Usual Clinical Parameters Underestimate the Incidence and Significance of Erythropoietin Deficiency as a Risk Factor for Death in Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3791-3791
Author(s):  
Santosh Saraf ◽  
Seema Sidhwani ◽  
Mohammed Farooqui ◽  
Stephen Vara ◽  
Joseph DeSimone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Early Death ◽  
Organ Damage ◽  
Endocrine Function ◽  
Clinical Parameters ◽  
Cell Disease ◽  
Epo Deficiency

Abstract A robust reticulocytosis is necessary to maintain hemoglobin levels compatible with life in patients with sickle cell disease. Relative reticulocytopenia, defined as a absolute reticulocyte count less than 250 x 109/L despite hemoglobin <9g/dl, has been identified as a risk factor for early death. RR could result from chronic bone marrow vaso-occlusive insult or a renal endocrine defect leading to erythropoietin (EPO) deficiency. In non-SCD patients, EPO levels and creatinine clearance are clinical parameters that are used to define patients with anemia from EPO deficiency. The normal ranges for these parameters may not apply to SCD, and therefore the incidence and significance of EPO deficiency in SCD may have been underestimated, compromising rational EPO replacement therapy. In a retrospective analysis of 417 patients with HbSS or S-β-thalassemia, confirming previous findings, RR was a risk factor for early death. There was a significant association between RR and proteinuria. Usually, there is an inverse correlation between hemoglobin and EPO levels (negative feed-back), this was seen in patients without RR. However, in patients with proteinuria, the correlation between hemoglobin and EPO levels was a positive one, suggesting hemoglobin dependence on EPO levels. Proteinuria or increased creatinine levels were a risk factor for early death but not if RR was included in the model, suggesting the increased risk of death associated with proteinuria and creatinine was mediated by RR. RR was also associated with decreased platelet and WBC counts, suggesting a contribution by cumulative vaso-occlusive bone marrow damage to RR. However, platelet and WBC counts were not risk factors for early death within the cohort. Damage to renal endocrine function/EPO deficiency should be added to the list of clinically significant chronic organ damage in SCD. EPO deficiency may precede and be causative of other end-organ damage, such as cardiac diastolic dysfunction and renal exocrine failure. Proteinuria should be recognized as a clinical parameter that should prompt consideration of EPO deficiency. Since EPO replacement is clinically feasible, renal endocrine dysfunctiton is a cause of symptoms, clinical deterioration and death that could be rationally addressed.

scholarly journals Hemopexin deficiency promotes acute kidney injury in sickle cell disease

Blood ◽  
2020 ◽  
Author(s):  
Solomon Ofori-Acquah ◽  
Rimi Hazra ◽  
Oluwaseun O Orikogbo ◽  
Danielle Crosby ◽  
Bethany Flage ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Risk Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Inflammatory Process ◽  
Clinical Evidence ◽  
Kidney Injury ◽  
Red Cell ◽  
Cell Disease

Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD however the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in alpha-1-microglobulin (A1M) resulting in up to 10-fold higher A1M/hemopexin ratio in SCD compared to health controls. The A1M/hemopexin ratio is associated with markers of hemolysis and AKI in both humans and mice with SCD. Studies in mice showed that excess heme is directed to the kidneys in SCD in a process involving A1M causing AKI while excess heme in controls is transported to the liver as expected. Using genetic and bone marrow chimeric tools, we confirmed that hemopexin deficiency promotes AKI in sickle mice under hemolytic stress. However, AKI was blocked when hemopexin deficiency in sickle mice was corrected with infusions of purified hemopexin prior to the induction of hemolytic stress. This study identifies acquired hemopexin deficiency as a risk factor of AKI in SCD and hemopexin replacement as a potential therapy.

Low Bone Density In Sickle Cell Disease Is a Risk Factor in The Development Of Avascular Necrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4688-4688
Author(s):  
Hassan A. Al-Jafar ◽  
Leena M Aytoglu ◽  
Jehan Al-Shemmari ◽  
Uzma Afzal ◽  
Iman Al-Shemmari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Bone Density ◽  
Sickle Cell Disease ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Bone Mineral ◽  
Cell Disease ◽  
Bone Marrow Scintigraphy ◽  
Low Bone Density

Introduction Sickle cell disease (SCD) is a highly prevalent disorder in the world, specifically in the region of Kuwait. A wide population suffers from sickle cell anaemia. It has been known that bone involvement is one of the most common clinical manifestations of sickle cell disease, both in the acute setting such as painful vaso-occlusive crises, and as a chronic, progressive process such as osteoporosis ,osteopenia and avascular necrosis (AVN), which can develop due to the low bone mass and the deterioration of the micro architecture of bone tissue. In this ongoing project, we used the radionuclide imaging technique for bone and bone marrow scintigraphy and dual-energy x-ray absorptiometry (DEXA). We attempted a correlation between low bone density and the bone infarct for SCD, and identified if low bone density is a risk factor for the severity and development of osteonecrosis in an at-risk population of sickle cell patients. Patients and Methods A total of 13 sickle cell patients participated in this correlation study; 5 males and 8 females, ages ranged from 16 to 55 years with a mean age of 35.5 years. To meet the participant selection criteria, patients were selected if they were never prescribed bisphosphonates or any type of medicine used to help strengthen bones weakened by osteoporosis, nor exposed to any other AVN risk factors other than SCD. Subjects were subjected to a scintigraphy (3-phase bone SPECT-CT, bone marrow) and bone mineral density scan (BMD). All subjects consented to the study approved by the ethics committee. Bone scintigraphy was performed by Tc-99m MDP, HDP 20mCi / 70kg intravenous injection. Bone Marrow Scintigraphy was performed by Tc-99m sulfur or tin colloid, 10-15 mCi / 70 kg I.V, Bone with Bone marrow scintigraphy imaging is required to assess bone marrow infarction and infection. BMD dual-energy x-ray absorptiometry (DEXA) was also performed to indicate the reliably changes in bone mineral content of the lumbar spine and proximal femur. Statistical analysis involved descriptive statistics and chi-square test. Results According to the WHO criteria used; low bone density was found in 9/13 (69%) while normal bone density was found in 4/13 patients (31 %). Based upon the application of a chi-square test, all those subjects 9/9 having a low bone density were showing AVN in several severity and multiple sites of the skeleton; it was found that there is an association between low bone density and incidents of AVN. However, it is of importance to note that 2/4 (50%) of the normal bone density patients were found to have AVN. Conclusion The preliminary conclusion discern from this ongoing project suggest that low bone mineral density in SCD could be considered a risk factor contributing to the development of AVN. We hypothesise that the severity of AVN develops due to the low bone mass and the deterioration of the micro architecture of bone tissue. The results have shown that low bone density is highly associated with osteonecrosis. Further case studies are needed to confirm or disprove these findings. The findings of this project could inspire new protocols required for effective management of this disease. Our findings could also potentially point out and diagnose new clinical cases, which would normally not be clinically suspected. We also speculate that increasing bone density of this patient population may decrease the severity and incidents of AVN. References 1-Sch2-nog JB, Duits AJ, Muskiet FA, ten Cate H, Rojer RA, Brandjes DP. Sickle cell disease; a general overview. Neth J Med. 2004 Nov;62(10):364-74. Review. PubMed citation 2-Digiovanni, Cw; Patel, A; Calfee, R; Nickisch, F (Apr 2007). “Osteonecrosis in the foot”. The Journal of the American Academy of Orthopaedic Surgeons 15 (4): 208–17. ISSN 1067-151X. PMID 17426292. 3-eMedicine Specialties > Avascular NecrosisAuthor: Jeanne K Tofferi, MD, MPH, FACP; Coauthor: William Gilliland, MD, MPHE, FACP, FACR. Updated: Dec 17, 2009 4-Baksi, Dp (May 1983). “Treatment of post-traumatic avascular necrosis of the femoral head by multiple drilling and muscle-pedicle bone grafting. Preliminary report”. The Journal of bone and joint surgery. British volume 65 (3): 268–73. ISSN 0301-620X. PMID 6341373. Disclosures: No relevant conflicts of interest to declare.

Low Mortality In Sickle Cell Patient Cohort with Elevated Tricuspid Regurgitant Jet Flow Velocity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1641-1641
Author(s):  
Eduard J. Beers van ◽  
Charlotte F.J. Tuijn ◽  
Erfan Nur ◽  
Anita W. Rijneveld ◽  
M. R. Mac Gillavry ◽  
...  
Keyword(s):  
Risk Factor ◽  
Sickle Cell Disease ◽  
Mortality Rate ◽  
Pulmonary Function ◽  
Brain Natriuretic Peptide ◽  
Sickle Cell ◽  
Plasma Levels ◽  
Early Death ◽  
Cell Disease

Abstract Abstract 1641 Elevated tricuspid regurgitant jet flow velocity (TRV) occurs in approximately 30% of adults with sickle cell disease (SCD) and is reported to be an independent risk factor for early death with a mortality rate as high as 40% after 4 years. We previously presented the results on a cohort of 85 consecutive ambulatory sickle cell patients that were prospectively screened for elevated TRV (2.5 m/sec) using trans-thoracic echocardiography. We aimed to determine the mortality rate in relation to TRV and associated factors in a well characterized cohort of sickle cell disease patients in the Netherlands. Follow up consisted of regular outpatient visits including laboratory testing and repeated echocardiography every 2 years. Baseline hemoglobin (Hb), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP), N-terminal pro brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA) and arginine plasma levels were related to outcome, as were baseline pulmonary function tests and coagulation studies. The prevalence of elevated TRV in the cohort at baseline was 30% (41% in HbSS/HbS0-thalassemia patients and 13% in HbSC/HbS+-thalassemia patients). Median (IQR) follow-up for the whole group was 53 months (50-57). No patients were lost to follow-up. Four patients (3 HbSS and 1 HbSβ0-thalassemia) died during follow-up. Two of these patients had an elevated TRV at baseline while the other two initially had immeasurable TRV, resulting in a death rate for patients with an elevated TRV of 8% and a ratio for early death in of 2.3 (95 percent confidence interval, 0.3 to 16.6; p=0.40) However, the two patients with immeasurable TRV at baseline had an elevated TRV (2.55 m/sec and 2.92 m/sec) on repeated echocardiography two years later. Median age of the patients who died was 48 (34-58) years compared to 29 (21-44) years of those who survived (p=0.18). Baseline plasma levels (medians (IQR)) of Hb and LDH in the deceased were 4.7 (4.3-5.0) mmol/L and 676 (575-801) U/L compared to 5.4 (4.8-6.0) and 410 (341-629) in the survivors (p=0.075 and p=0.049) respectively. Baseline median NT-proBNP plasma levels in the deceased were 278 (131-686) pg/mL and 520 (154-3957) pg/mL compared to 45 (26-94) and 91 (52-150) in the survivors (p=0.007 and p=0.03) respectively. Pulmonary function testing, coagulation studies and plasma levels of ADMA and arginine were not associated with mortality in this cohort. Conceding the relative young age of our cohort, we conclude that the mortality in sickle cell patients with elevated TRV values was far lower as compared to the published literature. Although an elevated TRV could still be an important risk factor for early death, mortality may in fact be much lower than previously reported which is in line with more recent observations by other groups. With respect to biomarkers, we confirmed that NT-pro BNP and BNP levels were significantly higher in patients who died, with a trend toward a higher rate of hemolysis as well. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Molecular Weight Kininogen Contributes to End-Organ Damage and Mortality in a Mouse Model of Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 268-268 ◽  
Author(s):  
Erica Sparkenbaugh ◽  
Kathryn Wilson ◽  
Malgorzata Kasztan ◽  
David M. Pollock ◽  
Keith R. McCrae ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bone Marrow ◽  
Sickle Cell Disease ◽  
High Molecular Weight ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Organ Damage ◽  
High Molecular Weight Kininogen ◽  
Cell Disease

Abstract Introduction: Recent advances in preventive care, such as hydoxyurea and prophylactic antibiotics, have reduced the mortality of children with sickle cell disease (SCD) s in developed countries. Yet, the chronic hemolytic anemia and recurrent vaso-occlusive crises result in systemic inflammation and coagulopathy. Markers of coagulation activation correlate with painful crises, acute chest syndrome, stroke, venous thromboembolism, pulmonary hypertension, left ventricular diastolic heart disease, and sickle nephropathy. These complications result in end-organ failure that causes increased morbidity and mortality in adult SCD patients. We have shown that tissue factor (TF), the primary initiator of extrinsic coagulation, contributes to inflammation and coagulation in mouse models of SCD. (1,2). It has also been demonstrated that long-term reduction in thrombin protects from cardiopulmonary dysfunction and reduces mortality of sickle cell mice (3). Recent work from our laboratory demonstrates that high molecular weight kininogen (HK) promotes thrombin generation and inflammation in sickle mice. HK is proteolytically cleaved into bradykinin and cleaved HK fragments (HKf) by kallikrein and other proteases. HKf induces TF expression and activity on monocytes dependent on Mac-1 (CD11b/CD18). We found that Mac-1 inhibition attenuates thrombin generation and inflammation in sickle cell mice. Hypothesis: Long-term HK deficiency in sickle cell mice will attenuate TF-mediated coagulation and inflammation, and protect against end-organ damage and mortality. Methods and Results: To evaluate the effect of long-term HK deficiency on outcomes in sickle cell disease, we used bone marrow from Townes sickle (SS) and wild type (AA) mice to generate chimeras in lethally irradiated HK+/+ (WT) and HK-/- (KO) mice to create AA/WT, AA/KO, SS/WT, and SS/KO mice. Efficient reconstitution of bone marrow was confirmed by hemoglobin electrophoresis. Eight months after chimeras were generated, endpoints were assessed. SS/WT mice had early mortality (median survival 209 days, 6/23 mice survived to 250 days); HK deficiency significantly prolonged survival in SS mice (median survival 240 days, 24/29 mice survived to 250 days; p<0.01). Plasma levels of interleukin-6 were significantly higher in SS/WT mice compared to AA/WT controls (21 ± 3.7 ng/mL vs 6.6 ± 2.2 ng/mL in AA/WT, p<0.001); HK deficiency attenuated this increase (5.1 ± 1.2 ng/mL, p<0.001). The neutrophil-lymphocyte ratio was also elevated in SS/WT mice (0.47 ± 0.004 vs 0.3 ± 0.05 in AA/WT, p<0.05), yet not in the SS/KO group (0.25 ± 0.07, p<0.05), indicating that HK deficiency protects against inflammation in SS mice. Analysis of urine for renal injury markers revealed that SS/WT mice had elevated urine albumin/creatinine ratios (652 ± 34 mg albumin/g creatinine vs. 276 ± 54, p<0.01), which was significantly decreased in SS/KO mice (321 ± 49, p<0.01). Moreover, SS/WT mice had significantly reduced urine osmolality compared to AA/WT controls (2116 mOsm/kg vs 1208 mOsm/kg, p<0.05), which was reversed in SS/KO mice (1842 mOsm/kg, p<0.05). This suggests that HK deficiency protects against kidney injury and preserves urinary concentrating ability. We also observed increases in the relative left ventricle (LV+S/BW; 4.9 ± 0.2 vs 3.3 ± 0.1, p<0.05) and right ventricle (RV/BW; 1.4 ± 0.4 vs 0.99 ± 0.09, p<0.05) size in SS/WT mice compared to AA/WT controls, which was prevented in SS/KO mice (LV+S/BW: 4.0 ± 0.2, p<0.05 and RV/BW: 1.1 ± 0.06, p<0.05). Conclusions: These data indicate that HK deficiency attenuates chronic inflammation, kidney failure, and heart hypertrophy, and improves survival of sickle cell mice. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals Evidence for complement-mediated bone marrow necrosis in a young adult with sickle cell disease

2021 ◽  
Vol 86 ◽  
pp. 102508
Author(s):  
Melissa Azul ◽  
Surbhi Shah ◽  
Sarah Williams ◽  
Gregory M. Vercellotti ◽  
Alexander A. Boucher
Keyword(s):  
Bone Marrow ◽  
Young Adult ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Bone Marrow Necrosis

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

2010 ◽  
Vol 16 (2) ◽  
pp. 263-272 ◽  
Author(s):  
Mark C. Walters ◽  
Karen Hardy ◽  
Sandie Edwards ◽  
Thomas Adamkiewicz ◽  
James Barkovich ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Bone Marrow Transplantation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Marrow Transplantation ◽  
Cell Disease

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Kelly M. Knee ◽  
Amey Barakat ◽  
Lindsay Tomlinson ◽  
Lila Ramaiah ◽  
Zane Wenzel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Organ Damage ◽  
Complete Elimination ◽  
Cell Disease ◽  
The Impact ◽  
2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

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