RV dysfunction by MRI is associated with elevated transpulmonary gradient and poor prognosis in patients with sickle cell associated pulmonary hypertension

Patients with sickle cell disease (SCD) and pulmonary hypertension (PH) have increased mortality. SCD-PH is often complicated by high cardiac output (CO) related to anemia. The transpulmonary gradient (TPG) reflects a pressure differential across the pulmonary vascular bed without the confounding effect of CO (PVR=TPG/CO). Based on the cardiac transplant literature, a TPG ≥ 12 mmHg indicates significant pulmonary arterial hypertension (PAH). With PH, there is often morphologic adaptation by the right ventricle (RV). In idiopathic PAH, RV dilation and decreased function have been correlated with poor prognosis. We hypothesize that patients with SCD and a TPG ≥ 12 mmHg would have lower functional capacity, increased mortality, and evidence of RV dysfunction on cardiac MRI (CMR)

Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study.

BACKGROUND: Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort. METHODS: Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation. RESULTS: Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p \u3c 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p \u3c 0.0001) were also independent risk factors for mortality. CONCLUSIONS: Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov

Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design

Experimental and Psychological Pain Phenotyping In Adults With Sickle Cell Anemia and Normal Volunteers

Abstract Introduction Sickle cell anemia (SCA) is the most prevalent Mendelian disease in the U.S. and is characterized by HbS polymerization, hemolytic anemia and vaso-occlusion. The hallmark clinical manifestation of SCA is acute vaso-occlusive pain crisis (VOC) with severe episodes requiring hospitalization for pain management. Vaso-occlusion resulting in pain is believed to occur with hypoxia, intra-vascular erythrocyte sickling and ischemia reperfusion injury. Recurring episodes of VOC often have no clear causation and may have effects upon physiological pain perception and intrinsic psychological characteristics like catastrophizing. It is not presently known if physiological pain processing or psychological factors influence pain in SCA compared to normal volunteers (NV). We hypothesized that adults with SCA would experience hypersensitivity to painful stimuli compared to NV as seen in other chronic painful conditions. Methods 18 subjects with SCA and 19 age and sex matched NV underwent quantitative sensory testing (QST) for thermal, pressure and ischemic experimental pain phenotypes. Thermal testing (cold and heat) was performed at 4 sites on the volar forearm for temperature at first detection, threshold for sensing pain, and pain tolerance. Pressure pain threshold and tolerance were measured bilaterally at the thumb, forearm, and trapezius with an algometer. Ischemic pain testing was performed on the non-dominant arm inflating a blood pressure cuff of 220 mmHg and determining time to threshold and tolerance. Subjects were also administered the Pain Catastrophizing Scale (PCS-E) which is composed of 13 questions that address 3 dimensions: rumination, magnification, and helplessness. SCA and NV subjects with chronic pain unrelated to complications of SCA were excluded. All SCA subjects tested at baseline pain levels at least 2 weeks since their last painful event requiring intravenous narcotics. Non-parametric t-tests were used to compare results between SCA subjects and NV. Results The mean age of SCA subjects was 33.4 (range 21-47) and NV was 32.1 (range 18-44). The only significant difference for thermal QST was temperature at first cold detection (SCA mean 24.5±6.3 ¢ªC vs. NV mean of 26.6±4.7 ¢ªC, P=0.05). There were no other significant thermal differences between SCA subjects and NV for cold pain threshold (P=0.84), cold pain tolerance (P=0.82), first heat detection (P=0.21), heat pain threshold (P=0.68) or heat pain tolerance (P=0.38). Furthermore, there were no differences in pressure between SCA and NV for pain thresholds at the thumb (P=0.31), forearm (P=0.44) or trapezius (P=0.10), nor were there pain tolerance differences at the thumb (P=0.63), forearm (P0.98) or trapezius (P=0.44). Surprisingly, ischemic pain QST showed no differences for initial pain threshold (468.3±263.1 seconds for SCA vs. 569.6±395.8 seconds for NV, P=0.69) or pain tolerance (642.5±245.4 seconds for SCA vs. 774.4±453.5 seconds for NV). Compared to NV, SCA subjects had significantly higher total catastrophizing (SCA median 30 vs. NV median 7, P=0.0005), rumination (SCA median 12 vs. NV median 3, P=0.0038), magnification (SCA median 8 vs. NV median 3, P=0.0006), and helplessness scores (SCA median 13 vs. NV median 3, P=0.0004). Conclusions Thermal detection of cold temperature change was the only observed difference, despite our hypothesis that recurrent painful episodes from SCA would alter sensitivity to experimental stimuli. Of particular interest are the results of ischemic pain QST, where SCA subjects appear to tolerate ischemia as well as NV despite the expectation this test would promote earlier forearm hypoxia, erythrocyte sickling and potentially vaso-occlusion. No significant difference in onset of ischemic pain between SCA and NV subjects appears to contradict the predominant pain vaso-occlusion paradigm for SCA. In addition, SCA subjects report significant levels of pain castastrophizing. Catastrophizing in other pain conditions may contribute to a psychological state that increases the severity of pain perception and a fear that pain control is impossible. Thus, catastrophizing may enhance chronic pain, pain impact, and its refractory response to pharmacotherapy. Further studies are necessary to determine if experimental pain or catastrophizing are associated with acute pain or chronic pain in SCA and to further elucidate the pathophysiology of pain in SCA. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Thrombin Generation in Sickle Cell Disease: Insights From Computerized Automated Thrombography.

Abstract Abstract 2587 Poster Board II-563 Background: SCD is considered to be a hypercoagulable state. Because of the great complexity of the hemostatic system it has not been easy to establish an etiological link between hypercoagulability and SCD vascular pathology. In this study we evaluate hemostatic perturbations in adult SCD patients by employing the computerized automated thrombogram (CAT), a novel thrombin generation assay that provides a global measure of coagulation potential and a direct assessment of the coagulation phenotype (Hemker HC et al.,Thromb Haemost. 2006; 96:553–61). We aim to characterize the coagulation phenotype of the SCD patient by a panel of CAT assay parameters. Methods: A total of 23 SCD patients (HbSS and HbSbeta0Thalassemia; 18 –58 years) were evaluated. Control group consisted of 6 age-matched controls (males=3, females=3). SCD plasma samples were obtained at baseline during routine clinic visits. Platelet poor plasma (PPP) ± corn trypsin inhibitor (CTI) - to minimize variability from activation of contact pathway during sample collection- was analyzed by CAT using 2 different triggers for initiation of thrombin generation: i) High trigger –5pM Tissue factor (TF) with 4uM phospholipid (PL) and ii) Low trigger- 1pM TF with 4uM PL. Five CAT assay parameters were studied – Lag time, Endogenous thrombin potential (ETP), Peak thrombin (Peak), Time to peak (ttPeak) and Start Tail. Students t-test was used to compare means of CAT assay parameters between SCD patients and controls. Lactate dehydrogenase (a biomarker of hemolysis-associated nitric oxide resistance and endothelial dysfunction) correlated with CAT assay parameters including lagtime (r= −0.35, p=0.05); ttPeak (r=−0.45, p&lt;0.02) and start tail (r=−0.47, p=0.01). Summary: In this study interesting differences in kinetics of thrombin generation were noted between SCD patients and controls as follows: Thrombin generation with high trigger demonstrated a rapid burst of thrombin generation in SCD plasma (shorter lagtime, lesser ttpeak) vs. controls. Overall lower and less sustained thrombin generation (i.e. decreased ETP and early start tail) followed this rapid burst in SCD. Thrombin generation with low trigger also showed significantly decreased ttpeak of thrombin generation in SCD with similar overall lower thrombin generation and early start tail. ETP, Peak thrombin level, and ttPeak have shown correlations with clinical hypercoagulable states evaluated by the CAT assay. We speculate that this paradoxical upsurge of thrombin generation with swift attenuation suggests the presence of a compensatory upregulation of Tissue Factor Pathway Inhibitor (TFPI) or anticoagulant responses in SCD that results in rapid quenching of thrombin generation. Additionally, we have previously shown that heme, a product of intravascular hemolysis, upregulates endothelial TF (J Thromb Haemost. 2008; 12:2202–9). The observed relationship between increased LDH and evidence of rapid response of thrombin generation is in keeping with this result. These preliminary data support the use of the CAT assay in further detailed analyses of mechanisms of thrombin generation in SCD. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Hemodynamic Parameters Predict Mortality In Sickle Cell Disease-Related Pulmonary Hypertension

Abstract Abstract 2668 Background: Indirect markers of pulmonary hypertension (PH) are associated with significant risk of early mortality in adults with sickle cell disease (SCD). Currently, there are limited data on hemodynamic predictors of mortality in PH patients with SCD. Objective: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patient with SCD-related PH documented by right heart catheterization (RHC). Methods: We collected hemodynamic data from 86 consecutive adults with SCD who underwent RHC based on elevated tricuspid regurgitant velocity (TRV) on echocardiography and clinical suspicion of PH. Survival rates from the time of diagnosis of PH by RHC and dates of enrollment were estimated by the Kaplan-Meier method. Mortality risk factors were analyzed by the Cox proportional hazards regression. Patients found to have PH by RHC (mean pulmonary artery pressure ≥25 mmHg). were compared to 447 general sickle patients for hemolytic markers, TRV, exercise capacity and overall survival. For a highly stringent definition of pulmonary arterial hypertension (PAH), we utilized a highly conservative pulmonary vascular resistance (PVR) cutoff of 3 Woods' units, approximately six standard deviations (SD) above normal in adults with SCD. Pulmonary venous hypertension (PVH) was defined by pulmonary capillary wedge pressure &gt;15 mmHg. Results: Fifty six (65%) patients from the RHC cohort had PH. The PH group had significantly higher hemolytic markers (serum lactate dehydrogenase (LDH), aspartate aminotransferase, bilirubin), higher TRV (3.3 ± 0.5 vs. 2.3 ± 0.5 m/s, mean ± SD, P&lt;0.001), and lower six minute walk distance (358 ± 113 vs. 486 ± 88 m, P&lt;0.001) as compared to the general sickle cell group. Further hemodynamic characterization of the PH group showed 25 (44.6%) patients with PVH, 16 (28.6 %) patients with PAH and 15 (26.8 %) patients having PH with less elevated resistance and normal PCWP characterized by very high cardiac output (mean CO=9.6 ± 2.5 L/min). During a median follow-up of 4 years, the overall mortality rate was higher in the PH group (19 deaths, 34%) than either the group without PH by RHC (3 deaths, 10%) (hazard ratio [HR] 3.55, P=0.03 ) or the general sickle cell group (50 deaths, 13%) (HR 2.49, P &lt;0.001). Survival estimates for the PH versus without PH were 88.7% vs. 100% at 1 year; 73.2% vs. 92% at 3 years; and 61.5% vs. 84.9% at 5 years. The estimated median survival time was 6.4 years for patients with PH. Survival was not significantly different between the three PH subgroups. All three of the PH subgroups showed significantly high LDH levels: PVH (458 ± 252 IU/L, P=0.011), PAH (430 ± 189 IU/L, P=0.027), and PH with less elevated PVR/normal PCWP (525 ± 262 IU/L, P=0.002), compared to SCD controls (339 ± 151 IU/L). All three PH groups also showed functional impairment in their six minute walk distance: PVH (331 ± 116 m, P&lt;0.001), PAH (350 ± 115 m, P&lt;0.001), and PH with less elevated PVR/normal PCWP (416 ± 90 m, P=0.004), compared to SCD controls (486 ± 88 m). Univariate Cox regression analysis identified the following predictors of overall survival: pulmonary artery systolic pressure (HR 1.02; P=0.041), pulmonary artery diastolic pressure (HR 1.06; P=0.008), mean pulmonary artery pressure (HR 1.04; P=0.015), transpulmonary gradient (HR 1.05; P=0.014), indexed pulmonary vascular resistance (HR 1.18 each Wood's unit; P=0.005) and six minute walk distance (HR 0.60 each 100 m change; P=0.01). Conclusion: Mortality in SCD related PH is high and is directly correlated with typical indicators of PH severity, including specific hemodynamic measures and impaired exercise capacity. This suggests that PH is contributing significantly to early mortality in SCD adults. Less conservative cutoffs for PVR are accepted by many authorities in the setting of high flow, and this would result in even a higher percentage of PAH diagnoses in our analysis. Disclosures: No relevant conflicts of interest to declare. </jats:sec