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Giuseppe Micieli Dip. Neurologia dUrgenza IRCCS Istituto Neurologico C Mondino Pavia Manifestazioni cliniche di sanguinamento: Il sanguinamento cerebrovascolare.

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Presentazione sul tema: "Giuseppe Micieli Dip. Neurologia dUrgenza IRCCS Istituto Neurologico C Mondino Pavia Manifestazioni cliniche di sanguinamento: Il sanguinamento cerebrovascolare."— Transcript della presentazione:

1 Giuseppe Micieli Dip. Neurologia dUrgenza IRCCS Istituto Neurologico C Mondino Pavia Manifestazioni cliniche di sanguinamento: Il sanguinamento cerebrovascolare

2 Cerebrovascular Disease Stroke Subtypes Albers GW et al. Chest. 1998;114:683S-698S. Rosamond WD et al. Stroke. 1999;30:736-743. Ischemic stroke (83%)Hemorrhagic stroke (17%) Atherothrombotic disease (20%) Embolism (20%) Lacunar small vessel disease (25%) Cryptogenic (30%) Intracerebral hemorrhage (59%) SAH (41%)

3 Possible causes of spontaneous nontraumatic ICH Hypertension Hematologic disorders –Thrombocytopenia –Platelet dysfunction –Coagulopathies Blood vessel abnormalities –Arteriovenus malformation –Aneurism –Moyamoya disease –Amyloid angiopathy Tumors –Primary brain tumor (much less common than metastatic tumor) –Metastatic brain tumor (melanoma, choriocarcinoma, thyroid carcinoma, renal cell carcinoma, bronchogenic carcinoma, breast carcinoma) Drugs –Illicit drugs (cocaine, amphetamine) –Over-the-counter medications (phenylpropanolamine) –Prescription medications (warfarin, aspirin, TPA, heparin)

4 Quality-of-care indicators and accepted reasons for nontreatment Neurology 2005;65:360–365 InterventionImplementationAcceptable reason far nontreatment Thrombolysis within 3 hoursIV-tPA, IA-tPA, tenecteplaseArrival > 3 hours after symptom onset, unknown time of symptom onset, uncontrolled hypertension, rapid improvement, stroke too mild or too severe, seizure at onset, recent surgerv, refusal, history of intracranial bleeding or arteriovenous malformation, on-going bleeding, platelet count 400 mg/dL, life expectancy I year, dementia Antithrombotic medication within 48 hours Antiplatelet agents, anticoagulants thrombolysis Bleeding risk, terminal illness DVT prophylaxis by hospital day 2 Anticoagulants or vascular support hose with paeumatic compression devices Patient ambulatory Smoking cessation counselingCounseling the stop smoking or smoking advice Current nonsmoker, no history of smoking, death in hospital Lipid-lowering medication at discharge Lipid-lowering medicationsLDL < 100 mg/dL, death in hospital Antithrombotic medication at discharge With atrial fibrillation: anticoagulants; without atrial fibrillation: antiplatelet agents, anticoagulants Bleeding risk (e.g., liver disease, active peptic ulcer disease, fall risk), refusal, terminaI ill, impaired mental status, planned surgery, death in hospital

5 IH1: small petechiae IH2: more confluent petechiae PH1: haematoma in <30% of the infarcted area; slight space-occupying effect PH2: dense haematoma >30% of the infarcted area; substantial space-occupying effect ICH after thrombolysis

6 ICH: epidemiology and relationship with antithrombotic treatment Nicolini A et al. Haematologica 2002;87:948-956

7 Volume of haemorrhage, AC and AP use Stead LG et al. Clin Neurol Neurosurg 2009

8 AP or OA therapy effect on unfavorable outcome and in-hospital mortality Saloheimo P et al. Stroke 2006;37:129-133

9 ICH: stima della frequenza assoluta Popolazione generale ASA ASA + Clopidogrel Warfarin Warfarin + ASA 0.15 % FA: 0.2% CVD: 0.3% FA: 0.3% CVD: 0.4% FA: 0.3-0.6% CVD: 0.4-1.0% 0.5-1.0% Hart RG et al. Stroke 2005;36:1588-1593

10 Da soli o in associazione?

11 Rates of CNS bleeding during antiplatelet therapy with ASA and Clopidogrel Hart RG et al. Stroke 2005;36:1588-1593

12 MATCH: life-threatening and major bleeding Type of Bleeding Events (%) Placebo + Clopidogrel (n=3,781) ASA + Clopidogrel (n=3,759) % Absolute Difference (95% CI) p value Defined as Life-threatening Events (%) 49 (1.3)96 (2.6) 1.26 (0.64, 1.88) <0.001 Gastrointestinal21 (0.6)51 (1.4) Intracranial25 (0.7)40 (1.1) Major Bleeding Events (%)22 (0.6)73 (1.9) 1.36 (0.86, 1.86) <0.001 Gastrointestinal11 (0.3)42 (1.1) Life threatening: any fatal bleeding event, or a drop in haemoglobin of 5g/d, or significant hypotension with the need of inotropes (hemorrhagic shock) or, symptomatic intracranial haemorrhage, or requiring transfusion of 4 units of RBC or equivalent amount of whole blood Major bleeding: significantly disabling (with persistent sequelae), or intraocular bleeding leading to significant loss of vision or, requiring transfusion of 3 units of RBC or equivalent amount of whole blood Diener HC, et al. Lancet 2004;364:331-337

13 CHARISMA: Overall Population Safety Results Endpoint* - N (%) Clopidogrel + ASA (n=7802) Placebo + ASA (n=7801) p value GUSTO Severe Bleeding 130 (1.7)104 (1.3)0.09 Fatal Bleeding26 (0.3)17 (0.2)0.17 Primary ICH26 (0.3)27 (0.3)0.89 GUSTO Moderate Bleeding 164 (2.1)101 (1.3)<0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006 – In press

14 ASA and ER- Dipyridamole versus Clopidogrel for recurrent stroke: primary and secondary outcomes Sacco R et al. NEJM 2008;359:1-14

15 Prasugrel vs Clopidogrel in Acute Coronary Syndromes Wiviott SD et al. NEJM 2007;357:2001-2015

16 Platelet antiaggregants and anticoagulants within 48 hours of acute ischemic stroke Coull BM et al, Stroke 2002

17 SPREAD: Terapia anticoagulante in prevenzione secondaria Raccomandazione 10.12 Grado D In pazienti con qualunque eziologia cardioembolica, escludendo i casi a rischio emboligeno molto elevato, qualora vi sia una lesione estesa alla TC a 48 ore, è indicato procrastinare di almeno 14 giorni linizio del trattamento anticoagulante, per il maggior rischio di trasformazione emorragica sintomatica. Qualora una TC abbia documentato una lesione minore del 30% dellemisfero colpito senza trasformazione emorragica in forma di ematoma, il trattamento può essere iniziato precocemente. 2003 Raccomandazione 10.10 Grado D In pazienti con qualunque etiologia cardioembolica, in assenza delle controindicazioni elencate al Capitolo 5, è indicato iniziare il trattamento anticoagulante orale tra 48 opre e 14 giorni tenendo conto di: Gravità clinica Estensione della lesione alle neuroimmagini Comorbosità cardiologica (definita anche con ecocardiografia) 2007 (&2010)

18 ECASS study: ICH following thrombolysis Derex L, Nighoghossian N. JNNP 2008;79:1093-1099

19 Thrombolysis-related ICH Acute Myocardial Infarction:0.6% Pulmonary Embolism:3% Ischaemic Stroke*:6-11% –Intravenous thrombolytic therapy6% –Intra-arterial thrombolytic therapy11% *ICH in brain areas outside the vascular distribution of the ischaemic stroke: 20% Mac Carron MO & Nicol JAR, Lancet Neurology 2004;3(8):484

20 Tissue Plasminogen Activator – Possible Reasons for Temporal Restriction rt-PA Cleavage Fibrin Plasmin ogen rt-PA Plasmin Second Generation: Recombinant Proteins Multi-tasking: Additional physiological functions of tPA turn deleterious in the ischemic setting tPA, a neurotoxic agent: Endogenous glutamate can cause neurotoxicity, e.g. under ischemic conditions; tPA is able to aggravate this toxicity. Benchenane et al, Trends Neurosci 27: 155 (2004)

21 Caso clinico: maschio, 71 anni, emiparesi sinistra, esordita da circa 45 Plavix 75 mg cp 1 cp dopo pranzoPlavix 75 mg cp 1 cp dopo pranzo Cardioaspirin 100 mg cp 1 cp dopo cenaCardioaspirin 100 mg cp 1 cp dopo cena Torvast 10 mg cp 1 cp alla sera Triatec 5 mg cp 1 cp al mattino Bisoprololo 2.5 mg cp 1 cp al mattino Dopo circa 2 h dalla trombolisi

22 AP treatment and thrombolysis: distribution of the mRS scores at 3 months Diedler J et al. Stroke 2010;41:288-294

23 AP treatment and thrombolysis: causes of death Diedler J et al. Stroke 2010;41:288-294

24 Cerebral microbleeds Prevalence: No CVD: 4.7% Ischemic CVD: 40% Ischemic CVD with cerebral microangiopathy: 57% Hemorrhagic CVD: 68% Location: Cortical-subcortical area Koennecke HC, Neurology 2006;66(2):165


26 Leukoaraiosi e ICH TAO-relata Valori espressi in n(%) Smith EE et al, Neurology 2002 Presenza: OR: 12.9 (95%CI: 2.8-59.8) Grado 3-4: OR: 24.9 (95% CI: 4.5-137.4)

27 Anticoagulant-related ICH Hart R, Stroke 1995;26:1471

28 Anticoagulant-related ICH Anticoagulation to conventional intensities increases the risk of intracranial hemorrhage 7- to 10-fold, to an absolute rate of nearly 1%/y for many stroke-prone patients. Most (70%) anticoagulant-related intracranial hemorrhages are intracerebral hematomas (approximately 60% are fatal); the bulk of the remainder are subdural hematomas. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age (>75 yrs), race, prior ischemic stroke, hypertension (systolic BP >160 mmHg), intensity of anticoagulation, concomitant use of antiplatelet drug, and cerebral amyloid angiopathy. In approximately half of anticoagulated patients with intracerebral hematoma the bleeding evolves slowly over 12 to 24 hours, and emergency reversal of anticoagulation is crucial Hart R mod, Stroke 1995;26:1471

29 Kaplan-Meier estimate of rate of hemorrhage expansion Flibotte Neurology, 2004;63(6):1059

30 The increasing incidence of anticoagulant-associated intracranial haemorrhage 1988 1993-1994 1999 All ischemic stroke NA 140.0 (133.2-146.8) 142.6 (135.8-149.3) Cardioembolic strokeNA 31.1 (27.9-34.3) 30.4 (27.3-33.5) Cardioembolic ischemic stroke due to AF NA 22.0 (19.3-24.8) 20.6 (18.1-23.2) All ICH 16.5 (14.1-18.9) 22.1 (19.4-24.8) 24.6 (21.8-27.4) AAICH 0.8 (0.3-1.3) 1.9 (1.1-2.7) 4.4 (3.2-5.5) Flaherty ML et al. Neurology 2007;68:116-121

31 Racial/ethnic differences in the risk of ICH among patients with AF Shen A Y-J et al. J Am Coll Med 2007;50:309-315

32 Predittori di ICH durante TAO Età Fang MC et al, Ann Intern Med 2004

33 Ipertensione arteriosa Predittori di ICH durante TAO Ipertensione arteriosa PROGRESS trial Il rischio assoluto passava da 0.6%/anno a 0.3%/anno e 0.2%/anno rispettivamente Pressione arteriosa sistolica Chapman N et al, Stroke 2004

34 Rischio emorragico e valori di INR Aumento rischio ICH di 2-5 volte, direttamente correlato ai valori di INR. Buona parte delle ICH occorrono, tuttavia, con INR in range terapeutico 40% Cantalapiedra A et al, J Thromb Thrombolysis 2006


36 Risk analysis of thrombo-embolic and recurrent bleeding events in AC-related ICH De Vleeschouwe S et al, Acta Chir Bel 2005;105:268-274 TE risk: 0,66/1000 pts-day at risk (8/11590 pts-day) Recurrent ICH: 8/108 pts (before restarting OAC)

37 Discontinued anticoagulation for intracranial haemorrhage In a patient who is taking warfarin and experiences an intracranial haemorrhage, warfarin should be stopped and its effects reversed fully with vitamin K orally, subcutaneously or intravenously and clotting factor replacement. The timing of recommencing anticoagulation will depend on the risk of embolisation and on the risk of rebleeding. It is possible to resume warfarin therapy quite early, even within the first 7-14 days, without high risk of recurrent bleeding in patients with a high risk of re-embolisation and a small intracranial bleed.

38 Avoiding CNS bleeding during antithrombotic therapy Hart RG et al. Stroke 2005;36:1588-1593


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