The myeloproliferative disorders are believed to represent clonal malignancies resulting from transformation of a pluripotent stem cell. X-inactivation patterns of peripheral blood cells have been proposed as a useful diagnostic tool but this method is limited by the finding of a clonal X-inactivation pattern in a significant proportion of normal elderly women. There is no pathognomonic chromosomal abnormality associated with the myeloproliferative disorders. However, consistent acquired cytogenetic changes include del(20q), del(13q), trisomy 8 and 9 and duplication of segments of 1q, all of which have been observed at diagnosis or before cytoreductive therapy and therefore represent early lesions which contribute to the pathogenesis of these disorders. Although, the acquired molecular defects underlying most myeloproliferative disorders have not yet been elucidated, translocations associated with the rare 8p11 syndrome have permitted identification of a novel fusion protein. The role of a number of candidate genes in the other myeloproliferative disorders has also been studied, but no mutations have been identified so far. It is likely that a number of genes will be involved, given the varied phenotypes of the diseases. Identification of causal genes will be of considerable interest to both clinicians, who currently lack a specific and sensitive diagnostic test, and scientists interested in fundamental issues of stem cell behaviour.
The discovery of the role of PF4 in the development and pathogenicity of heparin-dependent antibodies which trigger heparin-induced thrombocytopenia (HIT), a rare but severe adverse effect of heparin therapy, has allowed us to revisit the diagnosis of this complication and the pathological mechanisms involved. In this review, diagnostic tests available for confirmation or prediction of HIT are analysed, and new diagnostic strategies are discussed. Factors involved in the development of the heparin-dependent immune response in some heparin-treated patients are then presented. Lastly, it is hypothesized that the presence of antibodies is a risk factor for HIT. The mechanisms which contribute to the development of complications and the role of additional risk factors, including the patient's clinical state and the type of heparin used, are discussed (Magnani, 1993).
A complete spectrum of genetic lesions affecting the beta-globin gene giving rise to a complete spectrum of phenotypic severity is described. Although most of the molecular lesions involve the structural beta gene directly, some down regulate the gene through in-cis effects at a distance while trans-acting factors are implicated in a few cases. The remarkable phenotypic diversity can be related ultimately to the degree of alpha-globin-beta-globin chain imbalance and arises from variability of mutations affecting the beta gene itself and from interactions with other genetic loci, such as the alpha- and gamma-globin genes. The presence of other interacting loci is implicated by their interactions in increasing gamma gene expression or by an increased proteolytic capacity of the erythroid precursors. It is hoped that observations from the genotype-phenotype relationship might form the basis for a comprehensive diagnostic database that will be useful not only for genetic counselling and prenatal diagnosis but also for providing prognostic information for decision making in bone marrow transplantation and gene therapy programmes in the future. However, it is clear from recent analyses that, apart from the two categories of triplicated alpha genes with heterozygous beta-thalassaemia and inheritance of mild beta(+)-thalassaemia alleles, it is still not possible to predict consistently phenotype from alpha and beta genotypes alone owing to the influence of the other modulating factors, some implicated (such as inheritance of hereditary persistence of fetal haemoglobin) and others as yet unidentified.
Most of the major clinical manifestations of the beta-thalassaemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and red cell survival. The destruction of red cell progenitors and their progeny results from an extremely complex series of mechanisms all related to the presence of excess alpha-globin chain production. These include mechanical damage, interference with cell division and oxidative destruction of both organelles and components of the red cell membrane. The unequal distribution of gamma-globin chains between different precursors, and the intense selection of those with relatively higher levels of gamma chain production, lead to an extremely heterogeneous cell population in the peripheral blood. Iron overload, due to increased gastrointestinal absorption and blood transfusion is the major cause of tissue damage, morbidity and death.
Immune thrombocytopenic purpura (ITP) is a relatively common immune-mediated disorder characterized by thrombocytopenia due to clearance of opsonized platelets by the reticuloendothelial system. The acute form, more common in children, is a self-limiting, often post-viral disease. In contrast, the adult form is typically a chronic disorder, which initially responds to corticosteroids. Splenectomy offers a 70% chance of cure. Major progress has been achieved in the elucidation of the immune pathology in ITP, and we review contemporary advances in the treatment of chronic ITP. Practical guidelines for the diagnosis and treatment of various aspects of ITP were established in 1996 by the American Society of Hematology. Since these recommendations will most probably substantially influence patient care, they are discussed in detail. Human immunodeficiency virus (HIV)-associated ITP is a common problem in countries with a high prevalence of HIV infection. The pathogenesis of this subtype probably differs from that of classic ITP, and is considered separately.
Thrombotic thrombocytopenic purpura (TTP) is an uncommon multisystem disorder, sometimes associated with predisposing conditions such as pregnancy, cancer, exposure to certain drugs, bone marrow transplantation and HIV-1 infection. An abnormal interaction between the vascular endothelium and platelets which occurs in certain organs leads to thrombosis, endothelial proliferation, minimal inflammation and micro-angiopathic haemolysis. Recent studies suggest that endothelial cell perturbation and apoptosis caused by an as yet unknown plasma factor(s) may lead to the release of abnormal von Willebrand factor which facilitates the deposition of platelet microthrombi. Exchange transfusions of plasma or plasma-cryosupernatant remain the cornerstone of the treatment of TTP along with corticosteroids, platelet inhibitor drugs, vincristine and splenectomy. In most cases remissions can be attained, and cures are now common—although approximately one-half of the patients will relapse. While relapses are usually milder, they still carry a significant mortality and preventive therapies are not always effective.
Heparin-induced thrombocytopenia (HIT) is a severe immunological adverse effect of heparin treatment. Recently the pathogenesis of HIT has been resolved regarding the mechanisms of platelet activation, the nature of the most important antigens and the involvement of the clotting cascade. HIT seems to be associated with massive generation of thrombin, which contributes to the thromboembolic complications. Based on these findings, treatment of patients with acute HIT should include cessation of all heparins and further treatment with an anticoagulant with antithrombin activity. Currently, the two most important compounds for further anticoagulation of HIT-patients are danaparoid-sodium and recombinant hirudin.
The management of pregnant patients with chronic myeloproliferative disorders (MPD) is a difficult problem. Patients with essential thrombocythaemia (ET), and, less frequently, those with chronic myeloid leukaemia (CML) or polycythaemia vera (PV), present at a childbearing age. Pregnancy itself does not appear to affect adversely the natural course and prognosis of the MPD. However, fertility might be reduced, and an adverse outcome of pregnancy due to thrombotic or bleeding complications is a matter of concern. In ET, first-trimester abortion is the most frequent complication but increased perinatal mortality and premature delivery are also observed. Placental infarction due to thrombosis seems to be the most consistent event, Maternal thrombotic or haemorrhagic complications are rare but are more common than seen in normal pregnancy. The outcome of pregnancy seems to be positively influenced by aspirin, at least in some cases. The value of cytoreduction and/or heparin prophylaxis has not been established but may have a role in selected cases. In CML, the potential adverse effects of hyperleukocytosis, and sometimes thrombocytosis, generally make myelosuppressive treatment essential. In PV, the number of reported pregnancies is low. Maintaining the PCV below 0.45 is of the utmost importance relating to the outcome of pregnancy. Although cytoreductive drugs should generally be avoided, if possible, until at least after the first trimester of pregnancy, interferon-alpha seems to be the drug of choice when myelosuppression is indicated.
This chapter discusses the histopathology of five groups of chronic myeloproliferative diseases: chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, chronic idiopathic myelofibrosis and unclassifiable myeloproliferation. Histological staging of the four haematologically defined diseases is performed by grading the three most prominent variables: megakaryocytes, fibres and blasts. Histological outcome is correlated to the staging of diagnostic bone marrow biopsies; megakaryocytic involvement is correlated with the risk of myelofibrosis. An excess of blasts is related to the risk of leukaemic transformation. The progression of myelofibrosis depends on the grade of fibre increase at diagnosis. These three statements are highly significant and valid for all types of chronic myeloproliferative disorders. The results of cytogenetics are discussed in relation to the histological classification for these patient groups. Changes in bone marrow histology following myelosuppressive therapy is presented. Prospective studies under standardized protocol therapy are recommended, so that the long-term effects of therapy can be assessed.
Venous thromboembolism is a common medical condition in both out-patients and inpatients. Despite the development of non-invasive tests, the diagnosis of deep vein thrombosis and pulmonary embolism remains a clinical challenge. In an effort to improve diagnostic accuracy and to reduce the necessity of serial testing, laboratory markers of thrombin generation and fibrinolysis have been investigated as first-line screening tests. Although the majority of markers are elevated in acute thrombosis, D-dimer, a specific derivative of cross-linked fibrin, appears to have the most potential clinical utility. Accuracy studies and preliminary management trials suggest that rapid D-dimer enzyme-linked immunosorbent assays and the whole blood agglutination assay, SimpliRED D-dimer (Agen Biomedical, Brisbane, Australia), have, strong potential as exclusionary tests in patients with suspected venous thrombosis.
Collectively sickle cell disease and beta-thalassaemia are the most commonly inherited single-gene defects world-wide and were the first group of diseases for which DNA-based detection strategies were utilized. Although genotypically distinct, these two groups of diseases exhibit several common clinical features: moderate-to-severe haemolytic anaemia, acute and progressive tissue damage, disease- or treatment-related organ failure and premature death. Within the last two decades, a striking improvement in life expectancy in the two patient populations has been observed, by dint of primary and secondary prevention strategies. However, apart from bone marrow transplantation, a generally applicable, specific and non-toxic form of treatment remains unavailable for these disorders. Nonetheless, a greater appreciation of the developmental control of human globin gene expression coupled with observations of the effects of certain classes of agents to 'reverse' erythroid cellular phenotype in in vitro and animal models have led to pharmacological trials to obtain meaningful increases in haemoglobin F production in patients affected by these two severe beta-globin disorders. Contemporary understanding of the quantitative relationship between the abnormal molecules in the red cells (aggregates of sickle haemoglobin) in the sickle cell syndromes and aggregated alpha-globin polypeptides in the beta-thalassemia syndromes, and the extent of the red cell and/or organ involvement, has now enabled investigators to predict how much inhibition of these intracellular pathogenic processes might be necessary to achieve partial or total abrogation of disease manifestations. The results of the Multicenter Study of Hydroxyurea and other controlled trials now bear out these predictions.
A complete spectrum of genetic lesions affecting the beta-globin gene giving rise to a complete spectrum of phenotypic severity is described. Although most of the molecular lesions involve the structural beta gene directly, some down regulate the gene through in-cis effects at a distance while trans-acting factors are implicated in a few cases. The remarkable phenotypic diversity can be related ultimately to the degree of alpha-globin-beta-globin chain imbalance and arises from variability of mutations affecting the beta gene itself and from interactions with other genetic loci, such as the alpha- and gamma-globin genes. The presence of other interacting loci is implicated by their interactions in increasing gamma gene expression or by an increased proteolytic capacity of the erythroid precursors. It is hoped that observations from the genotype-phenotype relationship might form the basis for a comprehensive diagnostic database that will be useful not only for genetic counselling and prenatal diagnosis but also for providing prognostic information for decision making in bone marrow transplantation and gene therapy programmes in the future. However, it is clear from recent analyses that, apart from the two categories of triplicated alpha genes with heterozygous beta-thalassaemia and inheritance of mild beta(+)-thalassaemia alleles, it is still not possible to predict consistently phenotype from alpha and beta genotypes alone owing to the influence of the other modulating factors, some implicated (such as inheritance of hereditary persistence of fetal haemoglobin) and others as yet unidentified.
Acquired von Willebrand disease (AvWD) is an acquired bleeding disorder which may suddenly become manifest in individuals, usually in the absence of a personal or family history of bleedings and frequently in association with monoclonal gammopathies, lymphoproliferative, myeloproliferative and autoimmune disorders. In a minority of the cases AvWD may develop in association with drugs or solid tumours, Pathogenetic mechanisms involve autoantibodies directed against von Willebrand factor (VWF) resulting in a rapid clearance of VWF from the circulation and/or inactivation of plasma VWF; absorption or adsorption of plasma VWF to malignant cells; drug-induced or cell-mediated proteolysis of plasma VWF; acquired decrease in synthesis of VWF and/or release of VWF from storage sites; or precipitation of plasma vWF Treatment options include-whenever possible-treatment of the underlying disorder or symptomatic treatment aimed at replacing the loss of vWF by either infusion of vWF-rich concentrates or administration of desmopressin (DDAVP). In selected cases with anti-vWF antibodies, administration of high-dose intravenous gammaglobulin, plasma exchange or extracorporeal immunoadsorption may be successful.
Of all pregnant. women 1.2% have platelet counts below 100x10(9)/l. Only a small proportion of these have immune thrombocytopenic purpura (ITP). ITP is caused by antibodies directed against one's own platelets and may affect the mother as well as the fetus. No cases with documented intrauterine fetal bleeding have been reported. The most critical time for the fetus is usually a few days after birth. Hitherto the patient's history has been the best predictor of maternal and neonatal complications. Diagnostic cordocentesis entails a considerable risk and is to be discouraged in most situations. Intrauterine transfusions are effective only for a very limited period. There is no evidence that caesarean section protects the thrombocytopenic infant from intracranial haemorrhage. We therefore recommend restricting caesarean section to obstetric indications and to situations with proven fetal thrombocytopenia and enhanced obstetric risk. The safe cut-off level has yet to be ascertained. It is mandatory to control the newborn's platelet count during the first three days of life.
Childhood acute autoimmune thrombocytopenia is defined as a bleeding disorder in otherwise healthy children caused by transient destruction of platelets. It is benign, presenting mostly with skin purpura and minor bleeds. The diagnosis requires information about previous infections or immunizations, a physical examination looking for signs or symptoms for other causes of thrombocytopenia and a complete blood count with examination of the peripheral blood smear focusing on the number and morphology of platelets. Bone marrow examination is indicated only when in doubt and should be considered if prednisone therapy is planned. A threshold platelet count dividing high- and low-risk groups in immune thrombocytopenia (ITP) is not known because of problems with platelet counting in thrombocytopenia and the lack of clinical data. Immunoglobulins or glucocorticoids increase the platelet count, probably by blockage of the phagocytic monocyte-macrophage system. However, it is unclear whether this increase influences bleeding or mortality or whether the disadvantages of these medications might outweigh their benefits.
Oral anticoagulation has been the mainstay of therapy for the long-term treatment of venous thromboembolism since the 1940s. The rationale for the use of oral anticoagulation is based on the results of both empirical clinical evidence and animal models of thrombosis in the 1950s and 1960s. Higher-quality studies emerged in the 1970s and 1980s demonstrating the benefit of initial heparinization for venous thromboembolism followed by long-term oral anticoagulation. Good clinical outcomes with oral anticoagulation are highly dependent on the quality of dose management. Excellent management is best achieved in a programme of focused and co-ordinated care, often referred to as an anticoagulation clinic. Such programmes achieve better outcomes at reduced costs because of fewer adverse events. New models of anticoagulation management are emerging with the development of point-of-care testing that enables patients to do their own prothrombin time monitoring and anticoagulation dose adjustment. These models have the potential to improve care further, to increase patient satisfaction and to reduce costs.
Idiopathic myelofibrosis is the least common and carries the worst prognosis of the chronic myeloproliferative disorders. The primary disease process is a clonal haematopoietic stem cell disorder which results in a chronic myeloproliferation and an atypical megakaryocyte hyperplasia. In contrast, the characteristic stromal proliferation is a reactive phenomenon, resulting from the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta bFGF and calmodulin. The median survival is approximately 4 years, although individual survival varies greatly. A variety of prognostic schema have been developed which enable the identification of high-risk patients, for whom bone marrow transplantation should be considered. Management for the majority of patients, however, is directed towards the alleviation of symptoms and improvement in quality of life. This review summarizes the recent advances in our understanding of the disease's pathogenesis and discusses the limited therapeutic options available to clinicians.
Advances in the management of thalassaemia major have greatly improved the prognosis for patients with this disease. In countries able to afford programmes of regular transfusion and iron-chelating therapy, survival to the fourth decade is now common, and most complications associated with the primary disease are now infrequently observed. This situation stands in contrast to that in emerging countries, where the widespread implementation of these expensive treatment regimens is still awaited. This review will focus on recent advances in the treatment of thalassaemia and briefly review the progress in experimental approaches to treatment of this disorder.
Excessive intravascular platelet agglutination in patients with thrombotic thrombocytopenic purpura (TTP) appears to be associated with excessive release from endothelial cells of unusually large von Willebrand factor (vWF) multimers and/or impaired degradation of these multimers by a 'depolymerase' cleaving vWF to smaller, non-agglutinating molecular forms. We studied the activity of a recently described vWF-cleaving protease in four patients, including two brothers, with chronic relapsing TTP. All four patients had lacking or strongly reduced vWF-cleaving protease activity. In another patient with chronic relapsing TTP, the protease deficiency was due to the presence in the patient plasma of an inhibitor that was found to be an IgG. We conclude that constitutional as well as acquired deficiency of vWF-cleaving protease may predispose to clinical manifestation of TTP.
