ABC of clinical haematology

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Oxford: Blackwell Scientific, Google Scholar. Clinical haematology. Vol 6. The haemoglobinopathies. ABC of Clinical haematology: Iron deficiency anaemia. ABC of clinical haematology. Geneva, WHO,. Journal of Laboratory and Clinical Medicine, 72,. If for good Resuscitation ABC.. Clinical and haematological signs of disseminated intravascular.. This topic review discusses the clinical manifestations and diagnosis Clinical and molecular analysis of haemoglobin H disease in Sardinia: haematological, obstetric and cardiac aspects in In: Hematology: Basic Principles and Practice, 3rd ed, Hoffman R,.

Daniel I. Principe de eds , Clinical Oncology, 3rd edition. Palliative Medicine Handbook 3rd edition. Clinical Haematology: theory and procedures. Lippincot Williams and Wilkins. Veterinary Haematology. This is the first edition of this guideline. It acts by specifically inhibiting the enhanced protein tyrosine kinase activity of the BCR-ABL oncoprotein and thus reversing the pathologically perturbed signal transduction. Toxicity seems to be relatively mild. It was until recently the drug of choice for managing chronic myeloid leukaemia in the chronic phase.

Other more persistent side effects include anorexia, weight loss, depression, alopecia, rashes, neuropathies, autoimmune disorders, and thrombocytopenia. In transplantation. The patient then receives high dose unselected newly diagnosed patients. The procedure may prolong life in some cases, and remains experimental. At times the advanced phase can be difficult to distinguish In most cases the blast crisis is myeloid that is, resembling from the chronic phase and can be diagnosed with confidence acute myeloid leukaemia , and in a fifth of cases lymphoid blast only in retrospect crisis occurs.

Occasionally patients progress to a myelofibrotic phase of the disease, in which intense marrow fibrosis predominates, blast cells proliferate less aggressively, and the clinical picture is Chronic phase. They may also respond to hydroxyurea or busulphan if they have not previously received these agents. Splenectomy may be useful to Figure 5. Chronic myeloid leukemia.

N Engl J Med ; not be forgotten. For those patients with myeloid The molecular biology of leukaemia will control the leukaemic proliferation for a time. Blood ; A new prognostic compatible with a normal lifestyle for months or years. Patients score for survival of patients with chronic myeloid leukemia treated with interferon alfa. JNCI ; Interferon alpha 2b appropriate to adult acute lymphoblastic leukaemia. N Engl J Med ; Chronic myeloid leukemia: current transformation. Patients restored to second chronic phase treatment options.

Hematologic and cytogenetic responses to imatinib mesylate in chronic five or six intrathecal injections of methotrexate, but there is myelogenous leukemia. N Engl J Med ;; Acute leukaemia is a clonal that is, derived from a single cell Box 6. Classification Acute leukaemia is subdivided into a acute lymphoblastic leukaemia ALL , in which the abnormal proliferation is in the lymphoid progenitor cells that is, immature lymphocytes and b acute myeloid leukaemia AML , which involves the myeloid lineages that is, cells from which neutrophils, Box 6.

The distinction between the two leukaemias is based on morphological, cytochemical, immunological and M0 Acute myeloid leukaemia with minimal evidence of myeloid differentiation cytogenetic differences and is of paramount importance as the M1 Acute myeloblastic leukaemia without maturation treatment and prognosis are usually different.

B cell lineage is further subdivided: early B precursor acute lymphoblastic leukaemia is the most immature and is negative for the common acute lymphoblastic leukaemia antigen CD 10 ; common acute lymphoblastic leukaemia and pre-B cell acute lymphoblastic leukaemia are more mature and are CD 10 positive; and B cell acute lymphoblastic leukaemia is the most mature and is the only one to express surface immunoglobulin.

Little correlation exists between morphological subtype and immunophenotype or prognosis in L1 or L2 acute lymphoblastic leukaemia. L3 morphology is almost exclusively found in B cell acute lymphoblastic leukaemia. In acute myeloid leukaemia immunophenotyping may not help to distinguish between leukaemias of the myeloid M0 to M3 , the myelomonocytic M4 , and the monocytic M5 lineages, and special cytochemical stains are usually used to support morphological findings. In erythroleukaemia M6 and megakaryoblastic leukaemia M7 , however, the surface antigen expression is often diagnostic.

The FAB classification system, while essentially simple, has several deficiencies, not least a lack of clear Figure 6. A Clinical Advisory Committee to the World Health Organization WHO has now published a new classification system which is based around cytogenetic abnormalities, and which thereby seeks to define biological and clinical entities more closely. It is likely that this will be adopted in the near future. Incidence Acute lymphoblastic leukaemia Acute lymphoblastic leukaemia is most common in the age range years, with a peak at years.

The incidence then Figure 6. The incidence increases with age, and the median age at presentation is 60 years. Presentation Acute leukaemia is always serious and life threatening, and all patients suspected of having this condition should be immediately referred for urgent assessment. Common symptoms and signs at presentation result from bone marrow failure or, less commonly, organ infiltration.

Anaemia can result in pallor, lethargy, and dyspnoea. Neutropenia results in predominantly bacterial infections of Figure 6. Thrombocytopenia may present as spontaneous bruising, menorrhagia, bleeding from venepuncture sites, gingival bleeding, or prolonged nose bleeds. A common presenting feature resulting from organ infiltration in childhood acute lymphoblastic leukaemia is bone pain, but acute lymphoblastic leukaemia can also present with superficial lymphadenopathy, abdominal distension due to abdominal lymphadenopathy and hepatosplenomegaly, respiratory embarrassment due to a large mediastinal mass, testicular enlargement, or a meningeal syndrome.

Gum hypertrophy and skin infiltration are more commonly seen in acute myeloid than in acute lymphoblastic leukaemia. Investigations Figure 6. Full blood count usually but not invariably shows reduced haemoglobin concentration and platelet count. The white cell Box 6.

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In childhood acute lymphoblastic leukaemia lytic bone lesions may also be seen. Bone marrow aspiration with or without trephination is essential to confirm acute leukaemia. The marrow is usually hypercellular, with a predominance of immature blast cells. Immunophenotyping of the antigens present on blasts isolated from the bone marrow or peripheral blood is the most reliable method of determining whether the leukaemia is lymphoid or myeloid, and cytochemistry helps to confirm myeloid or monocytic origin.

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Cytogenetics and molecular studies often detect abnormalities within the leukaemic clone that can have diagnostic or prognostic value—for example, the Philadelphia chromosome, which is the product of a translocation between chromosomes Figure 6. Left: Normal cell showing two red dots two normal in cases of acute lymphoblastic leukaemia.

Right: Atraumatic lumbar puncture with cerebrospinal fluid cytospin Cell from child with Ph chromosome positive acute lymphoblastic leukaemia with translocation of chromosomes 9 and 22 is an important initial staging investigation in ALL or AML with neurological symptoms to detect leukaemic cells in the cerebrospinal fluid, indicating involvement of the central nervous system. Box 6. Children and young adults should always be treated in recognized specialist centres to maximise the chance of cure with minimal toxicity.

On admission to a specialist unit the patient will need chemotherapy to treat the leukaemia and Adequate hydration and allopurinol are essential at the start of treatment to reduce the risk of hyperkalaemia, supportive care to ameliorate or correct the effects of the hyperuricaemia, and renal damage leukaemia and to facilitate treatment. Supportive care The numerical threshold for blood product transfusion has progressively lowered. Bleeding episodes predominantly result from thrombocytopenia and should be treated accordingly. Clotting abnormalities may result from a consumptive coagulopathy where infusions of fresh frozen plasma and cryoprecipitate may be beneficial.

Packed red cell transfusions are given for symptomatic anaemia, though these are contraindicated if the white cell count is extremely high. In most patients a central venous catheter has to be inserted to facilitate blood product support, administration of chemotherapy and antibiotics, and frequent blood sampling.

Serious infection is a common cause of death in patients with acute leukaemia, as bone marrow failure due to the leukaemia and to chemotherapy often results in profound neutropenia for two weeks or more. Reverse-barrier nursing techniques should therefore be used for such patients, and Figure 6. The drugs damage the capacity of the leukaemic cells to divide and replicate, and using cyclical combinations of three or more drugs increases. Each course entails up to 10 days Sex Male of chemotherapy.

In acute myeloid leukaemia M3 the Remission problems Failure to remit after first induction drug ATRA all-trans-retinoic acid is used as an adjunct to treatment chemotherapy as it causes differentiation of the malignant Cytogenetics Philadelphia positive—that is, clone.

This has been shown to improve long term cure rates in acute lymphoblastic leukaemia, though not in Factors Acute myeloid leukaemia acute myeloid leukaemia. Treatment Box 6. Transplantation reduces relapse risk but has been associated with high procedural mortality. The development of peripheral rather than Table 6. The concept of allogeneic transplantation—where healthy stem cells from a sibling or unrelated donor are given to replace diseased marrow—has always been appealing.

Realisation of a graft versus leukaemia GVL effect has enhanced enthusiasm, though this effect is more pronounced in chronic myeloid leukaemia. Patient selection for BMT remains a subject of controversy. Some patients will self-exclude on personal, age or health grounds. Others may be suitable for BMT but not have an appropriate donor. This problem is likely to worsen as family size reduces and volunteer healthy donors are harder to attract. Novel developments Box 6. This agent is being incorporated into the latest AML studies. STI is a tyrosine kinase TK inhibitor which has good activity in chronic myeloid leukaemia due to the presence of the Philadelphia chromosome associated with aberrant TK production.

Acute myeloid leukaemia Clin Haematol ;14 1. Inhibitory drugs to this process are in ;14 6 and ;15 1. New developments in the therapy of acute myelocytic leukaemia. Am Soc Hematol Educ Progr ; Acute myeloid anti-leukaemic vaccines and tumour-specific cytotoxic T cell leukaemia. Acute leukaemias in adults. In Oxford highly heterogeneous condition which requires an textbook of oncology, 2nd edn. Oxford: Oxford University Press, individualised approach to management. Attempts to improve treatment and renal and hepatic dysfunction. Blood ;98 5 Br J Haematol ; Efficacy and safety of Mylotarg gemtuzumab Late effects ozogamicin in patients with CDpositive acute myeloid leukemia in first relapse.

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J Clin Oncol in press. All treatments for acute leukaemia can result in long term side effects that may bring appreciable morbidity or even lead to death. Patients must therefore be followed up in a specialist unit for at least 10 years. Particular attention must be paid to The interphase fluorescent in situ hybridisation was provided by the long term problems with growth and endocrine function in Brian Reeves and Helen Kempski, Department of Haematology, children.

Megakaryocytes are derived from the haemopoetic stem cell, which is stimulated to differentiate to mature megakaryocytes under the influence of various cytokines, including thrombopoietin. Once released from the bone marrow young platelets are trapped in the spleen for up to 36 Normal platelet function hours before entering the circulation, where they have a Fibrinogen primary haemostatic role.

Although platelets are non-nucleated cells, those that have recently been released from the bone marrow contain RNA and are known as reticulated platelets. The platelet membrane has integral glycoproteins essential in the initial events of adhesion and aggregation, leading to Collagen fibres Endothelial cell formation of the platelet plug during haemostasis.

Glycoprotein receptors react with aggregating agents such Figure 7. Following adhesion, the platelets are stimulated to release the contents of their granules essential for platelet aggregation. The platelets also provide an extensive phospholipid surface for the interaction and activation of clotting factors in the coagulation pathway. Congenital abnormalities Congenital abnormalities of platelets can be divided into disorders of platelet production and those of platelet function.

Figure 7. In general they cause moderate to severe syndrome bleeding problems. The cardinal laboratory feature is abnormal chromosomal fragility. The condition can be cured with bone marrow transplantation BMT. This should be distinguished from amegakaryocytic thrombocytopenia, another leukaemia predisposition syndrome, in which severe neonatal thrombocytopenia is present with or without somatic Figure 7.

Bernard-Soulier syndrome or May Hegglin anomaly. The Wiskott-Aldrich syndrome is an X-linked disorder with a triad of thrombocytopenia, eczema, and immunodeficiency. The former is a benign condition, but the latter is associated with progressive hereditary nephritis and deafness. Box 7.

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Viral infection is the most common cause of mild transient thrombocytopenia. Increased platelet consumption may be due to immune or non-immune mechanisms. Idiopathic thrombocytopenic purpura ITP is a relatively common disorder and is the most frequent cause of an isolated thrombocytopenia without anaemia or neutropenia. In adults it often presents insidiously, most frequently in women aged years and can be associated with other autoimmune diseases, in particular systemic lupus erythematosus or the primary antiphospholipid syndrome.

In children the onset is more acute and often follows a viral infection. The autoantibody produced is usually IgG, directed against antigens on the platelet membrane. Antibody-coated platelets are removed by the reticuloendothelial system, reducing the life span of the platelet to a few hours. Post-transfusion purpura PTP is a rare complication of blood transfusion. It presents with severe thrombocytopenia days after the transfusion and usually occurs in multiparous women who are negative for the human platelet antigen 1a HPA1a.

Antibodies to HPA1a develop, and in some way this alloantibody is responsible for the immune destruction of autologous platelets. Neonatal alloimmune thrombocytopenia NAITP is similar to haemolytic disease of the newborn except that the antigenic stimulus comes from platelet specific antigens rather than red cell antigens. Fetal platelet destruction results from transplacental passage of these antibodies and severe bleeding, Figure 7. Firstborns are frequently affected and successive pregnancies are equally or more affected. It may become manifest when arterial or venous thrombosis occurs during a fall in the platelet count and is thought to be due to the formation of antibodies to heparin that are bound to platelet factor 4, a platelet granule protein.

The immune complexes activate platelets and endothelial cells, resulting in thrombocytopenia and thrombosis coexisting. Heparin-induced thrombocytopenia carries an appreciable mortality risk if the diagnosis is delayed. She responded well to large volume plasma exchange for features can be fever, fluctuating neurological signs, renal one week impairment, and intravascular haemolysis, resulting in thrombocytopenia. Recent evidence suggests that the condition is caused by an autoantibody to a protease enzyme which is Box 7.

The effects of a single dose Autoimmune: idiopathic thrombocytopenic purpura of aspirin last for the lifetime of the platelet days. Alloimmune: post-transfusion purpura, neonatal Clopidogrel, a thienopyridine derivative, has now been alloimmune thrombocytopenia introduced as an oral antiplatelet agent which inhibits ADP Infection associated: infectious mononucleosis, HIV, binding to the platelet membrane and is useful in patients who malaria Drug induced: heparin, penicillin, quinine, are intolerant or resistant to aspirin.

In essential primary thrombocytosis ET and reactive secondary thrombocytosis the platelet count is raised above the Box 7. Malignant disease Antiplatelet drugs can be useful to prevent thrombosis in high Acute and chronic inflammatory diseases risk patients, for example, postoperatively. Some Pregnancy myelodysplastic syndromes may be complicated by an acquired After splenectomy Iron deficiency storage pool type platelet disorder.

History and examination of patients Full blood count and blood film Abnormal bleeding associated with thrombocytopenia or abnormal platelet function is characterised by spontaneous skin purpura and ecchymoses, mucous membrane bleeding and Normal platelet count Low platelet count protracted bleeding after trauma. Prolonged nose bleeds can occur, particularly in children, and menorrhagia or postpartum In vitro bleeding time Monospot and viral serology haemorrhage is common in women.

If the bleeding is severe the patient may need urgent hospital referral for prompt evaluation, diagnosis, and treatment, which may entail blood product support. All patients should have a full blood count, blood film, coagulation, and biochemical screen, followed by further investigations depending on the results of these. Thrombocytopenia can be artefactual and due to platelet clumping or a blood clot in the sample, which should be excluded in all cases.

The skin bleeding time, which is invasive, variable and not reliable in screening mild platelet disorders, has been replaced by devices which perform an in vitro bleeding time on small volumes of citrated blood and simulate platelet function in a high shear rate situation. The sensitivity of these devices for all platelet disorders is still under investigation.

Mild or trivial bleeding due to a transient postviral thrombocytopenia or Box 7. This avoids exposure to Anticoagulation but without heparin blood products but is expensive.

In adults the condition rarely With disseminated intravascular coagulation it is essential to remits without treatment and is more likely to become chronic. Post- value. Usually treatment may only be necessary to cover surgical transfusion purpura may respond to intravenous procedures or major haemorrhage.

Platelet transfusions should be avoided. It is essential to withdraw directions. Thromb Haemostas ; Platelet functional disorders. In: Lilleyman J, avoiding all forms of heparin. Warfarin, synthetic heparinoids Hann I, Blanchette V, eds. Pediatric hematology, 2nd edn. Edinburgh: Churchill Livingstone, Platelets thrombocytopenic purpura. If the latter is suspected clinically ; Platelet function disorders.

Haemophilia ;6: exchange should be started immediately and continued daily Inherited and congenital thrombocytopenia. Pediatric hematology, 2nd results of haematological tests have normalised. Aspirin can be edn. The term myelodysplastic syndromes was introduced in by Figure 8. The risk is highest years after treatment with alkylating agents, such as chlorambucil and cyclophosphamide. The hypothesis that patients who develop myelodysplastic Inherited syndrome following chemotherapy or exposure to DNA damage Myeloid stem cell environmental toxins may have inherited an impaired ability to Acquired metabolise and detoxify potential carcinogens or repair DNA damage is currently being investigated.

Myelodysplastic clone The combination of peripheral blood cytopenias and a Increased apoptosis hypercellular bone marrow found in the majority of patients with myelodysplastic syndromes can be explained by an Immune damage Abnormal marrow Microenvironment increased susceptibility to apoptosis programmed cell death of bone marrow precursor cells. Secondary genetic and epigenetic abnormalities Diagnosis Patients present with the features of bone marrow failure— Acute myeloid leukaemia.

Increasingly, myelodysplastic syndrome is an incidental finding in elderly patients whose routine blood count shows an unexplained anaemia, macrocytosis, neutropenia, monocytosis, or thrombocytopenia. The myelodysplastic syndromes can be diagnosed only by a haematologist, primarily on the basis of characteristic full blood count indices, morphological abnormalities on the peripheral blood film, and characteristic bone marrow appearances. Although myelodysplastic syndrome may sometimes be diagnosed on the basis of a blood film alone, a bone marrow aspirate and trephine are necessary to make a confident diagnosis and to assess the severity of the disease.

Marrow examination can safely be omitted only in elderly, infirm patients with mild cytopenias who would not need treatment Figure 8. Diagnosis is frequently straightforward, particularly if Table 8. However, morphological dysplasia is not synonymous shape and chromatin with myelodysplastic syndrome, and similar morphological chromatin pattern abnormalities to those found in early myelodysplastic syndromes Basophilic stippling Ring sideroblasts may be seen in vitamin B12 deficiency or folate deficiency, Myeloid Hypogranular neutrophils alcohol excess, after cytotoxic chemotherapy, HIV infection, and Hypolobated even in a minority of cells in the bone marrow of normal neutrophil nuclei individuals.

Problems also arise if morphological abnormalities Megakaryocytic Agranular platelets Micromegakaryocytes are subtle, if they involve only one cell lineage, or if the staining Mononuclear of blood and marrow slides is suboptimal. It is valuable both prognostically and when the morphological diagnosis is difficult. A clonal chromosome abnormality—that is, the same abnormality appearing in more than one cell—confirms the presence of a primary bone marrow disorder and excludes the reactive causes of dysplasia listed above.

Specific chromosomal abnormalities may be associated with particular clinical and a haematological features. The recent introduction of new and more powerful techniques to detect genetic abnormalities and study both gene b and protein expression should lead to the identification of the key genetic events which initiate myelodysplastic syndromes and result in disease progression and evolution to acute leukaemia. Table 8. Classification In the FAB group divided the myelodysplastic syndromes into five subgroups based on a the percentage of immature myeloid cells blast cells and ring sideroblasts immature red cells with iron granules arranged in a ring around the nucleus in the bone marrow and b the presence or absence of a raised peripheral blood monocyte count.

This classification was rapidly adopted worldwide and had prognostic significance. Chronic myelomonocytic leukaemia is now classified Table 8. The median survival of patients with myelodysplastic syndrome is 20 months and for all subtypes is shorter than that of age matched controls. Box 8. Allogeneic Myeloablative For most patients treatment is palliative, and the possibility Non-myeloablative of cure applies only to the minority of young patients suitable. Non-myeloablative transplantation which utilises less intensive pretransplant chemotherapy and relies on a graft versus leukaemia effect to eradicate the malignant clone, significantly reduces transplant-related mortality.

If ongoing studies demonstrate both longer term safety and efficacy then this procedure could be considered for patients up to the age of 65 years providing a suitable donor is available. Patients with low risk disease defined by the International Prognostic Scoring System require observation only. The option of allogeneic transplantation should be discussed with intermediate I patients under the age of 65 years.

Cytopenic patients who either decline or are unsuitable for transplantation may respond to immunosuppressive therapy with anti-lymphocyte globulin or cyclosporin, particularly if the bone marrow is hypocellular. Patients in the intermediate II and high risk groups under the age of 65 should be considered for intensive chemotherapy and responders then offered a transplant procedure since the median duration of response to chemotherapy alone is months. It should be stressed that all active treatment for the myelodysplastic syndrome and particularly transplant procedures should be conducted within clinical trials wherever possible.

Low dose cytotoxic treatment with hydroxyurea or etoposide may reduce spleen size and improve the blood count in patients with intermediate and poor risk chronic myelomonocytic leukaemia, but the median survival remains poor at less than two years. The cornerstone of treatment remains the judicious use of Figure 8. Iron chelation therapy should be considered for patients who need red cell transfusion long term. Recombinant growth factors have been used to treat both neutropenia and anaemia in the myelodysplastic syndromes. Myelodysplastic of cases but long term intermittent G-CSF should only be syndromes.

In: Jaffe ES et al. WHO classification of tumours. Myelodysplasia and myelopreoliferative disorders in childhood: an update. The addition of proposals for a new classification of primary myelodysplastic G-CSF improves the response rate, particularly in patients with syndromes: a retrospective analysis of patients. Leukaemia ring sideroblasts.

Growth factors are response to treatment with G-CSF plus erythropoietin for the expensive, however, and the least effective in patients with anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Antithymocyte globulin require treatment. Therapy- related acute myeloid leukaemia and myelodysplasia after high dose chemotherapy and autologous stem cell transplantation. Establishing the incidence of myeloid leukaemia following MDS. A heterogeneous group of conditions are associated with Box 9.

Myeloma is extremely rare in people aged under 40 years, but its incidence increases to over 30 per in those aged over The median age at diagnosis is 69 years, with slight male predominance. Box 9. Myeloma in which the cells secrete IgD, two clonal proteins, IgM, or no protein at all are rare. Free light chains are detectable in urine as Bence Jones protein.

Accumulation of M protein may lead to hyperviscosity especially IgA and IgM due to the size of the Ig molecule or deposition of the protein in renal tubules, resulting in renal failure. Bone destruction is a characteristic feature of myeloma, and the associated bone pain is a major cause of morbidity in myeloma. Myeloma is associated with abnormal bone remodelling due to increased osteoclastic bone resorption and inhibition of osteoblastic bone formation. This results in pronounced bone loss and the characteristic osteolytic lesions predisposing to pathological fractures.

Widespread bone destruction may lead to hypercalcaemia, resulting in a vicious cycle of dehydration, worsening hypercalcaemia, and renal failure. Interactions between marrow stroma cells including osteoclasts and myeloma cells play a critical role in myeloma cell proliferation and the development of bone disease. Binding of Figure 9. OPG Osteoclast precursor. Osteoprotogerin OPG is also produced by stroma cells, notably osteoblasts, which in experimental systems inhibits RANK-L binding and osteoclast formation.

Osteoblasts are inhibited and secretion of OPG is reduced in myeloma. Complex cytogenetic abnormalities are frequently found in myeloma using modern techniques. These most commonly involve chromosome 14q which is the site of the Figure 9. Symptoms of anaemia, renal failure, or infection are also frequent. Less common are Box 9. It is characterised by the triad of bone marrow or lytic lesion s plasmacytosis, lytic bone lesions on skeletal radiology, and the Diagnostic tests presence of M protein in the serum or urine or both.

Serum alkaline phosphatase concentration is invariably normal, reflecting suppressed osteoblast activity. Low serum albumin concentration reflects advanced disease. Serum betamicroglobulin and C-reactive protein may be used to provide a prognostic index. Bone scans are typically negative in multiple myeloma despite extensive bone damage and are of no value. Magnetic resonance imaging MRI is the most sensitive imaging technique for myeloma and is valuable in suspected cord compression.

Although not routine it is useful in selected patients. The extent of amyloid deposition can be assessed using serum amyloid P component SAP scanning procedures. The most important differential diagnosis is between multiple myeloma and monoclonal gammopathy of undetermined significance for which no treatment is indicated. No single test differentiates the two conditions reliably.

Figure 9. Deletion narrowing of spinal canal of chromosome 13q is an important adverse feature. Renal impairment is a risk factor due to its association with a high tumour burden. Management and clinical course Without treatment, a patient with multiple myeloma is likely to experience progressive bone damage, anaemia and renal failure. Initial management should prioritise general aspects of care. Infection is the most common cause of death. Initial treatment should consist of a adequate analgesia—opiates often, and local radiotherapy to fractures or osteolytic lesions Box 9.

The Intravenous bisphosphonate median survival is about three years. Long term bisphosphonates Further treatment with melphalan may induce another plateau Fixation of potential fractures phase if a durable first plateau has been achieved. This treatment is less toxic to haemopoietic progenitors than standard melphalan treatment or other alkylator- containing regimens and is therefore more widely used in patients under 65 in whom autologous stem cell collection is Box 9.

It is generally applicable only to carmustine, cyclophosphamide, and melphalan patients under Median duration of CR is two years and median overall survival is five years with this approach. Allogeneic bone marrow transplantation may cure myeloma but carries significant treatment-related morbidity and mortality. It is generally restricted to patients under 50 with a compatible sibling. In resistance plateau phase cessation of chemotherapy is not followed by a rise in the M band or further signs of progression for many 2nd Plateau plateau months median Maintenance interferon alfa may phase prolong the plateau phase by six months, but little evidence exists of improved survival.

Bisphosphonate treatment reduces the rate of further bone damage and may have an additive Time months analgesic effect in patients with pre-existing damage. A survival benefit has been demonstrated in clinical trials and may reflect Figure 9. Disease progression With regular follow up, serological detection of disease allows chemotherapy to be restarted before new bone damage develops. In many patients several separate periods of plateau phase may be re-induced by chemotherapy.

Inevitably, myeloma becomes resistant to melphalan; oral dexamethasone may. Novel molecular therapies and derivatives of thalidomide show great potential. The prevalence of monoclonal gammopathy of undetermined significance is about 20 times greater than that of multiple Figure 9. Median survival is over 10 years. The median age at presentation is Box 9.

Weakness, fatigue, 2. Bone pain of cases is rare. Serum protein immunoelectrophoresis shows an IgM paraprotein. Monoclonal light chains may be present in the urine. Trephine biopsy often shows extensive infiltration with Box 9. Median survival is about ataxia, somnolence, and coma five years. Primary amyloidosis. Multiple myeloma. N Engl J Med monoclonal gammopathy of undetermined significance can ; Hematol Oncol Clin North Am patients with myeloma in whom treatment may not be ; Bone disease in multiple myeloma. Results of high dose treatment with dialysis may be appropriate supportive therapy for some autologous stem cell support in patients with multiple myeloma.

Br J Haematol curative ; Amyloidosis: a review of recent diagnostic and therapeutic developments. Monoclonal gammopathy of undetermined significance and solitary plasmacytoma. Mr Darren Costello supplied the protein electrophoresis strip. Blood within the vascular tree remains fluid throughout life, but Box Easy bruising, nosebleeds especially in children , and menorrhagia are common and do not necessarily signify a haemostatic defect unless they are persistent and severe.

Small bruises on the limbs in response to minor trauma and simple easy bruising are especially common in elderly people and those receiving long term corticosteroids. Large bruises after minimal trauma and on the trunk may indicate an important haemostatic defect. Abnormally prolonged bleeding from minor cuts and scratches and delayed recurrence of bleeding are also important, as is gum bleeding if there is no gingival disease and if it is unrelated to the trauma of brushing. Repeated nosebleeds lasting more than 10 minutes despite compression suggest a local cause or an underlying bleeding disorder.

The haemostatic response to previous haemostatic Persistent menorrhagia sufficient to cause iron deficiency challenges is informative, especially in mild conditions, when anaemia may indicate a bleeding disorder if no structural spontaneous bleeding is rare. A history of excessive bleeding or uterine abnormality is present recurrence of bleeding after dental extractions, circumcision, tonsillectomy, other previous surgical operations, and childbirth should be sought, as should a history of unexplained anaemia, gastrointestinal bleeding without the demonstration of a cause, and previous blood transfusion.

A drug history should be taken to assess intake of aspirins Table Laboratory investigation The vast majority of important bleeding disorders can be excluded if the findings are all normal for blood and platelet counts, blood film, prothrombin time, activated partial thromboplastin time, fibrinogen or thrombin time, and Patients who have unexplained abnormalities on screening investigations should be referred for specialist bleeding time.

These tests will reveal quantitative platelet investigation and management disorders and congenital or acquired deficiency of coagulation. The tests will Table As the genes for both proteins are on the X chromosome, both haemophilias have sex-linked inheritance— the daughters of a man with haemophilia are therefore obligate carriers. Management is highly specialised and consists of preventing or treating bleeding episodes with plasma-derived or recombinant clotting factors. Most cases are mild, with bleeding only after a haemostatic challenge.

Menorrhagia is common in affected women. Inheritance is autosomal dominant, with males and females equally affected. The condition is due to a reduction or structural abnormality of von Willebrand factor, which has the dual role of promoting normal platelet function and stabilising coagulation factor VIII. Most patients with mild disease respond to desmopressin DDAVP , but clotting factor concentrates are needed for a minority.

Figure Acquired disorders Most proteins of the coagulation cascade and their regulators and inhibitors necessary for haemostasis are synthesised in the liver. Acquired abnormalities can be due to impaired synthesis, increased consumption, or rarely the formation of autoantibodies against coagulation proteins. Liver disease can cause a severe bleeding disorder, with prolongation of the prothrombin time particularly, often with coexistent thrombocytopenia due to excessive pooling of platelets in an. Table Bruises Large, on body Small and limbs Table Malabsorption of vitamin K from the gut can Box Atherosclerotic lesions form in the vessel wall, resulting in narrowing and subsequent plaque rupture, which cause vessel occlusion.

Risk factors for atherosclerosis include smoking, hypertension, diabetes, hypercholesterolaemia, hyperlipidaemia, and hyperfibrinogenaemia. Platelet deposition occurs on a ruptured arteriosclerotic plaque, and the antiplatelet drugs aspirin and clopidogrel are widely used in the treatment and secondary prophylaxis of arterial thrombosis. Venous thrombosis Venous thrombosis results in deep vein thrombosis and pulmonary embolism and is due to a combination of blood stasis and hypercoagulability. The clinical diagnosis of venous thromboembolic disease is notoriously unreliable, and objective confirmation with ultrasonography or venography for deep vein thrombosis and ventilation perfusion scanning or pulmonary angiography for pulmonary embolus must be performed.

Recently it has become clear that venous thrombosis is frequently due to a combination of environmental factors such as surgery and pregnancy , with an underlying genetic predisposition due to inherited deficiencies Figure The familial thrombophilic disorders include factor V Leiden, prothrombin A and deficiencies of protein C, protein S, and antithrombin. Box Detection of one of these conditions may influence the future management of the individual with regard to Box Laboratory diagnosis of this condition entails the detection of antibodies to cardiolipin or a lupus anticoagulant, or both.

Lupus anticoagulants can also be induced by infections and drugs, and in these circumstances are not usually associated with thrombosis. Warfarin prolongs the prothrombin time, and dosage monitoring is achieved by a standardised form of this test, the international normalised ratio INR. Recommended target ranges and duration of treatment Figure Warfarin treatment requires regular monitoring as over-treatment carries an important haemorrhagic risk, and warfarin requirements may be affected by intercurrent illness Table In the absence of bleeding, Unexpected Consider unsuspected underlying omitting warfarin is usually sufficient.

Minor bleeding episodes bleeding at any INR structural lesion can be treated with local measures and small doses of vitamin K. Guidelines on oral anticoagulation: third edition. Interrelation of hyperhomocysteinemia, factor V potentiating the antithrombotic effects of antithrombin and Leiden, and risk of future venous thromboembolism. Circulation can be used for both prophylaxis and treatment of venous ; Homocysteine and thrombotic disease. Resistance to activated protein C as risk factor for activated partial thromboplastin time.

It has a narrow thrombosis: molecular mechanisms, laboratory investigation, and therapeutic range with complex pharmacokinetics and great clinical management. Semin Hematol ; Increased fetal loss in weight heparins are replacing unfractionated heparin for the women with heritable thrombophilia. Lancet ; A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood of venous thromboembolic disease.

They can be administered ; They are highly treatable and sometimes curable. Chronic lymphocytic leukaemia CLL , the commonest adult leukaemia, shares many features with these cancers. The Box Chronic Symptoms lymphocytic leukaemia is largely a B cell malignancy. The lymphomas are Box All patients with lymphoma or CLL require careful initial staging, usually comprising physical examination, measurement of an LDH level, computed tomography, and a bone marrow biopsy.

Increasingly, treatment is decided on the basis of allocated stage together with an examination of other known prognostic factors. Chronic lymphocytic leukaemia has a similar natural course. Diagnosis may be incidental for example, from a routine blood count, as in CLL or may follow a period of often fluctuating localised or generalised enlargement of lymph nodes or the spleen.

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Because of their indolent nature, however, there may be little or no initial effect on quality of life. Some patients, however, present with B symptoms or bulky widespread disease and need early treatment. The management of these cancers is adjusted to their natural course. Cure can rarely be achieved, and the median overall survival in most series is years. Prognosis relates to age poorer when older and particularly to the extent of disease judged in terms of bulk and effect of tumour.

The Figure Patients who are well with non-threatening disease eg low volume follicular lymphoma may initially be watched without. Initial treatment when needed generally comprises an alkylating agent-usually 80 intermittent chlorambucil—with or without steroids for months. This will often be highly successful in causing disease 60 regression; relapse is, however, inevitable. At relapse chlorambucil can be used again if initially 40 effective, or, particularly for CLL, fludarabine, an antimetabolite can be given orally.

Patients with follicular 20 lymphoma often respond well at relapse to rituximab, a monoclonal B cell antibody given intravenously. If this occurs then combination chemotherapy is Figure Extranodal lymphoma maltoma or marginal zone lymphoma Cell death. Gastric maltoma Antibody coupled to ricin can be successfully managed in most cases by treatment of H pylori with appropriate antibiotics. Complete response, which is sustained, occurs in most cases—a unique example of Figure The antibody delivers a toxin ricin to the lymphocytes bearing the appropriate regression of malignancy by treatment of infection.

Remaining surface antigen maltomas are generally managed with local radiotherapy with very high success rates. The maltomas can progress to intermediate grade lymphomas. In addition, they can metastasise, usually to the other malt sites described above.

It is rapidly increasing in incidence, although the reasons for this are uncertain. Two-thirds of cases of this type of cancer arise within lymph nodes—patients present because of lymph node enlargement. The remaining cases may arise in almost any other tissue or organ for example, gastrointestinal tract, skin, brain and bone , with symptoms appropriate to each site. The most common type is diffuse large B cell lymphoma.

These lymphomas occur at any age median 65 years and are rapidly progressive cancers that are often associated with B symptoms. Diagnosis and staging should be urgently performed then treatment with chemotherapy started. The standard chemotherapy is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone CHOP , given intravenously at intervals of three weeks in the outpatient clinic on six occasions and sometimes supplemented by radiotherapy. Relapse is not uncommon, and in the past it was associated with a poor outlook.

However, younger patients with disease that has remained sensitive to chemotherapy may now be cured Figure Survival in remaining patients is often measurable in months. Involvement of the bone marrow and central Figure This lymphoma also commonly spreads to the bone marrow and the central nervous system. Both these lymphoma types are curable with intensive combination chemotherapy. Treatment of these cancers is urgent and may, if adequate precautions are not taken, be complicated by the acute tumour lysis syndrome resulting from breakdown of the lymphoma.

This can lead to renal failure and possible death. Intrathecal chemotherapy to prevent relapse in the central nervous system is routinely used. These diseases arise in many cases because of uninhibited expansion of multiple clones of lymphocytes infected with Epstein-Barr virus. They are commonly high grade B cell neoplasms that arise at extranodal sites—for example, the brain Figure The outlook for patients with these tests revealed lymphoblastic lymphoma.

Modern management relies on Incidence Stable Increasing assessment of prognostic factors. The drug combination ABVD doxorubicin, bleomycin, vinblastine, and dacarbazine is accepted standard therapy, given intravenously every two weeks for six months. Fertility is usually preserved. If relapse occurs, the standard treatment approach is with high dose chemotherapy supported by peripheral blood stem cell infusion.

A particular concern, however, is an increased incidence of breast Figure A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Semin Oncol ; Chlorambucil in indolent chronic lymphocytic leukaemia. Monoclonal antibody based therapies for hematologic malignancies. J Clin Oncol ; Dr Dina Choudhury provided the blood film showing chronic lymphocytic leukaemia Figure History Early animal studies of bone marrow transplantation were translated into clinical practice with understanding of the Experiments in the s showed that haemopoiesis could be human leucocyte antigen HLA system and restored in irradiated animals by engraftment of transfused immunosuppressive therapy marrow.

Attempts to translate this into clinical practice were hindered by immunological problems of transfer between individuals which we now recognise as rejection and graft versus host disease. With further understanding of the human leucocyte antigen system, rapid clinical progress was made during the s such that bone marrow transplantation soon became an Method of stem Generic term Donor source cell procurement established treatment for some immune deficiency and malignant diseases. Bone marrow. Allogeneic What is a stem cell transplant?

Peripheral blood Transplantation is the reconstitution of the full haemopoietic system by transfer of the pluripotent cells present in the bone Haemopoietic transplantation marrow stem cells. The most appropriate generic term for the procedure is Autologous. Allogeneic transplantation is when another individual acts Figure Autologous transplantation is when the patient acts as his or her own source of stem cells. Originally, stem cells were procured from the bone marrow The aim of haemopoietic transplantation is the elimination by direct puncture and aspiration of bone marrow and of the underlying disease in the recipient, together with reinfused intravenously, a procedure known as bone marrow full restoration of haemopoietic and immune function transplantation.

Recently, it has been shown that stem cells derived from the bone marrow can be liberated into the peripheral blood, where the cells are harvested with a cell separation machine. Transplants with this stem cell material are known as peripheral blood stem cell transplants. Stem cells derived from the bone marrow or peripheral blood may be used in either an allogeneic or an autologous setting. As bone marrow contains B and T lymphocytes Chronic myeloid leukaemia along with macrophages the donor and recipient must be fully Myelodysplasia or near fully HLA matched to prevent life threatening graft Multiple myeloma versus host disease or rejection.

Conditions where there is probably benefit over conventional This restricts the availability of potential donors. An average recipient in Western countries has about a Acute lymphoblastic leukaemia first or second complete 1 in 4 chance of having a sibling who is fully HLA matched.

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This has been chemotherapy alone without resort to transplantation, which is achieved by the establishment of bone marrow registries in reserved for those who relapse. There are three such Box There is also an international registry known as Acute myeloid leukaemia first or second complete Bone Marrow Donors Worldwide. Autologous recipients therefore should still be otherwise healthy but can be aged up to about 70 years. Indications The indications for autologous transplantation are being continuously evaluated by a number of studies, including randomised control trials, in many diseases, particularly malignancy.

The indications can best be broken down into those in which there is now proved benefit in randomised controlled trials, those in which there is probable benefit, and those in which there is possible benefit. Results in solid tumours including RCTs in breast cancer have generally been disappointing. It is aspirated directly from the marrow cavity with marrow biopsy needles. Up to a litre of marrow may be needed to provide sufficient stem cells for transplantation. The procedure is well tolerated, requiring only simple analgesia postoperatively.

Serious complications are rare. In peripheral blood stem cell transplantation, stem cells are mobilised into the blood by single agent chemotherapy or a haemopoietic growth factor for example, granulocyte colony stimulating factor , or both. When the white blood count rises after days, the individual is connected to a cell separation machine, blood is drawn off and spun in a centrifuge, and stem cells are harvested while the remaining blood elements are returned to the patient.

The procedure takes hours and is well tolerated. Peripheral blood stem cell transplantation PBSCT is gradually replacing bone marrow transplantation as the. Higher rates of chronic GvHD? Lower survival rates in aplastic anaemia Figure Higher risk of GvHD?

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Sufficient stem cells for engraftment of large adults Processing and High costs of long term storage cryopreservation. Chemotherapy or procedure of choice as no general anaesthesia is needed, chemoradiotherapy engraftment is more rapid with earlier discharge from hospital, and the procedure is cheaper. Transplantation Transplantation of An alternative source of stem cells is umbilical cord blood of stem cells thawed stem cells which is gaining popularity as cord blood banks become established in the UK and Europe.

Severe Severe myelosuppression myelosuppression Transplantation procedures Allogeneic transplantation Engraftment Engraftment The recipient is treated with high dose chemotherapy or chemoradiotherapy to ablate the bone marrow conditioning. On the day after the treatment has ended, bone marrow or Figure After a period of severe myelosuppression lasting days, engraftment of the transplanted material takes place. The recipient then Recipient age Younger patients starts conditioning. One day after the conditioning has ended, Disease status Early in disease or first remission the stem cell product is thawed and infused intravenously.

The product is CMV serology Donor and recipient negative infused intravenously, rapidly through an indwelling central line. Myelosuppression and engraftment follow as described above. One major procedural difference between allogeneic and autologous transplantation is the requirement for Box This is achieved with combinations of Nausea and vomiting cyclosporin A and methotrexate or with in vitro or in vivo Reversible alopecia depletion of T cells using monoclonal antibodies.

Key ones are shown in Table Procedural complications Early complications Allogeneic and autologous procedures are associated with considerable morbidity and mortality. Nausea and vomiting from chemoradiotherapy is controllable with drugs, but the widespread mucosal damage to the gastrointestinal tract causes mucositis, which can be more difficult to control. Oral ulceration, buccal desquamation, oesophagitis, gastritis, abdominal pain, and diarrhoea may all be features. The severe myelosuppression after the transplant, together with immune dysfunction from delayed reconstitution or graft versus host disease, predisposes to a wide variety of potentially fatal infections with bacterial Gram positive and negative , viral, fungal, and atypical organisms.

Prophylactic antibiotics Figure Infection with the herpes simplex virus or the herpes zoster Box This may give rise to fulminant Profuse diarrhoea cytomegalovirus pneumonitis, which still has a high mortality Jaundice intrahepatic cholestasis despite newer antiviral drugs.

ABC of clinical haematology ABC of clinical haematology
ABC of clinical haematology ABC of clinical haematology
ABC of clinical haematology ABC of clinical haematology
ABC of clinical haematology ABC of clinical haematology
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