Thrombolytic therapy for the treatment of acute ischaemic stroke in adults with homozygous sickle cell disease

Abstract

Stroke is a significant cause of morbidity and mortality in patients with homozygous sickle cell disease (SCD). A specific large-vessel vasculopathy is often responsible for both haemorrhagic and ischaemic strokes in patients with SCD. Although intravenous thrombolysis has been considered as a therapeutic option for acute ischaemic strokes in SCD, its use remains debated because of an increased risk of spontaneous intracranial haemorrhage reported in this disease. This risk of haemorrhage is mainly supported by the presence of a Moyamoya syndrome often associated with the specific vasculopathy in patients with homozygous SCD. We report two cases of patients with homozygous SCD treated with intravenous thrombolysis for an acute ischaemic stroke without haemorrhagic transformation. Our cases suggest that reperfusion strategy in acute ischaemic stroke in patients with homozygous SCD can be considered once associated Moyamoya syndrome has been ruled out. An international registry would be of interest as these situations are rare.

Background

Stroke is one of the most critical complications associated with sickle cell disease (SCD), causing physical and cognitive disability and deaths.¹ The risk of stroke differs according to SCD genotype and is the highest in patients with homozygous SCD often due to a specific, mainly intracranial, vasculopathy.² Although intravenous thrombolysis has been considered as a therapeutic option for acute ischaemic strokes in SCD, its use remains debated because of an increased risk of spontaneous intracranial haemorrhage in that disease.^{3 4} We report here two cases of adult patients with homozygous SCD with acute ischaemic stroke treated with intravenous thrombolysis.

Case presentation

Case 1

An SS SCD 48-year-old man was admitted at the emergency department on January 2014 for sudden left hemiplegia. He had past medical history of previous transient ischaemic attack (TIA) of undetermined cause—intracranial vasculopathy had been rule out at that time, heart failure and hypertension. He had no vaso-occlusive crisis since 2000. He was treated with blood exchange transfusion (BET) every 6 weeks since TIA that occurred 13 years earlier. The last BET was performed the day before stroke onset (haemoglobin S (HbS) was 29.6% after BET). Other treatment included clopidogrel and bisoprolol. Examination at admission in the emergency room revealed dysarthria, left hemiparesis and hypoaesthesia with a National Institutes of Health Stroke Scale (NIHSS) of 10. Blood pressure was 149/105 mm Hg. ECG showed regular sinusal rhythm. On admission, brain MRI showed acute anterior cerebral artery (ACA) territory infarction (figure 1A,B), previous cerebral infarction in the left hemisphere (figure 1C) and no evidence of haemorrhagic lesions (figure 1D). There was neither occlusion nor proximal stenosis of intracranial arteries on MR angiography (MRA), nor sign of associated Moyamoya syndrome (figure 1E). Blood tests revealed haemoglobin of 9.8 g/dL, other haematological and biochemical findings were normal. Recombinant tissue plasminogen activator (tPA) was administered (0.9 mg/kg) intravenously 170 min after symptoms onset. The patient underwent neurological improvement with a NIHSS Score of 4 at 24 hours after thrombolysis. MRI performed 24 hours after thrombolysis showed partial reversal of ACA territory infarction (figure 2F,G,H) and no evidence for haemorrhagic transformation (figure 2I). The aetiological arterial workup including Doppler and CT angiogram did not show any arterial lesion. Standard blood tests and resistance test to antiplatelet therapy (clopidogrel) were normal. Cardiac investigations found a global hypokinesis and dilated left atrium. The high probability of cardioembolism led to the prescription of vitamin K antagonist. BETs were discontinued in favour of a treatment with hydroxyurea.

Figure 1.

Brain MRI of the first patient before thrombolysis: acute anterior cerebral artery (ACA) territory infarction (A, diffusion weighted imaging (DWI) and B, apparent diffusion coefficient (ADC) map), previous cerebral infarction in the left hemisphere (C, fluid attenuation inversion recovery (FLAIR)). There was no evidence of haemorrhagic lesions on T2 weighted (T2*) (D), no occlusion nor proximal stenosis of intracranial arteries and no sign of Moyamoya syndrome associated (E, 3D-time of flight (TOF)).

Figure 2.

Brain MRI of the first patient 24 hours after thrombolysis: partial diffusion weighted imaging (DWI) lesion reversal (F, DWI, G, apparent diffusion coefficient (ADC) map) of acute anterior cerebral artery (ACA) territory infarction (H, fluid attenuation inversion recovery (FLAIR)) and no evidence of haemorrhagic transformation on T2 weighted (T2*)(I).

Case 2

An SS SCD 20-year-old woman was admitted at the emergency department on July 2013 for sudden onset of slurred speech. She had past medical history of accelerated velocity on transcranial Doppler during childhood and was then treated by BET stopped 2 years earlier because of both normalisation of her transcranial Doppler and no evidence of vasculopathy on MRA. She reported one vaso-occlusive crisis per year and chronic headache. Previous treatment included folic acid. She had been suffering from headache for 2 days before symptoms onset for which a cerebral CT angiography performed did not found any abnormality. Examination at admission in the emergency room revealed right hemiparesis and hypoaesthesia and aphasia (NIHSS of 10). Blood pressure was 112/56 mm Hg. ECG showed regular sinusal rhythm. On admission, brain MRI showed an acute left insular ischaemic infarction. There was no sign of associated Moyamoya syndrome on MRA. Blood tests revealed haemoglobin of 6.5 g/dL, others haematological and biochemical findings were normal. tPA was administered (0.9 mg/kg) intravenously 190 min after symptoms onset. The patient underwent neurological improvement with an NIHSS Score of 2 at 24 hours after thrombolysis. Brain CT performed 24 hours after thrombolysis demonstrated no sign of haemorrhagic transformation. BETs were then started (target haemoglobin between 9 g/dL and 10 g/dL and HbS 30%). Despite a detailed aetiological workup, the cause of the ischaemic stroke remained undetermined.

Outcome and follow-up

The patients were discharged with no disability (modified Rankin Scale 0, NIHSS 0).

Discussion

We report two2 cases of intravenous thrombolysis with tPA at the acute phase of ischaemic stroke in homozygous SCD adults without haemorrhagic complication. Very recently, Adams et al, published a study which represents the largest report on acute stroke in SCD to date.⁵ They showed that symptomatic intracranial haemorrhage was not different between patients with and without SCD after tPA. However, the query on SCD contains no information on specific genotype in this study, the authors did not differentiate HbSC patients from HbSS patients even less patients with and without Moyamoya syndrome. Median age of patients with SCD was high (50 years), and patients with SCD had multiple vascular risk factors suggesting that some of the patients were HbSC and not HbSS and probably that most strokes were not related to the specific sickle cell vasculopathy.

The fear of using intravenous thrombolysis for treatment of acute ischaemic stroke in patients with homozygous SCD is mainly supported by the risk of Moyamoya syndrome often associated with the specific large-vessel vasculopathy in homozygous SCD.⁴ Indeed, the risk of haemorrhage in Moyamoya disease is high,⁶ mostly in adults, with mortality ranging from 7% to 20%.⁷ Thrombolytic therapy in acute ischaemic stroke in adults with SCD is then still debated and sometimes considered as an off-label use of these treatments.³ However, there are various causes of ischaemic stroke in adults with homozygous SCD.⁸ In our two cases, a Moyamoya syndrome associated with the specific SCD large-vessel vasculopathy had been ruled out before initiation of intravenous thrombolysis.

In our patients, we performed intravenous thrombolysis despite the absence of arterial occlusion as it is known that it should not currently influence thrombolysis decisions. Indeed, it is known that distal thrombi can be missed by MRI or CT angiography intravenously and that intravenous thrombolysis also improves in tissue microreperfusion.⁹ In our first case, early management led to a partial reversal of the diffusion weighted imaging (DWI) lesion, known to be associated with sustained tissue salvage mediated by early reperfusion and with favourable outcome.¹⁰

In the homozygous SCD context, combining intravenous thrombolysis with BET as soon as possible is needed to improve the SCD-impaired haemorheology and replace SS red blood cells presenting with procoagulant and abnormal adhesive properties.¹¹

These two cases of intravenous thrombolysis suggest that reperfusion strategy in acute ischaemic stroke in patients with homozygous SCD can be considered once associated Moyamoya syndrome has been ruled out. An international registry would be of interest as these situations are rare.

Learning points.

• Stroke is one of the most critical complications associated with sickle cell disease (SCD), causing physical and cognitive disability and deaths

• The risk of haemorrhage in patients with homozygous SCD is linked to the risk of haemorrhage in Moyamoya syndrome, often associated with a specific vasculopathy in these patients

• Reperfusion strategy with intravenous thrombolysis can be considered in acute ischaemic stroke in patients with homozygous SCD once associated Moyamoya syndrome has been ruled out

• Combining thrombolysis with BET as soon as possible is needed to improve the SCD-impaired haemorheology.