platelet aggregability was recorded by postope-rative day 12 despite strict clopidogrel and other platelet inhibitor withdrawal. Suspicion of Glanz-mann thrombastenia was excluded by fl ow cytometry. Two weeks after neurosurgery, the right fe-moral vein thrombosis was detected by color doppler ultrasonography and therapy with fractionated heparin was initiated, followed by warfarin. Th e risk and incidence of hemorrhagic complications of antiaggregation and anticoagulation therapy are discussed. Caution is warranted on prescribing this potentially harmful therapy to older patients, generally burdened with other chronic comorbidities.  Key words: Key words: Hematoma, subdural – diagnosis; Hematoma, subdural – etiology; Hematoma, subdural – therapy; Anticoagulants – therapeutic use; Disease progression; Aged; Case reportCorrespondence to: Vladimir Stančić, MD, PhD, Department of Hematology, University Department of Medicine, Sestre milo-srdnice University Hospital, Vinogradska c. 29, HR-10000 Za-greb, CroatiaE-mail: vladimir.stancic@zg.htnet.hrReceived December 23, 2009, accepted March 16, 2010Introduction Nontraumatic chronic subdural hematoma is a fre-quent clinical entity in daily neurosurgical routine. It usually occurs in elderly people with a peak incidence in the eighth decade of life1. Studies have identifi ed age, sex, falls, and anticoagulant or antithrombotic therapy as the major risk factors for the development of chronic subdural hematoma. Th e higher incidence of chronic subdural hematoma in those older than 65 is associated with fragility of the bridging cerebral veins due to brain atrophy, a higher tendency to falls, and more common use of anticoagulant (warfarin) and antithrombotic (aspirin and clopidogrel) therapy. In addition, brain movements facilitate arachnoid membrane tearing even with trivial trauma. Th e male predominance is also associated with greater exposure to injuries. Previous trauma in combination with anti-coagulant or antithrombotic therapy may also increase the risk of chronic subdural hematoma. Review ar-ticles report on a varying proportion of patients with chronic subdural hematoma, describing it as a condi-tion accompanying arterial aneurysm rupture, lumbar puncture, anticoagulant therapy, acquired coagulopa-thy and thrombocytopenia1-5.    Antonija Vuk et al. Nontraumatic bilateral subdural hematoma caused by antiaggregation therapy: ...164 Acta Clin Croat,  Vol. 49,  No. 2,  2010Case ReportA 64-year-old female patient was admitted for weakness, mental confusion, orthostatic instability, and urinary incontinence. Th e patient denied previ-ous injuries and bleeding episodes. Her mother died from cerebrovascular thrombosis and her father from myocardial infarction. Her personal medical history included long-term hypertension, type 2 diabetes, and hyperlipoproteinemia. Two years before, she had undergone percutaneous angioplasty for anterolateral (non-STEMI) myocardial infarction, upon which ischemic pain resolved and she was discharged from the hospital on dual antiaggregation therapy with aspirin and clopidogrel. In two months, however, the patient experienced recurrent episodes of ischemic chest pain; repeat coronarography revealed 60%-70% stenosis of a distal segment of the left coronary artery, 70% steno-sis of the left anterior descending artery (LAD), and 90% stenosis of the proximal D1 segment, which was managed by endoprosthesis placement. In addition, there was subocclusion of a proximal segment of the hypoplastic circumfl exed coronary artery, which had formed collaterals to the right coronary artery. Dual antiaggregation therapy (aspirin and clopidogrel) was continued and unfortunately complicated by bleeding duodenal ulcer four months later. After short therapy discontinuation, clopidogrel therapy was reintroduced because coronary disease was considered to pose greater risk than gastroduodenal bleeding.Ten months later, the patient presented with bi-lateral subdural hematoma (Fig. 1). Neurosurgical treatment was indicated but evacuation of the hema-toma had to be postponed due to reduced (13%) ADP pathway platelet aggregation. Other biochemical pa-rameters were normal (Table 1). Four days of clopi-dogrel withdrawal and platelet transfusion, the ADP-induced platelet aggregation normalized (78%) (Table Fig. 1. Computed tomography image of bilateral subdural hematoma.Table 1. Blood parameters at admissionParameter                                                                                Measured value            Unit              Reference valuePlatelet aggregation response to ADP Platelet aggregation response to epinephrinePlatelet aggregation response to collagenRed blood cells (female)Hemoglobin (female)White blood count (female)PlateletsProthrombin timeFibrinogenActivated partial thromboplastin timeTh rombin timeFibrinolysis1367674.51226.6227975.92619210%%%x106/μLg/dLx103/mm3x103/mm3%g/Lsecsecmin64-8659-9359-933.8 - 5.1   11-163.8-11150-35070-130ADP = adenosine diphosphateActa Clin Croat,  Vol. 49,  No. 2,  2010 165Antonija Vuk et al. Nontraumatic bilateral subdural hematoma caused by antiaggregation therapy: ...2). Bilateral trepanation and hematoma evacuation were performed and resulted in excellent neurologic recovery. Th e patient was discharged from the hospi-tal; however, on postoperative day 14 she was readmit-ted for the left iliofemoral vein thrombosis diagnosed by doppler ultrasound. Th e previous hypocoagulation condition caused by antiaggregation therapy had now turned to a thrombophilic (hypercoagulation) condi-tion due to recent brain surgery (thromboplastin re-lease), bed rest (retarded venous fl ow), and urinary infection (infl ammatory cytokines, fi brinogen). Th e patient was administered heparin, followed by war-farin in a slightly reduced dosage because of bleed-ing episodes in her recent medical history, with good clinical response. Aggregation tests were repeated to show reduced platelet aggregability in spite of taking no antiaggregation therapy (Table 3). Th is fi nding raised suspicion of underlying yet undiagnosed Glan-zmann thrombasthenia; however, fl ow cytometry was negative for CD42 (GPIIb) and CD61(GPIIIb) (Ta-ble 1). DiscussionTh e majority of patients with chronic subdural hematoma are men older than 65, with a history of head trauma, or taking anticoagulant and/or anti-aggregation therapy. Older age is associated with a higher likelihood of brain atrophy and bridging vein fragility, the risk of falls and frequent use of antico-agulant and antiaggregation therapy. Th e incidence of chronic subdural hematoma has been estimated to 5.3 per 100,000 surgically treated individuals. Previous head trauma is reported in 60%-80% of cases; howev-er, mild traumatic events may proceed unrecognized, leading to an increased proportion of allegedly ‘spon-taneous’ cases of chronic subdural hematoma6. Diagnostic procedure for chronic subdural hema-toma has been well established and includes neuroim-aging techniques of multi-slice computed tomography (MSCT) and magnetic resonance imaging (MRI)2,7. Density of blood coagulum varies with the age of he-matoma; therefore, after three weeks, a chronic hema-Table 2. Blood tests on day 4 of treatmentParameterMeasured valueUnitReference valuePlatelet aggregation response to ADP Platelet aggregation response to epinephrinePlatelet aggregation response to collagen787176%%%64-8659-9359-93ADP = adenosine diphosphate Table 3. Blood tests on day 15 of trephinationParameterPlatelet aggregation response to ADP Platelet aggregation response to epinephrinePlatelet aggregation response to collagenProthrombin timeFibrinogenActivated partial thromboplastin timePFA 100 collagen/epinephrinevon Willebrand's factor Measured value Unit Reference value565549955.026112>149.70%%%%g/Lsecsec64-8659-9359-9370-13082-150ADP= adenosine diphosphate; PFA = Dade Behring PFA-100 platelet function analyzer; it  also measures ex vivo platelet binding to collagen/epinephrine (CEPI) or collagen/adenosine diphosphate (CADP)Antonija Vuk et al. Nontraumatic bilateral subdural hematoma caused by antiaggregation therapy: ...166 Acta Clin Croat,  Vol. 49,  No. 2,  2010toma visualized by an imaging technique will appear as a hypodense area. Th e most common symptoms of chronic subdural hematoma are gait disturbance, hemiparesis, headache, dementia, urinary inconti-nence and consciousness disturbance1. Our patient developed urinary incontinence, mental confusion, headache and gait disturbance. Her risk factors for chronic subdural hematoma included repeat episodes of gastroduodenal bleeding, long-standing antiag-gregation therapy and infection. Bilateral hematomas and recurrent platelet aggregation reduction also sug-gested the possible development of thrombasthenia. In general, acquired or hereditary pathologic bleeding can result from defects in the procoagulant mechanisms, defects in the mechanisms of hemosta-sis control, and abnormal fi brinolysis. Defects in pro-coagulant mechanisms may include platelet count or function abnormalities, coagulation factor defects, or vascular defects. Platelet function disorders include defects of platelet adhesion, aggregation and activa-tion, secretion defects, signaling pathway defects, and defects in platelet size or membrane phospholipids. Th ese may be inherited, or more commonly, acquired. Inherited defects are von Willebrand’s disease and Bernard-Soulier syndrome (adhesion), Glanzmann thrombasthenia (aggregation) and Chédiak-Higashi syndrome (secretion defect). Our patient had normal platelet count and no signs of cardiovascular disease, therefore repeat tests occasionally indicating reduced platelet aggregability raised suspicion of Glanzmann thrombasthenia. Glanzmann thrombasthenia is an autosomal recessive syndrome with the incidence of 1 per million, and implies qualitative and quantitative abnormalities of the GpIIb/GpIIIa platelet membrane glycoprotein complex8-12.Acquired dysfunction is most commonly associ-ated with antiaggregation agents that are currently widely and frequently unselectively used. Th ere are many other drugs demonstrated to infl uence platelet Fig. 2. Ultrasonographic image of venous thrombosis.Komentar: TROMBOZIRANA VFC S Komentar: TROMBOZIRANA VSM SKomentar: TROMBOZIRANA VFC SActa Clin Croat,  Vol. 49,  No. 2,  2010 167Antonija Vuk et al. Nontraumatic bilateral subdural hematoma caused by antiaggregation therapy: ...function, e.g., non-steroidal anti-infl ammatory drugs (NSAIDs), thienopyridines, GPIIb/IIIa receptor an-tagonists, drugs that increase platelet cAMP, antico-agulant and fi brinolytic agents, cardiovascular drugs (nitrates, furosemide, angiotensin-converting enzyme inhibitors (ACEI), calcium channel blockers), cyto-statics (danorubicin, mitomycin), psychiatric drugs (chlorpromazine, haloperidol) and antihistamines. Dual antiplatelet therapy with aspirin (acetylsalicylic acid, ASA) and thienopyridine (clopidogrel) is stan-dard care after coronary stenting. Besides the use of ASA and clopidogrel, the use of nitrates, furosemide, ACEI and calcium channel blockers was also estab-lished by history data.   In a retrospective study of 123 patients with spon-taneous subdural hematoma, 76% of patients were found to take aspirin (n=78) and warfarin (n=15), sug-gesting the use of aspirin to increase signifi cantly the risk of cerebral hemorrhage and associated complica-tions13. Clinical evidence for the effi  cacy of clopidogrel bisulfate relies on two double-blind studies, CURE and CAPRIE. Th e CURE study demonstrated the risk of myocardial infarction and stroke to be reduced, while the rate of gastrointestinal hemorrhage was 1.3%, of intracranial hemorrhage 0.1% and of fatal hemorrhage 0.2%14-16.Th e eff ect of ASA and clopidogrel on platelets lasts throughout the platelet life span, for about 7 days; therefore, in our patient platelet aggregation tests yielded abnormal results on admission. Later on, ag-gregation tests normalized due to transfused platelets and platelets formed de novo in the body. Th e addition of transfused platelets, post-hemorrhage reactive hy-percoagulation, operative procedures (hyperfi brino-genemia, tissue thromboplastin release) and bed rest with venous stasis probably favored the development of iliac vein thrombosis on day 14 of craniotomy.Th e complications of hemorrhage and chronic sub-dural hematoma call for due caution on the selection and follow up of patients prescribed antiaggregation agents. Th is in particular applies to elderly patients, where the risk of bleeding is already increased due to fragile capillaries, and in a very small but signifi cant group of patients with inborn platelet function dis-order. However, due to limited resources, testing for platelet aggregation cannot be routinely done prior to introducing antiaggregation therapy. Th erefore, due attention should be paid to patients with a history of mucocutaneous bleeding, thrombosis or skin necrosis. Some new drugs like direct thrombin and Factor X inhibitors (dabigatran and rivaroxaban) have already passed phase III clinical trials on prophylaxis and pre-vention of venous thrombosis. Th ese agents may com-pletely replace warfarin and vitamin K antagonists in the treatment and prevention of venous thromboem-bolism because they require no activity monitoring or dose adjustment. For now, studies of their potential eff ects in the prevention of arterial thromboembolism are yet to be expected. Th us, due caution is still war-ranted on selecting patients prescribed antiaggrega-tion agents,  and their side eff ects should be strictly monitored.References  1. KENTARO MORI K, MAEDA M. Surgical treatment of chronic subdural hematoma in 500 consecutive cases: clini-cal characteristics, complications, and recurrence rate. Neurol Med Chir (Tokyo) 2001;41:371-81.  2. KARNATH B. Subdural hematoma: presentation and man-agement in older adults. Geriatrics 2004;58:18-23.  3. BAECHLI H, BUCHER HC, GRATZL O. Demograph-ics and prevalent risk factors of chronic subdural hematoma: results of a large single-center cohort study. Neurosurg Rev 2004;27:263-6.  4. KUROKAWA Y, ISHIZAKI E, INABA K. Bilateral chronic subdural hematoma cases showing rapid and progres-sive aggravation. Surg Neurol 2005;64:444-9.  5. CALVO-ROMERO JM. Bilateral subacute-chronic sub-dural hematoma. JCMU 2008;10:1,5.  6. STANISIC M, LUND-JOHANSEN M, MAHESPARAN R. Treatment of chronic subdural hematoma by burry-hole craniostomy in adults: infl uence of some factors on postopera-tive recurrence. Acta Neurochir (Wien) 2005;147:1249-57.  7. THIERRY A, HUISMAN GM. Intracranial hemorrhage: ultrasound, CT and MRI fi ndings. Eur Radiol 2005;15:434-40.  8. NURDEN AT. Glanzmann thrombasthenia. Orphanet J Rare Dis 2006;1:10.  9. CATE HT, BRANDJES M, SMITH PHM, Van MOURIK JA. Th e role of platelets in venous thrombosis: a patient with Glanzmann’s thrombasthenia and a factor V Leiden mutation suff ering from deep venous thrombosis. International Society on Th rombosis and Hemostasis, 2003.  10. SIMON D, KUNICKI T, NUGENT D. Platelet function defects. Haemophilia 2008;14:1240-9.11. SPILBERG O, RABI I, SCHILLER K, WALDEN R, HARATS D, TYRRELL KS, COLLER B, SELIG-Antonija Vuk et al. Nontraumatic bilateral subdural hematoma caused by antiaggregation therapy: ...168 Acta Clin Croat,  Vol. 49,  No. 2,  2010SOHN U. Patients with Glanzmann thrombasthenia lack-ing platelet glycoprotein αIIbβ3 (GPIIb/GPIIIa) and αvβ3 receptors are not protected from atherosclerosis. Circulation 2002;105:1044-8.12. PHILLIPS R, RICHARDS M. Venous thrombosis in Glan-zmann’s thrombasthenia. Hemophilia 2004;13:758-9.13. O’BRIEN DF, BASU S, O’DONNELL JR, PHILLIPS JP, ROBERTS GA. Th e impact of aspirin therapy and antico-agulation on the prevalence of spontaneous subdural haema-toma. Ir Med J 2000;93:244-6.14. FOX KA, MEHTA SR, PETERS R. Benefi ts and risks of the combination of clopidogrel and aspirin in patients under-going surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circula-tion 2004;110:1202-8.15. CAPRIE Steering Committee. A randomized, blinded trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996;348:1329-39.16. BHATT DL, FLATHER MD, HACKE W, et al. Patients with prior myocardial infarction, stroke, or symptomatic pe-ripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982-8.SažetakNETRAUMATSKI OBOSTRANI SUBDURALNI HEMATOM UZROKOVAN ANTIAGREGACIJSKOM TERAPIJOM: PRIKAZ SLUČAJA I PREGLED LITERATUREA. Vuk, V. Stančić, G. Rinčić, M. Ledinsky, Lj. Grbac i N. StančićU 64-godišnje bolesnice koja je zbog ne-STEMI srčanog infarkta dobivala aspirin i klopidogrel razvio se netraumatski obostrani subduralni hematom praćen smušenošću, vrtoglavicom i glavoboljom. Kod prijma je utvrđena smanjena agrega-cija trombocita u ADP testu pa je kraniotomija i dekompresija odgođena za 4 dana. Četiri dana nakon prestanka uzimanja klopidogrela i aspirina te uz transfuziju od 12 doza trombocita prolazno se normalizirala agregabilnost trombocita pa je učinjena obostrana trepanacija i uklonjeni su hematomi. Slijedio je odličan neurološki oporavak. Smanjena agregabilnost trombocita bila je prisutna do 12. poslijeoperacijskog dana. Sumnja na Glanzmannovu trombasteniju isključena je pro-točnom citometrijom. Četrnaestoga poslijeoperacijskog dana nastala je tromboza desne femoralne vene koja je liječena smanjenim dozama heparina i varfarina. Uz prikaz bolesnice analizira se rizik od krvarenja i tromboze u bolesnika koji uzimaju antitrombocitne lijekove. Preporuča se oprez u starijih bolesnika kod kojih su prisutne i druge teške bolesti, što povećava rizik od krvarenja. Ključne riječi: Ključne riječi: Hematom, subduralni – dijagnostika; Hematom, subduralni – etiologija; Hematom, subduralni – terapija; Antikoagulansi – terapijska primjena; Progresija bolesti; Starija osoba; Prikaz slučaja

Netraumatski obostrani subduralni hematom uzrokovan antiagregacijskom terapijom: Prikaz slučaja i pregled literature

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Netraumatski obostrani subduralni hematom uzrokovan antiagregacijskom terapijom: Prikaz slučaja i pregled literature

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