Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia
brief summary
Hypothesis Efficient unloading of oxygen to regions of high metabolic demand requires a healthy microvasculature to sense local oxygen tension and regulate flow, accordingly. In sickle cell disease patients, the investigators have demonstrated oxygen supply-demand mismatch, or SDM, in proportion to anemia severity. SDM occurs in both the peripheral circulation and the brain, and four characteristics: 1) Hyperemia beyond expected for the level of anemia, 2) Corresponding loss of vascular dilatory reserve, 3) Impaired oxygen unloading to the tissues, and 4) Tissue hypoxia. In sickle cell disease, red blood cell (RBC) and white blood cell (WBC) adhere to vascular endothelium triggering transient or irreversible microvascular damage as well as releasing vasoactive substances that contribute to microvascular dysregulation. The investigators postulate that ongoing microvascular damage/dysregulation in the setting of increased total blood flow contributes to SDM. The investigators believe SEG101, by lowering RBC and WBC adhesion to the microvasculature, will improve SDM and tissue oxygenation. Objectives * Primary - The investigators will test whether SEG101 improves SDM in patients with sickle cell anemia by measuring the change in tissue oxygenation measured by near infrared spectroscopy (NIRS). * Secondary/Exploratory - The investigators will identify end-organ disease and whether improvement of SDM by SEG101 occurs in patients with sickle cell anemia.
detailed description
Objectives Primary Objectives 1. The investigators will test whether SEG101 improves Supply-Demand Matching in patients with sickle cell anemia measured by the change in tissue oxygenation by NIRS.
a) This is measured as a percent oxyhemoglobin saturation (%).
Secondary Objectives
1. Secondary measures to assess the change in tissue oxygenation will be
1. In the somatic peripheral circulation - microcirculatory perfusion at rest and post-ischemia by laser doppler, venous oxygen saturation by venous blood gas and co-oximetry, and vasoconstriction by plethysmography. 2. In the cerebral circulation - blood flow by arterial spin labeling, function brain MRI and response to CO2 challenge, sagittal sinus saturation by TRUST and tissue oxygen extraction by asymmetric spin echo. 3. In the pulmonary vasculature - Pulmonary circulation - sleep study pulse oximetry for oxygenation and vasoconstriction by plethysmography, tricuspid regurgitant jet velocity (TRV) with echo markers of diastolic function to balance pulmonary vascular vs. left heart etiology of TRV. 2. Determine the relationship between SDM biomarkers and hemoglobin level (anemia).
a) Hemoglobin and hematocrit for interaction between SDM and anemia 3. The investigators will determine whether low SDM predicts end-organ function in sickle cell anemia as compared to controls. These endpoints will be organ specific associations:
a) eGFR and urinalysis for kidney, myocardial fibrosis, systolic/diastolic heart function, troponin and NT-pro-BNP 4. Relationship between markers of cellular adhesion, oxidative stress and inflammation, soluble VCAM and soluble P-selection.
a) Interaction of SDM with soluble markers of adhesion and inflammation. 5. The investigators will identify interactions based on age and sex.
a) Sex and gender related differences will act as covariates for all measures because many cardiovascular metrics have significant sex differences 6. Clinical Outcome Measures
1. VOC history and prospective VOC burden. 2. Blood pressure and ECG abnormalities/arrhythmias
Overall Design: The study will be performed at a single large sickle cell disease Centers of Excellence, Children's Hospital of Los Angeles in California, in 20 patients with sickle cell disease who will receive SEG101 therapy and 10 sickle cell anemia subjects who will not receive therapy. Full inclusion and exclusion criteria are defined in the human subjects section but sickle cell disease patients will be 16 years of age, or older (to be able to cooperate with the MRI examination without anesthesia), and free from hospitalization or emergency room visit for one month prior to the study. Entire cohort will be gender balanced.