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The blood in systemic disease
BLOOD IN SYSTEMIC DISEASE
Causes of anaemia in systemic disease
The blood in systemic disease
Anaemia of chronic disease • Bacterial endocarditis • Osteomyelitis • Tuberculosis • Bronchiectasis • Rheumatoid arthritis • Systemic lupus erythematosus • Inflammatory bowel disease • Metastatic carcinoma • Myeloma • Hodgkin’s disease • Congestive heart failure • Type 1 diabetes mellitus without significant renal failure
Judith C W Marsh Ted Gordon-Smith
Anaemia of chronic disease Definition: anaemia of chronic disease (ACD) is the most common anaemia (more common than iron-deficiency anaemia) in hospitalized patients. It occurs in those with chronic infection, chronic inflammation or malignancy (Figure 1). A similar anaemia has recently been recognized in congestive heart failure and type 1 diabetes without significant renal failure. ACD presents as normocytic, normochromic anaemia associated with low serum iron and reduced transferin saturation (reduced total iron-binding capacity) and normal or elevated serum ferritin. It is not caused by bleeding, marrow replacement by tumour or deficiency of vitamin B12, folate or iron, though over time the anaemia may become hypochromic and microcytic as a result of impaired release of iron from the reticuloendothelial system. In malignancy, other causes of anaemia such as tumour infiltration of bone marrow and bleeding may further reduce haemoglobin levels.
Iron deficiency from blood loss • Gastrointestinal and gynaecological tumours • Non-steroidal anti-inflammatory drugs and corticosteroids • Bleeding varices Haemolytic anaemia • Microangiopathic • Autoimmune (ovarian cancer, lymphoma, chronic lymphocytic leukaemia, systemic lupus erythematosus, rheumatoid arthritis) Leucoerythroblastic anaemia Red-cell aplasia • Thymoma • Lymphoma • Drugs (e.g. azathioprine, isoniazid, phenytoin, erythropoietin therapy rarely) • Parvovirus infection
Pathogenesis: ACD is characterized by: • relatively low erythropoietin level for the degree of anaemia • reduced RBC survival as a result of phagocytosis by macrophages • reduced intestinal iron absorption • retention of iron in macrophages. Hepcidin is a polypeptide hormone produced in the liver that impairs iron release from macrophages and intestinal iron absorption. It is induced by inflammation and is a key mediator of ACD. Cytokines such as interleukin-1 (IL-1), IL-6, tumour necrosis
Bone marrow suppression • Chemotherapy • Radiotherapy Dyserythropoietic anaemia • Myelodysplastic syndrome as late complication of chemotherapy ± radiotherapy Megaloblastic anaemia • Alcoholic liver disease (folate deficiency) • Ileocaecal tuberculosis (folate/B12 deficiency)
Judith C W Marsh is Professor of Clinical Haematology and Honorary Consultant Haematologist at St George’s Hospital Medical School, London, UK. She qualified from the University of Birmingham, and trained in general medicine in Birmingham and in haematology at Hammersmith Hospital, London. Her research interests include bone marrow failure disorders, particularly aplastic anaemia, and autoimmune blood diseases.
Sideroblastic anaemia • Alcoholism • Isoniazid • Penicillamine • Myelodysplastic syndrome
Ted Gordon-Smith is Professor of Haematology and Honorary Consultant Physician at St George’s Hospital Medical School, London, UK. He qualified from the University of Oxford and Westminster Hospital, London, and worked at the Royal Postgraduate Medical School and Hammersmith Hospital, London. His main interests are aplastic anaemia, stem cell transplantation and disorders of RBCs.
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BLOOD IN SYSTEMIC DISEASE
factor α and interferons are often elevated in ACD and may contribute to reduced erythropoietin production by the kidneys.
hypersplenism. Thrombocytopenia may also be part of disseminated intravascular coagulation (DIC).
Management: the severity of the anaemia parallels the activity of the underlying chronic disease, and treatment of the disease results in gradual improvement of the haemoglobin level. ACD is not improved by iron therapy unless there is associated iron deficiency. In some patients, the anaemia responds to recombinant human erythropoietin (rHuEpo).
Coagulation defects include low-grade or subacute DIC seen in patients with metastatic carcinoma of the pancreas, lung or stomach. Acute DIC is common in acute promyelocytic leukaemia. Rarely, acquired inhibitors of coagulation (e.g. factor VIII) are produced.
Renal disease Malignancy
Polycythaemia is a rare complication of malignancy. It may occur in patients with hypernephroma or other tumours such as hepatoma, uterine myoma and cerebellar haemangioblastoma. It is usually caused by inappropriate secretion of erythropoietin or erythropoietin-like peptides from tumour cells.
Anaemia is the most important haematological abnormality in renal disease. Patients with acute or chronic renal failure develop normocytic, normochromic anaemia with burr cells (echinocytes) in the blood film. Reticulocyte count is normal or slightly low. The anaemia is principally caused by low erythropoietin levels, which can be fully corrected by rHuEPO therapy. Very rarely, use of rHuEPO in patients with renal failure is complicated by severe red-cell aplasia associated with anti-erythropoietin antibodies, necessitating discontinuation of the drug. Other causes of anaemia in renal failure include reduced RBC survival, iron deficiency (blood loss during haemodialysis and frequent blood sampling) and bleeding as a result of defective platelet function, folate deficiency (chronic haemodialysis), hyperparathyroidism or aluminium toxicity.
Reactive bone marrow changes in the absence of infection include leucocytosis from neutrophilia or monocytosis, and mild thrombocytosis.
Secondary polycythaemia may occur in patients with hypernephroma, renal cysts, hydronephrosis or nephrotic syndrome, and transiently after renal transplantation.
Thrombocytopenia may be caused by bone marrow infiltration resulting in failure of production of megakaryocytes (and other haemopoietic cell lineages). In chronic lymphocytic leukaemia and lymphoma, thrombocytopenia may result from immune destruction of platelets as a consequence of associated idiopathic thrombocytopenic purpura (ITP), or splenic infiltration causing
Haemostatic abnormalities: there is an increased risk of bleeding as a consequence of abnormal platelet function with prolonged bleeding time. Patients with nephrotic syndrome are at increased risk of thrombosis (particularly of the renal vein). Thrombocytopenia may occur as part of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura (TTP).
Anaemia is the most common abnormality in cancer patients and has many causes (Figure 1). ACD occurs most commonly and is often associated with raised ESR. Disseminated malignancy often produces leucoerythroblastic anaemia or microangiopathic haemolytic anaemia (MAHA) (Figure 2). A leucoerythroblastic blood film plus evidence of MAHA is virtually pathognomonic of disseminated malignancy with marrow involvement.
Features of leucoerythroblastic anaemia and microangiopathic haemolytic anaemia
Features
Leucoerythroblastic anaemia Presence of granulocytic and erythrocytic precursors in peripheral blood; anaemia not always present; platelet count usually normal, but may be raised or occasionally low
Pathogenesis
Occurs when normal marrow environment disrupted by fibrosis, tumour metastases or granuloma; accompanies extramedullary haemopoiesis
Systemic associations
Metastatic carcinoma of bone marrow; granulomatous disease on marrow (tuberculosis, fungal); myelofibrosis
Microangiopathic haemolytic anaemia Mild-to-moderate haemolysis with reticulocytosis, fragmented RBCs, free haemoglobin in plasma and urine, and urine haemosiderinuria; can be associated with disseminated intravascular coagulation, resulting in thrombocytopenia and coagulation disorder Abnormalities of microvascular microcirculation caused by tumour, vasculitis or fibrin strands deposited in infection, resulting in physical disruption of RBCs; haemolysis is intravascular Malignant disease (e.g. mucin-secreting adenocarcinoma of stomach, breast); vasculitis (particularly involving kidney); infection (meningococcal sepsis); haemolytic uraemic syndrome
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a Infectious mononucleosis – reactive lymphocyte.
b Liver disease – macrocytes, target cells.
c Malaria – Plasmodium falciparum.
d Leishmaniasis.
e Microangiopathic haemolytic anaemia – fragmented RBCs, spherocytes.
f Microangiopathic haemolytic anaemia with leucoerythroblastic changes.
Liver disease
Systemic autoimmune disorders
Anaemia of chronic liver disease is macrocytic with target cells and acanthocytes. Blood loss (from bleeding varices) produces iron deficiency, and folate deficiency from poor nutritional intake may occur. Thrombocytopenia may result from hypersplenism, folate deficiency or alcohol toxicity. Alcohol produces macrocytosis in the absence of anaemia or liver damage, sideroblastic anaemia and severe haemolysis (Zieve’s syndrome). Liver disease increases the risk of bleeding because all of the clotting factors are synthesized in liver hepatocytes. DIC can also occur; this is usually mild.
ACD occurs commonly in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Iron deficiency from gastrointestinal bleeding may occur in those taking non-steroidal antiinflammatory drugs (NSAIDs) or corticosteroids. Aplastic anaemia may complicate therapy with gold, penicillamine, sulfasalazine or NSAIDs. Felty’s syndrome in RA is associated with splenomegaly and neutropenia, often associated with large granular lymphocyte syndrome; anaemia and thrombocytopenia may also be present. Autoimmune cytopenia is common in many systemic autoimmune
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BLOOD IN SYSTEMIC DISEASE
disorders. Lupus anticoagulant is found in 10% of patients with SLE and is associated with an increased risk of thrombosis.
Haemophagocytic syndrome: systemic infection with cytomegalovirus, fungi or TB can sometimes produce severe pancytopenia as a result of intense phagocytosis of blood cells in the bone marrow by macrophages (haemophagocytosis). It is also sometimes seen in patients presenting with lymphoma. It is particularly common in those who are immunocompromised or acutely ill (e.g. with septicaemia); mortality is high.
Infections Bacterial: acute bacterial infection causes neutrophilia, often with a left shift and toxic granulation of the neutrophils. ACD and thrombocytopenia may also occur in acute or chronic infection. Severe haemolytic anaemia can occur in patients with severe Gram-negative septicaemia (particularly Clostridium perfringens) or sepsis with Staphylococcus aureus, often in association with DIC. Mycoplasma pneumoniae infection is often associated with coldtype autoimmune haemolytic anaemia. Bacterial endocarditis is often associated with ACD and monocytosis. Tuberculosis (TB) can cause ACD, leucoerythroblastic anaemia, monocytosis, and pancytopenia with bone marrow involvement and fibrosis. Ileocaecal TB can produce malabsorption resulting in B12 or folate deficiency. Side-effects of antituberculous therapy include thrombocytopenia (rifampicin) and sideroblastic anaemia (isoniazid). Helicobacter pylori infection can result in gastrointestinal blood loss and has recently been associated with some cases of ITP. Viral: autoimmune haemolytic anaemia may occur with Epstein– Barr virus and other viral infections. Transient red-cell aplasia is seen in parvovirus B19 infection in patients with haemolytic anaemias (‘aplastic crisis’) such as sickle cell disease and hereditary spherocytosis. Aplastic anaemia occasionally occurs after an episode of acute hepatitis (usually non-A, B, C, E). Neutropenia, lymphocytosis and thrombocytopenia are often seen in acute viral infections. ‘Reactive lymphocytes’ are classically seen in infectious mono-nucleosis, other viral infections and toxoplasmosis. Haematological features of AIDS include lymphopenia, anaemia (usually normocytic, sometimes macrocytic and rarely microangiopathic with a TTP-like picture), neutropenia and thrombocytopenia. The bone marrow is initially hypercellular and there may be dysplastic and/or megaloblastic changes. Later, bone marrow failure with hypocellular marrow may occur. The marrow may become infiltrated with non-Hodgkin’s lymphoma, Hodgkin’s disease, granulomata (TB and atypical mycobacterial infection) or fungal disease (Candida, Cryptococcus, histoplasmosis). Drug-induced side-effects include neutropenia (ganciclovir), pancytopenia (co-trimoxazole, zidovudine) and megaloblastic anaemia (zidovudine).
FURTHER READING Bosman D R, Osborne C A, Marsden J T et al. Erythropoietin response to hypoxia in patients with diabetic autonomic neuropathy and non-diabetic chronic renal failure. Diabetic Med 2002; 19: 65–9. (Examines further the mechanism of anaemia in diabetic patients with early nephropathy and neuropathy.) Bowman S J. Haematological manifestations of rheumatoid arthritis. Scand J Rheumatol 2002; 31: 251–9. Casadevall N, Nataf J, Viron B et al. Pure red cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346: 469–75. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation. Blood 2003; 102: 783–8. Macdougall I C. Present and future strategies in the treatment of renal anaemia. Nephrol Dial Transplant 2001; 16: (Suppl. 5): 50–5. Mehta A, Hoffbrand A V. Haematological aspects of systemic disease. In: Hoffbrand A V, Lewis S M, Tuddenham E G D, eds. Postgraduate haematology. 4th ed. Oxford: Butterworth-Heinemann, 1999: 675–93. (A comprehensive review of more detailed aspects of the topics discussed in this contribution.) Silverberg D S, Iaina A, Wexler D et al. The pathological consequences of anaemia. Clin Lab Haematol 2001; 23: 1–6. (Reviews the pathophysiology and treatment of ACD in congestive heart failure.) Weatherall D J. The blood in systemic disease. In: Weatherall D J, Ledingham J G G, Warrell D A, eds. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press, 1996: 3677–87. Weinstein D A, Roy C N, Fleming M D et al. Inappropriate expression of hepcidin is associated with iron refractory anaemia: implications for the anaemia of chronic disease. Blood 2002; 100: 3776–81. (The first report discussing the role of hepcidin as a key mediator of anaemia of chronic disease.) Winkler A S, Marsden J, Chaudhuri K R et al. Erythropoietin depletion and anaemia in diabetes mellitus. Diabetic Med 1999; 16: 813–19.
Malaria: anaemia is most marked in malaria caused by Plasmodium falciparum. Parasitic invasion of RBCs produces intravascular haemolysis, which may be severe with haemoglobinuria and renal failure (‘black-water fever’). Survival of uninfected RBCs is also reduced, with increased clearance by macrophages, and Coombs’ test may be positive. Mild/moderate thrombocytopenia is common and may be caused by immune mechanisms, splenic sequestration and DIC. Monocytosis is also common. Other parasitic infections: hookworm infection is the most common cause of iron deficiency worldwide. Eosinophilia is a typical finding in parasitic infections in general. Kala-azar (visceral leishmaniasis) is associated with pancytopenia, hepatosplenomegaly and lymphadenopathy, and bone marrow aspirates may reveal large numbers of parasitized macrophages.
MEDICINE
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© 2004 The Medicine Publishing Company Ltd
Causes of anaemia in systemic disease
The blood in systemic disease
Anaemia of chronic disease • Bacterial endocarditis • Osteomyelitis • Tuberculosis • Bronchiectasis • Rheumatoid arthritis • Systemic lupus erythematosus • Inflammatory bowel disease • Metastatic carcinoma • Myeloma • Hodgkin’s disease • Congestive heart failure • Type 1 diabetes mellitus without significant renal failure
Judith C W Marsh Ted Gordon-Smith
Anaemia of chronic disease Definition: anaemia of chronic disease (ACD) is the most common anaemia (more common than iron-deficiency anaemia) in hospitalized patients. It occurs in those with chronic infection, chronic inflammation or malignancy (Figure 1). A similar anaemia has recently been recognized in congestive heart failure and type 1 diabetes without significant renal failure. ACD presents as normocytic, normochromic anaemia associated with low serum iron and reduced transferin saturation (reduced total iron-binding capacity) and normal or elevated serum ferritin. It is not caused by bleeding, marrow replacement by tumour or deficiency of vitamin B12, folate or iron, though over time the anaemia may become hypochromic and microcytic as a result of impaired release of iron from the reticuloendothelial system. In malignancy, other causes of anaemia such as tumour infiltration of bone marrow and bleeding may further reduce haemoglobin levels.
Iron deficiency from blood loss • Gastrointestinal and gynaecological tumours • Non-steroidal anti-inflammatory drugs and corticosteroids • Bleeding varices Haemolytic anaemia • Microangiopathic • Autoimmune (ovarian cancer, lymphoma, chronic lymphocytic leukaemia, systemic lupus erythematosus, rheumatoid arthritis) Leucoerythroblastic anaemia Red-cell aplasia • Thymoma • Lymphoma • Drugs (e.g. azathioprine, isoniazid, phenytoin, erythropoietin therapy rarely) • Parvovirus infection
Pathogenesis: ACD is characterized by: • relatively low erythropoietin level for the degree of anaemia • reduced RBC survival as a result of phagocytosis by macrophages • reduced intestinal iron absorption • retention of iron in macrophages. Hepcidin is a polypeptide hormone produced in the liver that impairs iron release from macrophages and intestinal iron absorption. It is induced by inflammation and is a key mediator of ACD. Cytokines such as interleukin-1 (IL-1), IL-6, tumour necrosis
Bone marrow suppression • Chemotherapy • Radiotherapy Dyserythropoietic anaemia • Myelodysplastic syndrome as late complication of chemotherapy ± radiotherapy Megaloblastic anaemia • Alcoholic liver disease (folate deficiency) • Ileocaecal tuberculosis (folate/B12 deficiency)
Judith C W Marsh is Professor of Clinical Haematology and Honorary Consultant Haematologist at St George’s Hospital Medical School, London, UK. She qualified from the University of Birmingham, and trained in general medicine in Birmingham and in haematology at Hammersmith Hospital, London. Her research interests include bone marrow failure disorders, particularly aplastic anaemia, and autoimmune blood diseases.
Sideroblastic anaemia • Alcoholism • Isoniazid • Penicillamine • Myelodysplastic syndrome
Ted Gordon-Smith is Professor of Haematology and Honorary Consultant Physician at St George’s Hospital Medical School, London, UK. He qualified from the University of Oxford and Westminster Hospital, London, and worked at the Royal Postgraduate Medical School and Hammersmith Hospital, London. His main interests are aplastic anaemia, stem cell transplantation and disorders of RBCs.
MEDICINE
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© 2004 The Medicine Publishing Company Ltd
BLOOD IN SYSTEMIC DISEASE
factor α and interferons are often elevated in ACD and may contribute to reduced erythropoietin production by the kidneys.
hypersplenism. Thrombocytopenia may also be part of disseminated intravascular coagulation (DIC).
Management: the severity of the anaemia parallels the activity of the underlying chronic disease, and treatment of the disease results in gradual improvement of the haemoglobin level. ACD is not improved by iron therapy unless there is associated iron deficiency. In some patients, the anaemia responds to recombinant human erythropoietin (rHuEpo).
Coagulation defects include low-grade or subacute DIC seen in patients with metastatic carcinoma of the pancreas, lung or stomach. Acute DIC is common in acute promyelocytic leukaemia. Rarely, acquired inhibitors of coagulation (e.g. factor VIII) are produced.
Renal disease Malignancy
Polycythaemia is a rare complication of malignancy. It may occur in patients with hypernephroma or other tumours such as hepatoma, uterine myoma and cerebellar haemangioblastoma. It is usually caused by inappropriate secretion of erythropoietin or erythropoietin-like peptides from tumour cells.
Anaemia is the most important haematological abnormality in renal disease. Patients with acute or chronic renal failure develop normocytic, normochromic anaemia with burr cells (echinocytes) in the blood film. Reticulocyte count is normal or slightly low. The anaemia is principally caused by low erythropoietin levels, which can be fully corrected by rHuEPO therapy. Very rarely, use of rHuEPO in patients with renal failure is complicated by severe red-cell aplasia associated with anti-erythropoietin antibodies, necessitating discontinuation of the drug. Other causes of anaemia in renal failure include reduced RBC survival, iron deficiency (blood loss during haemodialysis and frequent blood sampling) and bleeding as a result of defective platelet function, folate deficiency (chronic haemodialysis), hyperparathyroidism or aluminium toxicity.
Reactive bone marrow changes in the absence of infection include leucocytosis from neutrophilia or monocytosis, and mild thrombocytosis.
Secondary polycythaemia may occur in patients with hypernephroma, renal cysts, hydronephrosis or nephrotic syndrome, and transiently after renal transplantation.
Thrombocytopenia may be caused by bone marrow infiltration resulting in failure of production of megakaryocytes (and other haemopoietic cell lineages). In chronic lymphocytic leukaemia and lymphoma, thrombocytopenia may result from immune destruction of platelets as a consequence of associated idiopathic thrombocytopenic purpura (ITP), or splenic infiltration causing
Haemostatic abnormalities: there is an increased risk of bleeding as a consequence of abnormal platelet function with prolonged bleeding time. Patients with nephrotic syndrome are at increased risk of thrombosis (particularly of the renal vein). Thrombocytopenia may occur as part of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura (TTP).
Anaemia is the most common abnormality in cancer patients and has many causes (Figure 1). ACD occurs most commonly and is often associated with raised ESR. Disseminated malignancy often produces leucoerythroblastic anaemia or microangiopathic haemolytic anaemia (MAHA) (Figure 2). A leucoerythroblastic blood film plus evidence of MAHA is virtually pathognomonic of disseminated malignancy with marrow involvement.
Features of leucoerythroblastic anaemia and microangiopathic haemolytic anaemia
Features
Leucoerythroblastic anaemia Presence of granulocytic and erythrocytic precursors in peripheral blood; anaemia not always present; platelet count usually normal, but may be raised or occasionally low
Pathogenesis
Occurs when normal marrow environment disrupted by fibrosis, tumour metastases or granuloma; accompanies extramedullary haemopoiesis
Systemic associations
Metastatic carcinoma of bone marrow; granulomatous disease on marrow (tuberculosis, fungal); myelofibrosis
Microangiopathic haemolytic anaemia Mild-to-moderate haemolysis with reticulocytosis, fragmented RBCs, free haemoglobin in plasma and urine, and urine haemosiderinuria; can be associated with disseminated intravascular coagulation, resulting in thrombocytopenia and coagulation disorder Abnormalities of microvascular microcirculation caused by tumour, vasculitis or fibrin strands deposited in infection, resulting in physical disruption of RBCs; haemolysis is intravascular Malignant disease (e.g. mucin-secreting adenocarcinoma of stomach, breast); vasculitis (particularly involving kidney); infection (meningococcal sepsis); haemolytic uraemic syndrome
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BLOOD IN SYSTEMIC DISEASE
a Infectious mononucleosis – reactive lymphocyte.
b Liver disease – macrocytes, target cells.
c Malaria – Plasmodium falciparum.
d Leishmaniasis.
e Microangiopathic haemolytic anaemia – fragmented RBCs, spherocytes.
f Microangiopathic haemolytic anaemia with leucoerythroblastic changes.
Liver disease
Systemic autoimmune disorders
Anaemia of chronic liver disease is macrocytic with target cells and acanthocytes. Blood loss (from bleeding varices) produces iron deficiency, and folate deficiency from poor nutritional intake may occur. Thrombocytopenia may result from hypersplenism, folate deficiency or alcohol toxicity. Alcohol produces macrocytosis in the absence of anaemia or liver damage, sideroblastic anaemia and severe haemolysis (Zieve’s syndrome). Liver disease increases the risk of bleeding because all of the clotting factors are synthesized in liver hepatocytes. DIC can also occur; this is usually mild.
ACD occurs commonly in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Iron deficiency from gastrointestinal bleeding may occur in those taking non-steroidal antiinflammatory drugs (NSAIDs) or corticosteroids. Aplastic anaemia may complicate therapy with gold, penicillamine, sulfasalazine or NSAIDs. Felty’s syndrome in RA is associated with splenomegaly and neutropenia, often associated with large granular lymphocyte syndrome; anaemia and thrombocytopenia may also be present. Autoimmune cytopenia is common in many systemic autoimmune
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© 2004 The Medicine Publishing Company Ltd
BLOOD IN SYSTEMIC DISEASE
disorders. Lupus anticoagulant is found in 10% of patients with SLE and is associated with an increased risk of thrombosis.
Haemophagocytic syndrome: systemic infection with cytomegalovirus, fungi or TB can sometimes produce severe pancytopenia as a result of intense phagocytosis of blood cells in the bone marrow by macrophages (haemophagocytosis). It is also sometimes seen in patients presenting with lymphoma. It is particularly common in those who are immunocompromised or acutely ill (e.g. with septicaemia); mortality is high.
Infections Bacterial: acute bacterial infection causes neutrophilia, often with a left shift and toxic granulation of the neutrophils. ACD and thrombocytopenia may also occur in acute or chronic infection. Severe haemolytic anaemia can occur in patients with severe Gram-negative septicaemia (particularly Clostridium perfringens) or sepsis with Staphylococcus aureus, often in association with DIC. Mycoplasma pneumoniae infection is often associated with coldtype autoimmune haemolytic anaemia. Bacterial endocarditis is often associated with ACD and monocytosis. Tuberculosis (TB) can cause ACD, leucoerythroblastic anaemia, monocytosis, and pancytopenia with bone marrow involvement and fibrosis. Ileocaecal TB can produce malabsorption resulting in B12 or folate deficiency. Side-effects of antituberculous therapy include thrombocytopenia (rifampicin) and sideroblastic anaemia (isoniazid). Helicobacter pylori infection can result in gastrointestinal blood loss and has recently been associated with some cases of ITP. Viral: autoimmune haemolytic anaemia may occur with Epstein– Barr virus and other viral infections. Transient red-cell aplasia is seen in parvovirus B19 infection in patients with haemolytic anaemias (‘aplastic crisis’) such as sickle cell disease and hereditary spherocytosis. Aplastic anaemia occasionally occurs after an episode of acute hepatitis (usually non-A, B, C, E). Neutropenia, lymphocytosis and thrombocytopenia are often seen in acute viral infections. ‘Reactive lymphocytes’ are classically seen in infectious mono-nucleosis, other viral infections and toxoplasmosis. Haematological features of AIDS include lymphopenia, anaemia (usually normocytic, sometimes macrocytic and rarely microangiopathic with a TTP-like picture), neutropenia and thrombocytopenia. The bone marrow is initially hypercellular and there may be dysplastic and/or megaloblastic changes. Later, bone marrow failure with hypocellular marrow may occur. The marrow may become infiltrated with non-Hodgkin’s lymphoma, Hodgkin’s disease, granulomata (TB and atypical mycobacterial infection) or fungal disease (Candida, Cryptococcus, histoplasmosis). Drug-induced side-effects include neutropenia (ganciclovir), pancytopenia (co-trimoxazole, zidovudine) and megaloblastic anaemia (zidovudine).
FURTHER READING Bosman D R, Osborne C A, Marsden J T et al. Erythropoietin response to hypoxia in patients with diabetic autonomic neuropathy and non-diabetic chronic renal failure. Diabetic Med 2002; 19: 65–9. (Examines further the mechanism of anaemia in diabetic patients with early nephropathy and neuropathy.) Bowman S J. Haematological manifestations of rheumatoid arthritis. Scand J Rheumatol 2002; 31: 251–9. Casadevall N, Nataf J, Viron B et al. Pure red cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346: 469–75. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation. Blood 2003; 102: 783–8. Macdougall I C. Present and future strategies in the treatment of renal anaemia. Nephrol Dial Transplant 2001; 16: (Suppl. 5): 50–5. Mehta A, Hoffbrand A V. Haematological aspects of systemic disease. In: Hoffbrand A V, Lewis S M, Tuddenham E G D, eds. Postgraduate haematology. 4th ed. Oxford: Butterworth-Heinemann, 1999: 675–93. (A comprehensive review of more detailed aspects of the topics discussed in this contribution.) Silverberg D S, Iaina A, Wexler D et al. The pathological consequences of anaemia. Clin Lab Haematol 2001; 23: 1–6. (Reviews the pathophysiology and treatment of ACD in congestive heart failure.) Weatherall D J. The blood in systemic disease. In: Weatherall D J, Ledingham J G G, Warrell D A, eds. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press, 1996: 3677–87. Weinstein D A, Roy C N, Fleming M D et al. Inappropriate expression of hepcidin is associated with iron refractory anaemia: implications for the anaemia of chronic disease. Blood 2002; 100: 3776–81. (The first report discussing the role of hepcidin as a key mediator of anaemia of chronic disease.) Winkler A S, Marsden J, Chaudhuri K R et al. Erythropoietin depletion and anaemia in diabetes mellitus. Diabetic Med 1999; 16: 813–19.
Malaria: anaemia is most marked in malaria caused by Plasmodium falciparum. Parasitic invasion of RBCs produces intravascular haemolysis, which may be severe with haemoglobinuria and renal failure (‘black-water fever’). Survival of uninfected RBCs is also reduced, with increased clearance by macrophages, and Coombs’ test may be positive. Mild/moderate thrombocytopenia is common and may be caused by immune mechanisms, splenic sequestration and DIC. Monocytosis is also common. Other parasitic infections: hookworm infection is the most common cause of iron deficiency worldwide. Eosinophilia is a typical finding in parasitic infections in general. Kala-azar (visceral leishmaniasis) is associated with pancytopenia, hepatosplenomegaly and lymphadenopathy, and bone marrow aspirates may reveal large numbers of parasitized macrophages.
MEDICINE
91
© 2004 The Medicine Publishing Company Ltd