Haemorrhagic Transformation of Ischaemic Stroke

Haemorrhagic transformation is bleeding into an area of ischaemic infarction, ranging from small petechial change to a space occupying parenchymal haematoma. Symptomatic intracerebral haemorrhage is the most feared complication of reperfusion therapy and anticoagulation.

Haemorrhagic transformation occurs in about 10 to 40% of ischaemic strokes on imaging, and symptomatic haemorrhage in about 2 to 7% after intravenous thrombolysis and 3 to 5% after thrombectomy.

Classification. Haemorrhagic infarction type 1 (small petechiae) and type 2 (confluent petechiae without mass effect); parenchymal haematoma type 1 (under 30% of the infarct, with mild mass effect) and type 2 (over 30%, with significant mass effect). Symptomatic haemorrhage is any haemorrhage with neurological deterioration of 4 or more NIHSS points.

Risk factors. Large infarct, high NIHSS, older age, hyperglycaemia, hypertension, cardioembolic cause, thrombolysis, anticoagulation or dual antiplatelet therapy, early signs of large infarct on CT, low platelet count and renal impairment.

Pathophysiology.

Ischaemia damages the blood brain barrier and the basal lamina. Reperfusion by recanalisation, collateral flow or thrombolysis allows red cells to extravasate through weakened vessels.

Fibrinolysis, matrix metalloproteinase activation and reduced coagulation factors worsen bleeding.

• Neurological deterioration, new or worsening headache, vomiting and reduced consciousness, often in the first 24 to 36 hours after thrombolysis.
• Acute rise in blood pressure, seizures or Cushing response.
• Many petechial haemorrhagic infarcts cause no symptoms.

Red flags.

• Fall of 4 or more NIHSS points or 2 or more Glasgow Coma Scale points.
• New headache, vomiting or agitation during or after thrombolysis.
• Rising blood pressure with bradycardia.

• Stop thrombolysis infusion at once if symptoms arise during treatment, and perform emergency non-contrast CT.
• Blood tests: full blood count, platelets, INR, activated partial thromboplastin time, fibrinogen, group and save with crossmatch, creatinine and anti-factor Xa activity or dabigatran level where available.
• Review of anticoagulant and antiplatelet drug type, dose and timing.
• CT angiography to look for a leak when atypical; follow up CT at 24 hours and with any decline.

Differential diagnosis. Contrast staining after thrombectomy, new infarction, cerebral oedema with mass effect, seizure with postictal deficit, hypertensive encephalopathy, hypoglycaemia and primary haemorrhage.

• Stop thrombolytic and antithrombotic drugs, secure the airway and manage in a stroke or neurocritical unit.
• Blood pressure: lower systolic pressure to 140 mmHg (range 130 to 150) within 1 hour of diagnosis and avoid falls under 130 mmHg.
• Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, repeated or doubled every 10 minutes to a maximum of 300 mg, or an infusion of 0.5 to 2 mg/minute. Monitor blood pressure, heart rate (stop if under 55 beats/minute) and ECG. Avoid in asthma, severe chronic obstructive disease, second or third degree heart block and decompensated heart failure; reduce dose in hepatic impairment; no renal adjustment; acceptable in pregnancy.
• Thrombolysis related bleeding: cryoprecipitate 10 units intravenously over 10 to 30 minutes, with a repeat dose adjusted to fibrinogen to keep it over 1.5 g/L (maximum 20 units in the first 24 hours), and tranexamic acid 1 g intravenously over 10 minutes. Monitor fibrinogen, coagulation, platelets and renal function. Reduce tranexamic acid dose when creatinine is 120 to 250 micromol/L (15 mg/kg twice daily), 250 to 500 micromol/L (15 mg/kg daily) and over 500 micromol/L (7.5 mg/kg daily); avoid with active thromboembolic disease; evidence of benefit is limited.
• Warfarin: prothrombin complex concentrate 25 to 50 units/kg intravenously adjusted to INR (maximum 5000 units) with phytomenadione 5 to 10 mg intravenously by slow injection over 10 to 20 minutes. Monitor INR at 30 minutes and every 6 to 12 hours. Avoid in heparin induced thrombocytopenia and with active thrombosis unless benefit outweighs risk; phytomenadione needs a repeat dose when INR rebounds.
• Dabigatran: idarucizumab 5 g intravenously (2 doses of 2.5 g given within 15 minutes of each other). Maximum 5 g, with a second 5 g dose only for recurrent bleeding with rising coagulation times. Monitor coagulation and thrombosis signs; no renal adjustment; use with caution in hereditary fructose intolerance.
• Apixaban or rivaroxaban: andexanet alfa, low dose 400 mg intravenous bolus at 30 mg/minute then 4 mg/minute for up to 120 minutes, or high dose 800 mg bolus then 8 mg/minute for up to 120 minutes (high dose when apixaban exceeds 5 mg, rivaroxaban exceeds 10 mg, the dose is unknown, or the last dose was under 8 hours ago). Alternatively prothrombin complex concentrate 50 units/kg (maximum 5000 units). Monitor thrombosis signs and anti-factor Xa levels; avoid in recent thrombosis unless benefit outweighs risk; resume anticoagulation as soon as safe.
• Platelet transfusion is not advised for antiplatelet related bleeding unless surgery is planned.
• Correct glucose, temperature and seizures; levetiracetam 500 mg orally or intravenously twice daily, increased as needed to a maximum of 1500 mg twice daily, only for clinical seizures. Reduce dose when creatinine clearance is 50 to 80 mL/min (500 to 1000 mg twice daily), 30 to 50 mL/min (250 to 750 mg twice daily) and under 30 mL/min (250 to 500 mg twice daily).
• Neurosurgery review for large haematoma with mass effect or hydrocephalus; haemicraniectomy or evacuation is considered case by case.
• Restart antithrombotic therapy later by the underlying indication, usually 1 to 4 weeks after stable repeat imaging.

Monitoring. Neurological observations every 15 minutes at first; repeat CT at 6 and 24 hours and with any change; track coagulation and platelets.

Referral and escalation. Immediate neurosurgical and intensive care contact for deterioration; haematology for reversal difficulties.

Special groups. Older adults and those with renal impairment have higher risk and need closer monitoring of anticoagulant levels.