Treatment

The treatment of aplastic anaemia depends first on providing total support for the patient while awaiting bone marrow recovery and, second, on attempts to accelerate that recovery. It should be emphasized that support and encouragement may be required for months or years before some sort of remission occurs and that disappointment and anxiety bedevil the management of aplastic anaemia. Patients, relatives and staff all need help in maintaining morale. Support for the aplastic anaemia patient...

Syphilis

Each donation is tested by a serological test for syphilis. Although Treponema pallidum does not survive well at 4 C and red cell preparations are likely to be non-infective after 4 days' refrigeration, storage does not affect the positive serology. Passive transmission of the antibody to a recipient could cause diagnostic confusion. The organism is more likely to be transmitted in platelet concentrates, due to their room temperature storage and short shelf-life. Any donation from an individual...

Desferoxamine

Desferrioxamine mesylate (DFX) is the main agent licensed in all countries in clinical use at present. It is not absorbed orally and, after parenteral injection, it is rapidly cleared from the plasma, being excreted in the urine, taken up by hepatocytes or metabolized in the tissues (Table 4.3). This accounts for the much greater mobilization of iron by continuous intravenous (i.v.) or slow subcutaneous (s.c.) infusions, which allow more prolonged exposure of the drug to the chelatable iron...

Severe combined immunodeficiency

The majority of patients with SCID present with severe persistent infection in infancy or early childhood. A typical scenario is failure to thrive during the first 2 years of life, episodes of protracted diarrhoea and persistent cough due to an opportunistic fungal respiratory infection (Figure 22.1). However, there are many exceptions to this 'classical' presentation, some patients having features that are not directly related to infection, such as skin rashes, severe autoimmune phenomena,...

The red pulp splenic blood flow

The circulation within the spleen is illustrated in Figure 21.2. Blood is brought to the spleen via the splenic artery, and then, through its branches (the trabecular arteries), into the central arteries, which are sited in the white pulp. These central arteries run in the central axis of periarteriolar lymphatic sheaths they give off many arterioles and capillaries, some of which terminate in the white pulp whilst others go on to enter the red pulp. In the red pulp there are sinuses, 20-40 im...

M

Figure 2.3 The specification and terminal differentiation of erythroid cells from haemopoietic stem cells. Above, the estimated times for maturation of terminally differentiating cells are shown. The abbreviations are as follows pronormoblasts (Pro), basophilic erythroblasts (Bas), polychromatic erythroblasts (Pol), orthochromatic erythroblasts (Ort), reticulocytes (retic), mature red blood cells (RBCs). The number of divisions from pronormoblasts to orthochromatic normoblasts (1-16) are also...

Hazards of allogeneic blood transfusion

A number of diseases have the potential to be transmitted by transfusion of blood or its components. Donor selection criteria and subsequent testing of all donations are designed to prevent such transmission (Table 16.3). The viruses that pose the greatest potential risk for transmission by transfusion are those that have long incubation periods (often causing subclinical infection), and especially those that may be carried by asymptomatic individuals for many years, or even lifelong....

Chemical and physical agents

Oxidative substances may cause haemolysis in people with normal red cell metabolism and normal HbA if the oxidative stimulus is large enough. The major causes of oxidative haemolysis in normal subjects are shown in Table 10.7. The clinical features of this condition are dependent on the main sites of oxidative attack, whether on the membrane of the red cell, the globin chains or the haem group. Figure 10.5 Oxidative haemolysis caused by drug (phenacetin). Note red cells with contracted...

General management of megaloblastic anaemia

It is usually possible to establish which of the two deficiencies, folate or cobalamin, is the cause of the anaemia and to treat only with the appropriate vitamin. In patients who enter hospital severely ill, however, it may be necessary to treat with both vitamins in large doses once blood samples have been taken for cobalamin and folate assay and a bone marrow has been performed (if deemed necessary). Transfusion is usually unnecessary and inadvisable. If it is essential, packed red cells...

Antigens

Mediated by antibodies only specific cell-mediated immunity to red cell alloantigens or autoantigens has not been described. The parts of an antigen that bind antibodies or cellular receptors are called antigenic determinants or epitopes, and those parts of the antibodies that bind to them are called paratopes. Most antigens that occur naturally are of high molecular weight, and each antigenic molecule may have several different or several identical epitopes. As antibodies are specific for the...

Operational alternatives

Treatment of preoperative anaemia with haematinics, if appropriate, in a timely way at preassessment clinics. Autologous transfusion in all its forms. It seems that cell salvage is considerably more cost-effective than pre-deposit auto-logous transfusion. The value of preoperative haemodilution needs further assessment. Re-evaluation of transfusion triggers and algorithms for estimation of acceptable blood loss in surgery. Adherence to guidelines. Alternative fluid replacement (i.e. replace...

Aceruloplasminaemia

This is also a rare recessive disorder in which there is a deficiency of ferroxidase activity as a consequence of mutations in the ceruloplasmin gene on chromosome 3q. Clinically, the condition presents in middle age, with progressive degeneration of the retina and basal ganglia and with diabetes mellitus. Iron accumulates in the liver, pancreas and brain with smaller amounts in the heart, kidneys, thyroid, spleen and retina. The serum iron is low. The total iron-binding capacity of transferrin...

Acquired abnormality of cobalamin metabolism nitrous oxide inhalation

Nitrous oxide irreversibly oxidizes methyl cobalamin from its active, fully reduced CobI state to an inactive precursor with the CobII state. This has been shown to inactivate methylcobalamin and methionine synthase. This occurs in both humans and experimental animals and is of importance in the megaloblastic anaemia that occurs in patients undergoing prolonged N2O anaesthesia (e.g. in intensive care units). A neuropathy resembling cobalamin neuropathy has been described in dentists and...

IgM and IgG antibodies

IgM or 'complete' antibodies agglutinate red cells when they are suspended in saline. They are often called saline or directly agglutinating antibodies in laboratory parlance. Conversely, 'incomplete', IgG antibodies will not agglutinate saline-suspended red cells. However, lack of agglutination does not mean that the antibodies have not bound to their antigen, and it can be shown that they have reacted by using antiglobulin reagents, which facilitate agglutination (see below). Most naturally...

Rare ABO variants

Rare ABO variants are usually disclosed because an expected ABO antibody is missing. A sample typed as group O that has anti-B but no anti-A will usually prove to be a weak A variant. The presence of weak A or B antigens can be demonstrated either by using potent antisera or by absorption and elution. Rare ABO variants can arise from 1 Rare ABO genes. These include A3, A , Aend, Am and Ad variants. All are extremely rare and are usually recognized by their variable reactions with anti-A and or...

Laboratory diagnosis

The peripheral blood film shows typical features of haemolysis but the red cell morphology may be normal. Occasionally, there is mild hypochromia and microcytosis. Heinz bodies are present in the peripheral blood after splenectomy. The most characteristic feature of the unstable haemoglobins is their heat instability. If a dilute haemoglobin solution is heated at 50 C for 15 min, the unstable haemoglobins precipitate as a dense cloud. A similar effect can be induced by isopropanalol. Some of...

Dyskeratosis congenita

Dokal I (2000) Dyskeratosis congenita in all its forms. British Journal of Haematology 110 768-79. Heiss NS, Knight SW, Vulliamy TJ etal. (1998) X-linked dysker-atosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genetics 19 32-8. Knight SW, Heiss NS, Vulliamy TJ et al. (1999) Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1....

Neutropenia

Neutropenia increases in incidence as HIV disease progresses, although it may be present in asymptomatic individuals. Impaired haemopoiesis, as discussed above, is the major factor, although in some patients immune neutrophil destruction may contribute. Antineutrophil antibodies have been detected in some HIV antibody-positive patients by using a granulocyte immunofluo-rescence technique, but there is poor correlation with the neut-rophil count. In general, neutropenia is well tolerated in...

Type 2 juvenile haemochromatosis

Juvenile haemochromatosis is a rare autosomal recessive disease, with clinical symptoms appearing in the second and third decades of life, characterized by cardiomyopathy and hypogonadism. The hemojuvelin locus has been mapped to chromosome 1q21. Iron absorption is greater than in type 1 haemochromatosis. Like hepcidin, hemojuvelin modulates hep-cidin expression and hepcidin levels are low in homozygous individuals with hemojuvelin mutations. Mutations were found in Greek, Canadian and French...

Clinical features

The commonest initial complaint in PNH is fatigue, due to anaemia, which may range from mild to very severe. Sometimes the patient reports that one morning he or she passed very dark urine (e.g. 'it looked like Coca-Cola' or 'it looked like blood rather than urine'). This 'classical' presentation occurs in only a minority of patients. However, if specific questions are asked, or if serial urine specimens are collected and inspected (Figure 11.1), haemoglobinuria can be documented at some time...

Treatment of folate deficiency

There is probably never any need to give folic acid parenterally, except in patients receiving parenteral nutrition who cannot swallow tablets. Oral doses of 5-15 mg folic acid daily are satisfactory, as sufficient folate is absorbed from these extremely large doses even in patients with severe malabsorption. The length of time therapy must be continued depends on the underlying disease. It is customary to continue therapy for about 4 months, when all folate-deficient red cells will have been...

Rhnull syndrome

The Rh system forms a large complex traversing the lipid bilayer several times, containing extracellular thiol groups. In the RhnuU phenotype, the complex is absent. The condition is very rare and is inherited as a recessive disorder. Patients have mild to moderate haemolytic anaemia that may respond to splenectomy, and the blood film shows occasional stomatocytes. The Rh complex involves two genes, one encoding for the D polypeptide, the other for the Cc and Ee polypeptide, depending on...

Definition and classification

The thalassaemias are a heterogeneous group of genetic disorders of haemoglobin synthesis, all of which result from a reduced rate of production of one or more of the globin chains of haemoglobin (Table 6.1). They are divided into the a-, P-, SP- or ySP-thalassaemias, according to which globin chain is produced in reduced amounts. In some thalassaemias, no globin chain is synthesized at all, and these are called a0- or P0-thalassaemias in others, designated a+- or P+-thalassaemias, the globin...

Prognosis

The prognosis in warm AIHA depends on a number of variables, including age, associated diseases and severity of haemolysis. In all patients, AIHA should be considered a serious and potentially life-threatening disease. Estimates of mortality of idiopathic AIHA in adults vary from 10 at 5 years to 40 at 7 years. The higher figures are mainly in patients aged over 50 years. Most deaths occur in the first 2 years after diagnosis. In children, mortality is much lower, probably about 5 , with the...

Residual microbial risk of allogeneic blood transfusion

The residual risks of microbial transmission are now so low in the UK that prospective studies to determine them would need to be too large to be practical. Risk is therefore calculated from the length of the 'window period' (prior to laboratory delectabil-ity of the infection) and the rate of new infections for specific viruses. The calculated residual risks per donation in England and Wales for HIV, HBV and HCV are approximately 1 in 8 million, 1 in 1 million and 1 in 30 million respectively....

AntiH

1 Clinically significant 'true' anti-H occurs in the serum of persons with Bombay phenotype and is very rare. When it does occur, it is very important from the point of view of selecting blood for transfusion as the antibody is active at 37 C, only Bombay phenotype blood may be transfused. 2 Anti-H and anti-HI, commonly found in the serum of group A1, B and A1B persons, react much more strongly with adult than with cord red cells. Anti-H is inhibited by secretor saliva anti-HI is not. Although...

The D antigen RH1

In 1939, Levine and Stetson reported that a patient, who had delivered a stillborn infant and then suffered a severe reaction to transfusion of her husband's blood, had an antibody that agglutinated the red cells of 85 of ABO-compatible donors. In 1940, Landsteiner and Wiener found that guinea pigs and rabbits injected with rhesus monkey red cells made an antibody that not only agglutinated rhesus monkey red cells, but also the red cells of 85 of people of European origin. The human and animal...

Haematological changes

Haemoglobin values on presentation range from 2 to 8 g dL. The red cells show marked hypochromia and variation in shape and size, and many hypochromic macrocytes and misshapen microcytes, some ofwhich are mere fragments of cells (Figure 6.7). There is moderate anisochromia and basophilic stippling. There are always some nucleated red cells in the peripheral blood, after splenectomy they appear in large numbers. There is a slight elevation in the reticulocyte count. The white cell and platelet...

Functional ironcontaining proteins

Haemoglobin (molecular weight 64 500) contains four haem groups linked to four globin chains, and can bind four molecules of oxygen. Myoglobin (mol. wt 17 000) accounts for 4-5 of body iron and has a single haem group attached to its one polypeptide chain. It has a higher affinity for oxygen than haemoglobin and behaves as an oxygen reserve in muscles. The mitochondria contain a series of haem and non-haem iron proteins (including the cytochromes a, b and c, succinate dehy-drogenase and...

Allogeneic bone marrow transplantation for severe aplastic anaemia

Allogeneic bone marrow transplantation (BMT) for aplastic anaemia was first introduced by E Donnall Thomas and Rainer Storb and colleagues in 1969. BMT or peripheral blood stem cell (PBSC) transfusion is the treatment of choice for young patients with SAA who have an HLA-identical sibling donor. The age at which transplantation is no longer the treatment of choice depends upon the severity of the disease, the general health of the patient and the nature of the presenting symptoms. The results...

Priapism

Priapism occurs in two-thirds of males with SCD, with a peak incidence in the second and third decades. It is caused by vaso-occlusion leading to obstruction of venous drainage from the penis. It typically affects the corpora cavernosa alone, resulting in a hard penis with a soft glans. Episodes can be brief (stuttering) or prolonged, when they last for longer than 3 h. Recurrent priapism leads to fibrosis and eventual impotence. Young boys require explanation of symptoms and the need to seek...

ABO genes

The ABO gene is located on the long arm of chromosome 9, comprises seven exons and encodes proteins with a structure characteristic of glycosyltransferases. Products of the A and B alleles differ by four amino acids encoded by exon 7, two of which determine whether the enzyme product has GalNAc-transferase (A) or Gal-transferase (B) activity. The majority of O alleles (called O1) resemble A, but have a single base deletion in exon 6, which creates a shift in the reading frame and scrambles the...

The alternative pathway

The alternative pathway does not necessarily involve antibody and represents non-specific 'innate' immunity. The proteins of the alternative pathway form a feedback loop for the conversion of C3 to C3b the latter is both a product and reactant of this loop. The alternative pathway can be activated by aggregated IgA, zymosan, bacterial cells or lipopolysaccharides. Initiation of the alternative pathway is a two-step process (i) binding of C3b to an activator and (ii) interaction of bound C3b...

Complications of massive transfusion

Massive transfusion is usually defined as the replacement of the total blood volume within a 24-h period. Although a number of different problems may result from changes that occur in stored blood, it should not be forgotten that any patient who needs a massive blood transfusion is by definition already seriously ill. Too much attention may be paid to the theoretical problems caused by metabolic changes in stored blood, and not enough to the underlying clinical condition. The coagulopathy...

And i antigens

The antigens I and i are not controlled by allelic genes i is the biosynthetic precursor of I. I and i antigens are carbohydrates and are on the interior structures of the complex oligosacchar-ides that carry ABO, H and Lewis antigens. The i antigen represents linear structures that are converted to I-active branched structures by the product of the I gene (GCNT2), a P1,6-N-acetylglucosaminyltransferase. This enzyme is not active in newborn infants. Consequently, red cells of most adults are...

Platelet preparations

Platelets do not survive well in stored blood. For all practical purposes, there are no viable platelets remaining in blood stored for 48 h at 4 C. Blood donations should be kept at room temperature after collection, and platelets separated as soon as possible. Although function is maintained when platelet preparations are stored at 4 C, post-transfusion survival is poor and any haemostatic effect is short lived. Storage at 20-22 C is therefore preferable. Platelets have a shelf-life of 5 days,...

Geographic distribution of sickle mutation

Several distinct P-globin gene haplotypes are associated with the sickle mutation, and their distribution provides evidence for origin of the mutation in several locations within Africa (the Senegal, Benin and Bantu haplotypes) and Asia (the Arab-Indian haplotype). The sickle trait bestows survival benefit in areas endemic for falciparum malaria, and the distribution of SCD historically paralleled this disease. The sickle haemoglobin-containing red cells inhibit proliferation of Plasmodium...

Preparation and storage of other separate blood components Figures 161 and 162

After initial centrifugation, three components can be obtained from a whole blood donation red cells, buffy coat and plasma (Figure 16.1). Fresh plasma is expressed from the top and red cells from the bottom of the pack, leaving the buffy coat in the original pack. The red cells are transferred to a pack containing an optimal additive solution (OAS) to preserve red cell function during storage. The plasma is then kept to resuspend the platelets, or frozen either for clinical use as fresh-frozen...

The lytic phase of the complement sequence

The lytic phase starts with the activation of C5 by C3b, yielding membrane-bound C5b and fluid-phase C5a. This step is followed by non-enzymatic interaction of C5b with C6, C7, C8 and C9. These molecules adhere to each other to form the MAC and insert themselves into the lipid bilayer of the red cell membrane. C8 catalysed by C9 produces protein-lined cylinders in the red cell membrane and are about 10 nm in diameter. They form pores through which ions and water can enter. The osmotic pressure...

D immunization

The realization that D-negative women without anti-D who had just delivered a D-positive child could be protected from forming anti-D by the injection of IgG anti-D soon after delivery has been a powerful stimulus for experimental work on D-negative volunteers. About 90 of D-negative people will make anti-D after the transfusion of a large volume of D-positive cells, and 70 will respond to repeated small volumes. Res-ponders to D can usually be identified from survival curves after a single...

Diamond Blackfan anaemia

Have been reported but have not clarified the mechanism of in vivo erythroid failure. For many years, based on the typical selective deficiency in red cell precursors, many researchers believed that DBA is due to an intrinsic problem with erythroid proliferation differentiation. On the other hand, the observation of a wide range of somatic abnormalities in a significant proportion of patients and case reports of thrombocytopenia, neutropenia and AA, together with the recent evidence for a...

Pulmonary complications

Acute Chest Syndrome

Acute and chronic pulmonary complications are the leading cause of death in older patients. The acute chest syndrome is characterized by hypoxia, tachypnoea, fever, chest pain and pulmonary infiltrate on chest radiographs (Figure 7.4c). Acute chest syndrome often follows a painful event, particularly in adults (Table 7.3). The pathogenesis of acute chest syndrome involves vaso-occlusion, infection or both. Infections due to Mycoplasma, Table 7.3 Presenting symptoms of acute chest syndrome....

The origins of blood during development

Endothelium Developing haematopoietic cells Neural tube Somite Dorsal aorta Hindgut Neural tube Somite Dorsal aorta Hindgut Figure 2.1 An outline of the origin and development of erythropoiesis during embryogenesis. Although both primitive (blood islands) and definitive (AGM, liver and bone marrow) haemopoiesis are derived from mesoderm, probably via a haemangioblast, the true origin of these early cells is not yet clear. The figure shows the formation of embryonic blood islands in the...

Cell death apoptosis

The final stage in the life of a blood cell is death and disposal by apoptosis. Apoptotic cell death is a mechanism for disposing of unwanted or excess cells, and it occurs widely in biological systems. It ensures the destruction of cells without releasing any lysosomal or granule contents that would cause an inflammatory reaction. Apoptosis involves a complex series of events that culminate in the activation of the caspase proteases, fragmentation of DNA and phagocytosis of apoptotic bodies by...

Dangerous universal donors

Good practice in pretransfusion testing requires compatibility testing, which consists of incubating the patient's serum with the Table 15.5 Some properties of immune and naturally occurring anti-A and -B. Table 15.5 Some properties of immune and naturally occurring anti-A and -B. Inhibited by soluble A or B substances (e.g. saliva) *IgG ABO antibodies are usually inhibited only by large amounts of specific substance. 2-ME, 2-mercaptoethanol DTT, dithiothreitol. *IgG ABO antibodies are usually...

Minor red cell abnormalities

Donors with minor red cell abnormalities, such as thalassaemia trait, sickle cell trait and hereditary spherocytosis, are perfectly acceptable, providing that the haemoglobin (Hb) screening test excludes anaemia. Red cells containing HbS have a limited survival under conditions of reduced oxygen tension and so should not be transfused to newborn infants and patients with hypoxia or sickle cell disease. Red cells with HbS obstruct leucodepletion filters and it is therefore advisable, in the UK,...

Gene therapy

The self-renewal and expansion capacities of haemopoietic stem cells make them the ideal vehicle for gene therapy of genetic disorders. The transduced genes will be expressed for long periods of time in the stem cell population and in their differentiating and mature descendants (see Chapter 27). Almeida-Porada G, Porada CD, Chamberlain J et al. (2004) Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 104 2582-90. Bacigalupo A (2004) Mesenchymal stem cells and...

Blood grouping reagents

To avoid potential fatalities due to errors in ABO and D grouping, it is essential that the chosen ABO typing reagents have suitable potency and comply with the European Directive on in vitro diagnostic devices and the associated Common Technical Specifications and carry the 'CE' mark to show they are in conformance. Blood grouping reagents prepared from polyclonal antisera should be free of unwanted antibodies and should have been exhaustively tested with an extensive panel of cells to exclude...

Cryoprecipitatepoor plasma cryosupernatant

This term is used for the remaining plasma after the removal of cryoprecipitate. The main and specific indication for cryosuper-natant is for plasma exchange in TTP. This is an immunemediated condition in which there is an autoantibody directed against a vWF cleaving metalloproteinase. The resulting accumulation of high-molecular-weight (HMV) vWF multimers contributes to the pathophysiology of the condition with thrombosis in the microvasculature. Cryosupernatant supplies both more of the...

Crossmatching for immunologically refractory patients

The major cause of immunological refractoriness to platelet transfusion is, by far, the presence of HLA-A and or HLA-B antibodies in multitransfused patients. Quite often, such antibodies are found to react with the lymphocytes from the majority (and sometimes all) of the donors included in the panel. Platelet-specific antibodies may occur in 3-9 or less of refractory patients. Implicated specificities have included anti-HPA-la and anti-HPA-lb, as well as anti-HPA-3a, anti-HPA-2b, HPA-15b, and...

Hazards of blood donation

The most common hazard of blood donation is fainting, reported in between 2 and 5 of all donors, but being especially common in young people and in those donating for the first time, particularly if they are nervous or apprehensive. A sympathetic approach by blood collection staff, enforcement of an adequate rest period, and constant vigilance to detect warning signs of an impending vasovagal attack can help to avert this problem. Once a faint occurs, the standard treatment of rest in a...

Newborn screening

Universal newborn screening is recommended to identify SCD in the neonatal period. The efficacy of penicillin prophylaxis in preventing death from early sepsis in SCD provided the rationale for development of screening programmes. Blood samples obtained by heel prick are spotted onto filter paper and tested by electrophoresis or chromatography. Neonates with HbSS disease and HbS P -thalassaemia have an FS pattern (the order of haemoglobins indicates their relative abundance in the sample). In...

Naturally occurring and immune antibodies

Antibodies are naturally occurring when they are produced without any obvious immunizing stimulus such as pregnancy, transfusion or injection of blood. These antibodies are not present at birth and, in the case of anti-A and anti-B, start to appear in the serum of children with the appropriate ABO groups at about 3-6 months of age. ABO antibodies are probably produced in response to antigens of bacteria, viruses and other substances that are inhaled or ingested many Gram-negative organisms have...

Granulocyte concentrates

Granulocytes are extremely labile they must be separated from whole blood immediately after collection and transfused within hours of preparation. Granulocytes prepared from routine blood donations ('buffy coats') are heavily contaminated with red cells and platelets. Buffy coats from at least 10 donors are required to produce a therapeutic dose for an adult (at least 1 X 1010 granulocytes). Ten buffy coats also contain the equivalent of two units of red cells and 2.5 pools of platelets....

Other anticoagulants and additive solutions

Heparin is now rarely used, and it can only be useful for blood that is to be transfused within 12 h of collection. This is because heparin is gradually broken down in storage and the blood then clots. Heparinized blood for neonatal cardiac surgery and exchange transfusion has been replaced by citrate-phosphate-dextrose-adenine (CPD-AI) blood, less than 3-5 days old, with no untoward effects. Some neonatologists use SAGM red cells for newborn infants, with success. For intrauterine transfusion,...

Molecular pathology

The a0-thalassaemias result from deletions of both a-globin genes. There are many different-sized deletions however, one is particularly common in South-East Asia and another occurs mainly in Mediterranean populations (Figure 6.11). a0-Thalassaemia may also result from deletions about 40 kb upstream from the a-globin gene cluster, which involve the HS40 region. The molecular basis of the a+-thalassaemias is more complicated. In some cases, they result from deletions that remove one of the...

Selected bibliography

Chu X, Thompson D, Yee LJ, Sung LA (2000) Genomic organization of mouse and human erythrocyte tropomodulin genes encoding the pointed end capping protein for the actin filaments. Gene 256 271-81. Davies KA, Lux SE (1989) Hereditary disorders of the red cell membrane skeleton. Trends in Genetics 5 222-7. Delaunay J (2002) Molecular basis of red cell membrane disorders. Acta Haematologica 108 210-8. Delaunay J, Dhermy D (1993) Mutations involving the spectrin heterodimer contact site clinical...

Antenatal assessment of maternal blood

Rarely, anti-D may develop in a first pregnancy in a woman who has had no previous transfusions. However, it is not common for the antibody to reach high levels, and it is not usually detectable before 28 weeks most of such cases become apparent after delivery. Conversely, in women who have had previous pregnancies or transfusions with Rh-positive red cells, anti-D may be detected early in pregnancy regular monitoring of the level is necessary in order to plan the best type and timing of...

Deoxyuridine suppression test

In normal bone marrow, deoxyuridine (dU) considerably suppresses the uptake of radioactive thymidine into DNA. This is thought to be due to conversion of dU to thymidine triphosphate (dTTO) via dU monophosphate (dUMP), which inhibits thymidine kinase, on which thymidine uptake depends (Figure 5.1). Deoxyuridine suppresses radioactive thymidine incorporation less effectively in megaloblastic anaemia due to folate or cobalamin deficiency because of the block in dUMP methylation to dTMP. In...

Thrombopoietin

Thrombopoietin (TPO) is an essential growth factor for stem cell maintenance and proliferation, although its major role is to enhance platelet production and function. It is the ligand for the receptor c-mpl, which is a member of the cytokine receptor superfamily and is expressed on megakaryocytes, platelets and also on pluripotential stem cells. TPO is mainly synthesized in the liver, and its levels are regulated by clearance through platelet binding. The effect of TPO in culture is to...

Causes of iron deficiency Table

Renal tract Pulmonary tract Widespread bleeding disorders Self-inflicted Malabsorption Gluten-induced enteropathy (child or adult), gastrectomy, atrophic gastritis, chronic inflammation, clay eating, etc. Dietary Especially vegetarian diet Menorrhagia, post-menopausal bleeding, parturition Oesophageal varices, hiatus hernia, peptic ulcer, aspirin ingestion, hookworm, hereditary telangiectasia, carcinoma of the stomach, caecum or colon, ulcerative colitis,...

Diagnosis of folate deficiency Serum folate

This may be measured microbiologically with Lactobacillus casei, by radioassay or by an enzyme-linked immunosorbence assay (ELISA) technique. The serum folate level is low in all folate-deficient patients. In most laboratories, the normal range is quoted as from 2.0 g L (11 nmol L) to about 15 g L. The serum folate is markedly affected by recent diet inadequate intake for as little as 1 week may cause the level to become subnormal. Because of this, the serum folate assay is a very sensitive...

The transcription factor programme underlying erythropoiesis

Particularly relevant for erythropoiesis. Both are expressed in multipotent progenitors, although GATA-2 appears to be more important than GATA-1 at this stage, when GATA-2 plays an important role in the expansion and maintenance of haemopoi-etic progenitors. During erythroid differentiation the level of GATA-2 declines as GATA-1 increases. In mouse embryos lacking GATA-2, erythrocytes are present, but in severely reduced numbers. There appears to be some overlap and redundancy between the...

Hallervorden Spatz syndrome

This is an autosomal recessive neurodegenerative disorder associated with iron accumulation in the brain. Clinical features include extrapyramidal dysfunction, onset in childhood and a relentlessly progressive course. Histological study reveals iron deposits in the basal ganglia. Hallervorden-Spatz syndrome is caused by a defect in a novel pantothenate kinase gene that causes accumulation of cysteine. Iron binding by cysteine may cause iron accumulation and oxidative stress which is a likely...

Human immunodeficiency virus HIVl and HIV2

The classical descriptions and the vast majority of the literature on AIDS refer to HIV-1 a second retrovirus capable of causing AIDS, HIV-2, mainly occurs in West Africa. Human immunodeficiency virus (HIV) can be transmitted both in cellular and plasma components. Most of the patients infected by the transfusion of blood components were transfused before the introduction of the screening of blood donations for HIV antibodies. The majority of recipients of blood products who were infected in...

Cryoprecipitate

Cryoprecipitate is prepared from blood within 8 h of collection (Figure 16.1). Plasma is separated, frozen and allowed to thaw (classically at 4 C, overnight). After removal of the supernatant, the factor VIII C, vW factor, fibrinogen, fibronectin and FXIII are left as a precipitate, which is then refrozen in approximately 15 mL of plasma, and stored at -30 C or below for up to 24 months. Each unit should contain a minimum of 70 IU of factor VlII C and 140 mg of fibrinogen. Cryoprecipitate is...

Tn activation

Tn activation, unlike T and Tk, is a persistent abnormality caused by an abnormal clone of stem cells arising by somatic mutation. Tn is often associated with other haematological abnormalities, such as chronic haemolytic anaemia, leucopenia or thrombocy-topenia, but may be present in healthy individuals. Somatic mutation leads to a deficiency of the galactosyltransferase that elongates the O-linked oligosaccharides on GPA, so that many of the O-glycans consist of only N-acetylgalactosamine,...

Thrombocytosis

In the immediate postoperative period in uncomplicated splenectomy patients, the platelet count rises steeply to a maximum of usually 600-1000 X 109 L, with a peak at 7-12 days. In a number of patients, the thrombocytosis persists indefinitely after splenectomy. This usually appears to be a consequence of continuing anaemia with a hyperplastic marrow an inverse relationship exists between the severity of the anaemia and the height of the platelet counts. Although a reactive thrombocytosis is...

HLA nomenclature

The naming of HLA specificities falls under the remit of the WHO Nomenclature Committee for Factors of the HLA System. The Committee names HLA genes, alleles and serologically defined antigenic specificities. The names of the antigens, which were originally defined using either serological or cellular techniques, are a combination of letters that indicate the gene encoding the antigen and numbers assigned in chronological order of their description. An example of an individual's HLA type...

Immune responses

The previous sections have indicated that antigen-driven T- and B-cell activation leading to antibody production or the generation of effector T cells requires a complex series of interactions between cells. In most primary immune responses this will occur only within secondary lymphoid tissue. The lymph nodes, mucosal lymphoid tissues and spleen contain the bulk of secondary lymphoid tissue. The outward appearance of the various secondary lymphoid tissues is markedly different, but their fine...

Congenital intrinsic factor deficiency or functional abnormality

The affected child usually shows no demonstrable IF but has a normal gastric mucosa and normal secretion of acid. The inheritance is autosomally recessive. These patients usually present with megaloblastic anaemia in the first, second or third year of life when stores of cobalamin accumulated from the mother in utero are used up a few have presented as late as the second decade. Parietal cell and IF antibodies are absent. Variants have been described in which the child is born with IF that can...

Weak D Du

Cells that have the weak D phenotype (previously known as Du) should, for most transfusion purposes, be regarded as D-positive. Weak D red cells have fewer D sites per cell than normal D-positive red cells. In a white population, the gene for weak D is commonly accompanied by RHCE encoding C or E antigen (DuCe or DucE), and Duce is rare. Weak D is more common in Africans and is usually produced by Duce. It is important that anti-D typing reagents should detect most weak D phenotypes, especially...

T activation

T activation occurs transiently in some patients with an obvious microbial infection, especially Vibrio cholerae, Clostridium perfringens, Diplococcus pneumoniae, various streptococci and the influenza virus. These microbes produce sialidases, which remove sialic acid (N-acetylneuraminic acid, NANA) from the oligosaccharides of membrane sialoglycoproteins (Table 15.13) to expose the hidden T antigen (galactose linked to N-acetyl-galactosamine), with an accompanying loss of negative surface...

Transfusion haemosiderosis

Haemosiderosis is a very real complication of repeated blood transfusions, and is being seen more commonly as long-term blood transfusion therapy improves the survival of patients suffering from some chronic anaemias. It is most commonly seen in thalassaemic individuals, who commence transfusions in early childhood. Each unit of blood has approximately 200 mg of iron, whereas the daily excretion rate is about 1 mg the body has no way of excreting the excess. Unless a patient is actively...

Excess utilization or loss Pregnancy

Folate requirements are increased by 200-300 g to about 400 g daily in a normal pregnancy, partly because of transfer of the vitamin to the fetus, but mainly because of increased folate catabolism due to cleavage of folate coenzymes in rapidly proliferating tissues at the C-9-N-10 bond. Megaloblastic anaemia due to this deficiency is now largely prevented by prophylactic folic acid therapy. It occurred in 0.5 of pregnancies in the UK and other Western countries, but the incidence is much higher...

Reactions due to plasma protein antibodies

Mild urticarial reactions without other symptoms are not uncommon during blood transfusion they occur with an approximate incidence of 1 and are mediated by IgE antibodies, usually against plasma proteins or other allergens present in donor plasma. Mild urticarial reactions may be treated effectively with antihistamines, and do not always recur. There is no necessity to avoid transfusion of standard 'bank blood' unless symptoms are recurrent and severe. On the other hand, severe anaphylactic...

Blood grouping methods

American Association of Blood Banks (2002) American Association of Blood Banks Technical Manual, 14th edn. AABB, Bethesda, MD. BCSH Blood Transfusion Task Force (1996) Guidelines for pretrans-fusion compatibility procedures in blood transfusion laboratories. Transfusion Medicine 6 273-83. Guidelines for the Blood Transfusion Services in the United Kingdom (2002) The Stationery Office, London van der Schoot CE, Tax GHM, Rijnders RJP, de Haas M, Christaens GCML (2003) Prenatal typing of Rh and...

Info

Figure 15.2 Diagrammatic representation of H and Lewis antigens. Lea requires the action of the Lewis a1,4-fucosyltransferase, H the action of the H a1,2-fucosyltransferase, Leb the action of both Lewis and H fucosyltransferases, and ALeb and BLeb the action of Lewis and H fucosyltransferases and the A or B glycosyltransferases. tions and in plasma. The Lewis antigens on red cells are adsorbed passively from the plasma, and the constant presence of plasma is needed to maintain Lewis antigen on...

Hereditary persistence of fetal haemoglobin

This is a heterogeneous group of conditions in which there is persistent fetal haemoglobin production in adult life in the absence of major haematological abnormalities. Although of little clinical importance, it may modify the phenotype of the P-haemoglobinopathies. Some forms of hereditary persistence of fetal haemoglobin (HPFH) result from long deletions of the P-globin gene cluster, similar to those that cause 8P-thalassaemia (Figure 6.8). Homozygotes, with 100 HbF, have a mild...

Paroxysmal cold haemoglobinuria

The rare syndrome usually occurs in children following acute viral infections. The original cases were described by Donath, Landsteiner and Ehrlich in congenital and tertiary syphilis but such cases are no longer encountered. A history of cold exposure is not always present and presentation is with sudden intravas-cular haemolysis, haemoglobinuria, abdominal pain, pallor and prostration. The cold antibody is IgG, which is biphasic, reacting with red cells below 20 C in the peripheral...

Effect on erythrocytes

Red cells acquire the sickle or elongated shape upon deoxy-genation as a result of intracellular polymerization of HbS, a phenomenon that is reversible upon reoxygenation. Even in the normally shaped red cells, however, the presence of HbS polymer reduces deformability, with consequent increase in blood viscosity. Repeated or prolonged sickling progressively damages the red cell membrane, which is a phenomenon of primary importance in the pathophysiology of SCD. Membrane damage causes movement...

Antibody screening and identification

Patients' sera should be screened against unpooled group O cells from selected individuals known to carry the following antigens between them D, C, E, c, e, M, N, S, s, P1, Lea, Leb, K, k, Fya, Fyb, Jka and Jkb. Ideally, one cell sample should be R1R1 (DCe DCe) and the other R2R2 (DcE DcE), and a minimum homozygous expression of Fya and Jka should be present on one of the red cell samples. It is generally possible to meet these requirements with two cells but, if more antigens are required with...

The polymorphism of major histocompatibility complex molecules

Mhc Class Molecules Diagram

There is extensive polymorphism of the major histocompatibility complex (MHC) class I and class II molecules (Figure 20.5). Figure 20.4 The aP T-cell receptor complex. The aP TCR is composed of two polypeptide chains, each with a variable (open ovoid) and constant (closed ovoid) domain. Peptide plus MHC is recognized by the combined variable regions. The TCR is surrounded by the CD3 complex of transmembrane signalling molecules. This is composed of four types of polypeptide chain, Y, S, e and Z...

Premature delivery

Modern neonatal intensive care has dramatically increased survival rates of very premature infants born at 24-30 weeks' gestation. Nevertheless, morbidity is high and premature delivery is now, due to the success of intrauterine transfusions, rarely performed. It is sometimes considered at 36 weeks for Figure 16.7 Middle cerebral artery Doppler. Peak velocity of systolic blood flow in the middle cerebral artery in 111 fetuses at risk for anaemia due to maternal red cell alloimmunization. Open...

Pyrimidine 5nucleotidase deficiency

Pyrimidine 5'-nucleotidase deficiency is not uncommon, although only some 40 or 50 families have been reported in the literature. It is probably the third most common enzyme deficiency causing haemolytic anaemia, perhaps equal to GPI deficiency. Nearly all reported cases have shown homozygosity for the mutation, and the mutation has been specific for individual families. There is, however, a suggestion that certain mutations (Del G576 and INS GG743) might be more prevalent in southern Italy or...

The white pulp immunological function

The spleen is the largest single accumulation of lymphoid tissue in the body. It contains 25 of the T-lymphocyte pool and 10-15 of the B-lymphocyte pool. T cells are found predominantly in periarteriolar lymphatic sheaths, and B cells in germinal centres in the white pulp. These cells do not appear to arise in the spleen but to have migrated there from other sites of origin, such as the bone marrow and thymus. There is a constant flow of both T and B cells through the spleen T cells are the...

Dietary and luminal factors

Much of dietary iron is non-haem iron derived from cereals Dietary factors Increased haem iron Increased animal foods Ferrous iron salts Luminal factors Acid pH (e.g. gastric HCl) Low-molecular-weight soluble chelates (e.g. vitamin C, sugars, amino acids) Ligand in meat (unidentified) Systemic factors Iron deficiency Increased erythropoiesis (e.g. after haemorrhage) Ineffective erythropoiesis Pregnancy Hypoxia (commonly fortified with additional iron in the UK), with a lesser component of haem...

Optimal additive solutions eg salineadenineglucosemannitol SAGM

Optimal additive plasma replacement solutions have been developed to improve viability of plasma-depleted red cells on storage, by maintaining both ATP and 2,3-DPG levels. SAGM (as well as ADSOL and Nutricel) medium provides good red cell storage conditions and is now the most usual preservative solution for red cells in the UK. A multiple 'top and bottom' blood collection pack is used (Figure 16.1). The blood donation is taken into the main pack, which contains standard CPD anticoagulant....

Acquired pure red cell aplasia

Casadevall N, Nataf J, Viron B et al. (2002) Pure red cell aplasia and Anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. New England Journal of Medicine 346 469-75. Charles RJ, Sabo KM, Kidd PG etal (1996) The pathophysiology of pure red cell aplasia Implications for therapy. Blood 87 4831-8. Dessypris EN (2002) Pure red cell aplasia. In Hematology, Basic Principles and Practice, 3rd edn (R Hoffman, EJ Benz, SJ Shattil etal., eds). Successful treament of pure...

Cell and molecular biology

Cells from FA patients show an abnormally high frequency of spontaneous chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC). A laboratory test is available for FA. This is based on the increased chromosomal breakage seen in FA cells compared with normal control subjects after exposure to low concentrations of DEB or MMC ('DEB MMC stress test') (Figure 12.2). Other features of the FA cell phenotype...

The ability of the antibody to bind complement

Why some antibody molecules bind complement easily and others do not is not fully understood, but several factors seem to be important. 1 The immunoglobulin class and subclass of the antibody, as discussed later. 2 At least two Clq binding sites properly aligned and close together are necessary for complement fixation. One molecule of IgM antibody carries several Clq binding sites, whereas one molecule of IgG carries only one, and will therefore need another molecule of IgG alongside it (IgG...

Combined immunodeficiency

A number of rare inherited defects significantly compromise both humoral and cellular immunity but do not usually lead to early death from severe infection (Table 22.1). These include defects in CD40 ligand (HIM-1), ataxia telangiectasia (AT) and other defects in DNA repair systems, and the Wiskott-Aldrich syndrome (WAS). A predisposition to cancer, particularly lymphoma, occurs in many of these syndromes. In WAS, the clinical features range from thrombocytopenia alone to a severe disease...

Phagocytic killing antimicrobial proteins

Phagocytic cells such as neutrophils can kill micro-organisms using proteins present in various granules. The importance of such non-oxidative killing is evident in chronic granulomatous disease neutrophils that are still capable of killing many potent micro-organisms. Furthermore, this process is important for defence against organisms such as Escherichia coli and Salmonella typhimurium, which do not produce their own source of oxid-ants and are killed under anaerobic conditions. The contents...

The biological significance of blood group antigens

The functions of several red cell membrane protein structures bearing blood group antigenic determinants are known, or can be deduced from their structure (Table 14.1). Some are membrane transporters, facilitating the transport of biologically important molecules through the lipid bilayer band 3 membrane glycoprotein, the Diego antigen, provides an anion exchange channel for HCO- and Cl- ions the Kidd glycoprotein is a urea transporter the Colton glycoprotein is aquaporin 1, a water channel the...

Red cell antigens

In Alloimmune Disorders of Pregnancy (A Hadley, P Soothill, eds), pp. 121-39. Cambridge University Press, Cambridge. Avent ND, Reid ME (2000) The Rh blood group system a review. Blood 95 375-87. Cartron JP, Colin Y (2001) Structural and functional diversity of blood group antigens. Transfusion Clinical Biology 8 163-99. Chester MA, Olsson ML (2001) The ABO blood group gene a locus of considerable genetic diversity. Transfusion Medicine Reviews 15 177-200. Danek...

Measurement of splenic phagocytic and immunological function

Irreversible trapping of particulate matter is a function of the reticuloendothelial system. Colloid particles 1 im in size or less will be taken up by the liver, larger particles by the spleen. There is a well-established relationship between splenic reticuloendo-thelial function and the rate at which heat-damaged red cells are removed from the circulation. The half-clearance time in normal subjects is about 8-16 min. Post splenectomy, the time is increased to 60-120 min or longer and...

White cell and platelet antigens

Blanchette VS, Johnson J, Rand M (2000) The management of alloimmune neonatal thrombocytopenia. Bailli re's Clinical Haematology 13 365-90. Hurd C, Cavanagh G, Ouwehand WH et al. (2002) Genotyping for platelet-specific antigens - techniques for the detection of single nucleotide polymorphisms. Vox Sanguinis 83 1-12. International Forum (2003) Detection of platelet-reactive antibodies in patients who are refractory to platelet transfusions, and the selection of compatible donors. Vox Sanguinis...

Pathophysiology

The molecular defects in P-thalassaemia result in absent or reduced P-chain production. a-Chain synthesis is unaffected and hence there is imbalanced globin chain production, leading to an excess of a-chains. In the absence of their partners, they are unstable and precipitate in the red cell precursors, giving rise to large intracellular inclusions that interfere with red cell maturation. Hence there is a variable degree of intramedullary destruction of red cell precursors, i.e. ineffective...

Antigens with high or low frequency

There are many other antigens, of either very high or very low incidence, that have not been assigned to blood group systems. Anti-Vel, -Lan, -Ata, -AnWj and -MAM are examples of antibodies to high-frequency antigens (HFAs) that have caused HDN and or HTRs. For those rare individuals who have formed antibodies to HFAs, the provision of compatible blood can be a problem it is often necessary to approach the national or international panels of rare donors for compatible units. Antibodies to...

Other defects of the enzymes of the glycolytic system

Compared with PK deficiency, the other defects of the glycolytic pathway are very rare. The main features of these disorders are summarized in Table 9.1. Hexokinase (HK1) catalyses the phosphorylation of glucose to G6P, the first step in the glycolytic pathway. The enzyme in the red cell differs from that in nucleated cells, which have oxidative respiration, by lacking a porin-binding domain that links the enzyme to the mitochondrial membrane. The red cell enzyme is derived from alternative...