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					   Manifestazioni cliniche di sanguinamento:
Il sanguinamento cerebrovascolare


                     Giuseppe Micieli
               Dip. Neurologia d’Urgenza
          IRCCS Istituto Neurologico C Mondino
                          Pavia
                            Cerebrovascular Disease
                                Stroke Subtypes
 Hemorrhagic stroke (17%)                              Ischemic stroke (83%)

                                                               Lacunar small vessel
                                                               disease (25%)
                        Intracerebral
                        hemorrhage (59%)

                                                               Atherothrombotic
                                                               disease (20%)



                                     SAH (41%)
                                                                Embolism (20%)



Albers GW et al. Chest. 1998;114:683S-698S.      Cryptogenic (30%)
Rosamond WD et al. Stroke. 1999;30:736-743.
          Possible causes of spontaneous
                 nontraumatic ICH

• Hypertension                      • Tumors
• Hematologic disorders                – Primary brain tumor (much less
    –   Thrombocytopenia                 common than metastatic tumor)
    –   Platelet dysfunction           – Metastatic brain tumor
    –   Coagulopathies                   (melanoma, choriocarcinoma, thyroid
                                         carcinoma, renal cell carcinoma,
• Blood vessel abnormalities             bronchogenic carcinoma, breast
    –   Arteriovenus malformation        carcinoma)
    –   Aneurism                    • Drugs
    –   Moyamoya disease
                                       – Illicit drugs (cocaine, amphetamine)
    –   Amyloid angiopathy
                                       – Over-the-counter medications
                                         (phenylpropanolamine)
                                       – Prescription medications
                                         (warfarin, aspirin, TPA, heparin)
    Quality-of-care indicators and accepted reasons
                   for nontreatment
        Intervention                        Implementation                    Acceptable reason far nontreatment

Thrombolysis within 3 hours    IV-tPA, IA-tPA, tenecteplase              Arrival > 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 <100,000, abnormal
                                                                         aPPT or PT, glucose <50 mg\dL or >400 mg/dL,
                                                                         life expectancy I year, dementia
Antithrombotic medication      Antiplatelet agents, anticoagulants       Bleeding risk, terminal illness
within 48 hours                thrombolysis

D’VT prophylaxis by hospital   Anticoagulants or vascular support hose   Patient ambulatory
day 2                          with paeumatic compression devices

Smoking cessation counseling   Counseling the stop smoking or smoking    Current nonsmoker, no history of smoking,
                               advice                                    death in hospital
Lipid-lowering medication at   Lipid-lowering medications                LDL < 100 mg/dL, death in hospital
discharge
Antithrombotic medication at With atrial fibrillation: anticoagulants;   Bleeding risk (e.g., liver disease, active
discharge                    without atrial fibrillation: antiplatelet   peptic ulcer disease, fall risk), refusal,
                             agents, anticoagulants                      terminaI ill, impaired mental status, planned
                                                                         surgery, death in hospital
     ICH after thrombolysis



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: epidemiology and relationship
  with antithrombotic treatment




            Nicolini A et al. Haematologica 2002;87:948-956
Volume of haemorrhage, AC and
            AP use




              Stead LG et al. Clin Neurol Neurosurg 2009
AP or OA therapy effect on unfavorable
  outcome and in-hospital mortality




                 Saloheimo P et al. Stroke 2006;37:129-133
ICH: stima della frequenza assoluta



              FA: 0.2%    FA: 0.3%      FA: 0.3-0.6%
              CVD: 0.3%   CVD: 0.4%     CVD: 0.4-1.0%
  0.15 %                                                  0.5-1.0%


Popolazione     ASA          ASA +        Warfarin       Warfarin +
 generale                 Clopidogrel                      ASA




                               Hart RG et al. Stroke 2005;36:1588-1593
Da soli o in associazione?
Rates of CNS bleeding during antiplatelet
   therapy with ASA and Clopidogrel




                    Hart RG et al. Stroke 2005;36:1588-1593
MATCH: life-threatening and major bleeding

                                                  Placebo +                   ASA +                 % Absolute
Type of Bleeding Events (%)                      Clopidogrel               Clopidogrel              Difference          p value
                                                  (n=3,781)                 (n=3,759)                (95% CI)

Defined as Life-threatening
                                                    49 (1.3)                 96 (2.6)
Events (%)
                                                                                                       1.26
  Gastrointestinal                                  21 (0.6)                 51 (1.4)                                   <0.001
                                                                                                   (0.64, 1.88)

  Intracranial                                      25 (0.7)                 40 (1.1)

Major Bleeding Events (%)                           22 (0.6)                 73 (1.9)
                                                                                                       1.36
                                                                                                                        <0.001
                                                                                                   (0.86, 1.86)
 Gastrointestinal                                   11 (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
             CHARISMA: Overall Population
                    Safety Results

                                          Clopidogrel                         Placebo
                                             + ASA                             + ASA                   p value
Endpoint* - N (%)
                                           (n=7802)                          (n=7801)
GUSTO Severe
                                            130 (1.7)                       104 (1.3)                    0.09
Bleeding
Fatal Bleeding                               26 (0.3)                        17 (0.2)                    0.17
Primary ICH                                  26 (0.3)                        27 (0.3)                    0.89
GUSTO Moderate
                                            164 (2.1)                       101 (1.3)                  <0.001
Bleeding
*Adjudicated outcomes by intention to treat analysis
ICH= Intracranial Hemorrhage
                                                       Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006 – In press
ASA and ER-
Dipyridamole
versus Clopidogrel
for recurrent
stroke: primary and
secondary
outcomes




   Sacco R et al. NEJM 2008;359:1-14
   Prasugrel vs Clopidogrel
in Acute Coronary Syndromes




          Wiviott SD et al. NEJM 2007;357:2001-2015
Platelet antiaggregants and anticoagulants within 48
           hours of acute ischemic stroke




                                     Coull BM et al, Stroke 2002
  SPREAD: Terapia anticoagulante in prevenzione
                   secondaria
             2003                           2007 (&2010)
Raccomandazione 10.12                Raccomandazione 10.10
Grado D                              Grado D
In pazienti con qualunque            In pazienti con qualunque
eziologia cardioembolica,            etiologia cardioembolica, in
escludendo i casi a rischio          assenza delle controindicazioni
emboligeno molto elevato,            elencate al Capitolo 5, è indicato
qualora vi sia una                   iniziare il trattamento
lesione estesa alla TC a 48 ore, è   anticoagulante orale tra 48 opre
indicato procrastinare di            e 14 giorni tenendo conto di:
almeno 14 giorni l’inizio del
trattamento anticoagulante, per      •Gravità clinica
il maggior rischio di                •Estensione della lesione alle
trasformazione emorragica              neuroimmagini
sintomatica.                         •Comorbosità cardiologica
                                      (definita anche con
Qualora una TC abbia                  ecocardiografia)
documentato una lesione minore
del 30% dell’emisfero colpito
senza trasformazione emorragica
in forma di ematoma, il
trattamento può essere iniziato
precocemente.
ECASS study: ICH following
      thrombolysis




        Derex L, Nighoghossian N. JNNP 2008;79:1093-1099
      Thrombolysis-related ICH
• Acute Myocardial Infarction:                             0.6%
• Pulmonary Embolism:                                      3%
• Ischaemic Stroke*:                                       6-11%
   – Intravenous thrombolytic therapy                      6%
   – Intra-arterial thrombolytic therapy                   11%

* ICH in brain areas outside the vascular
  distribution of the ischaemic stroke:                     20%



                    Mac Carron MO & Nicol JAR, Lancet Neurology 2004;3(8):484
Second Generation: Recombinant Proteins
                                                Tissue Plasminogen Activator –
                                          Possible Reasons for Temporal Restriction

                                                                                                     rt-PA
                                                        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)

                                                       Cleavage


                                             rt-PA Plasminogen    Plasmin
                                                            Fibrin
        Caso clinico: maschio, 71 anni, emiparesi
              sinistra, esordita da circa 45’
•   Plavix 75 mg cp 1 cp dopo pranzo
•   Cardioaspirin 100 mg cp 1 cp dopo cena   Dopo circa 2 h
•   Torvast 10 mg cp 1 cp alla sera          dalla trombolisi
•   Triatec 5 mg cp 1 cp al mattino
•   Bisoprololo 2.5 mg cp 1 cp al mattino
      AP treatment and thrombolysis:
distribution of the mRS scores at 3 months




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




                Diedler J et al. Stroke 2010;41:288-294
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
   Leukoaraiosi e ICH TAO-relata

                          • Presenza:
                           OR: 12.9 (95%CI: 2.8-59.8)
                          • Grado 3-4:
                           OR: 24.9 (95% CI: 4.5-137.4)




Valori espressi in n(%)

                             Smith EE et al, Neurology 2002
Anticoagulant-related ICH




             Hart R, Stroke 1995;26:1471
               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
Kaplan-Meier estimate of rate of
    hemorrhage expansion




                 Flibotte Neurology, 2004;63(6):1059
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 stroke       NA             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
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
Predittori di ICH durante TAO
            Età




               Fang MC et al, Ann Intern Med 2004
   Predittori di ICH durante TAO
      Ipertensione arteriosa
                 PROGRESS trial
              Pressione arteriosa sistolica
   0
             -9 mmHg                 -12 mmHg
  -10

  -20

  -30

% -40

  -50

  -60

  -70

  -80


• Il rischio assoluto passava da 0.6%/anno a 0.3%/anno e
  0.2%/anno rispettivamente
                                     Chapman N et al, Stroke 2004
   Rischio emorragico e valori di INR



                                                      40%




• Aumento rischio ICH di 2-5 volte, direttamente correlato ai
  valori di INR. Buona parte delle ICH occorrono, tuttavia, con INR
  in range terapeutico


                        Cantalapiedra A et al, J Thromb Thrombolysis 2006
        Risk analysis of thrombo-embolic and
     recurrent bleeding events in AC-related ICH




                                                 Recurrent ICH: 8/108 pts (before restarting OAC)



                                                 TE risk: 0,66/1000 pts-day at risk (8/11590 pts-day)




De Vleeschouwe S et al, Acta Chir Bel 2005;105:268-274
   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.
Avoiding CNS bleeding during
  antithrombotic therapy




              Hart RG et al. Stroke 2005;36:1588-1593