Paroxysmal Nocturnal Hemoglobinuria in ESUS & ETUS
Paroxysmal Nocturnal Hemoglobinuria in ESUS & ETUS
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematological disorder,
 which can cause arterial or venous thrombosis. The frequency of PNH in young patients (< 50
 years old) with embolic stroke (ESUS), transient ischemic attack (ETUS) or superior sagittal
 sinus cerebral venous thrombosis (SSS-CVTUS) of undetermined source, is currently unknown.
 This study proposes to recruit ESUS, ETUS, SSS-CVTUS patients to determine the frequency of
 PNH diagnosis confirmed by flow cytometry in these patient populations.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematological disorder
 leading to red blood cells hemolysis and thrombosis. PNH has been reported to be the cause of
 cerebral venous thrombosis and embolic ischemic strokes and is sometimes diagnosed after the
 ischemic event. In young patients with embolic ischemic stroke of undetermined source (ESUS),
 thrombophilia is usually investigated. However, access to PNH testing is limited. PNH is
 rarely investigated in stroke patients and its contribution to the pathophysiology of ESUS is
 unknown. The investigators hypothesize that this condition is underdiagnosed, resulting in
 potential preventive opportunities being lost, since PNH can be successfully treated.

 This observational study aims to determine the frequency of PNH among young (≤50 years old)
 patients with recent ESUS or embolic transient ischemic attacks (TIA) of undetermined source
 (ETUS) and patients with SSS-CVT of undetermined source (SSS-CVTUS).

 Patients with ESUS or ETUS will be first screened for: (a) evidence of hemolysis based on
 their plasma lactate dehydrogenase (LDH) levels, (b) unexplained anemia based on their
 hemoglobin (Hb) levels, and (c) unexplained cytopenia (e.g., neutropenia and
 thrombocytopenia). Flow cytometry analysis for PNH will be performed with blood samples
 collected from subjects with abnormal level of plasma LDH (1.5X ULN) or unexplained anemia or
 cytopenia.

 Patients with SSS-CVTUS will undergo flow cytometry without prior screening.

 In addition, plasma and DNA samples will be collected in an optional sub-study for future
 analysis of DNA mutations related to specific PNH phenotypes in patients with stroke.
Inclusion Criteria:

 General:

 -  Participants with embolic ischemic stroke (ESUS), embolic transient ischemic attack
 (ETUS) or cerebral venous thrombosis (CVTUS) of undetermined source.

 For transient ischemic attack (TIA):

 One of the following criteria needs to be fulfilled to be considered as embolic TIA:

 -  Focal symptoms suggesting involvement of de cerebral cortex in the middle cerebral
 artery (MCA) territory (e.g., aphasia, neglect, apraxia, dystextia, anosognosia,
 isolated leg, arm or hand weakness). Some of these symptoms have been described as
 associated with subcortical fibers connecting cortical areas as well but, despite
 this, they are usually related to cortical localizations. Patients with hemianopia
 will be included only if hemianopia is not the primary symptom or an isolated symptom.

 -  Rapidly resolving hemispheric symptoms. This concept comprises two components: (a)
 sudden onset hemispheric syndrome: sudden onset of symptoms and signs implicating
 extensive ischemia in the internal carotid artery (ICA) or MCA territories, including
 hemiparesis, hemianopia, conjugate eye deviation, other cortical signs, or altered
 consciousness; and (b) spectacular shrinking deficit: improvement within 24 hours
 (approximately).

 -  Symptoms involving more than one vascular territory within a single hemisphere (e.g.
 left sided weakness + left homonymous hemianopia) or both (e.g., left sided weakness
 and aphasia in a right-handed patient).

 -  Simultaneous embolization to other organs (e.g., bowel, spleen, liver, kidneys, toes).

 -  Transient monocular blindness (amaurosis fugax) with no evidence of giant cell
 arteritis (e.g., normal erythrocyte sedimentation rate).

 -  No definite cortical symptoms but neuroimaging evidence of prior (chronic) typical
 infarct (wedge shaped, involving the cerebral cortex).

 All of the following criteria must be fulfilled to be considered as TIA of undetermined
 source:

 -  No neuroimaging evidence of an acute brain infarct within the brain region(s)
 responsible for the presenting symptoms.

 -  Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis
 in arteries supplying the area of ischemia.

 -  No major-risk cardioembolic source of embolism.

 -  No other specific cause of stroke identified (e.g., arteritis, dissection, migraine,
 vasospasm, or drug abuse).

 -  No persistent neurological focal symptoms at the time of neurological examination. The
 presence of persistent neurological focal symptoms in the absence of a visible brain
 infarct on DWI MRI will be regarded as a "clinically confirmed stroke with negative
 DWI MRI".

 Exclusion Criteria:

 General:

 -  Inability to provide informed consent

 For stroke patients:

 -  Evidence of >50% stenosis of the internal carotid artery (ICA) or MCA ipsilateral to
 the qualifying ischemic stroke on neurovascular imaging studies.

 -  Ischemic stroke involving deep structures and measuring < 15 mm on diffusion-weighted
 (DWI) magnetic resonance imaging (MRI). Cortical strokes measuring <15 mm will qualify
 to be included in the study.

 -  Evidence of a cause explaining the stroke (e.g. hypercoagulable state or any other
 major source of cardiac embolism).

 For TIA patients:

 -  Patients no fulfilling the criteria for ETUS.

 For cerebral venous thrombosis patients:

 -  Subjects without involvement of the superior sagittal sinus (SSS)

 -  Subjects with an evident cause explaining the thrombosis (e.g., thrombophilia)