Transfusion Science

Editorial

G Rock — 2000-12-01

Exciting news for the readers of Transfusion Science: things are progressing well towards having Transfusion Science serve as the official journal for the World Apheresis Association. This will greatly broaden our readership and allow us to bring you an increasingly varied representation of papers from different areas of the world. The immediate past President of the WAA, Dr. Horst Klinkmann, is in the process of finalizing the documents for this arrangement. Hopefully, by the time the next edition comes out, it will be time for an official announcement outlining this very significant step.

Single automated donor plateletpheresis increases the plasma level of proinflammatory cytokine tumor necrosis factor-α which does not associate with endothelial release markers von Willebrand factor and fibronectin

İhsan Karadoğan, Mustafa Özdoğan, Levent Ündar — 2000-12-01

Abstract: The effect of plateletpheresis on endothelium, which has strong effects on blood coagulation, fibrinolysis and platelet function, is not known. Activation of leukocytes and subsequent generation of proinflammatory cytokines during the extracorporeal circulation may activate the endothelium. To test this hypothesis we measured plasma levels of tumor necrosis factor (TNF)-α as a prototype of the proinflammatory cytokines, and von Willebrand factor (vWF) and fibronectin as endothelial release/damage markers before and after a single plateletpheresis procedure on an intermittent-flow machine Haemonetics MCS 3p in 17 healthy donors. We found a significant increase in median plasma level of TNF-α following plateletpheresis (3.5 vs 26.5 pg/ml, P=0.02). Such increases in vWF and fibronectin were not observed. The increase in plasma TNF-α indicates that a single plateletpheresis procedure causes leukocyte activation which does not seemingly impair endothelial cell function. The relation of plateletpheresis-induced proinflammatory cytokine release to some adverse effects observed in both donors and recipients, and the effect of repeated plateletpheresis on endothelium deserve further studies.

Preoperative autologous blood donation in hip surgeries

Teruhiko Azuma, Shuji Takahashi, Akio Kawamura — 2000-12-01

Abstract: We evaluated the effectiveness of preoperative autologous blood donation in reduction of the need for transfusion of homologous blood in hip surgeries at our hospital. The cases of 55 patients who had 67 hip surgeries, including 17 total hip arthroplasties (THA) and 41 rotational acetabular osteotomies (RAO), were studied. The patients predeposited an average of 995 ml of blood for each procedure. The calculated blood loss was an average of 961 ml. Ninety-seven percent of the procedures for which autologous blood had been predeposited were performed without transfusion of homologous blood. In the group for THA, an average of 981 ml of autologous blood was transfused for a blood loss of 1417 ml; hemoglobin levels after operation averaged 103 g/l. From this data, a 1000 ml donation seemed to be an optimal blood deposit for THA and a 800 ml blood deposit seemed sufficient for RAO, where the patients are younger.

Primary and secondary haemochromatosis

J.J.M Marx — 2000-12-01

Iron-related diseases are a major problem all over the world. In transfusion medicine physicians may relieve discomfort caused by acute or chronic iron deficiency anaemia by giving red cell transfusion. On the other hand they may induce iron deficiency in donors. More important, however, is that they may cause secondary iron overload in all those patients needing erythrocyte transfusions for reasons other than iron deficiency anaemia. Finally, blood bank officials cause frustration, in many countries, by prohibiting blood donation by healthy subjects with primary haemochromatosis. For a Journal devoted to Transfusion Science there are enough reasons to publish a special issue on Haemochromatosis.

The importance of non-transferrin bound iron in disorders of iron metabolism

W Breuer, C Hershko, Z.I Cabantchik — 2000-12-01

Abstract: The concept of non-transferrin bound iron (NTBI) was introduced 22 years ago by Hershko et al. (Brit. J. Haematol. 40 (1978) 255). It stemmed from a suspicion that, in iron overloaded patients, the large amounts of excess iron released into the circulation are likely to exceed the serum transferrin (Tf) iron-binding capacity (TIBC), leading to the appearance of various forms of iron not bound to Tf. In accordance with this assumption, NTBI was initially looked for and detected in patients with ⩾100% Tf-saturation. As techniques for its detection became more sophisticated and sensitive, NTBI was also found in conditions where Tf was not fully saturated, leading to a revision of the original view of NTBI as a simple spillover phenomenon. In this review, we will discuss some of the properties of NTBI, methods for its detection, its significance and potential value as an indicator for therapeutic regimens of iron chelation and supplementation.

Clinical aspects of hemochromatosis

2000-12-01

Abstract: Hemochromatosis is one of the most frequent genetic diseases among the white populations, affecting one in three hundred persons. Its diagnosis has been radically transformed by the discovery of the HFE gene. In a given individual, the diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST. Family screening is mandatory, primarily centered on the siblings. The treatment remains based on venesection therapy which improves many features of the disease (one of the most refractory, however, being the joint signs) and permits normal life expectancy provided the diagnosis is established prior to the development of cirrhosis or of insulin-dependent diabetes. In view of the prevalence, the non-invasive diagnosis, the spontaneous severity and the efficacy of a very simple therapy, hemochromatosis should benefit from population screening. This screening could be based, first, on the assessment of transferrin saturation, followed – when elevated – by the search for the C282Y mutation. The discovery of the HFE gene has also paved the road for the individualization of other types of iron overload syndromes which are not HFE-related.

The design and properties of 3-hydroxypyridin-4-one iron chelators with high pFe3+ values

Robert C. Hider, Zu D. Liu, S. Piyamongkol — 2000-12-01

Transfusion-dependent patients such as those suffering from β-thalassaemia develop a fatal secondary haemosiderosis and consequently, a selective iron chelator must be used to relieve such iron overload. Desferrioxamine-B (DFO) (1), the most widely used iron chelator in haematology over the past 30 years, has a major disadvantage of being orally inactive . Consequently, the successful design of an orally active, non-toxic, selective iron chelator has been a much sought after goal for medicinal chemists for the past 25 years. In designing iron chelators for clinical application, metal selectivity and ligand–metal complex stability are of paramount importance . A suitable comparator for ligands is the pFe3+ value, defined as the negative logarithm of the concentration of the free iron(III) in solution . The comparison of ligands using this parameter is useful, since pFe3+, unlike the corresponding stability constants, takes into account the effects of ligand basicity, denticity and degree of protonation, as well as differences in metal–ligand stoichiometries. Chelators with high pFe3+ values are predicted not only to scavenge iron more effectively at low ligand concentrations, but also dissociate less readily and therefore form lower concentrations of the partially coordinated complexes.

Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)

2000-12-01

Abstract: Iron is essential for all living organisms. Under normal conditions there is no regulatory and rapid iron excretion in humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood transfusions in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs deferoxamine (DF) and deferiprone (L1). Effective chelation therapy in chronically transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body from transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both chelating drugs have to be administered almost daily and at high doses. This form of administration also requires that a chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the last 40 years. It is mostly administered by subcutaneous infusion (40–60 mg/kg, 8–12 h, 5 days per week), is effective in iron removal and has low toxicity. However, less than 10% of the patients requiring iron chelation therapy worldwide are able to receive DF because of its high cost, low compliance and in some cases toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000 patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a negative iron balance at doses of 50–120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible increased risk of toxicity, all the toxic side effects of L1 are currently considered reversible, controllable and manageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%) and zinc deficiency (1%). The incidence of these toxic side effects could in general be reduced by using lower doses of L1 or combination therapy with DF. Combination therapy could also benefit patients experiencing toxicity with DF and those not responding to either chelator alone. The overall efficacy and toxicity of L1 is comparable to that of DF in both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and by identifying new applications in other diseases of iron imbalance.

Regulation of intracellular iron levels in iron-acceptor and iron-donor cells

Manuela Santos, Maria de Sousa, J.J.M. Marx — 2000-12-01

Abstract: In recent years many new genes and proteins were identified with crucial functions in iron metabolism. This gave an explosion of our knowledge and understanding of iron related disorders. Mutations have been found that are responsible for disturbances in iron transport, leading to either iron overload or iron deficiency. For experts in the field, these new findings clarify the sky and open new routes for exploring hitherto hidden fields of research. For the physician, however, iron metabolism may become even more complicated. In this review, we have tried to assemble all new iron related genes into the context of pathophysiology. Important results from animal experiments, mainly derived from knockout mouse models, are included in this review as they often explain the phenotype of human disease.

Free radical formation and oxyhemoglobin oxidation in β-thalassemic red blood cells in the presence of prooxidants: effects of the free radical scavenger rutin and oral chelator L1

Igor B Afanas'ev, Ilya I Afanas'ev, Irina B Deeva, Ludmila G Korkina — 2000-12-01

It is widely assumed that red blood cells (RBC) from patients with thalassemia (Th-RBC) are subjected to oxidative stress due to abnormal iron deposits on the membrane cytoplasmic surface originated from the hemoglobin instability and continuous blood transfusion. In this work, we were interested in the effects of exogenous prooxidants on Th-RBC, bearing in mind that exposure of thalassemic patients to various environmental and food prooxidants may exaggerate the conditions of oxidative stress in these cells. We found that free radical production (measured via cytochrome c reduction) and oxyhemoglobin oxidation were from 5 to 10 times higher in Th-RBC comparing to normal RBC. All the prooxidants studied (primaquine (PQ), menadione (MD), and 1,4-naphthoquinone-2-methyl-3-sulphonate (NQMS)) significantly enhanced the rate of oxyhemoglobin oxidation and free radical production by both normal RBC and Th-RBC. The effects of prooxidants on free radical production in Th-RBC were significantly (by 1.5–3 times) enhanced, however, surprisingly, their effects on oxyhemoglobin oxidation in RBC and Th-RBC were practically the same. Equal oxidizibility of normal and Th-HbO2 in our experiments apparently indicate that prooxidants are able to attack hemoglobin directly without participation of iron ions, which are responsible for the enhanced oxyhemoglobin oxidation in Th-RBC in the absence of exogenous prooxidants. Therefore, antioxidants and chelators probably cannot prevent the HbO2 oxidation in the presence of exogenous prooxidants. However, antioxidants and chelators can protect Th-RBC from the destructive effects of excessive free radical formation. We studied the effects of oral chelator L1 and free radical scavenger bioflavonoid rutin (vitamin P) on oxygen radical production (measured by cytochrome c reduction) by Th-RBC and RBC (). It is seen that while L1 is able to inhibit oxygen radical formation only in Th-RBC, rutin, being an antioxidant and a chelator, is capable of suppressing free radicals in both normal RBC and Th-RBC. These findings highlight an importance of free radical-mediated damaging processes catalyzed by free iron ions in Th-RBC.

The Sydney Children's Hospital experience with the oral iron chelator deferiprone (L1)

2000-12-01

The oral iron chelator deferiprone (L1) has now been in use in humans with iron overload for a number of years . Olivieri and Brittenham have presented data indicating a concern that the drug in long term use may become ineffective and cause increased hepatic fibrosis.

Desferrioxamine-chelatable iron (DCI), a component of serum non-transferrin-bound iron (NTBI) used for assessing iron chelation therapy

2000-12-01

Non-transferrin-bound iron (NTBI) represents various forms of labile iron appearing in the plasma of patients with various pathological conditions. NTBI is most commonly found in patients whose transferrin iron binding capacity has been exceeded by iron overload, such as in transfusional hemosiderosis (HS) and hereditary hemochromatosis (HC) . Since some forms of NTBI constitute potential sources of catalytically active iron as well as substrates for unregulated uptake into cells, they should to be considered as therapeutic targets for iron chelation.

The effect of deoxynucleosides on cell proliferation of peripheral blood lymphocytes treated with deferoxamine or hydroxyurea

2000-12-01

Deferoxamine (DFO) has anti-retroviral properties for which two mechanisms have been proposed. First, DFO inhibits NF-κB activation by preventing the formation of hydroxyl radicals in the iron-catalyzed Fenton reaction. Second, by inhibiting the iron-dependent enzyme ribonucleotide reductase the concentration of cellular deoxynucleoside triphosphates (dNTPs) is decreased, particularly dATP. As a consequence, cellular proliferation is halted at a stage in the cell cycle just before commencing DNA-synthesis. In addition, reverse transcription is blocked since there is no adequate supply of dATP. Like DFO, hydroxyurea (HU) inhibits ribonucleotide reductase, blocks cell proliferation and reduces HIV-1 replication by depleting cells from dNTPs. In the current study it was investigated whether it was possible to restore peripheral blood lymphocyte (PBL) proliferation by adding exogenous deoxynucleosides (especially dA) in the presence of DFO or HU. Ideally, if the inhibition of ribonucleotide reductase can be bypassed by exogenous dA, it provides the opportunity to study whether DFO and HU can still affect HIV-1 replication in proliferating PBL. Under these conditions, the importance of NF-κB can be further clarified.

Non-transferrin-bound iron, iron-related oxidative stress and lipid peroxidation in β-thalassemia intermedia

2000-12-01

Non-transferrin-bound iron (NTBI) is a low molecular weight (LMW) form of iron supposed to arise from iron challenge and to exert direct pro-oxidant catalysis in lipid peroxidation associated to disorders with iron overload such as β-thalassemia . Nevertheless, only weak associations between NTBI and iron status have been documented in β-thalassemia and influences of other factors, such as ineffective erythropoiesis, may be hypothesised. To test this hypothesis, we measured serum NTBI, indicators of oxidative stress (GSH, MDA, 4NHE), indirect indices of iron overload and erythropoietic activity in 22 untransfused β-thalassemia intermedia (TI) patients (mean age: 28±8 yr, M9/F13, 15 splenectomized, spx).

Multiple effects of iron chelators on molecules controlling cell cycle progression

J Gao, D.R Richardson — 2000-12-01

Considering the potential utility of iron (Fe) chelators as anti-neoplastic agents we have examined a wide variety of analogues of pyridoxal isonicotinoyl hydrazone (PIH) as effective anti-proliferative agents . One of the most promising compounds identified was 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) . In order to understand the mechanism involved in the anti-neoplastic effect of this chelator we have examined its effect on the expression of a number of molecules involved in cell cycle control. Considering this, in preliminary studies we have assessed the effect of 311 on the p53-responsive genes WAF1 and GADD45. WAF1 is a potent universal inhibitor of cyclin-dependent kinases, and can induce a G1/S arrest. GADD45 is induced upon DNA damage and can arrest the cell cycle. Interestingly, both the expression of WAF1 and GADD45 can also be controlled by p53-independent pathways.

Combining iron chelators with the nucleoside analog didanosine in anti-HIV therapy

2000-12-01

Iron chelation which would make iron unavailable for redox reactions could influence HIV replication in two possible ways: first, by inactivation of the iron-dependent cellular enzyme ribonucleotide reductase (RR) which is responsible for generating the building blocks for viral DNA. Deferoxamine (DF) was indeed shown to reduce dATP and dGTP pools by ≈95% . A second mechanism would be via reduction of nuclear factor-κB (NF-κB) activation .

Endocrine problems in ex-thalassemic patients

2000-12-01

Many of the transfused thalassemic patients present endocrine dysfunction and growth disturbances . Bone marrow transplantation (BMT) is the only curative treatment for thalassemia major. We studied the endocrinology function and growth in ex-thalassemic patients, in order to establish whether transplantation alters their clinical course.

L1 effects on reactive oxygen (ROS) and nitrogen species (RNS) release, hemoglobin oxidation, low molecular weight antioxidants, and antioxidant enzyme activities in red and white blood cells of thalassemic patients

L Korkina, C De Luca, I Deeva, S Perrotta, B Nobili, S Passi, P Puddu — 2000-12-01

It has been demonstrated in a number of papers that patients suffering from β-thalassemia are subjected to in vivo oxidative stress due to the excessive production of reactive oxygen (ROS) by the reaction of abnormal hemoglobin with molecular oxygen. The crucial role of “loose free” iron ions in the ROS formation has been clearly recognized . On these grounds, the application of iron chelators as the essential part of conventional therapy of β-thalassemia is thought to be relevant both for iron removal and amelioration of iron-related oxidative stress. The effects of iron overload and iron chelation to ROS and nitrogen species (RNS) forming enzymes as well as to main endogenous antioxidant defence systems remain obscure. In the present work, the comparative study of the pattern of low molecular and enzymatic antioxidants such as tocopherols, reduced form of coenzyme Q (CoQ10H2) and glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and glutathione peroxidase (GSHpx) in the blood of transfusion-dependent patients with β-thalassemia major treated with desferal (conventional scheme, n=48) and deferiprone (75 mg/kg daily for 1.5 years; n=5) as well as transfusion-independent non-chelated patients with intermedia form (n=11) has been performed. The clinical laboratory and analytical procedures were as previously described . The effects of desferal and deferiprone treatment on hemoglobin oxidation and ROS release from erythrocytes and the ROS and RNS production by thalassemic white blood cells (WBC) have been studied as well. Evidence for severe oxidative stress was obtained by: (1) the dramatically decreased levels of plasma and WBC low molecular antioxidants (mainly CoQ10H2 and α-tocopherol, p<0.001) and increased activity for the erythrocyte SOD and GSHpx activities and (2) the depletion of erythrocyte GSH (p<0.01) for all three groups studied. The comparison between the groups treated with desferal and deferiprone showed that the activities of SOD and GSHpx were increased and the activities of CAT and GST were reduced in the group with deferiprone. Moreover, deferiprone protected more effectively cellular antioxidants (α-tocopherol, CoQ10H2 and GSH) against oxidation, that was accompanied by an increase of the content of polyunsaturated (oxidizable) fatty acids in both erythrocyte and WBC cellular membranes. On these grounds, we concluded that deferiprone, unlikely desferal, shifted the equilibrium between superoxide and hydroxyl radicals in favor of superoxide and exerted its chelating and antioxidant effects mainly intracellularly.

Morbidity and mortality of iron intoxication in adult patients with thalassemia major, and effectiveness of chelation

2000-12-01

Thalassemic patients under conventional treatment, with frequent transfusions and intensive chelation with Desferrioxamine, achieve a substantial increase in survival, supplemented by a considerable improvement of the quality of life. On the other hand, poor compliance with chelation has been implicated as a major factor of increased morbidity and mortality, especially for patients at puberty and early adolescence.

Using SQUID biomagnetic liver susceptometry in the treatment of thalassemia and other iron loading diseases

P Nielsen, R Engelhardt, M Duerken, G.E Janka, R Fischer — 2000-12-01

In iron overload diseases in humans, the liver is the main place of iron storage accounting for at least 70–90% of the excessive iron burden. SQUID biomagnetic liver susceptometry (BLS) has become a routine method in monitoring iron overload in post-transfusions siderosis, iron loading anemias, or hereditary haemochromatosis. In the last decade, we have measured the liver iron concentration (LIC) in patients with β-thalassemia major (n=722), β-thalassemia intermedia (n=40), sickle cell/β-thalassemia (n=20), β-thalassemia minor (n=11), ex-thalassemia after bone marrow transplantation (n=26), sickle cell disease (n=11), aplastic anemia (n=10), Diamond Blackfan syndrome (n=6), and ex-leukemic patients after bone marrow or stem cell transplantation (n=76). LIC was also measured in 661 subjects suspected for hereditary haemochromatosis. In 141/149 subjects (94.6%) with LIC>1000μg/g, a homozygous C282Y-mutation was found, indicating the typical genetic haemochromatosis in Northern Europe.

Competition studies of L1-deferiprone with copper and iron. Possible implications on efficacy, toxicity and new therapeutic applications

I Pashalidis, G.J Kontoghiorghes — 2000-12-01

1,2-Dimethyl-3-hydroxypyrid-4-one (L1, INN: deferiprone) is a new, orally active chelating drug used worldwide for the treatment of transfusional iron overloading conditions. It shows comparable in vivo and clinical activity to deferoxamine, the widely used injectable iron chelating drug. L1 was one of over 100 α-ketohydroxypyridines which have been designed to mimic the naturally occuring, orally active α-ketohydroxy iron chelators maltol, mimosine and tropolone . The selection of L1 for clinical development was based on a structure activity correlation studies in vitro and in vivo . For example, other chelators such as L1NAll, which is a second generation α-ketohydroxypyridine and the most effective of the series in iron removal in vivo, is also promising but more toxic in animals than L1 . Despite that all the known toxic side effects of L1 including agranulocytosis, joint/musculoskeletal pains and gastric intolerance could be controlled, their cause is not known and attempts have been made to identify the possible mechanisms. Knowing and preventing the cause of L1 toxic side effects could result in its safer and wider use.

Haematopoietic stem cell transplantation for the management of haemoglobinopathies in Greek patients

2000-12-01

β-thalassaemia major is a common genetic disease in Greece. Although successful prenatal diagnosis has markedly reduced the incidence of the disease, 5–10 thalassaemic children are still born each year . We report our results from the 47 allogeneic transplants performed on 41 thalassaemic patients (18 boys) over a period of 5 years. Forty patients had β-thal major and one had β/s disease. Median age was 10.2 years (1.5–23.9). They were classified according to the Pesaro criteria as class I: 4, class II: 16, class III: 21. Most of the class III patients were regarded as high risk patients because of inadequate chelation therapy. All the donors were siblings, 39 fully matched and 2 with 1 Ag-mismatch. The haematopoietic graft was bone marrow (BM) in 40 transplants, one peripheral blood stem cells (PBSC), three cord blood (CB) and in three cases was CB, supplemented with BM from the same donor. The first seven patients were prepared with busulphan 16 mg/kg and cyclophosphamide 200 mg/kg, but five of them rejected the graft. Since then antilymphocyte globulin (ALG) was added to the conditioning regimen. Adult patients received reduced doses (Bu: 14 mg/kg, Cy: 150 mg/kg). All patients received cyclosporine A plus short methotraxate as GVHD prophylaxis. CyA was administered at full dose from day −1 till day +180 and then tapered and discontinued 1 year post-transplant. All but one patient initially engrafted. ANC exceeded 0.5×109/l at a median of 26 days (15–24) and non-transfused platelets of 40×109/l at a median of 26 days (15–49).

Hydroxamate analog libraries and evaluation of their iron affinity

2000-12-01

The shortcomings of current chelation therapy in iron-overload diseases require the development of novel iron chelators that would be superior to desferrioxamine B (DFO) and more patient-friendly . In our search for orally active iron chelators, we used a combinatorial chemistry approach that has recently become a dominant strategy in drug development . This approach focused on the optimization of the DFO structure (1) that was selected as a suitable lead compound based on its iron affinity and long-term clinical use.

A relationship between glucose metabolism and NO-mediated iron mobilization from cells

R.N Watts, D.R Richardson — 2000-12-01

Nitrogen monoxide (NO) has been shown to have a pronounced effect on intracellular iron (Fe) metabolism due to its high affinity for this metal ion. For example, NO can increase RNA-binding activity of the iron-regulatory protein. In addition, part of the anti-neoplastic action of macrophages may be due to their ability to produce NO that results in the release of Fe from tumour target cells .

The design and properties of 3-hydroxypyridin-4-one iron chelators with high pFe3+ values

Zu D Liu, S Piyamongkol, Robert C Hider — 2000-12-01

Transfusion dependent patients such as those suffering from β-thalassaemia develop a fatal secondary haemosiderosis and consequently, a selective iron chelator must be used to relieve such iron overload. Desferrioxamine-B (DFO), the most widely used iron chelator in haematology over the past 30 yr, has a major disadvantage of being orally inactive . Consequently, the successful design of an orally active, non-toxic, selective iron chelator has been a much sought after goal for medicinal chemists for the past 25 yr. In designing iron chelators for clinical application, metal selectivity and ligand–metal complex stability are of paramount importance . A suitable comparator for ligands is the pFe3+ value, defined as the negative logarithm of the concentration of the free iron(III) in solution. Typically pFe3+ values are calculated for total [ligand] = 10−5 M, total [iron] = 10−6 M at pH 7.4. The comparison of ligands using this parameter is useful, since pFe3+, unlike the corresponding stability constants, takes into account the effects of ligand basicity, denticity and degree of protonation, as well as differences in metal–ligand stoichiometries. Chelators with high pFe3+ values are predicted not only to scavenge iron more effectively at low ligand concentrations, but also dissociate less readily and, therefore, form lower concentrations of the partially co-ordinated complexes.

Post-transfusion thrombocytopenia in recipients with anti-HLA antibody

Hitoshi Ohto, Hiroyasu Yasuda, Hiroo Maeda, Shoichi Inaba — 2000-12-01

Abstract: Allogeneic red cell transfusion produced a significant decrease in the platelet counts of recipients who possessed anti-HLA antibodies.

Patent report

2000-12-01

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