complications of thrombolysis in stroke Dr Rahi kiran.B SR Neurology GMC Kota

1. Dr Rahi kiran.B
SR Neurology
GMC Kota

2.  r-tPA was approved for use in AIS by FDA in 1996.
 Approximately 2% to 5% of patients with AIS receive r-tPA.
 6.4% risk of sICH,
 a 1.6% risk of serious systemic hemorrhage,
 30% to 50% greater chance of improvement to no or minimal disability at 3 months

3.  Dose –0.9 mg/kg with a maximum dose of 90 mg Ten percent given as iv bolus over
one minute and the remainder is infused over one hour
 Alteplase is an enzyme
 Binds to fibrin in clots - Converts plasminogen to plasmin - initiates local fibrinolysis
 Circulating fibrinogen drops by a third
 onset 30min, peak 1 hr, >50% in plasma cleared ~5 minutes after infusion
terminated, ~80% cleared within 10 minutes
 fibrinolytic activity persists for up to 1 hour after infusion terminated
 Effects on the coagulation profile may last 24 hours or more postinfusion

4.  within the 4.5 hour
 persistent, measurable neurologic deficit
 Eligibility criteria are met
 Serum glucose
 NCCT or brain MRI
 Blood pressure parameters
 Two intravenous lines, preferably large bore, are in place
 Accurate body weight has been determined

6.  below 185 mmHg systolic and 110 mmHg diastolic before administering
 must be maintained below 180/105 mmHg during and for 24 hours following
thrombolytic therapy
 monitoring every 15 minutes for the first 2 hours after starting thrombolytic
treatment, then every 30 minutes for the next 6 hours, then every hour until 24
hours
 frequency increased if >180/105 mmHg.
 optimal lower end of the range-not defined - target SBP to <140 mmHg once
reperfusion is achieved (consensus statement)

7.  Symptomatic Intracerebral
Hemorrhage
 Postthrombolysis Reperfusion Injury
 Orolingual angioedema
FREQUENCY NOT DEFINED
 Accelerated idioventricular rhythm
 Pulmonary edema
 Arterial embolism
 Bruising
 Bleeding
 DVT
 Hypotension
 GI/GU hemorrhage
 Pulmonary embolism
 Fever/chills
 Nausea/vomiting
 Sensitivity reaction
 Sepsis
 Shock
 Cerebral edema
 Cerebral herniation
 Seizure
 Ischemic stroke
 Thromboembolism

8.  “tPA” abbreviation should not be used when writing orders - has been misread as
TNKase (tenecteplase)
 Avoid IM injections and trauma to patient while on therapy
 Cholesterol embolism reported rarely
 Consider risk of reembolization from lysis of underlying DVT in patients with PTE
 Internal or external bleeding, at arterial and venous puncture sites may occur

9.  Perform venipunctures carefully and only as required
 Minimize bleeding from noncompressible sites by avoiding internal jugular and
subclavian venous punctures
 If arterial puncture necessary during therapy infusion, use upper extremity vessel
that is accessible to manual compression, apply pressure for at least 30 min, and
monitor puncture site closely

10.  P2Y12 inhibitors, NSAIDs, SSRIs-Antiplatelet Properties-May enhance the
anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
 Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May
enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk
D: Consider therapy modification
 Nitroglycerin: May decrease the serum concentration of Alteplase. Risk C: Monitor
therapy

11.  risk of bleeding may be increased in pregnant women
 a relative contraindication for its use
 should not be withheld from pregnant women in life-threatening situations but
should be avoided when safer alternatives are available
 It is not known if alteplase is present in breast milk.

14.  NINDS- CT documented hemorrhage within 36 hours of treatment, which was
temporally related to deterioration in the patient’s clinical condition in the
judgment of the clinical investigator - 6.4%
 Drawback- it includes small petechial hemorrhages associated with minimal
deterioration that are unlikely to have altered long-term functional outcome
 ECASS III – CT/MRI documented hemorrhage associated with clinical deterioration
defined as an increase in the NIHSS score of 4 points or more or led to death and
was determined to be the predominant cause of neurological deterioration-2.4%.

16. Category Points (15)
Aspirin + clopidogrel therapy 2
Aspirin monotherapy 1
NIHSS > 13 2
NIHSS 7–12 1
Blood glucose ≥ 180 mg/dl* 2
Age ≥ 72 years 1
Systolic BP ≥ 146 mmHg 1
Weight ≥ 95 kg 1
History of hypertension 1
Onset-to-treatment time ≥ 180 min 1
Components of SITS score and overall risk level
the risk ranged from 0.2% (score of 0) to 9.2% (score ≥ 9)

17.  Larger, multifocal, perihematomal edema and contain a blood fluid level.
 usually occurs at the site of ischemic brain tissue though can present at a distant,
unrelated site
 after thrombolytic therapy is administered, sICH should be suspected in any patient
▪ sudden neurologic deterioration
▪ a decline in level of consciousness
▪ new headache
▪ nausea and vomiting
▪ sudden rise in blood pressure

18.  Most sICH will occur within the first 24 hours with the bulk of fatal hemorrhages
occurring within the first 12 hours
 The risk of sICH after IA thrombolysis with or without IV r-tPA is estimated at 10%-
mortality rates up to 83%-many of these occur in already infarcted fields - do not
clearly alter final outcome

19. HI 1 small petechiae infarct margins
HI 2 confluent petechiae within inf. No SOE
PH 1 clots exceeding 30% of infarct
PH2 clots exceeding 30% of infarct with SOE- poor prognosis
PHr1 bleed away from the infarct mild SOE
PHr2 large bleed away from inf. Sig. SOE

20. HEMORRHAGIC INFARCTIONS (HI)
 benign,
 associated with the natural course of ischemic
brain infarctions,
 not linked to hemostasis
 within 1-2 weeks after stroke onset
 no specific prevention is required.
 Baseline clinical severity, Early CT findings
affects
 Not related
 No
PARENCHYMAL HEMATOMAS (PH)
 serious pathology
 immediately symptomatic or not
 is linked to hemostasis
 within 24hrs after rTPA
 a prevention is necessary-monitoring of
coagulation.
 Not related
 Affected by Previous aspirin, FDP coagulopathy
 Poor day 90 outcome

21.  solitary or multiple , in brain regions without visible ischemic damage
 suggest pre-existing brain pathology, especially cerebral amyloid angiopathy
 incidence - 1.3% in NINDS, 2 % - ECASS2
 female with a higher median age,
 history of previous nonrecent stroke (>3 months),
 a/w cerebral amyloid angiopathy (CAA)
 less likely to have
 severe strokes,
 early infarct signs,
 hyperdense cerebral artery signs,
 lower frequency of atrial fibrillation (AF) and diabetes

22.  < 60yrs - < 2 % sICH risk
 NINDS- > 80yrs- 3 times risk increases
 Further studies showed no difference in the rates of sICH
 To date, studies have not shown age alone to negate the beneficial effects of r-tPA
and should not be used to exclude patients from treatment within the 3-hour
treatment window.

23.  SITS-MOST study - Male gender and weight were independently associated.
 NINDS ,PROACT II trial -serum glucose >200 - 36% had sICH

24.  stroke severity alone cannot be used to select or exclude
 minor strokes or imaging negative infarcts- low risk - 0% to 3%.
 Large –
 2014 meta-analysis found that benefit of alteplase was similar regardless of stroke
severity.

25.  NINDS- rate of sICH - uncontrolled hypertension at presentation - 26%
without uncontrolled hypertension - 12%
 Target - pretreatment <185/110mmHg and posttreatment <180/105 mm Hg.

26.  30% of patients have taken an aspirin prior to hospitalization

 ECASS III- no increase the rate of sICH
 combination use with aspirin and clopidogrel -associated with increased rates of
sICH, but outcomes not affected - not an exclusion criterion for IV r-tPA.

27.  correlation between dabigatran plasma concentrations and aPTT is nonlinear and linear
with ECT and TT.
 Twelve hours after a dose, approximately 50% of the drug is eliminated
 At 150 mg twice daily, less than 10% of patients have aPTTs greater than 65 seconds (or
2 times control) at 12 hours after dosing.
 If rapid testing is not available, the time of the last dose may be useful in decision.
 Recommendation - AHA/ASA 2013 guidelines - allow the use of alteplase in patients on
DTI or F Xa inhibitors when aPTT, INR, ECT, TT or FXa activity assays are normal or the
patient has not received these agents for >2 days (assuming normal RFT)

28.  Larger clots are more resistant to thrombolysis
 More proximal sites of occlusion -more resistant than more distal sites.
 ICA occlusions are more resistant than MCA occlusions to IV tPA.
 Clot occluding the cervical ICA may promote adjacent thrombosis extending to the
intracranial ICA - very long thrombus - unlikely to be lysed by iv tPA alone.

29.  In large vessels, in situ thromboses associated with atherosclerotic lesions may be
more resistant to recanalization than fibrin rich embolic occlusions arising from the
heart.
 Clot age and composition –The ability to recanalize - inversely related to the
volume of emboli and to the fibrin content and density of the clots .Thrombolytic
drugs are unlikely to disrupt other types of embolic material, such as calcific plaque
and fat.

30.  EICs alone should not be a reason to exclude a patient from treatment < 3-hour
window
 Includes –
▪ Hypodensity
▪ loss of gray–white differentiation
▪ cerebral edema
▪ hyperdense artery sign
▪ EICs involving >one third of MCA territory
▪ ASPECTS<7,

31.  best visualized on susceptibility-weighted MRI sequences.

 >10 – high risk of sICH

33.  cardiac – AF, CCF
 Lower platelet counts
 Hyperlipidemia or use of lipid-lowering medications
 Preexisting leukoaraiosis, or chronic white matter ischemic disease

34.  occur in approximately 16% to 32.6% regardless of the clinical setting.
 Mortality-Inclusion and exclusion criteria, posttreatment protocols of BP
management, and use of antiplatelet/anticoagulant medications.
 sICH - stroke or head trauma within 3 months, ICH, and use of anticoagulants with
INR >1.7.

36.  Head 300 jugular venous drainage - ICP
 The use of PCC, fibrinogen, or FFP with or without recombinant factor VII, has been
investigated and usefulness in postthrombolysis ICH is unknown
 target blood pressure of 160/90 mm Hg
 surgical intervention - only after adequate reversal of the fibrinolytic effects of r-tPA
 cerebellar hemorrhages with brain stem compression
 development of hydrocephalus
 lobar hemorrhage within 1 cm of the surface and measuring >30 mL

37.  Stop alteplase infusion
 CBC, PT (INR), aPTT, fibrinogen level, and type and cross-match
 Emergent nonenhanced head CT
 Cryoprecipitate (includes factor VIII): 10 U infused over 10–30 min (onset in 1 h,
peaks in 12 h); administer additional dose for fibrinogen level of <200 mg/dL
 Tranexamic acid 1000 mg IV infused over 10 min OR ε-aminocaproic acid 4–5 g over
1 h, followed by 1 g IV until bleeding is controlled (peak onset in 3 h)
 Hematology and neurosurgery consultations

38.  Supportive therapy, including BP management, ICP, CPP, MAP,
 temperature, and glucose control
 PCC/FFP as adjunctive therapy to cryoprecipitate(if not available) for patients
on warfarin prior to alteplase treatment
 Vitamin K as adjunctive therapy for patients on warfarin prior
to alteplase treatment
 Six to eight units of platelets for patients with thrombocytopenia (platelet
count <100,000/microL)
 In patients receiving UFH for any reason, it is reasonable to treat with 1 mg of
protamine for every 100 units of UFH given in the preceding 4 hours

39.  Unproven
 GUSTO-I trial in MI-
▪ 30-day survival was significantly higher with neurosurgical hematoma
evacuation than without,
▪ higher incidence of nondisabling stroke in those with evacuation compared
with those without

41.  NINDS 1.6%
 Mild- oozing from iv sites, ecchymoses , gum bleeding – no need to stop
 highest risk- excluded- history of MI < 1 month, GI or urinary tract hemorrhage <21
days, major surgery <14 days, and arterial puncture at a noncompressible site <7
days

42.  40% of patients had hyperperfusion within hours and 50% within 1 week.
 early hyperperfusion-no clinical significance
 Late hyperperfusion - larger infarct volume

43.  generally transient, self-limited swelling of the tongue and lips but can potentially
cause airway obstruction and respiratory compromise,
 u/l or b/l, If u/l - tongue swelling is typically contralateral to the affected hemisphere
 1.3% and 5.1%.
 Timing: Angioedema and anaphylaxis upto 2 hours after IVrtPA
 Risk factors – female sex , use of ACE inhibitor, frontal and insular strokes
 Alteplase infusion can be continued if ABC is not compromised

45.  Laryngeal oedema, bronchospasm, hypotension
 Stop alteplase infusion
 Horizontal bed raise foot end
 Airway patent
 Adrenaline 1:10,000 five ml -1ml/min
 Chlorpheniramine 10mg slow iv
 Hydrocortisone 200 mg iv

46.  reported rarely in patients treated with thrombolytic agents
 may present with livedo reticularis, “purple toe” syndrome, acute renal failure,
gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral
infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or
rhabdomyolysis and can be fatal.

47.  may increase risk of thromboembolic events in patients with high probability of left
heart thrombus (eg, patients with mitral stenosis or atrial fibrillation).

48.  alteplase treatment is 10 times more likely to help than to harm eligible patients
when given within 3 hours
 can cause severe bleeding in the brain in about 1 of every 15 patients
 “On average the potential benefits outweigh the risks; however, in any individual
patient it is a very personal decision.“
 new doses of rt-PA (possibly lower) or new thrombolytic drugs, with a still a higher
fibrin specificity and a less frequent attack of circulating fibrinogen.
 telemedicine
 "drip and ship strategy "

49. Thank you