In November 2017, the American Heart Association / American Stroke Association released a scientific statement on the treatment of TPA related symptomatic intracranial hemorrhage (sICH). Full text can be found here. The 7 questions below represent a summary of the recommendations.

1)What is the rate of symptomatic intracranial hemorrhage after TPA? 2-7%

TPA risk of symptomatic intra-cranial hemorrhage is cited by the AHA/ASA as 2-7% due to variability in definition.4

  • 1996 Original NINDS1 trial = 6.4%
  • 2007 SITS-MOST2 = 3.7% sICH, 2.7% Fatal ICH
  • 2008 ECAS III3 = 6.8% 

2)Is there a standard for defining the type of intracranial hemorrhage? Yes

The ASA recommends utilizing the ECASS method for classification: 

  • (HI-1) Hemorrhagic Infarction type 1: small petechial infarction
  • (HI-2) Hemorrhagic Infarction type 2: confluent petechiae 
  • (PH-1) Parenchymal Hematoma type 1: <30% of the infarcted area with mild mass effect
  • (PH-2) Parenchymal Hematoma type 2: >30% of the infarcted area with significant mass effect
  • Remote ICH: distant from the infarcted zone

Outcomes have only been consistent in the PH-2 category, with an almost 50% mortality. 

Examples from the AHA/ASA summary4:


Figure 1(4). Radiographic classification of hemorrhagic transformation with the purple arrow in each figure showing the hemorrhage. Top left, Hemorrhagic infarction type 1. Top right, Hemorrhagic infarction type 2. Bottom left, Parenchymal hematoma type 1. Bottom middle, Parenchymal hematoma type 2. Bottom right, Extraischemic hematoma.

3)When does sICH after TPA occur? Within 36 hours.

Half will occur in the first 10 hours.

4)When should repeat imaging occur? At 24 hours after TPA infusion, and anytime there is clinical deterioration.

Examples symptoms of neurologic deterioration include:

  • Increasing NIHSS
  • Headache
  • Nausea
  • Vomiting
  • Seizures

5)Are there variables associated with increased risk of sICH after TPA? Yes

Variable associated with increased risk of sICH include: 

  • Older age
  • Higher stroke severity (High NIHSS)
  • Increased glucose
  • Hypertension
  • Congestive heart failure
  • Renal impairment
  • Diabetes mellitus
  • Ischemic heart disease
  • Atrial fibrillation
  • Antiplatelet use
  • Leukoaraiosis (small vessel white disease of white matter regions)
  • Infarct visible on initial brain imaging

6)Is there a scoring system to reliably determine the exact risk of sICH in patient with the variable above? No

Based on these variable, 7 risk scores have been published and reviewed by the ASA. Table 3 in their document includes a description of the components and sensitivity/specificity of each method.  However the AHA/ASA recommends the following:

“Although these scores generally are effective at estimating the incremental sICH risk facing individual patients, the upper range of absolute sICH risk predicted by the scores does not justify withholding thrombolytic therapy. Patients who may be at highest predicted risk for sICH are also likely to have very poor outcomes without thrombolytic therapy. Indeed, the International Stroke Trial-3 showed the greatest benefit of alteplase versus placebo in the subgroup predicted to be at highest risk of sICH…Risk scores for sICH can be helpful for guiding patients’ and their families’ expectations and perhaps to inform the intensity of medical monitoring required for individual patients after alteplase administration. Patients at high risk of sICH based on prediction scores likely still have benefit from alteplase. Therefore, it is critical that sICH prediction scores and risk factors not be used to select patients for thrombolysis.”

7)What is recommended for reversal of TPA in patients with sICH? 

Table 4. Suggestions for Reversal Agents That May Be Considered on the Basis of the Mechanisms of Action of the Agent and Alteplase in Patients With sICH Occurring Within 36 Hours After Alteplase Infusion

Reversal AgentSuggested DosePotential for BenefitAdverse Effects
CryoprecipitateConsider sending a fibrinogen level immediately and empirically transfusing with 10 U cryoprecipitate, and anticipate giving more cryoprecipitate as needed to achieve a normal fibrinogen level of ≥150 mg/dL (10 U cryoprecipitate increases fibrinogen by nearly 50 mg/dL)Potential for benefit in all sICHTransfusion reaction and transfusion-related lung injury
Platelets2 donors (8–10 U)Potential for benefit is unclear except in patients with thrombocytopenia (platelets <100 000/µL), who may possibly benefitTransfusion reaction, transfusion-related lung injury, volume overload
FFP12 mL/kgPotential for benefit is unclear except in patients on warfarin, in whom FFP may be consideredTransfusion reaction, transfusion-related lung injury, volume overload
PCC25–50 U/kg (based on INR level)Potential for benefit is unclear except in patients on warfarin, in whom PCC may be considered and is the preferred adjunctive treatmentThrombotic complications
Vitamin K10 mg intravenouslyPotential for benefit is unclear except in patients on warfarin, in whom vitamin K may be used as an adjunctive treatmentAnaphylaxis
rFVIIa20–160 µg/kgPotential for benefit is unclearThrombotic complications
Antifibrinolytic agentsAminocaproic acid: 4 g IV during first hour followed by 1 g/h for 8 hTranexamic acid: 10 mg/kg 3–4 times/d (adjustment based on kidney function may be necessary)Potential for benefit in all patients with sICH, particularly when blood products are contraindicated or declined by patient/family or if cryoprecipitate is not availableThrombotic complications

FFP indicates fresh-frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa; and sICH, symptomatic intracranial hemorrhage.

Sources:

  1. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-7. PubMed
  2. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369(9558):275-82. PubMed , Full Text , International Registry 
  3. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-29. Full text , PubMed 
  4. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2017;48(12):e343-e361. Full Text , PubMed

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