Hematological disease

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Clinical medicine by Kumar and Clark, edition 8. Pages 371-400

CHAPTER 8 HEMATOLOGICAL DISEASE

INTRODUCTION

Blood consists of red cells, white cells, platelets and plasma.

The haemopoietic system inclues the bone marrow, liver, spleen, lymph nodes and thymus. Blood islands are formed in the yolk sac in the 3^rd week of gestation and produce primitive blood cells, which migrate to liver and spleen. These organs are the chief sites of haemopoiesis from 6 weeks to 7 months, when the bone marrow becomes the main source of blood cells. Pathological processes interfering with normal haemopoiesis may result in resumptions of haemopoietic activity in th liver and spleen = extramedullary haemopoiesis.

All blood cells are derived from pluripotent stem cells. The stem cell has two propoperties: self-renewal and proliferation and differentiation into progenitor cells. The major ancestral cells lines derived from the pluripotente stem cell: lymphocytic and myeloid cells.

Haemopoiesis is under control of growth factors and inhibitors. These Haemopoietic growth factos incl. eyrthripoietin (EPO), interleukins, Fns-tyrosine kinase 3 etc. TPO (thrombopoeitin) controls platelet production along with IL-6 and IL-11.

Haemopoesis inhibiting factors are TNF (tumor necrosis factor) and TGF-β (transforming growth factor- β)

Uses of haemopoiesis growth factors in treatment

1. G-CSF (Granulocyte-colony-stimulating factor) is used to accelerate haemopoietic recovery after chemotherapy and haemopoietic cell transplantation.
2. EPO is used to treat anaemia in patients with chronic kidney disease.
3. Thrombopoietin receptor agonists are being used to treat patients with immune thrombocytopenic purpura.

THE RED CELL

Red cell precursors pass through several stages in the bone marrow: pronormoblast à erythroblast à normoblast à reticulocyte à erythrocyte. Precursors at each stage progressively contain less RNA and more Hb in the cytoplasm.

-        Normoblasts are not normally present in peripheral blood, but are present if there is extramedullary haemopoiesis and in some marrow disorders.

-        Reticulocytes contain residual ribosomal RNA are still able to synthesize Hb. When released into circulation they lose their RNA and become mature red cells after 1-2 days.

Erythropoietin (EPO) is a hormone which controls erythropoiesis. EPO is produced by the kidney (90%) and liver (10%), its production is regulated mainly by tissue oxygen tension. Production is increased if there is hypoxia from whatever cause, e.g. anemia or cardiac or pulmonary disease. Increased ‘inappropriate’ production of erythropoietin occurs in certain tumours such as renal cell carcinoma and other causes.

Haemoglobin synthesis

Each normal adult Hb molecule (HbA) consists of two α and two β globin polypeptide chains. HbA compromises about 97% of the Hb in adults. Two other haemoglobin types HbA2 and HbF are found in adults in small amounts. Haemoglobin synthesis occurs in the mitochondria of the developing red cell. Vitamin B6 is a coenzyme for this reaction, which is inhibited by haem and stimulated by EPO.

ANEMIA

Anemia is present when there is decrease in Hb in the blood below the reference level for the age and sex (adult male: 8.5-11 mmol/L, adult female: 7.5-10 mmol/L). Alterations in the Hb occur as a result of changes in the plasma volume. A reduction in the plasma volume will lead to a spuriously high Hb – this seen with dehydration and in the clinical condition of apparent polycythaemia. A raised plasma volume produces a spurious anaemia, even when combined with a small increase in red cell volume as occurs in pregnancy.

There are 3 major types of anemia classified by MCV (Mean Corpsular Volume):

-        Hypochromic microcytic with a low MCV (<80 fL)

-        Normochromic normocytic with a normal MCV (80-96 fL)

-        Macrocytic with a high MCV (>96 fL)

Clinical features

Patients with anaemia may be asymptomatic. A slowly falling level of Hb allows for haemodynamic compensation and enhancement of the oxygen-carrying capacity of the blood.

Symptoms (all nonspecific)

-        Fatigue, headaches and faintness

-        Breathlessness

-        Angina

-        Intermittent claudication

-        Palpitations

Sings

-        Pallor

-        Tachycardia

-        Systolic flow murmur

-        Cardiac failure

Specific signs

-        Koilonychia - spoon-shaped nails seen in longstanding iron deficiency anaemia.

-        Jaundice - found in haemolytic anaemia.

-        Bone deformities – found in thalassaemia major.

-        Leg ulcers – occur in association with sickle cell disease.

MICROCYTIC ANEMIA

Iron deficiency is the most common cause of anaemia in the world, affecting 30% of the world’s population. The other cause of microcytic anaemia are anaemia of chronic disease, sideroblastic anaemia and thalassaemia.

IRON

Non-haem iron is mainly derived from cereals and haem iron is derived from haemoglobin and myoglobin in red or organ meats. Haem iron is better absorbed than non-haem iron, whose availability is more affected by other dietary constituents. Most haem is absorbed in the proximal intestine, with absorptive capacity decreasing distally. The intestinal haem transporter HCP1 (haem carrier protein 1) is highly expressed in the duodenum and it is up regulated by hypoxia and iron deficiency. Non-haem iron absorption occurs primarily in the duodenum. Non-haem iron is dissolved in the low pH of the stomach and reduced from the ferric to ferrous form by a brush border ferrireductase.

Once inside the mucosal cell, iron may be transferred across the cell to reach the plasma, or be stored as ferritin. Iron stored as ferritin will be lost into the gut lumen when the mucosal cells are shed. The body iron content is closely regulated by the control of iron absorption but there is no physiological mechanism for eliminating excess iron from the body. The key molecule regulating iron absorption is hepcidin, synthesized in the liver.

! Hepicidin acts by regulating the activity of the iron exporting protein ferroportin by binding to ferroportin causing its internalization and degradation, thereby decreasing iron efflux from iron exporting tissues into plasma

Þ    High levels of hepcidin (inflamed state) will destroy ferroportin and limit iron absorption.

Hereditary haemochromatosis (mutation in gene HFE) will interrupt hepcidin synthesis thus will lead to more iron being released into the plasma. Preliminary evidence suggests that the increased iron absorption in β-thalassaemia is mediated by down regulation of hepcidin and up regulation of ferroportin.

Iron is transported in the plasma bound to transferring, a β-globulin that is synthesized in the liver. Most of the iron bound to transferring comes from macrophages in the reticuloendothelilal system and not from iron absorbed by the intestine. Transferrin-bound iron becomes attached by specific receptors to erythroblasts and reticulocytes in the marrow and the iron is removed. Iron is stored in reticuloendothelilal cells, hepatocytes and skeletal muscle cells, about 2/3 of this is stored as ferritin and 1/3 as haemosiderin in normal individuals.

-        Ferritin is a water-soluble comples of iron and protein. It is more easily mobilized than haemosiderin for Hb formation.

-        Haemosiderin is an insoluble iron-protein comples found in macrophages in the bone marrow, liver and spleen. It’s Perls’ reaction positive.

IRON DEFICIENCY

Iron deficiency anaemia develops when there is inadequate iron for haemoglobin synthesis. The causes are:

-        Blood loss

-        Increased demand such as growth and pregnancy

-        Decreased absorption (e.g. post-gastrectomy)

-        Poor intake

Clinical features

-        Brittle nails

-        Spoon-shaped nails (koilonychias)

-        Atrophy of the papillae of the tongue

-        Angular stomatitis

-        Brittle hair

-        A syndrome of dysphagia and glossitis (àPlummer-Vinson or Paterson-Bown-Kelly syndrome)

Investigation

-        Blood count and film

-        Serum iron and iron-binding capacity

-        Serum ferritin

-        Serum soluble transferring receptors

-        Other investigation as indicated by the clinical history and examination.

Differential diagnosis: thalassaemia, sideroblastic anaemia and anaemia of chronic disease.

Treatment

The correct management of iron deficiency is to find and treat the underlying cause, and to give iron to correct the anaemia and replace iron stores.

Orally ferrous sulphate: 200mg 3x daily. In case of side effects ferrous gluconate: 300mg x2 daily.

The commonest cause of failure to respond to oral iron are:

-        Lack of compliance

-        Continuing haemorrhage

-        Incorrect diagnosis (e.g. thalassaemia trait)

These possibilities should be considered before parenteral iron is used. However parenteral iron is required by occasional patients e.g. intolerant to oral preparation, sever malabsorption, chronic disease.

ANAEMIA OF CHRONIC DISEASE

One of the most common types of anaemia is the anaemia of chronic disease, occurring in patients with chronic infections such as tuberculosis or chronic inflammatory disease such as Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), polmyalgia rheumatic and malignant disease. There is decreased release of iron from the bone marrow to developing erythroblasts, an inadequate erythropoietin response to the anaemia, and decreased red cell survival.

! Serum ferritin is normal of raised because of the inflammatory process.

! Patients do not respond to iron therapy.

Recombinant erythropoietin therapy is used in the anaemia of renal disease and occasionally in inflammatory disease (rheumatoid arthritis, inflammatory bowel disease)

SIDEROBLASTIC ANAEMIA

Sideroblastic anaemias are inherited or acquired disorders characterized by a refractory anaemia, a variable number of hypochromic cells in the peripheral blood, and excess iron and ring sideroblasts in the bone marrow.

! The presence of ring sideroblasts is the diagnostic feature of sideroblastic anaemia. There is accumulation of iron in the mitochondria of erythroblasts owing to disordered haem synthesis forming a ring of iron granules around the nucleus that can be seen with Perls’ reaction.

Inherited as an X-linked disease, acquired cases incl. myelodysplasia, myeloproliferative disorders, myeloid leukaemia, drugs, alcohol misuse and lead toxicity. It can also occur in other disorders such as rheumatoid arthritis, carcinomas, megaloblastic and haemolytic anaemia.

Treatment

-        Withdrawing causative agents e.g. drugs, alcohol.

-        Pyridoxine

-        Folic acid to treat accompanying folate deficiency.

NORMOCYTIC ANAEMIA

Normocytic, normochromic anaemia is seen in anaemia of chronic disease, in some endocrine disorders (e.g. hypopituitarism, hypothyroidism and hypoadrenalism) and in some haematological disorders (e.g. aplastic anaemia and some haemolytic anaemias). In addition, blood loss.

MACROCYTIC ANAEMIA

Marcocytic anaemia can be divided into megaloblastic and non-megaloblastic anaemia.

MEGALOBLASTIC ANAEMIA

Megaloblastic anaemia is characterized by the presence in the bone marrow of erythroblasts with delayed nuclear maturation because of defective DNA synthesis (megaloblasts).

Megaloblastic changes occur in:

-        Vitamin B12 deficiency or abnormal vitamin B12 metabolism

-        Folic acid deficiency or abnormal folate metabolism

-        Other defects of DNA synthesis, such as congenital enzyme deficiencies in DNA synthesis or resulting from therapy with drugs interfering with DNA synthesis

-        Myelodysplasia due to dyserythropiesis

  

Vitamin B12

Vitamin B12 is synthesized by certain microorganisms, and humans are ultimately dependent on animal sources. The average adult stores some 2-3 mg, mainly in the liver and it may take 2 years or more after absorptive failure before B12 deficiency develops.

Measurement of methylmalonic acid in urine was used as a test for vitamin B12 deficiency but it is no longer carried our routinely.

Intrinsic factor is a glycoprotein secreted by gastric parietal cells. It combines with vitamin B12 and carries it to specific receptors on the surface of the mucosa of the ileum. Vitamin B12 enters the ileal cells and intrinsic factors remains in the lumen and is excreted.  Vitamin B12 in plasma is mainly bound to TCI (90%), about 1% of an oral dose of B12 is absorbed ‘passively’ without the need for intrinsic factor.

Pernicious anaemia

The most common cause of vitamin B12 deficiency is pernicious anaemia (PA). PA is an autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in the gastric mucosa with consequent failure of intrinsic factor production and vitamin B12 malabsorption. Parietal cell antibodies are present in the serum in 90% of patients and intrinsic factors antibodies in about 50% of the patients. Two types of intrinsic factor antibodies are found:

-        blocking antibody: inhibits binding of intrinsic factor to B12

-        precipitating antibody: inhibits the binding of the B12-intrinsic factor complex to its receptor site in the ileum.

PA occurs more frequently in fair-haired, blue eyed individuals and those who have blood group A. There is association with other autoimmune diseases, particularly thyroid disease, Addison’s disease and vitiligo.

Clinical features

PA patients are sometimes said to have a lemon-yellow colour owing to a combination of pallor and mild jaundice caused by breakdown of haemoglobin. A red sore tongue (glossitis) and angular stomatitis are sometimes present.

The classical neurological features are those of a polyneuropathyprogressively involving the peripheral nerves and the posterior and eventually lateral colums of the spinal cord. Patients present with symmertrical paraesthesiae in the fingers and toes, early loss of vibration sense and proprioception, and progressive weakness and ataxia. Neurological changes, if left untreated for a long time, can be irreversible.

Dementia, psychiatric problems, hallucinations, delusions and optic atrophy may occur from vitamin B12 deficiency.

Investigation

-        Haematological finding

-        Bone marrow: typical feature of megaloblastic erythropoiesis.

-        Serum bilirubin

-        LDH (raised due to haemolysis)

-        Serum methylmalonic acid (MMA) and homocysteine (HC) à raised.

-        Serum vitamin B12

-        Serum folate level à normal or high

-        Red cell folate à normal or reduced

-        Schilling test = vit B12 absorption test.

Folic deficiency

The cause of folate deficiency are

-        Poor intake

-        Poor intake due to anorexia e.g. Crohn’s disease, coeliac disease

-        Antifolate drugs e.g. methotrexate

-        Physiological: pregnancy, lactation, prematurity

-        Pathological e.g. malignancy, inflammatory disease.

-        Malabsorption

On a deficient diet, folate deficiency develops over the course of about 4 months, but folate deficiency may develop rapidly in patients who have both poor intake and excess utilization of folate.

Clinical features; patients with folate deficiency may be asymptomatic or present with symptoms of anaemia or of the underlying cause. Glossitis can occur.

Treatment; folate deficiency van be corrected by giving 5 mg of folic acid daily; the treatment should be given for about 4 months to replace body stores. Any underlying cause should be treated. Prophylatic folic acid is recommended for all women planning a pregnancy to reduce neural tube defects.

NON-MGEALOBLASTIC ANAEMIA

A common cause of macrocytosis is pregnancy. Common pathological causes are:

-        Alcohol excess

-        Liver disease

-        Reticulocytosis

-        Hypothyroidism

-        Some haematological disorders e.g. aplastic anaemia, sideroblastic anaemia, pure red cell aplasia

-        Drugs

-        Cold agglutinins due to autoagglutination of red cells

APLASTIC ANAEMIA

Aplastic anaemia is due to reduction in the number of pluripotential stem cells together with a fault in those remaining or an immune reaction against them so that they are unable to repopulate the bone marrow. Failure of only one cell line may also occur, resulting in isolated deficiencies such as the absence of red cell precursors in pure red cell aplasia. Evolution to myelodysplasia, paroxysmal nocturnal haemoglobinuria (PNH) or acute myeloblastic leukaemia occurs in some cases.

Causes

Primary

-        Inherited e.g. Fanconi’s anaemia

-        Idiopathic acquired (67% of the cases)

Secondary

-        Chemicals

-        Drugs e.g. chemo, antibiotics

-        Insectides

-        Ionizing radiation

-        Infections e.g. hep, HIV, EBV, TBC

-        Paroxysmal nocturnal haemoglobinuria

-        Miscellaneous e.g. pregnancy

Immune mechanisms are probably responsible for most cases of idiopathic acquired aplastic anaemia. Activated cytotoxic T cells in blood and bone marrow are responsible for the bone marrow failure.

Clinical feature

Clinical manifestation of marrow failure from any cause is anaemia, bleeding and infection. Physical findings include ecchymoses, bleeding gums and epistaxis. Mouth infections are common. Lymphadenopathy and hepatosplenomegaly are rare in aplastic anaemia.

Investigation

-        Pancytopenia

-        The virtual absence of reticulocytes

-        A hypocellular or aplastic bone marrow with increased fat spaces.

Treatment

Treatment includes providing supportive care, while awaiting bone marrow recovery and specific treatment to accelerate marrow recovery. The main danger if infection and stringent measure should be undertaken to avoid this. Any suspicion of infection in a severely neutropenic patient should lead to immediate institution of broad-spectrum parenteral antibiotics. Supportive care including transfusions of red cells and platelets should be given as necessary.

Bone marrow transplantiation is the treatment of choice for patients under the age of 40 with an HLA-identical sibling donor, where it gives a 75-90% chance of long-term survival.
Immunosuppressive therapy is recommended for:

-        Patients with severe disease over the age of 40

-        Younger patients with severe disease without an HLA-identical sibling donor

-        Patients who do not have severe disease but who are transfusion- dependent.

The standard immunosuppressive treatment is antithymocyte globulin (ATG) and ciclosporin.

Acute pure red cell aplasia is associated with a thymoma in 5-15% of cases and thymectomy occasionally induces a remission.

HAEMOLYTIC ANAEMIAS

Haemolytic anaemias are caused by increased destruction of red cells. Shortening of red cells survival does not always cause anaemia as there is a compensatory increase in red cell production by the bone marrow.  In the red cell loss can be contained within the marrow’s capacity for increased output, and then an haemolytic state can exist without anaemia (compensated haemolytic disease). The bone can increase its output by six to eight times by increasing the proportion of cells committed to erythropoiesis (erythroid hyperplasia) and by expanding the volume of active marrow. In addition reticulocytes are released prematurely.

Sites of haemolysis

Extravascular haemolysis: in most conditions red cell destruction is extravascular. The red cells are removed from the circulation by macrophages in the reticuloendothelial system, particularly the spleen.

Intravascular haemolysis: when red cells are rapidly destroyed within the circulation, haemoglobin is liberated. This is initially bound to plasma haemoglobin but these soon become saturated. Excess free plasma haemoglobin is filtered by the renam glomerulus and enters the urine, although small amounts are reabsorbed by the renal tubules. In the renal tubular cell, haemoglobin is broken down and becomes deposited in the cells as haemosiderin.

INHERITED HAEMOLYTIC ANAEMIA

Causes of inherited anaemia

Red cell membrane defect

-        Hereditary spherocytosis

-        Hereditary elliptocytosis

Haemoglobulin abnormalities

-        Thalassaemia

-        Sickle cell disease

Metabolic defects

-        Glucose-6-phophate dehydrogenase deficiency

-        Pyruvate kinase deficiency

-        Pyrimidine kinase deficiency

HEREDITARY SPHEROCYTOSIS (HS)

HS is inherited in an autosomal dominant manner but in 25% of patients, neither parent is affected and it is presumed that HS has occurred by spontaneous mutation or is truly recessive. HS is due to defects in the red cell membrane, resulting in the cells losing part of the cell membrane as they pass through the spleen.

Clinical features

The condition may present with jaundice at birth, but some patients go through life symptomless. The patient may eventually develop anaemia, splenomegaly and ulcers on the leg. As in many haemolytic anaemia’s the course of the disease may be interrupted by aplastic, haemolytic and megaloblastic crises.

Investigation

-        Anaemia

-        Blood film, shows spherocytes

-        Haemolysis

-        Osmotic fragility, to confirm a suspicion of spherocytosis on a blood film.

-        Direct antiglobulin (Coombs’) test is negative in HS

Treatment

Splenectomy is indicated in HS to relieve symptoms due anaemia or splenomegaly. It is best to postpone splenectomy until after childhood, as sudden overwhelming fatal infections, usually due to encapsulated organisms such as pneumococci. Splenectomy should be preceded by appropriate immunization and followed by lifelong penicillin prophylaxis.

THALASSAEMIA

Normally, there is balanced (1:1) production of α and β chains. The defective synthesis of globin chains in thalassaemia leads to ‘imbalanced’globin chain production, leading to precipitation of globin chains within the red cell precursors and resulting in ineffective erythropoiesis.

β-Thalassaemia

In homozygous β-thalassaemia, either no normal β chains are produced or β -chain production is reduced. There is an excess of α chains, which precipitate in erythroblasts and red cells causing ineffective erythropoiesis and haemolysis. The excess α chains combine with whatever β, δ and γ chains are produced, resulting in increased quantities of HbA2 and HbF and, at best, small amounts of HbA. 

Clinical syndromes

Clinically, β-thalassaemia can be divided into the following:

-        Thalassaemia minor, the symptomless heterozygous carrier state

-        Thalassaemia intermedia, a moderate anaemia, not requiring regular transfusions

-        Thalassaemia major, severe anaemia requiring regular transfusions

Thalassaemia minor

This common carrier state is asymptomatic. Anaemia is mild or absent. The red cells are hypochromic and microcytic with a low MCV and MCH, and it may be confused with iron deficiency. The two are easily distinguished by serum ferritin and the iron stores, it is normal in thalassaemia minor. Hb electrophoresis usually shows a raised HbA2 and often a raised HbF.

Thalassaemia intermedia

Intermedia may be due to a combination of homozygous mild β+- and α-thalassaemia, where there is reduced α-chain precipitation and less ineffective erythropoiesis and haemolysis.

Patients may have splenomegaly and bone deformities. Recurrent leg ulcers, gallstones and infections are also seen. It should be noted that these patients may be iron overloaded (àdue to underlying dyserythropoiesis) despite a lack of regular blood transfusion.

Thalassaemia major (Cooley’s anaemia)

Most children affected by homozygous β-thalassaemia present during the first year of life with:

-        Failure to thrive and recurrent bacterial infections

-        Severe anaemia from 3-6 months when the switch from γ- to β-chain production should normally occur

-        Extramedullary haemopoiesis that soon leads to hepatosplenomegaly and bone expansion, giving rise to the classical thalassaemia facies

Skull X-rays in these children show the characteristic ‘hair on end’ appearance of bony trabeculation as a result of expansion of the bone marrow into cortical bone.

Management

The aims of treatment are to suppress ineffective erthropiesis, prevent bony deformaties and allow normal activity and development

-        Long-term folic acid supplements

-        Regular transfusions to keep the Hb above 100g/L.

-        If tranfusion requirements increase à splenectomy.

-        Iron overload caused by repeated transfusions may lead to damage to the endocrime glands, liver, pancrease and myocardium by the time patients reach adolescence. The standard iron-chelating agent remains desferrioxamine (parenterally, 5-7 nights each week) Ascorbic acid 200 mg daily is given, as it increased the urinary excretion of iron in response to desferrioxamine. Deferiprone, an oral iron chealtor, is being increasingly used.

-        Intensive treatment with desferrioxamine has been reported to reverse damage to the heart in patients with severe iron overload, but excessive doses of desferrioxamine may cause cataracts, retinal damage and nerve deafness. Infections with Yersinia enterocolitica occurs aswell.

-        Bone marrow transplantation

-        Prenatal diagnosis and gene therapy

-        Patient’s partnerts should be tested. If both partners have β-thalassaemia trait, there is one in four chance of such pregnancy resulting in a child having β-thalassaemia major.

α-Thalassaemia

α-Thalassaemia is often caused by gene deletions, although mutations of the α-globin genes may also occur.

-        Four-gene deletion (deletion of both genes on both chromosomes). There is no α-chain synthesis and only Hb Barts is present. Hb barts can’t carry oxygen and is incompatible with life.

-        Three-gene deletion: HbH disease, has four beta chains with low levels of HbA and Hb Barts. There is moderate anaemia and splenomegaly. The patients are not usually transfusion-dependent.

-        Two-gene deletion (α-thalassaemia trait); there is microcytosus with or without mild anaemia.

-        One-gene deletion; the blood picture is usually normal.

SICKLE SYNDROMES

Sickle cell haemoglobin (HbS) results from a single-base mutation of adenine to thymine. In the homozygous state (sickle cell anaemia), both genes are abnormal (HbSS), whereas in the heterozygous state (sickle cell trait, HbAS) only one chromosome carried the gene.

Pathogenesis

Dexoygenated HbS molecules are insoluble and polymerize. The flexibility of the cells is decreased and they become rigid and take up their characteristic sickle appearance.

This process is initially reversible with repeated sicking, the cells eventually lose their membrane flexibility and become irreversibly sickled (à dehydrated and dense). Sickling can produce:

-        A shortened red cell survival

-        Impaired passage of cells through the microcirculation, leading to obstruction of small vessels and tissue infarction.

Sickling is precipated by infection, dehydration, cold, acidos or hypoxia. HbS releases its oxygen to the tissue more easily than doesormal Hb and patients therefore feel well despite being anaemic. Depending on the type of haemoglobin chain combinations, three clinical syndromes occur:

-        Homozygous HbSS have the most severe disease

-        Combined heterozygosity (HbSC) and HbS and C who suffer intermediate symptoms

-        Heterozygous HbAS (sickle cell trait) have no symptoms

SICKLE CELL ANAEMIA

Clinical features

Vaso-occlusive crises

An early presentation may be acute pain in the hand and feet (dactylitis) owing to vaso-occlusion of the small vessels. Severe pain in other bones occurs in older/adults. Fever often accompanies the pain.

Pulmonary hypertension

Occurs in about 30-40% of patients, and is associated with increased mortality. Hyperhaemolytic paradigm (HHP) proposes that haemolysis in sickle cell disease leads to increased cell-free plasma Hb, which consumes NO, leading to a state of NO deficiency, endothelial dysfunction and a high prevalence of pulmonary hypertension.

Acute chest syndrome

This occurs in up to 30% and pulmonary hypertension and chronic lung disease are the commonest causes of death in adults with sickle cell disease. The acute chest syndrome is caused by infection, fat embolism from necrotic bone marrow or pulmonary infarction due to sequestration of sickle cells. It compromises shortness of breath, chest pain, hypoxia and new chest X-ray changes due to consolidation.

Management is with pain relief, high-flow supplemental oxygen and antibiotics (cefotaxime and clarithromycin) which should be started immediately.

Anaemia

Acute fall in the haemoglobin level van occur owing to:

-        Splenic sequestration

-        Bone marrow aplasia

-        Further haemolysis due to drugs, acute infection or associated G6PD deficiency.

Splenic sequestration

Vaso-occlusion produces an acute paintful enlargement of the spleen. There is splenic pooling of red cells and hypovolaemia, leading in some circulatory collapse and death

Bone marrow aplasia

This commonly occurs following infection with erythrovirus B19, which invades proliferating erythroid progenitors. There is a rapid fall in haemoglobin with no reticulocytes in the peripheral blood, because of the failure of erythropoiesis in the marrow.

Long-term problems

-        Growth and development: Young children are short but regain their height by adulthood. They remain below the normal weight. There is often delayed sexual maturation à hormone therapy required.B

-        Bones are a common site for vaso-occlusive episodes, leading to chronic infarcts. Avascular necrosis and osteromyelitis is common. 

-        Infections are common in tissues susceptible to vasocclusion e.g. bones, lungs, kidneys.

-        Leg ulcers occur spontaneously (vaso-occlusive episodes) or following trauma. They often become infected and are quite resistant to treatment.

-        Cardiac problems occur, with cardiomegaly, arrhythmias and iron overload cardiomyopathy.

-        Neurological complication occurs in 25% of patients, with transient ischaemic attacks, fits, cerebral infarction, cerebral haemorrhage and coma.

-        Cholelithiasis. Pigment stones occur as a result of chronic haemolysis.

-        Liver. Chronic hepatomegaly and liver dysfunction are caused by trapping of sickle cells.

-        Renal. Chronic tubulointerstitial nephritis occus.

-        Priapism. An unwanted painful erection occurs from vasoocclusion and can be recurrent. This may result in impotence. Treament: α-adrengergic blocking drug, analgesia and hydration.

-        Eye. Background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments all occur.

-        Pregnancy. Impaired placental blood flow causes spontaneous abortion, intrauterine growth retardation, preeclampsia and fetal death.

Investigations

-        Blood count

-        Blood films à hyposplenism, sickling

-        Sickle solubility test

-        Hb electrophoresis à no HbA, 80-95% HbSS and 2-20% HbF.

-        The parents of the affected child will show features of sickle cell trait.

Management

Precipitating factors should be avoided or treated quickly. Acute painful attacks require supportive therapy with intravenous fluids, and adequate analgesia. Oxygen and antibiotics are only given if specifically indicated. Crises can be extremely painful and require strong narcotic (morphine). Prophylaxis is with penicillin 500mg and vaccination. Folic acid is givrn to all patients with haemolysis.

Anaemia

Blood transfusions should only be given for clear indications. Transfusions should be given for heart failure, TIA, strokes, acute hest syndrome, acute splenic sequestration and aplastic crises.

Hydroxycarbamide is the drug widely used as therapy for sickle cell anaemia. It acts, at least in part, by increasing HbF concentrations. Inhaled NO is a new approach to the treatment of painful crises in sickle cell anaemia.

Stem cell transplantation has been used to treat sickle cell anaemia although in fewer numbers than for thalassaemia.

RED CELL METABOLISM

The mature red cell has no nucleus, mitochondria or ribosomes and is therefore unable to synthesize proteins. RBC has only limited enzyme systems. The enzyme systems responsible for producing and reducing power are:

-        The glycotic pathway, in which glucose is metabolized to pyruvate and lactic acid with production of ATP.

-        The hexose monophosphate pathway, which provides reducing power for red cell in the form of NADPH.

About 90% of glucose is metabolized by the former and 10% by the latter. The hexose monophosphate shunt maintains glutathione (GSH) in a reduced state. Glutathione is necessary to combat oxidative stress to red cell, and failure of this mechanism may result in:

-        Rigidity due to cross-linking of spectrin à decreases membrane flexibility and causes leakiness of RBC memberane.

-        Oxidation of the Hb molecule, producing methaemoglobin and precipitation of globin chains as Heinz boedies localized on the inside of the membrane.

ACQUIRED HAEMOLYTIC ANAEMIA

Acquired haemolytic anaemia may be divided into those due to immune and non-immune or other causes.

Causes of immune destruction red cells

-        Autoantibodies

-        Drug-induced antibodies

-        Alloantibodies

Causes of non-immune destruction of red cells

-        Aquired membrane defects

-        Mechanical factors e.g. prosthetic heart valves, or microangiopathic haemolytic anaemia

-        Secondary to systemic disease e.g. renal and liver disease

Miscellaneous causes

-        Various toxic substances can disrupt the RBC membrane.

-        Malaria

-        Hypersplenism

-        Extensive burns

-        Some drugs (e.g. dapsone, sulfasalazine)

-        Ingested chemicals e.g. weedkillers such as sodium chlorate

AUTOIMMUNE HAEMOLYTIC ANAEMIAS

Autoimmune haemolytic anaemias (AIHA) results from increased RBC destruction due to red cell autoantibodies. These anaemias are charcterized by the presence of a positive direct antiglobulin (Coombs’) test, which detects the autoantibody on the surface of the patient’s red cells.

AIHA is divided into ‘warm’ and ‘cold’types, depending on whether the antibody attaches better to the red cells at body temperature (37 C) or at lower temperatures. In warm AIHA, IgG antibodies predominate and the direct antiglobulin test is positive with IgG alone, IgG and complement and complement only. In cold AIHA, the antibodies are usually IgM. The easily elute off red cells, leaving complement, which is detected as C3d.

Immune destruction of red cells

IgM or IgG red cell antibodies which fully activate the complement cascade cause lysis of red cells in the circulation (intravascular haemolysis). IgG antibodies frequently do not activate complement and the coated red cells undergo extravascular haemolysis. They are either completely phagocytosed in the spleen through and interaction with Fc receptors on macrophages, or they lose part of the cell membrane through partial phagocytosis and circulate as spherocytes until they become sequestrated in the spleen.

‘Warm’ autoimmune haemolytic anaemias

Clinical feature

Frequently affects middle-aged females. They can present as a short episode of anaemia and jaundice but they often remit and relapse and may progress to an intermittent chronic pattern. The spleen is often palpable. Infections or folate deficiency may provoke a profound fail in the haemoglobin level.

Investigation

-        Haemolytic anaemia

-        Spherocytosis

-        Direct antiglobulin test = +

-        Autoantibodies may have specificity for the Rh blood group system

-        Autoimmune thrombocytopenia and/or neutropenia may also be present (Evan’s syndrome)

-        Abdominal CT à detection splenomegaly or abdominal lymphoma

Treatment

Corticosteroids are effective in inducing a remission in about 80% of patients. Splenectomy is the most effective second-line therapy. Other immunosuppressive drugs, such as azathioprine and rituximab, may be effective in patients who fail to respond to steroids and splenectomy. Blood transfusion may be necessary if there is severe anaemia although compatibility testing is complicated by the presence of red cell autoantibodies.

‘Cold’ autoimmune haemolytic anaemias

Normally low titres of IgM cold agglutinis reacting at 4°C are present in plasma and are harmless. At low temperature, therse antibodies can attach to red cells and cause their agglutination in the cold pheripheries of the body. In addition, activation of complement may cause intravascular haemolysis when the cells return to the higher temperatures in the core of the body.

HAEMOSTASIS

Haemostasis is a complex process depeding on interactions between the vessel wall, leucocytes, platelets, coagulation and fibrinolytic mechanisms.

Vessel wall

Vessel wall is lined by endothelium which, in normal conditions, prevents platelet adhesion and thrombus formation. This property is partly due to its negative charge but also to:

-        Thrombomodulin and heparin sulphate expression

-        Synthesis is prostacyclin and NO, which cause vasodilation and inhibit platelet aggregation

-        Production of plasminogen activator.

Injury to vessel causes reflex vasoconstriction, while endothelial damage results in loss of antithrombotic properties, activation of platelets and coagulation and inhibition of fibronolysis.

Platelets

Platelet adhesion. When the vessel wall is damaged, the platelets escaping come into contact with and adhere to collagen and subendothelial bound von Willebrand factor. Wihtin seconds of adhesion to the vessel wall platelets begin to undergo a shape change, form a disc to a sphere, spread along the subendothelium and release the contents of their cytoplasmic ganules.