ABSTRACT
BACKGROUNDS AND PURPOSE: Philadelphia chromosome-negative myeloproliferative disorders (Ph-negative MPD) are a rare group of hematological diseases, including three distinct pathologies: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). They most often manifest with thrombotic complications, including cerebrovascular events. Covert brain infarcts (CBIs) are defin ed as predominantly small ischemic cerebral lesions that are detected using magnetic resonance imaging (MRI) in the absence of clinical stroke events. The relationship between MPD and CBIs remains unclear. METHODS: Included in the study were 103 patients with the diagnosis of Ph-MPD (according to WHO 2016 criteria) (median age-47 (35; 54) years; 67% female). In total, 38 patients had ET, 42 had PV, and 23 had PMF. They underwent clinical examination, routine laboratory analyses (complete blood count), brain MRI, ultrasound carotid artery, flow-mediated dilatation (as a measure of endothelial dysfunction-FMD). RESULTS: Overall, 23 patients experienced an ischemic stroke (as per MRI and/or clinical history), of which 16 (15.5%) could be classified as CBIs. The rate of CBIs per MPD subtype was statistically non-significant between groups (p = 0.35): ET-13.2%, PV-21.4%, and PMF-8.7%. The major vascular risk factors, including arterial hypertension, carotid atherosclerosis, and prior venous thrombosis, were not associated with CBIs (p > 0.05). Age was significantly higher in patients with CBIs compared to patients without MRI ischemic lesions: 50 (43; 57) years vs. 36 (29; 48) (p = 0.002). The frequency of headaches was comparable between the two groups. CBIs were associated with endothelial dysfunction (OR - 0.71 (95% CI: 0.49-0.90; p = 0.02)) and higher hemoglobin levels (OR-1.21 (95% CI: 1.06-1.55); p =0.03). CONCLUSIONS: CBIs are common in patients with Ph-negative MPD. Arterial hypertension and carotid atherosclerosis were not associated with CBIs in this group of patients. The most significant factors in the development of CBIs were endothelial dysfunction (as measured by FMD) and high hemoglobin levels. Patients with Ph-negative MPD and CBIs were older and had more prevalent endothelial dysfunction.
ABSTRACT
BACKGROUND: Disturbances of microcirculation play a significant role in the development and progression of both acute and chronic cerebrovascular diseases (CVD) and may be associated with different hemogram abnormalities. One of the reasons of the prothrombogenic state of the endothelium is the increase in the number of blood corpuscles leading to (non-Ph) myeloproliferative disorders (MPD) including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PM). MATERIALS AND METHODS: The study included 167 patients: 102 patients with Ph-MPD and the control group comprising 65 patients with CVD. According to MPD subtype, the patients were divided into three groups: patients with ET (37%, n = 38, male/female 7/31, age 52 ± 7 years), those with PV (40%, n = 41, male/female 20/21, age 50 ± 6 years) and those with PM (23%, n = 23, male/female 5/18, age 54 ± 4 years). RESULTS: In 79% (n = 81) of cases in the study group (with Ph-MPD), patients had chronic CVD, with the most frequently identified symptoms being asthenia (92%) and headache (72%). Headache in Ph-MPD patients was more frequently (86%) associated with PM, while in patients with PV and ET it was equally distributed (70%). Neurological symptoms in 53% of cases were associated with focal changes of the brain on MRI localized in the subcortical area of the frontal and parietal lobes. Twenty-one (21%) patients suffered an acute cerebrovascular accident, 8 of them had thrombotic occlusion of one of the internal carotid arteries leading to hemispheric infarcts. Endothelial function (as measured by flow-dependent dilation of the brachial artery) was severely impaired in all study groups (median 5% with normal cut-off at 10%), the lowest degree of vasodilator activity being specific for patients with a history of stroke (p = 0.011). CONCLUSION: Patients suffering from MPD had asymptomatic focal changes in the brain in the absence of concomitant vascular disease (hypertension, atherosclerotic vascular disease, heart rhythm disorders) in 50% of cases. MPD, while remaining un- or underdiagnosed, presents a major concern in the cerebrovascular setting. A large number of thrombotic strokes occurring in patients with ET underline the necessity of early diagnostics and preventive therapy in these patients.
ABSTRACT
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in the Notch3 gene altering the number of cysteine residues. METHODS: We directly sequenced exons 2-23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls. RESULTS: We identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations. CONCLUSIONS: In our sample, 60% of Russian patients with 'clinically suspected' CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening.
