Haematological disease

7 Haematological disease




Approach to the patient


Anaemia is present when the haemoglobin (Hb) level in the blood is < 11.5 g/dL in women and < 13.5 g/dL in men (reference ranges vary between laboratories). It is usually accompanied by a reduced red cell count (RCC) and packed cell volume (PCV). However, an increase in plasma volume (e.g. in massive splenomegaly) causes a low Hb level with a normal RCC.





Investigations



Blood count and blood film. The haemoglobin and mean corpuscular volume (MCV) help define the type of anaemia (Fig. 7.1). The red blood cell distribution width (RDW) is the ratio of the width of the red cell divided by the MCV, and is useful in the differential diagnosis of microcytosis but not macrocytosis. In a patient with microcytic anaemia, a raised RDW would favour iron deficiency and a normal RDW favours thalassaemia. The white blood cell count and platelet count can also be useful in the differential diagnosis. The blood film shows the red cell morphology (anisocytosis = variation in size; poikilocytosis = variation in shape). The reticulocyte count reflects marrow red cell activity; a high count would be expected following haemorrhage or haemolysis and during the response to treatment with haematinics. A low reticulocyte count occurs with bone marrow failure and with deficiency of haematinics.





Microcytic anaemias



Iron deficiency anaemia


In developed countries, menstrual blood loss or an increased iron requirement during pregnancy and lactation is a frequent cause in younger women. In males and post-menopausal females with no obvious sign of bleeding, occult blood loss from the gastrointestinal tract is the commonest cause. Malabsorption of iron can also occur, e.g. in coeliac disease, but dietary deficiency is relatively uncommon. However, in developing countries, inadequate diet associated with poverty, vegetarianism and parasitic infections are major factors. The most common cause worldwide is gastrointestinal blood loss from hookworm infection.




Management


Identification and treatment of the underlying cause are essential. Oral iron is given to correct the anaemia and replenish stores.





The thalassaemias


This group of inherited anaemias is characterized by precipitation of excess globin chains in red cells (and their precursors) as a result of unbalanced α- or β-globin chain production (normally 1 : 1). This leads to ineffective erythropoiesis and haemolysis of mature red cells. The prevalence is high in parts of Africa, the Mediterranean, the Middle East, India and Asia.




β-Thalassaemia


β-Globin production is reduced (β+-thalassaemia) or absent (β0-thalassaemia) due to abnormalities in one or both β-globin genes, leading to precipitation of excess α-globin chains.








Management of thalassaemia major




Iron chelation therapy is essential in order to reduce damage to endocrine glands, liver, pancreas and myocardium caused by transfusion haemosiderosis.







Anaemia of chronic disease


A normochromic normocytic anaemia commonly occurs in association with chronic inflammatory and infective conditions (e.g. rheumatoid arthritis, malignancy, TB). The exact pathogenesis is complicated and contributing factors include a cytokine-mediated failure of iron utilization during erythropoiesis and high levels of hepcidin, which destroy ferroportin, limiting iron absorption in the intestinal cell. Red cell survival is decreased and there is an inappropriately low erythropoietin response for the level of anaemia. The MCV can be normal, or low in longstanding disease (resembling iron deficiency). The serum ferritin is usually normal or raised because of the inflammatory process. Iron is present in the bone marrow but not in developing erythroblasts.




Treatment


Address the underlying disorder, e.g. treat infection with antibiotics. Red cell transfusions may be necessary for symptomatic anaemia. Patients do not respond to oral iron, but coexisting iron deficiency should be identified and treated with parenteral iron (p. 202). Recombinant erythropoietin therapy at relatively high doses, e.g. 150–300 U/kg SC three times per week, is used, e.g. in rheumatoid arthritis, or intravenously in chronic kidney disease. Pegylated (PEG) erythropoietin is an alternative, administered once every 2 weeks.




Macrocytic anaemias



Megaloblastic anaemia


Impaired DNA synthesis results in morphological abnormalities of blood cell precursors, characterized by delayed nuclear maturation (nuclear-cytoplasmic asynchrony). All haematopoietic cell lines (and other rapidly dividing cells) are affected, and in severe cases there may be pancytopenia (i.e. anaemia, leucopenia and thrombocytopenia). Causes are predominantly those leading to B12 and folate deficiencies, although drugs (azathioprine, hydroxycarbamide, zidovudine), myelodysplasia and rare enzyme deficiencies affecting DNA synthesis (e.g. orotic aciduria) can also cause macrocytosis and anaemia.







Treatment


Transfusion should be avoided in chronic compensated anaemia (increased risk of congestive cardiac failure, especially in the elderly). Concurrent administration of vitamin B12 and folic acid may be necessary in severely ill patients while investigation results are awaited.






Aplastic anaemia


Aplastic anaemia is defined as pancytopenia with a virtual absence of reticulocytes and hypocellularity (aplasia) of the bone marrow. Causes of aplasia include drugs, e.g. chemotherapy (busulfan, doxorubicin), chloramphenicol, penicillamine, carbamazepine, phenytoin, chemicals (e.g. benzene), insecticides, ionizing radiation, viruses (e.g. hepatitis, EBV, HIV, erythrovirus B19 (previously parvovirus B19)), TB, paroxysmal nocturnal haemoglobinuria, myelodysplasia and primary bone marrow disease, e.g. leukaemia, myeloma, myelofibrosis.





Treatment


For secondary aplastic anaemia, remove the cause if possible. Patients should be referred to a specialist centre as soon as possible for confirmation of the diagnosis and guidance on further management.


Supportive care. This is the mainstay of therapy whilst awaiting bone marrow recovery (including stringent measures to prevent infection). Rapid treatment of infection with broad-spectrum parenteral antibiotics is essential, as for neutropenic patients (p. 261). Red cell transfusion and platelets should be kept to a minimum (p. 231, platelet transfusion thresholds) if SCT is being considered, as alloimmunization by donor blood products increases the risk of graft rejection.




Pure red cell aplasia is rare but can be due to persistent erythrovirus B19. A thymoma is the underlying cause in about one-third of cases, and these patients may respond to thymectomy. An erythropoietin receptor agonist can correct the anaemia in those with anti-erythropoietin antibody.



Myelodysplastic syndromes


The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem-cell disorders, characterized by increased apoptosis of myeloid cell lines (red cells, granulocyte/monocytes and platelets), leading to ineffective haematopoiesis and peripheral cytopenias. They were reclassified by the WHO in 2008. Disease may be idiopathic, or secondary to previous chemoradiotherapy or exposure to environmental toxins. A small number of cases are associated with rare familial disorders, e.g. Fanconi’s anaemia. Transformation to acute myeloblastic leukaemia (AML) occurs in one-third of patients.






Treatment


This is mainly supportive in patients with low-risk MDS (< 5% blasts in the bone marrow and ≤ one type of cytopenia) or in elderly patients with coexisting medical problems.


Red-cell transfusions as required are used to treat symptomatic anaemia. Iron chelation with SC desferrioxamine or oral therapy (p. 204) should be considered once 25 U red cells (~5 g iron) have been transfused. Vitamin C 100–200 mg/day orally can be added after 1 month of therapy. Neutropenic sepsis requires urgent broad-spectrum IV antibiotics (p. 261). For thrombocytopenia, platelet transfusions are given to maintain a platelet count > 10 × 109/L, or higher in patients with active bleeding.





Intensive chemotherapy regimes, as for AML (p. 284), are sometimes used for younger patients with high-risk MDS and good performance status. However, unless followed by an SCT procedure, there is little or no benefit in terms of overall survival for most patients.



Haemolytic anaemias







Inherited haemolytic anaemias





Sickle syndromes


Sickle haemoglobin (HbS) is the result of a valine substitution for glutamic acid at position 6 in the β-globin chain, caused by a single-base mutation in the β-globin gene (α2β26glu→val). Two abnormal genes result in homozygous sickle cell anaemia (HbSS), and one abnormal gene results in the heterozygous carrier state, sickle cell trait (HbAS). Sickle cell disease is a collective term used to describe sickle cell anaemia and additional sickle syndromes caused by combined heterozygosity for HbS with other abnormal haemoglobins, e.g. HbC (HbSC disease), β-thalassaemia (HbS-β0+-thalassaemia) or HbD (HbSD disease). At low oxygen tension, HbS forms an insoluble polymer, which irreversibly distorts red cells into the characteristic sickle shape. Sickle cells are poorly deformable and show abnormally increased adherence to vascular endothelium. Obstruction of small blood vessels leads to painful tissue infarction (sickle cell crisis). Most patients with sickle cell disease are of African descent, although the disease is also found in India, the Middle East and Southern Europe. The presence of HbS offers some protection against malaria; therefore the frequency of HbS carriers is high.


Sickle cell trait is usually asymptomatic, unless extreme circumstances lead to anoxia, such as travel in non-pressurized aircraft or problems with anaesthesia.


HbSC disease shares many clinical features with HbSS disease, but patients usually have higher baseline Hb, and there is an increased incidence of thromboembolic disease (especially during pregnancy) and retinopathy.



Sickle cell anaemia (HbSS)




Clinical syndromes and management



General management. Patients should be advised to seek urgent treatment for infections, and to minimize other factors that may precipitate a crisis where possible, such as dehydration, hypoxia and acidosis (e.g. from vigorous physical exercise) or exposure to cold temperatures. Multiple splenic infarctions over time result in autosplenectomy; therefore all patients should receive appropriate antibiotic prophylaxis and vaccination (Box 7.1, p. 205).




Preventive therapy includes hydroxycarbamide (hydroxyurea), which reduces the frequency of painful crises and acute chest syndrome, and the need for blood transfusions (and iron chelation, p. 204) in adults with sickle cell disease. It increases the concentration of fetal Hb (HbF), which protects against sickling. The usual dose is 20–30 mg/kg/day orally. Long-term safety data suggest that there is a low incidence of secondary malignancy with prolonged use. Hydroxycarbamide is contraindicated during pregnancy and breast feeding, and should be avoided in both female and male patients who are trying to conceive. In an acute crisis, hydroxycarbamide must be stopped if platelets are < 100 × 109/L, neutrophils < 1 × 109/L or reticulocytes < 100 × 109/L.






Acute chest syndrome (Box 7.2)








Management of acute chest crises












Glucose-6-phosphate dehydrogenase (G6PD) deficiency


G6PD deficiency is a common X-linked disorder prevalent in Africa, the Mediterranean, the Middle East and South-East Asia. G6PD-deficient red cells are more susceptible to oxidative damage and subsequent haemolysis in the spleen. Several different types exist, with varying degrees of enzyme deficiency and clinical severity.



Clinical and laboratory features


Rapid intravascular haemolysis with symptomatic anaemia, jaundice and haemoglobinuria occurs 1–3 days after ingestion of certain drugs (Box 7.3). Infection can also precipitate haemolysis but the anaemia is usually mild. Favism (severe haemolysis after ingestion of fava beans) occurs with the Mediterranean variant and can be rapidly fatal. Chronic non-spherocytic haemolytic anaemia (in the absence of a precipitating cause) and neonatal jaundice are also seen in some types of G6PD deficiency.





Apr 2, 2017 | Posted by in GENERAL SURGERY | Comments Off on Haematological disease

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