Heparin Resistance and Anticoagulation Failure in a Challenging Case of Cerebral Venous Sinus Thrombosis.

We report a challenging case of cerebral venous sinus thrombosis (multiple etiologic factors) that was complicated by heparin resistance secondary to suspected antithrombin III (ATIII) deficiency. A 20-year-old female previously healthy and currently 8 weeks pregnant presented with worsening headaches, nausea, and decreasing Glasgow Coma Scale/Score (GCS), necessitating mechanical ventilatory support. Imaging showed extensive clots in multiple cerebral venous sinuses including the superior sagittal sinus, transverse, sigmoid, jugular veins, and the straight sinus. She was started on systemic anticoagulation and underwent mechanical clot removal and catheter-directed endovascular thrombolysis with limited success. Complicating the intensive care unit care was the development of heparin resistance, with an inability to reach the target partial thomboplastin time (PTT) of 60 to 80 seconds. At her peak heparin dose, she was receiving >35 000 units/24 h, and her PTT was subtherapeutic at <50 seconds. Deficiency of ATIII was suspected as a possible etiology of her heparin resistance. Fresh frozen plasma was administered for ATIII level repletion. Given her high thrombogenic risk and challenges with conventional anticoagulation regimens, we transitioned to argatroban for systemic anticoagulation. Heparin produces its major anticoagulant effect by inactivating thrombin and factor X through an AT-dependent mechanism. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and the AT. A deficiency of AT leads to a hypercoagulable state and decreased efficacy of heparin that places patients at high risk of thromboembolism. Heparin resistance, especially in the setting of critical illness, should raise the index of suspicion for AT deficiency. Argatroban is an alternate agent for systemic anticoagulation in the setting of heparin resistance.

Implementation of an institution-wide acute stroke algorithm: Improving stroke quality metrics.

BACKGROUND: In May 2012, an updated stroke algorithm was implemented at Vanderbilt University Medical Center. The current study objectives were to: (1) describe the process of implementing a new stroke algorithm and (2) compare pre- and post-algorithm quality improvement (QI) metrics, specificaly door to computed tomography time (DTCT), door to neurology time (DTN), and door to tPA administration time (DTT). METHODS: Our institutional stroke algorithm underwent extensive revision, with a focus on removing variability, streamlining care, and improving time delays. The updated stroke algorithm was implemented in May 2012. Three primary stroke QI metrics were evaluated over four separate 3-month time points, one pre- and three post-algorithm periods. RESULTS: The following data points improved after algorithm implementation: average DTCT decreased from 39.9 to 12.8 min (P < 0.001); average DTN decreased from 34.1 to 8.2 min (P ≤ 0.001), and average DTT decreased from 62.5 to 43.5 min (P = 0.17). CONCLUSION: A new stroke protocol that prioritized neurointervention at our institution resulted in significant lowering in the DTCT and DTN, with a nonsignificant improvement in DTT.

Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis.

BACKGROUND AND PURPOSE: A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial stenosis is cerebrovascular reactivity (CVR) mapping using noninvasive MRI. Here, abilities to measure CVR safely in the clinic using hypercarbic hyperoxic (carbogen) gas challenges, which increase oxygen delivery to tissue, are investigated. METHODS: In sequence with structural and angiographic imaging, blood oxygenation level-dependent carbogen-induced CVR scans were performed in patients with symptomatic intracranial stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow-weighted pseudocontinuous arterial spin labeling CVR. Subjects were stratified for 4 substudies to evaluate relationships between (1) carbogen and hypercarbic normoxic CVR in healthy tissue (n=10), (2) carbogen cerebral blood flow CVR and blood oxygenation level-dependent CVR in intracranial stenosis patients (n=57), (3) carbogen CVR and clinical measures of disease in patients with asymmetrical intracranial atherosclerotic (n=31) and moyamoya (n=29) disease, and (4) the CVR scan and immediate and longer-term complications (n=92). RESULTS: Noninvasive blood oxygenation level-dependent carbogen-induced CVR values correlate with (1) lobar hypercarbic normoxic gas stimuli in healthy tissue (R=0.92; P<0.001), (2) carbogen-induced cerebral blood flow CVR in patients with intracranial stenosis (R=0.30-0.33; P<0.012), and (3) angiographic measures of disease severity both in atherosclerotic and moyamoya patients after appropriate processing. No immediate stroke-related complications were reported in response to carbogen administration; longer-term neurological events fell within the range for expected events in this patient population. CONCLUSIONS: Carbogen-induced CVR elicited no added adverse events and provided a surrogate marker of cerebrovascular reserve consistent with intracranial vasculopathy.

ADHD drugs and serious cardiovascular events in children and young adults.

BACKGROUND: Adverse-event reports from North America have raised concern that the use of drugs for attention deficit-hyperactivity disorder (ADHD) increases the risk of serious cardiovascular events. METHODS: We conducted a retrospective cohort study with automated data from four health plans (Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente California, and OptumInsight Epidemiology), with 1,200,438 children and young adults between the ages of 2 and 24 years and 2,579,104 person-years of follow-up, including 373,667 person-years of current use of ADHD drugs. We identified serious cardiovascular events (sudden cardiac death, acute myocardial infarction, and stroke) from health-plan data and vital records, with end points validated by medical-record review. We estimated the relative risk of end points among current users, as compared with nonusers, with hazard ratios from Cox regression models. RESULTS: Cohort members had 81 serious cardiovascular events (3.1 per 100,000 person-years). Current users of ADHD drugs were not at increased risk for serious cardiovascular events (adjusted hazard ratio, 0.75; 95% confidence interval [CI], 0.31 to 1.85). Risk was not increased for any of the individual end points, or for current users as compared with former users (adjusted hazard ratio, 0.70; 95% CI, 0.29 to 1.72). Alternative analyses addressing several study assumptions also showed no significant association between the use of an ADHD drug and the risk of a study end point. CONCLUSIONS: This large study showed no evidence that current use of an ADHD drug was associated with an increased risk of serious cardiovascular events, although the upper limit of the 95% confidence interval indicated that a doubling of the risk could not be ruled out. However, the absolute magnitude of such an increased risk would be low. (Funded by the Agency for Healthcare Research and Quality and the Food and Drug Administration.).

Killer proteases and little strokes--how the things that do not kill you make you stronger.

The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.