Blood Reviews

Published by Elsevier
Online ISSN: 0268-960X
Publications
Article
The inherited marrow failure syndromes are a diverse set of genetic disorders characterized by hematopoietic aplasia and cancer predisposition. The clinical phenotypes are highly variable and much broader than previously recognized. The medical management of the inherited marrow failure syndromes differs from that of acquired aplastic anemia or malignancies arising in the general population. Diagnostic workup, molecular pathogenesis, and clinical treatment are reviewed.
 
Article
Platelets are essential for primary hemostasis, but they also play an important pro-inflammatory role. Platelets normally circulate in a quiescent state. Upon activation, platelets can secrete and present various molecules, change their shape as well as the expression pattern of adhesion molecules. These changes are associated with the adhesion of platelets to leukocytes and the vessel wall. The interaction of platelets with neutrophils promotes the recruitment of neutrophils into inflammatory tissue and thus participates in host defense. This interaction of neutrophils with platelets is mainly mediated through P-selectin and beta(2) and beta(3) integrins (CD11b/CD18, CD41/CD61). Platelets can also interact with endothelial cells and monocytes. Adherent platelets promote the 'secondary capture' of neutrophils and other leukocytes. In addition, platelets secrete neutrophil and endothelial activators inducing production of inflammatory cytokines. Thus, platelets are important amplifiers of acute inflammation.
 
Article
Natural killer cells are important innate immune effector cells with potentially broad applications in the treatment of human malignancy due to their ability to lyse neoplastic cells without the need for tumor-specific antigen recognition. Human NK cells can be divided into two functional subsets based on their surface expression of CD56; CD56(bright) immunoregulatory cells and CD56(dim) cytotoxic cells. In addition to functional differences, these NK cell subsets can be modulated differently by interleukin (IL)-2, which has permitted the development of lower dose, better tolerated IL-2 regimens for the in vivo expansion and activation of NK cells. The importance of early hematopoietic growth factors, such as c-kit ligand and flt-3 ligand, and their synergy with IL-15 in the development of human NK cells in the bone marrow has permitted the investigation of novel cytokine combinations for optimizing in vivo expansion of NK cell in the clinic. The importance of lymph nodes as a site for NK cell development has recently been elucidated. Furthermore, progress in the field of how NK cell recognize target cells via activating and inhibitory receptors, and how the balance of signals from these receptors can modulate NK cell activity has revolutionized our understanding of the selective killing of tumor cells by NK cells while sparing normal cells. In this review, we summarize current understanding of NK cell biology, and highlight how such knowledge may be translated to optimize the efficacy of using autologous or allogeneic NK cell for the immunotherapy of cancer.
 
Article
Thrombotic thrombocytopenic purpura is an acute life threatening disorder, characterised by thrombocytopenia, microangiopathic haemolytic anaemia and multi organ microvascular thrombi that results in variable clinical symptoms. Just over a decade ago, the missing enzyme required for von Willebrand cleavage was recognised in TTP patients, subsequently identified as ADAMTS 13. Assays have confirmed that the majority of TTP cases are idiopathic and are associated with inhibitors and or IgG antibodies to ADAMTS 13. Such cases take longer to treat and are more likely to relapse. Evidence to date suggests the majority of antibodies block the spacer domain of ADAMTS 13. There may be other antibodies binding to ADAMTS 13 domains but their overall clinical involvement remains to be determined. Immunosuppressive treatments have until now been unsatisfactory. However, monoclonal anti-CD 20 therapy, acting on B-lymphocytes involved in antibody production results in remission in most patients and prevention of recurrent relapse. Further investigation into the antibodies produced in TTP and other aspects of immune dysfunction, such as T cells will further our understanding of this devastating disorder.
 
Article
Mutational reports over the past two decades have accumulated an immense amount of literature for inherited Factor XIII deficiency. However, the genotype and phenotype correlations for inherited Factor XIII deficiency are complicated. While many studies clearly prove a cause and effect relationship for the reported mutations, others are lacking in this regard. The F13B gene remains an elusive component as far as inherited Factor XIII deficiencies are concerned. Also, an in-depth analysis into the heterozygous state of this deficiency is also lacking. In this review we have tried to analyze and present an exhaustive amount of mutational data from the past three decades. The source of our mutational data is our website dedicated to Factor XIII deficiencies (www.F13-database.de) as well as literature search done on the Pubmed (www.ncbi.nlm.nih.gov/pubmed).
 
Article
CD33 is a myeloid differentiation antigen with endocytic properties. It is broadly expressed on acute myeloid leukemia (AML) blasts and, possibly, some leukemic stem cells and has therefore been exploited as target for therapeutic antibodies for many years. The improved survival seen in many patients when the antibody-drug conjugate, gemtuzumab ozogamicin, is added to conventional chemotherapy validates this approach. However, many attempts with unconjugated or conjugated antibodies have been unsuccessful, highlighting the challenges of targeting CD33 in AML. With the development of improved immunoconjugates and CD33-directed strategies that harness immune effector cells, therapeutics with enhanced efficacy may soon become available. Toxic effects on normal hematopoietic cells may increase in parallel with this increased efficacy and demand new supportive care measures, including possibly rescue with donor cells, to minimize morbidity and mortality from drug-induced cytopenias and to optimize treatment outcomes with these agents in patients with AML.
 
Article
Erythroleukemia (EL) is a rare form of myelogenous leukemia the classification and definition of which has evolved over the course of its 80-year descriptive history. In 1976 the French American British (FAB) Cooperative Group included EL within the classification system of acute myelogenous leukemias as AML-M6, and agreed on a quantitative standard to be used in the diagnosis of this disorder. The standards were revised in 1985 to the form in use today. We selected a series of 15 cases from our records which specifically fit the FAB criteria for AML-M6. Extensive direct comparison between our series and the old literature is not practical because of the changes which have occurred in classification and definition of the disease. Overall we found a rough correlation between the clinical and laboratory data shown in the old literature on EL and data from our cases. These cases underscore characteristic laboratory features which correspond to what is now defined as AML-M6: these patients present with pancytopenia, frequent peripheral blood nRBCs and no, or few, peripheral blood blasts. In addition, we note the presence of a hybrid myeloid-erythroid blast in the bone marrow in this disease and suggest that this may be characteristic of this type of AML. Old literature on EL has generally shown it to be a disease of the elderly, yet we found a subset of younger patients whose clinical outcome was significantly better than that of the older patients. Finally, EL has historically been viewed as a disease in which patients progress from a prodrome through erythroleukemia to other acute myeloid leukemia (AML) subtypes. Consistent with this idea, half of our 15 patients had been previously diagnosed with myelodysplastic syndrome or received chemotherapy. On the other hand only one of the 15 patients converted to another type of AML during his course.
 
Article
There have been many advances in supportive treatment used for beta-thalassemia major. Survival has increased substantially, and an increasing number of patients reach adolescence and adulthood. These older patients present new clinical challenges. Complications of transfusion, most commonly hepatitis C, are still a cause of mortality and morbidity. The achievement of optimal growth and development, including fertility, is an important goal of conservative management. Long-term survival has also been achieved with bone marrow transplantation. Assessment of growth, development and iron balance in the years after transplantation reveals residual problems requiring treatment despite cure of thalassemia. New therapies of beta-thalassemia are still being developed, both supportive and curative in nature. Supportive care improvements include oral chelation and methods to increase HbF production. Advances in curative modalities include use of new sources of stem cells, such as cord blood and fetal liver. In the future, gene therapy may allow for cure of the older patient without the mortality and morbidity of allogenic transplantation. Treatment of thalassemia major requires consideration of the available therapeutic options for each patient, and the risk/benefit ratio of a supportive versus curative approach.
 
Article
Myeloid leukemias are clonal disorders originating in a primitive multipotential hematopoietic cell and characterized by aberrant proliferation, differentiation and maturation of leukemic progenitors and precursor cells. These diseases are the result of multiple genetic and epigenetic events, although the nature and number of events vary widely among patients. For over four decades, studies have identified sub-populations of leukemic cells possessing different functional capabilities. Investigators have struggled to understand the origin and significance of this heterogeneity. The stem cell model for myeloid malignancies has offered one potential explanation. Since 1994, experimental data supporting the presence of leukemia stem cells has been reported and validated in numerous studies. We will review the history of the model, data from the past decade supporting the stem cell model for myeloid malignancies, more recent data regarding patient specific variability in leukemic stem cell surface antigen phenotype and the impact the stem cell model has on the care of patients with myeloid malignancies.
 
Article
Polymorphisms of several clotting factors have been associated during the past few years with an increased risk of both venous or arterial thrombosis. However, final proof for the existence of a pathogenetic relationship between a given polymorphism and an increased risk for thrombosis is still lacking. Particular emphasis has been placed recently on a 20210 G to A prothrombin polymorphism. A critical review of available data indicates that such an abnormality may be associated with an increased risk of venous thrombosis but not arterial thrombosis (with a possible exception for myocardial infarction). However, this conclusion is based only on retrospective cohort studies which compared the prevalence of the abnormality in a group of patients with past venous or arterial thrombosis with a normal group (with no thrombosis). No prospective study has yet to show that patients with the abnormality, given similar additional acquired risk factors, have a higher incidence of thrombotic complications as compared with controls. The mechanism whereby the abnormality might cause thrombosis has been assumed to be an increase in prothrombin levels. Since an association between two phenomena does not necessarily mean that a causal relationship exists between the same events, it is important to be cautious before claiming that such abnormality is responsible for thrombosis. Therefore, although included commonly in the investigation profile, the search for the 20210 G to A prothrombin abnormality should not be considered yet to be an essential component in the routine study of hypercoagulable and/or thrombotic conditions.
 
Article
Increasing evidence supports the role of the tumor microenvironment in conferring drug resistance as a major cause of relapse and incurability of cancers. The tumor microenvironment consists of normal stromal cells, extracellular matrix, and soluble factors such as cytokines and growth factors. Tumor-tumor cell interaction, tumor-stromal cell interaction, as well as tumor-ECM interaction, all contribute to direct cell contact mediated drug resistance. In addition, soluble factors produced in the tumor microenvironment provide further signals for tumor cell growth and survival. Environment mediated-drug resistance (EM-DR) could be considered as the totality of cell adhesion mediated drug resistance (CAM-DR) and soluble factor mediated drug resistance (SM-DR) produced by the tumor-host interaction. This review focuses on the EM-DR model system and signaling pathways involved in cell survival of hematological malignancies.
 
Article
An association between the complete or partial loss of chromosome 7 and preleukaemic myelodysplasia or acute myeloid leukaemia has been recognized from the early days of tumour cytogenetic analysis. Detection of such abnormalities usually heralds a poor prognosis. The loss of DNA on chromosome 7 has led to speculation that tumour-suppressor genes may play a significant role in this form of leukaemogenesis, although it may be part of a multistep process. A further association with leukaemia secondary to carcinogen exposure including previous chemotherapy or a number of congenital anaemias has increased the interest in discovering the gene or genes on chromosome 7. Banded chromosome analysis has suggested that there are two broad critical regions on the long arm of chromosome 7 at bands 7q22 and 7q34-q36 that may contain the relevant genes. Initial molecular analysis has confirmed these two regions to be of significance. The advent of fluorescence in-situ hybridization techniques has facilitated some definition of the 7q22 region, with identification of candidate genes for further functional analysis. It is becoming clear that there will be more than one gene on chromosome 7 involved in the leukaemic process and with the definition of these genes it may be possible to look for associations with different phenotypes and prognosis. As for the reason for chromosome 7 showing a particular predisposition to total or partial loss we may speculate that the DNA sequence and structure may confer a 'fragility' on the chromosome. A greater understanding of the DNA structure of the long arm may provide real insight into the mechanisms of leukaemia. We would like to speculate in the long term that this could lead to the ability to screen for leukaemia susceptibility and avoidance of 'inducers' in those at risk.
 
Article
Molecular monitoring of BCR-ABL transcript levels by real-time quantitative PCR is increasingly used to assess treatment response in patients with chronic myeloid leukaemia (CML). This has become particularly relevant in the era of imatinib therapy when residual levels of leukaemia usually fall below the level of detection by bone marrow cytogenetic analysis. Studies of imatinib-treated patients have determined that BCR-ABL levels measured early in therapy can predict subsequent response and the probability of acquired resistance. The defining of a molecular level of response that indicates a high probability of progression-free survival highlights the relevance of molecular analysis for clinical management. Small increases in the BCR-ABL level can identify patients with kinase domain mutations that lead to imatinib resistance. Therefore, these assays can be used as a screening strategy for mutation analysis. As second generation kinase inhibitors commence clinical trials, the molecular response will be a primary end-point that determines efficacy.
 
Article
gene on chromosome 9 is the humanhomologue of a gene originally identified in a murineoncogenic virus, the Abelson murine leukaemia virus(A-MuLV). This retrovirus was isolated from a pred-nisolone treated mouse which developed lymphomafollowing innoculation with Moloney murineleukaemia virus (M-MuLV).
 
Article
The ABL proto-oncogene on the Philadelphia chromosome is 'activated' by its translocation in a manner similar to its activation by the murine Abelson leukemia virus--with the formation of a fusion protein with a new N-terminus and enhanced tyrosine kinase activity. Study of this BCR-ABL fusion gene has led to the development of molecular probes which are beginning to play an important role in the diagnosis and clinical management of chronic myelogenous leukemia, and may ultimately lead to better understanding of the biology of the disease. The role of ABL on the Philadelphia chromosome in acute lymphoblastic leukemia is only now beginning to be understood, but is likely to be similar, and a new ABL species has already been identified by several groups. It is likely that this protein is the product of a fusion gene, as it is in chronic myelogenous leukemia, but definitive proof awaits molecular cloning of the translocation breakpoint. Aside from its activation by the Ph1 chromosome, ABL has not been found to have a role in any other human cancer.
 
Article
Acute myeloid leukemia is caused by one or several transforming events which usually result in a block of myeloid precursor cell maturation. Human cell lines can serve as model for hematopoietic cells arrested at different stages of myeloid differentiation. These homogeneous populations help to dissect the cellular and molecular events involved in leukemogenesis, such as proto-oncogene activation. Furthermore, the efficacy and mechanism of action of compounds inducing differentiation of leukemic cells can be studied. Finally, these lines can permit the analysis of proliferation and differentiation of normal myeloid precursor cells.
 
Article
Rare individuals are known with erythrocytes which show an inherited deficiency of certain blood group antigens and also have abnormal red cell shape. Studies of these cells can give an insight into the functional role of blood group active components in maintaining the shape and membrane properties of the normal erythrocyte. The biochemical characterisation of the red cell membrane alterations occurring in two such rare erythrocyte phenotypes--the Leach phenotype and the Rhnull phenotype are reviewed here.
 
Article
Genetic abnormalities are found in 50% of cases of chronic lymphocytic leukaemia (CLL) by cytogenetic analysis and in a higher percentage of patients using molecular techniques. The commonest cytogenetic abnormalities are trisomy 12 and deletions or translocations of the long arm of chromosome 13 usually involving band q14. The genetic consequences of trisomy 12 are unknown but structural abnormalities of chromosome 13q14 frequently involve hetero or homozygous loss of a region distal to the retinoblastoma gene which may be the site of a tumour suppressor gene. Trisomy 12 or loss of one copy of the retinoblastoma gene have been detected by fluorescent in situ hybridisation (FISH) in interphase cells of patients with a normal karyotype. By combining FISH with immunophenotyping, it has been found that trisomy 12 occurs in only 30 to 40% of the malignant clone, suggesting that it is a secondary event in leukaemogenesis. Trisomy 12 is strongly associated with atypical lymphocyte morphology in patients with otherwise typical CLL. Complex karyotypic abnormalities, a high percentage of abnormal metaphases and trisomy 12 but not structural abnormalities of chromosome 13 are associated with a poor prognosis at all stages of the disease. Mutations or deletions of the P53 gene are found in 10 to 15% of patients with advanced CLL and correlate with resistance to treatment and poor survival.
 
Article
10 years ago, it became apparent that haemophiliacs were developing diseases which were indicative of underlying immunodeficiency. The results of investigation confirmed that many had abnormal immune systems, particularly with regard to cell-mediated immunity. These abnormalities were thought to be a consequence of the use of clotting factor concentrates, and indeed the discovery of HIV and its mode of transmission, confirmed these suspicions. However, it subsequently became clear that HIV infection did not explain all the abnormalities observed. Many in vivo studies have shown that the immune systems of HIV-negative haemophiliacs are not entirely normal, and in vitro studies have shown that clotting factor concentrates per se have a modulating effect on immune function. We have reviewed particularly the abnormalities seen in HIV-negative haemophiliacs and their possible causes, as well as the specific features of HIV infection in haemophiliacs.
 
Article
Acute lymphoblastic leukaemia (ALL) occurs at all ages but is the most common cancer of childhood. The current treatment of paediatric ALL is highly successful with up to 90% children being cured. In contrast, survival rates for adult ALL are significantly lower at around 40%. The discovery and characterisation of genetic abnormalities have increased our understanding of the biology of the disease and provided important prognostic and predictive markers which have improved patient outcome. Not only is the spectrum of these aberrations vast but, due to advances in technology, continually expanding. A wide range of chromosomal and genomic abnormalities have been reported as being associated with patient outcome but only a subset are currently used to risk stratify patients. This review highlights the main genetic abnormalities which are used to manage patients with B-cell precursor ALL and discusses the evidence which has been accumulated on several newly described genomic abnormalities.
 
Article
Hemostatic plugs consist of platelet aggregates and fibrin mesh containing blood cells and plasma components. Hemostatic efficiency depends on the rate of formation of hemostatic plugs as well as the structural integrity and stability of the formed hemostatic plugs. Fibrin elements are major constituents contributing to the structural integrity and stability, but they are subject to fibrinolytic activity occurring spontaneously after fibrin formation. Fibrinolysis is usually suppressed by endogenous inhibitors. Increase of a profibrinolytic component or deficiency of an inhibitor would result in an accelerated fibrinolysis, causing a premature lysis of hemostatic plugs before restoration of injured vessels, leading to a hemorrhagic tendency. Such a state can be seen typically in patients with congenital deficiency of alpha 2-plasmin inhibitor or a hereditary increase of plasminogen activator, and it is also seen in acquired situations such as amyloidosis, liver cirrhosis, disseminated intravascular coagulation (particularly in patients with acute promyelocytic leukemia) and thrombolytic therapy. The hemorrhagic tendency can be well controlled by an administration of an antifibrinolytic agent: epsilon-aminocaproic acid or tranexamic acid. In contrast to an accelerated fibrinolysis causing a hemorrhagic tendency, retarded fibrinolysis may predispose an individual to a thrombotic tendency. Retarded fibrinolysis may be due to either an increase in plasminogen activator inhibitors or decrease of plasminogen activators. Quantitative or qualitative deficiency of plasminogen may also lead to a thrombotic tendency.
 
Article
The recent description of a factor V abnormality (factor V Leiden) associated with an increased incidence of thrombosis has considerably increased interest in this clotting factor. The discovery of this new clinical entity indicated the need for an updated classification of factor V defects. These should be divided into hemorrhagic and thrombotic disorders. A proper classification of hemorrhagic disorders should include: 1) homozygous and heterozygous 'true' factor V deficiency; and 2) combined factor V and factor VIII deficiencies. The latter should be subdivided in Type I (association type) and Type II (common defect). A suitable classification of the thrombotic factor V defects should include: 1) homozygous and heterozygous factor V Leiden; and 2) combined heterozygous factor V Leiden and heterozygous 'true' factor V deficiency. The presence of thrombosis in these latter patients, often as severe as those seen in homozygous patients with activated protein C (APC) resistance, allows important considerations on the functions of factor V. It would seem that half the normal level of factor V activity and antigen is unable to protect against thrombosis in patients with heterozygous APC resistance. An accurate evaluation of factor V activity and antigen is indicated in all patients with suspected factor V defects. The first suspicion may be obtained by the presence of a mild prolongation of prothrombin time and of partial thromboplastin time. The suspicion should then be immediately confirmed by specific factor V activity and antigen assays. This approach is of great importance even for the presumptive diagnosis of pseudohomozygosis for APC resistance. In fact, in these cases, factor V activity is about 50% of normal, whereas factor V antigen is 100% of normal. In heterozygous 'true' factor V deficiency both activity and antigen are about 50% of normal.
 
Article
Chromosomal aberrations occur in both B-CLL and T-CLL. The polyclonal B-cell mitogens, in particular Epstein-Barr virus and lipopolysaccharide from E. coli, have been used successfully to reveal chromosomal abnormalities in 40-60% of patients with B-CLL, while T-cell mitogens have shown chromosomal aberrations in T-CLL. The most common clonal chromosomal aberration in B-CLL is an extra chromosome 12, alone or together with other abnormalities. Other common aberrations are 14q+, structural aberrations on 6, 11, 12 and 13. Proto-oncogenes are frequently located close to breakpoints. The proto-oncogene c-K-ras is located on chromosome 12 and an abnormal transcript has recently been implicated in a subset of B-CLL-patients. An extra chromosome 12 as well as multiple chromosomal abnormalities in B-CLL appear to predict a less favourable prognosis. T-CLL is in most patients characterized by an inv(14), an extra 8q and structural abnormalities in chromosome 7. The genes for the specific T-cell receptor as well as the immunoglobulin heavy chain are located on these chromosomes. Chromosomal aberrations appear to have pathogenetic importance in both B-CLL and T-CLL.
 
Article
Normal polymorphonuclear neutrophils (PMN) in the circulation are resting cells expressing small numbers of low affinity receptors. During inflammation they are upregulated to increase expression of high affinity receptors and discharge both primary and secondary granules. This is reflected by a pattern of changes which can be detected in PMN from the circulation of patients with infection, trauma or burns. Different patterns of abnormality occur in patients with systemic disease and increased risk of infection such as diabetes and renal failure. Functional defects also occur in PMN from patients with acquired blood disorders. It is likely that PMN contribute to tissue damage in inflammatory and vascular diseases so that drugs which modulate PMN function will be of future therapeutic benefit.
 
Article
In childhood acute lymphoblastic leukaemia (ALL), cytogenetics plays an essential role in diagnosis and prediction of outcome. Conventional cytogenetic analysis, complemented by fluorescence in situ hybridization (FISH), is highly effective in the accurate detection of chromosomal abnormalities. For the precise identification of specific genetic changes, molecular techniques may be applied. Chromosomal changes in ALL may be of structural or numerical type. A large number of established structural chromosomal rearrangements have now been described for which the genetic alterations and effect on prognosis are well known. These include t(9;22)(q34;q11) and BCR/ABL, rearrangements of 11q23 involving MLL, t(12;21)(p13;q22) with the ETV6/AML1 fusion, t(1;19)(q23;p13) with E2A/PBX1, t(8;14)(q24;q32) and the immunoglobulin genes. Genetic changes associated with T ALL are also known, although their effect on outcome is less pronounced. Rare chromosomal abnormalities are continually being discovered in small patient subgroups leading to the identification of new ALL associated genetic changes. Alterations in chromosome number have a strong impact on outcome in childhood ALL. The association of a high hyperdiploid karyotype (51-65 chromosomes) with a good prognosis has been known for more than 20 years. Conversely, the loss of chromosomes in the near-haploid group (23-28 chromosomes) indicates a poor outcome. New methods of cancer classification involving gene expression profiling may eventually supercede cytogenetic analysis in the diagnosis and prediction of outcome in leukaemia. It is more likely that they will be used in a complementary approach alongside cytogenetic, FISH and molecular analysis to guide patient management in childhood ALL.
 
Article
In many of the parts of the world where thalassaemia is common, the blood supply is inadequate or unsafe, and desferrioxamine is too expensive for routine use. We classify some patients as having 'severe thalassaemia intermedia', i.e. those with moderately severe thalassaemia who can survive without regular transfusions, but who are at risk of many complications which are reviewed here. These include bone deformity and fractures, extramedullary haemopoietic tumours, leg ulcers, autoimmune haemolysis and, especially after splenectomy, thromboembolism and infection. An increase in the quality and safety of the blood supply, and a cheaper and/or oral iron chelator, would enable more of these patients to be treated as thalassaemia major and have improved survival and quality of life.
 
Article
Chronic lymphocytic leukemia/small lymphocytic lymphoma is common in persons of predominately European descent but rare in Asians. Why is unknown but is likely genetically-determined. Environmental factors may also operate but are likely to be less important. When CLL occurs in Asians it has different features than CLL in persons of predominately European descent. The reason(s) for this is also not understood. We reviewed data on CLL in Asians (mostly Han Chinese but also other ethnic groups) and compared these data with those from persons of predominately European descent with CLL. CLL incidence was about 5-10-fold less in Asians. Asians with CLL are younger, have atypical morphologic and immunologic features, an increased proportion of IGHV mutations and rearrangements and briefer freedom-from-progression than persons of predominately European descent with CLL. These observations provide clues to the etiology and biology of CLL. But the mystery continues; more research is needed. Copyright © 2014 Elsevier Ltd. All rights reserved.
 
Article
We are often faced with the question as to the optimum duration of secondary prophylaxis with oral anticoagulants after an episode of venous thromboembolism. Theoretically if we know the recurrence rate, the case-fatality, the effectiveness of oral anticoagulant therapy, and the rate of fatal haemorrhage on treatment, we can calculate whether being on or off treatment is safest. Using these data and considering only the risk of death we would treat idiopathic deep vein thrombosis for six months. For those with DVT associated with a transient risk factor it would be reasonable to stop treatment after 3 months in those over 50 years old and we should certainly stop after 3 months in those over 70 years old. There are data to suggest that pulmonary embolism may have a higher case-fatality than deep vein thrombosis if there is a recurrence. If these data were accepted most patients with idiopathic pulmonary embolism would get long-term treatment. We can use these models to modify our assessment if other factors such as antiphospholipid antibodies or cancer are present.
 
Article
Venous access is an essential aspect of hemophilia care. When peripheral venipuncture is not feasible, central venous access devices (CVADs) or the creation of an arteriovenous fistula (AVF) allow the infusion of clotting factor concentrate to treat or prevent bleeding events or eliminate inhibitors. Infection is the primary complication associated with CVADs and the most common reason for their removal. Complications of AVF include occlusion and limb length discrepancies.
 
Article
As the biochemical mechanisms of hypercoagulable states are revealed, the syndromes of venous thromboembolism have been increasingly associated with specific aberrations. Most of these changes involve an increase in procoagulant potential, for example, by activation of the coagulation cascade, or by a defect or decrease in natural inhibitors of clotting. Similar abnormalities of the fibrinolytic pathways may contribute, as can loss of inhibitory mechanisms of endothelial cells, as well as changes in vascular anatomy and rheologic patterns of blood flow. All of these factors can directly influence thrombus formation and/or the physiologic response to the thrombus.(1)
 
Article
Outcome of patients with aplastic anaemia (AA), whether treated with allogeneic BMT or immunosuppressive therapy has steadily increased over the last three decades. However, there is a difference in quality of outcome between these two therapeutic modalities. There is no plateau for survival after ATG as patients are at later risk of transformation to myelodysplasia (MDS) or acute myeloid leukaemia (AML), paroxysmal nocturnal haemoglobinuria and relapse of their aplasia. In contrast, AA patients are not at risk of these later complications if they have undergone successful bone marrow transplantation. Long term survival after HLA identical sibling BMT is 80-90%, but GVHD and graft rejection remain to be addressed. The results of unrelated donor BMT for AA have shown considerable improvement over the last five years. Difficulties remain for those patients who fail immunosuppressive therapy and in whom BMT is not possible, since alternative immunosuppressive agents have so far proven to be somewhat disappointing.
 
Article
Antilymphocyte globulin is an immunoglobulin preparation prepared from heterologous serum after the animal (horse or rabbit) has been immunised with human lymphocytes, obtained from the thymus (antithymocyte globulin, ATG) or thoracic duct (antilymphocyte globulin, ALG). The rationale for the use of ALG in the treatment of chronic acquired marrow failure is based on its immunosuppressive activity and the fact that a proportion of cases of bone marrow failure, whether affecting single or multiple haemopoietic cell lines are due to immune-mediated suppression of haemopoiesis. In addition, in vitro studies have shown that ALG also has an immunostimulatory effect on lymphokine and haemopoietic growth factor production, and may therefore directly stimulate haemopoietic progenitor cells. ALG has been used for the treatment of aplastic anaemia and acquired chronic marrow failure affecting single cell lines namely pure red cell aplasia (PRCA), amegakaryocytic thrombocytopenia and chronic neutropenia due to immune inhibition of granulopoiesis ('acquired white cell aplasia'). ALG is used for treatment of non-severe aplastic anaemia (NSAA) and in those cases of severe aplastic anaemia (SAA) where allogeneic transplantation is not possible or is not indicated. Treatment with ALG results in 75% long term survival for NSAA and 40-50% for SAA although there is a very severe subgroup of SAA defined by peripheral blood neutrophils of less than 0.2 x 10(9)/l who rarely benefit from ALG therapy. For those patients who do not respond a second course of ALG can be given later using ALG from a different animal source.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the ‘a’ subunit, which is the active enzyme, and the ‘b’ subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an ε(γ-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (α-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts.
 
Article
In the majority of patients with congenital and acquired von Willebrand disease (vWD), desmopressin (DDAVP) is able to increase circulating factor VIII coagulant (VIII: C) to levels sufficient to secure satisfactory hemostasis. The bleeding time (BT) is also often normalized. In this review, all cases of vWD treated with DDAVP for the prevention or control of hemorrhage and reported in the literature for whom at least basal and peak values of VIII:C were available have been analysed. When reported, the effect on the BT was also considered. It appears that, in keeping with clinical experience gained with blood products, the correction of VIII:C defect is often sufficient to secure normal hemostasis. The only significant exception is mucosal bleeding, for which the correction of BT also appears to be necessary. Several patients (mainly with type I vWD) with basal VIII:C levels of 5-10% have been successfully treated to prevent bleeding after tooth extractions and minor surgery and to control spontaneous and post-traumatic bleeding. Experience with DDAVP in major surgery is still limited, so that the compound cannot be recommended for routine use. In acquired vWD, a trial with DDAVP is advised before resorting to substitutive therapy with blood derivatives. Since side effects to DDAVP treatment are limited and no major complications have been consistently demonstrated, DDAVP can be proposed as the treatment of first choice for most patients with vWD. The recent availability of concentrated preparations of DDAVP for intranasal administration and the demonstration that the subcutaneous route is an effective and simpler alternative to the intravenous route should further facilitate its use and make home-therapy feasible.
 
Article
Iron overload occurs in patients who require regular blood transfusions to correct genetic and acquired anaemias, such as beta-thalassaemia major, sickle cell disease, and myelodysplastic syndromes. Although iron overload causes damage in many organs, accumulation of cardiac iron is a leading cause of death in transfused patients with beta-thalassaemia major. The symptoms of cardiac iron overload will occur long after the first cardiac iron accumulation, at a point when treatment is more complex than primary prevention would have been. Direct measurement of cardiac iron using T2* magnetic resonance imaging, rather than indirect methods such as measuring serum ferritin levels or liver iron concentration have contributed to earlier recognition of myocardial iron loading and prevention of cardiac toxicity. Cardiac siderosis occurs in all transfusional anaemias, but the relative risk depends upon the underlying disease state, transfusional load, and chelation history. All three available iron chelators can be used to remove cardiac iron, but each has unique physical properties that influence their cardiac efficacy. More prospective trials are needed to assess the effects of single-agent or combination iron chelation therapy on the levels of cardiac iron and cardiac function. Ultimately, iron chelation therapies should be tailored to meet individual patient needs and lifestyle demands.
 
Article
New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs® immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences - lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM.
 
Article
Although the alkylating agents were amongst the first non-hormonal compounds to be shown to be active against malignant cells they still rank as some of the most valuable cytotoxic drugs available for the treatment of patients with leukaemia and lymphoma. Melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide and the nitrosoureas are all members of this class of drug, which are believed to exert their cytotoxic effects through the covalent linkage of alkyl groups to DNA. In the first report describing the use of alkylating agents in clinical practice the problem of drug resistance was recognised. In spite of this there is still comparatively little known about the mechanisms underlying the development of resistance as it occurs in patients. Studies using animal models and cell lines have suggested that both cellular and extracellular factors may be involved, but the precise relevance of these to the clinical setting is unclear. A greater understanding of the mode of action and mechanisms of resistance to alkylating agents should enable the development of modulators capable of the restoration of sensitivity to resistant cells, and the more effective use of these well established drugs.
 
Article
Among the components in snake venom are a number which have profound effects (either stimulatory or inhibitory) on haemostatic mechanisms, including coagulation, fibrinolysis, platelet function and vascular integrity. As a consequence, human victims of snakebite may suffer severe and sometimes fatal haemorrhagic and/or thrombotic sequelae. Many of these venom components have been isolated and their precise mechanisms of action established. Apart from direct fibrinolysins, procoagulants predominate, most of these exerting their effect late in the clotting cascade, activating factor X or prothrombin or directly converting fibrinogen to fibrin. Some of the procoagulants are, or have the potential to be, used as therapeutic agents. Some venom components have been put to use as laboratory reagents for diagnostic purposes or for characterising molecular defects of haemostasis, although because they often have unphysiological actions, results must be interpreted with caution. These and other useful constituents e.g. protein C activator and platelet aggregating agents are discussed.
 
Article
The factor VIII procofactor circulates as a metal ion-dependent heterodimer of a heavy chain and light chain. Activation of factor VIII results from limited proteolysis catalyzed by thrombin or factor Xa, which binds the factor VIII substrate over extended interactive surfaces. The proteases efficiently cleave factor VIII at three sites, two within the heavy and one within the light chain resulting in alteration of its covalent structure and conformation and yielding the active cofactor, factor VIIIa. The role of factor VIIIa is to markedly increase the catalytic efficiency of factor IXa in the activation of factor X. This effect is manifested in a dramatic increase in the catalytic rate constant, k(cat), by mechanisms that remain poorly understood.
 
Article
Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleeding episodes in haemophiliac patients with inhibitors. In haemostatic circles it has also been assessed in reversing oral anticoagulant therapy. Over the last few years, it has been used "off-label" in patients with uncontrolled bleeding due to haemostatic abnormalities due to trauma and/or massive blood loss, thrombocytopenia, platelet dysfunction or liver dysfunction. This review examines the proposed mechanism of action of rFVIIa in the context of current concepts of haemostasis and its pharmacological properties. The "off-license" use of rFVIIa is reviewed. The latter are reported mainly as case reports, case series. There is an overwhelming need for randomized controlled trials to assess rFVIIa's efficacy, dosing and safety in current "off-license" use.
 
Article
Interleukin-2 (IL-2) is the first of a growing list of lymphokines to be cloned and available for preclinical and clinical evaluation. A product of T-helper lymphocytes, IL-2 augments the cytolytic activity of T-lymphocytes and natural killer (NK) cells, stimulates the proliferation of these cells, and induces the formation of lymphokine-activated killer (LAK) cells. LAK cells exhibit cytolytic activity against a broad range of both freshly isolated and cultured tumor cells, while exhibiting limited cytolytic activity against normal cells. The apparently large therapeutic index suggested by in vitro studies is strongly supported by the antitumor responses seen in preclinical studies. Initial clinical studies reported encouraging response rates, but the actual role of IL-2 and/or LAK cell infusion in cancer therapy has yet to be determined, and may only represent the first step in managing the tumoricidal potential of the immune system.
 
Article
Arterial thrombosis, manifesting as acute myocardial infarction or ischaemic stroke, is the single most common cause of morbidity and mortality in industrialised societies. Platelets are a pre-requisite for the formation of arterial thrombi and, as a consequence, novel antiplatelet agents are sought to meet the significant clinical need for a potent, safe, and orally available therapy for the management of cardiovascular disease. Platelet thrombin receptors, termed protease-activated receptors (PARs), represent one promising candidate for the development of such therapy. This review outlines the role of platelet PARs in haemostasis and thrombosis and discusses the preclinical and clinical evidence supporting the potential of PAR antagonists as novel antiplatelet therapy.
 
Article
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are two of the growing number of recognized cytokines involved in the regulation of hematopoiesis. The purification of these factors and the subsequent cloning of the cDNAs which encode these proteins have led to their widespread clinical use in the setting of therapy or disease-induced myelosuppression. Although originally purified on the basis of their colony-stimulating properties, GM-CSF and G-CSF may also play important roles in the regulation of effector cell function. The mechanisms underlying progenitor cell proliferation and effector cell stimulation remain poorly understood. However, the characterization of the GM-CSF and G-CSF receptors and recent work in signal transduction are helping to elucidate these mechanisms. This paper will review the biology of the GM-CSF and G-CSF receptors, the mechanisms of post-receptor signal transduction, and the resultant effects on neutrophil function. In addition, the current and potential clinical uses of these factors will be examined in light of their ability to activate and perhaps enhance the function of neutrophils.
 
Article
Broad spectrum assays which measure a range of fibrinogen/fibrin derivatives (FDPs) in serum have become an established means of identifying activation of blood coagulation and/or fibrinolysis, such as occurs in disseminated intravascular coagulation (DIC). There is considerable interest in the application of these assays to the diagnosis of other hypercoagulable states, such as recurrent deep venous thrombosis and myocardial infarction. In recent years, more sensitive and specific FDP assays (e.g. for fragment E, fragment E neoantigen, D-dimer, fragment D neoantigen, fibrinopeptide A and fibrin fragment beta 15-42) have been devised, some of which allow measurement in plasma of FDPs without interference from fibrinogen or certain of its derivatives. It was predicted that these assays would both avoid the possibility of artifacts introduced as a consequence of serum preparation and improve detection of hypercoagulable states. In the light of these expectations we have reviewed data published on the use of assays to detect clinical hypercoagulability, giving prominence to assays of crosslinked fibrin derivatives and nothing particularly certain studies that have compared the performance of different assays on the same samples. The accumulating evidence indicates that all of the assays are adequate for detection of DIC. The same cannot be said for other hypercoagulable states. Here much variation is evident between different studies of similar patients in the ability of a particular marker to discriminate between a normal control group and patients determined to be hypercoagulable by an independent method. This variability would seem to be a function of patient group heterogeneity and selection, as assays that detect different antigenic determinants produce results on the same plasma samples that are well correlated. It appears that the precise antigenic determinant does not critically affect detection of hypercoagulability. Additionally, some studies have indicated that use of serum need not introduce artifacts. Despite there being no other obvious advantage, the convenience of some of the plasma assays may well encourage their widespread use. Assays have also been developed for measuring activation fragments of coagulation proteins (e.g. prothrombin fragment F1 + 2 and protein C activation peptide) and for proteinase inhibitor complexes (e.g. thrombin-antithrombin complex) generated during activation of coagulation. The latter assays have been useful in providing a biochemical definition of a 'prethrombotic state'.
 
Article
This review article describes the different receptors, second-messengers and mechanisms involved in platelet activation. Several platelet agonists have well-defined receptors at the platelet membrane of which a number are single polypeptides with 7 hydrophobic transmembrane domains. These receptors are connected, via GTP regulatory proteins, with cytoplasmic second-messenger-generating enzymes. Phospholipase C and adenylate cyclase are the two best-known enzymes, generating inositol triphosphate (IP3) and diacyl glycerol from phosphatidylinositol biphosphate and cyclic AMP from ATP respectively. The intraplatelet free calcium level, which is critical for the activation status of the platelet, is increased by IP3 and is lowered in the presence of rising cyclic AMP concentrations. Shape-change occurs with small increases in intraplatelet calcium, while aggregation and secretion of granules take place at higher calcium, levels. The role of myosin and actin filaments and of transmembrane glycoproteins is further discussed.
 
Top-cited authors
Paul Harrison
  • University of Birmingham
Martin Steinberg
  • Boston University
Gregory James Kato
Andrea Piccin
  • Northern Ireland Blood Transfusion Service Belfast UK
Owen Smith
  • Our Ladys Childrens Hospital, Crumlin