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Sickle cell trait doesn’t increase risk of death, study suggests
Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.
Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.
The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.
But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.
Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.
Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.
To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.
The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).
Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).
However, the risk of ER was also higher for the following groups:
- Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
- Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
- Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
- Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).
Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.
As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.
“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.
She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.
“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.
She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion. 
Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.
Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.
The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.
But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.
Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.
Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.
To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.
The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).
Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).
However, the risk of ER was also higher for the following groups:
- Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
- Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
- Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
- Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).
Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.
As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.
“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.
She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.
“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.
She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion.
Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.
Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.
The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.
But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.
Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.
Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.
To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.
The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).
Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).
However, the risk of ER was also higher for the following groups:
- Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
- Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
- Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
- Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).
Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.
As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.
“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.
She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.
“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.
She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion.
Method provides more accurate diagnosis of MDS, team says
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
Light-based therapy may treat thrombocytopenia
in the bone marrow
A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.
Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.
The team also identified the probable mechanism underlying this effect.
“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.
“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”
LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.
Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.
The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.
Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.
One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.
LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.
Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.
Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.
LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.
In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.
Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.
“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”
“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”
Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.
She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.
in the bone marrow
A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.
Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.
The team also identified the probable mechanism underlying this effect.
“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.
“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”
LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.
Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.
The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.
Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.
One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.
LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.
Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.
Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.
LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.
In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.
Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.
“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”
“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”
Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.
She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.
in the bone marrow
A low-intensity type of laser therapy could provide a non-invasive, drug-free treatment option for thrombocytopenia, according to research published in Science Translational Medicine.
Researchers found that low-level laser (LLL) therapy increased the generation of platelets from megakaryocytes in vitro and had the same effect in mouse models of thrombocytopenia.
The team also identified the probable mechanism underlying this effect.
“Our study reveals, for the first time, that low-level laser therapy enhances platelet production in animals with thrombocytopenia but not in normal controls,” said study author Mei X. Wu, PhD, of Massachusetts General Hospital in Boston.
“This result suggests that a safe, drug-free method that does not depend on donated blood products can be developed for treating or preventing thrombocytopenia.”
LLLs emit low-powered laser light that does not heat its target tissue. LLLs are known to protect the function of mitochondria, and several conditions associated with impaired platelet production are characterized by abnormalities in the mitochondria of cells that give rise to platelets.
Dr Wu and her colleagues conducted a number of experiments to investigate whether LLLs’ ability to protect mitochondrial function could mitigate several forms of thrombocytopenia.
The team found that LLL treatment of megakaryocytes increased their size, accelerated the formation of proplatelets, and doubled the production of platelets.
Infusion of LLL-treated megakaryocytes into mice led to greater platelet production than did infusion of megakaryocytes treated with normal light.
One of the keys to determining the number of platelets generated from megakaryocytes was mitochondrial production of the energy molecule ATP.
LLL treatment greatly increased mitochondrial generation in polyploid megakaryocytes, but the increase was only slight in less mature megakaryocytes with only 2 copies of each chromosome.
Whole-body LLL treatment of mice with radiation-induced thrombocytopenia spurred the rapid maturation of megakaryocytes and restored platelet levels in a light-dose-dependent fashion.
Platelets from LLL-treated mice had normal structure and function. LLL treatment of normal mice did not raise levels of either megakaryocytes or platelets.
LLL treatment also restored platelet levels in mice with the autoimmune form of thrombocytopenia or with thrombocytopenia caused by chemotherapy.
In cultured human megakaryocytes, LLL treatment at dosage levels similar to those used in mice increased ATP production and platelet generation.
Dr Wu noted that LLL’s lack of an effect in animals without thrombocytopenia indicates it would probably avoid the potential complications of current drug treatments for thrombocytopenia, which act by increasing the production of megakaryocytes from their progenitors in the bone marrow.
“Directly stimulating the differentiation of [megakaryocytes] the way all current drugs do risks clotting if platelet levels rise too high,” Dr Wu said. “LLL appears to enhance [megakaryocytes’] inherent ability to produce platelets most effectively in response to low platelet levels in the circulation, a response that stops when platelet levels are normalized.”
“The fact that treatment only has an effect in polyploid cells, which are very rare, implies that it would not increase production of mitochondria in cancer cells or other cells. In fact, while LLL has been employed in research and in clinical treatment for decades, this is the first study reporting that it can promote mitochondrial biogenesis.”
Dr Wu added that the current primary obstacle to testing LLL in humans is the lack of a device large enough to treat either the entire body or enough bones to stimulate sufficient platelet production by megakaryocytes within the bone marrow, something her team plans to address.
She also noted that, while LLL will probably be beneficial for treatment of many forms of acquired thrombocytopenia, it may not be effective when the condition is caused by inborn genetic defects.
Blood disorders prove costly for European economy
chemotherapy
Photo by Rhoda Baer
Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.
Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.
Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.
Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.
The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.
The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).
Malignant blood disorders
In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).
In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.
When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).
In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).
The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).
Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.
The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.
Non-malignant blood disorders
In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).
Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.
“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.
“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”
chemotherapy
Photo by Rhoda Baer
Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.
Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.
Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.
Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.
The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.
The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).
Malignant blood disorders
In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).
In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.
When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).
In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).
The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).
Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.
The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.
Non-malignant blood disorders
In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).
Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.
“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.
“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”
chemotherapy
Photo by Rhoda Baer
Malignant and non-malignant blood disorders cost 31 European countries a total of €23 billion in 2012, according to a pair of papers published in The Lancet Haematology.
Healthcare costs accounted for €16 billion of the total costs, with €7 billion for hospital inpatient care and €4 billion for medications.
Informal care (from friends and relatives) cost €1.6 billion, productivity losses due to mortality cost €2.5 billion, and morbidity cost €3 billion.
Researchers determined these figures by analyzing data from international health organizations (WHO and EUROSTAT), as well as national ministries of health and statistical institutes.
The team estimated the economic burden of malignant and non-malignant blood disorders in 2012 for all 28 countries in the European Union (EU), as well as Iceland, Norway, and Switzerland.
The costs considered were healthcare costs (primary care, accident and emergency care, hospital inpatient and outpatient care, and drugs), informal care costs (from friends and relatives), and productivity losses (due to premature death and people being unable to work due to illness).
Malignant blood disorders
In one paper, the researchers noted that the total economic cost of blood cancers to the 31 countries studied was €12 billion in 2012. Healthcare costs measured €7.3 billion (62% of total costs), productivity losses cost €3.6 billion (30%), and informal care cost €1 billion (8%).
In the 28 EU countries, blood cancers represented 8% of the total cancer costs (€143 billion), meaning that blood cancers are the fourth most expensive type of cancer after lung (15%), breast (12%), and colorectal (10%) cancers.
When considering healthcare costs alone, blood cancers were second only to breast cancers (12% vs 13% of healthcare costs for all cancers).
In 2012, blood cancers cost, on average, €14,674 per patient in the EU (€15,126 in all 31 countries), which is almost 2 times higher than the average cost per patient across all cancers (€7929 in the EU).
The researchers said this difference may be due to the longer length of hospital stay observed for patients with blood cancers (14 days, on average, compared to 8 days across all cancers).
Another potential reason is that blood cancers are increasingly treated with complex, long-term treatments (including stem cell transplants, multi-agent chemotherapy, and radiotherapy) and diagnosed via extensive procedures.
The costs of blood cancers varied widely between the countries studied, but the reasons for this were unclear. For instance, the average healthcare costs in Finland were nearly twice as high as in Belgium (€18,014 vs €9596), despite both countries having similar national income per capita.
Non-malignant blood disorders
In the other paper, the researchers said the total economic cost of non-malignant blood disorders to the 31 countries studied was €11 billion in 2012. Healthcare costs accounted for €8 billion (75% of total costs), productivity losses for €2 billion (19%), and informal care for €618 million (6%).
Averaged across the population studied, non-malignant blood disorders represented an annual healthcare cost of €159 per 10 citizens.
“Non-malignant blood disorders cost the European economy nearly as much as all blood cancers combined,” said Jose Leal, DPhil, of the University of Oxford in the UK.
“We found wide differences in the cost of treating blood disorders in different countries, likely linked to the significant differences in the access and delivery of care for patients with blood disorders. Our findings suggest there is a need to harmonize care of blood disorders across Europe in a cost-effective way.”
Radiologists no longer have higher risk of cancer-related death
Photo by Rhoda Baer
Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.
However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.
Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.
The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.
However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.
To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.
The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.
“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.
Results in males
The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).
In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.
They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).
They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).
And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).
The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).
The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.
“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”
Results in females
The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.
The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.
However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).
Photo by Rhoda Baer
Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.
However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.
Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.
The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.
However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.
To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.
The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.
“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.
Results in males
The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).
In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.
They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).
They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).
And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).
The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).
The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.
“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”
Results in females
The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.
The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.
However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).
Photo by Rhoda Baer
Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.
However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.
Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.
The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.
However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.
To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.
The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.
“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.
Results in males
The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).
In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.
They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).
They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).
And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).
The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).
The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.
“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”
Results in females
The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.
The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.
However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).
Study challenges previous notions about RBC disposal
A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.
The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron
recycling.
Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.
“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.
“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”
Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.
Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.
Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.
The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.
Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.
“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.
“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”
A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.
The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron
recycling.
Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.
“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.
“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”
Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.
Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.
Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.
The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.
Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.
“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.
“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”
A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.
The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron
recycling.
Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.
“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.
“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”
Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.
Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.
Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.
The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.
Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.
“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.
“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”
Immunotherapy may benefit relapsed HSCT recipients
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
COMP recommends orphan status for drug to treat PNH
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).
Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.
The drug is being developed by Akari Therapeutics.
In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.
In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.
Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.
Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.
About orphan designation
The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).
Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.
The drug is being developed by Akari Therapeutics.
In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.
In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.
Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.
Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.
About orphan designation
The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan designation for Coversin for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
Coversin is a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).
Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.
The drug is being developed by Akari Therapeutics.
In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and the drug can achieve full complement inhibition in the blood of PNH patients who are resistant to the drug eculizumab.
In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.
Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is administering the drug to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. And the only drug-related adverse event has been occasional local and transient irritation at the injection site.
Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.
About orphan designation
The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
Drug could be disease-modifying for SCD, team says
Image by Graham Beards
Researchers say the small molecule GBT440 could be a disease-modifying agent for patients with sickle cell disease (SCD).
Preclinical data showed that GBT440 can reduce sickling, extend the circulating half-life of red blood cells (RBCs), and decrease excessive erythropoiesis in SCD.
GBT440 binds specifically to hemoglobin and is designed to inhibit sickle hemoglobin (HbS) polymer formation.
“One promising strategy for preventing red blood cell sickling and subsequently modifying sickle cell disease over the long term involves inhibiting polymerization of HbS in red blood cells,” said David R. Archer, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“This can be achieved by increasing the proportion of oxygenated HbS in those cells. We believe our preclinical results provide strong evidence that GBT440 inhibits HbS polymerization and red blood cell sickling, which is important because it addresses the underlying pathophysiology of sickle cell disease and has the potential to change its devastating clinical course.”
Dr Archer and his colleagues reported these results in the British Journal of Haematology. The research was supported by Global Blood Therapeutics, Inc., the company developing GBT440.
The researchers reported that, in vitro, GBT440 dose-dependently increased the affinity of HbS for oxygen, delayed polymerization of HbS, and reduced the number of sickled RBCs in whole blood from SCD patients.
In an animal model of SCD, GBT440 inhibited RBC sickling, prolonged the half-life of RBCs, and reduced reticulocyte counts.
The researchers said the drug also exhibited favorable pharmacokinetic properties in various animal species, suggesting the potential for once-daily oral dosing in SCD patients.
“Our preclinical work has developed a foundation of evidence that GBT440 is a potent inhibitor of the polymerization of HbS,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc.
“We continue to build on these data with our ongoing phase 1/2 study, which has shown that GBT440 was well-tolerated over 90 days of dosing and that all SCD patients who received multiple doses of GBT440 exhibited improvements in one or more clinical markers of hemolysis and anemia. Our next step is to initiate a pivotal trial in adults with SCD later this year.”
Image by Graham Beards
Researchers say the small molecule GBT440 could be a disease-modifying agent for patients with sickle cell disease (SCD).
Preclinical data showed that GBT440 can reduce sickling, extend the circulating half-life of red blood cells (RBCs), and decrease excessive erythropoiesis in SCD.
GBT440 binds specifically to hemoglobin and is designed to inhibit sickle hemoglobin (HbS) polymer formation.
“One promising strategy for preventing red blood cell sickling and subsequently modifying sickle cell disease over the long term involves inhibiting polymerization of HbS in red blood cells,” said David R. Archer, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“This can be achieved by increasing the proportion of oxygenated HbS in those cells. We believe our preclinical results provide strong evidence that GBT440 inhibits HbS polymerization and red blood cell sickling, which is important because it addresses the underlying pathophysiology of sickle cell disease and has the potential to change its devastating clinical course.”
Dr Archer and his colleagues reported these results in the British Journal of Haematology. The research was supported by Global Blood Therapeutics, Inc., the company developing GBT440.
The researchers reported that, in vitro, GBT440 dose-dependently increased the affinity of HbS for oxygen, delayed polymerization of HbS, and reduced the number of sickled RBCs in whole blood from SCD patients.
In an animal model of SCD, GBT440 inhibited RBC sickling, prolonged the half-life of RBCs, and reduced reticulocyte counts.
The researchers said the drug also exhibited favorable pharmacokinetic properties in various animal species, suggesting the potential for once-daily oral dosing in SCD patients.
“Our preclinical work has developed a foundation of evidence that GBT440 is a potent inhibitor of the polymerization of HbS,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc.
“We continue to build on these data with our ongoing phase 1/2 study, which has shown that GBT440 was well-tolerated over 90 days of dosing and that all SCD patients who received multiple doses of GBT440 exhibited improvements in one or more clinical markers of hemolysis and anemia. Our next step is to initiate a pivotal trial in adults with SCD later this year.”
Image by Graham Beards
Researchers say the small molecule GBT440 could be a disease-modifying agent for patients with sickle cell disease (SCD).
Preclinical data showed that GBT440 can reduce sickling, extend the circulating half-life of red blood cells (RBCs), and decrease excessive erythropoiesis in SCD.
GBT440 binds specifically to hemoglobin and is designed to inhibit sickle hemoglobin (HbS) polymer formation.
“One promising strategy for preventing red blood cell sickling and subsequently modifying sickle cell disease over the long term involves inhibiting polymerization of HbS in red blood cells,” said David R. Archer, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“This can be achieved by increasing the proportion of oxygenated HbS in those cells. We believe our preclinical results provide strong evidence that GBT440 inhibits HbS polymerization and red blood cell sickling, which is important because it addresses the underlying pathophysiology of sickle cell disease and has the potential to change its devastating clinical course.”
Dr Archer and his colleagues reported these results in the British Journal of Haematology. The research was supported by Global Blood Therapeutics, Inc., the company developing GBT440.
The researchers reported that, in vitro, GBT440 dose-dependently increased the affinity of HbS for oxygen, delayed polymerization of HbS, and reduced the number of sickled RBCs in whole blood from SCD patients.
In an animal model of SCD, GBT440 inhibited RBC sickling, prolonged the half-life of RBCs, and reduced reticulocyte counts.
The researchers said the drug also exhibited favorable pharmacokinetic properties in various animal species, suggesting the potential for once-daily oral dosing in SCD patients.
“Our preclinical work has developed a foundation of evidence that GBT440 is a potent inhibitor of the polymerization of HbS,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc.
“We continue to build on these data with our ongoing phase 1/2 study, which has shown that GBT440 was well-tolerated over 90 days of dosing and that all SCD patients who received multiple doses of GBT440 exhibited improvements in one or more clinical markers of hemolysis and anemia. Our next step is to initiate a pivotal trial in adults with SCD later this year.”
Computer model shows how spleen filters blood
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.