Blood islands are formed in the yolk sac in the 3rd week of gestation and produce primitive blood cells, which migrate to the liver and spleen. After 6-7 weeks the formation moved to the bone marrow. The bone marrow is the only source of blood cells in a normal person. Pathological processes interfering with normal hemopoiesis may result in resumption of haemopoietic activity in the liver and spleen, which is referred to as extramedullary hemopoiesis.
There are two major ancestral cell lines derived from the pluripotential stem cell: lymphatic and myeloid. Lymphatic gives rise to T and B cells. The myeloid stem cell gives rise to the progenitor CFU-GEMM (colony-forming unit, granulocyte-erythrocyte-monocyte-megakaryocyte).
Haemopoietic growth factors
Haemopoietic growth factors are glycoproteins, which regulate the differentiation and proliferation of haemopoietic progenitor cells and the function of mature cells. Haemopoietic growth factors (erythropoietin, interleukin, catenin, stem cell factor, FMS tyrosine) act via their specific receptor on cell surfaces to stimulate the cytoplasmic janus kinase (JAK). This major signal transducer activates tyrosine kinase causing gene activation in the cell nucleus. Thrombopoietin (TPO) controls platelet production along with IL-6 and IL-11. Factors that inhibit the hematopoiesis process are tumour necrosis factor (TNF) and transforming growth factor beta (TGF-beta)
Many of the growth factors are produced by activated T cells, monocytes and bone marrow stromal cells (fibroblasts, endothelial cells) and macrophages.
! Stem cell plasticity: bone marrow stem cells can differentiate into other organ cell types e.g. heart, liver, nerves, bone
Evaluation of blood film
- The mean corpuscular volume (MCV) of red cells is a useful index and is used ti classify anaemia
- Reticulocyte. The reticulocyte count gives a guide to the erythroid activity in the bone marrow. An increased count is seen with increased marrow maturity (e.g. following haemorrhage or haemolysis) and during the response to treatment with a specific haematinic. A low count is the presence of anemia indicates an inappropriate response by the bone marrow and may be seen in bone marrow failure or where there is deficiency of a hematinic.
- Erythrocyte sedimentation rate (ESR) is a measure of the acute phase response.
- Plasma viscosity
- C-reactive protein (CRP) is a pentraxin, one of the proteins produced in the acute-phase response. The CRP level rises with fever and in inflammatory conditions and after trauma. Increased levels may predict future cardiovascular disease.
- The red cell distribution width
- The white cell count
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| Erythropoiesis |
Erythropoiesis
Red cell precursors pass through several stages in the bone marrow. Precursors at each stage progressively contain less RNA and more Hb in the cytoplasm. The nucleus becomes more condensed and is eventually lost from the late normoblast in the bone marrow when the cell becomes a reticulocyte.
- Reticulocytes contain residual ribosomal RNA and are still able to synthesize Hb. They remain in the marrow for about 1-2 days and are released into the circulation where they lose their RNA and become mature red cells.
- Normoblasts are not normally present in peripheral blood but are present if there is extramedullary haemopoiesis and in some marrow disorders.
- About 10% of erythroblasts die in the bone marrow during normal erythropoiesis. it is increased in some anaemias such as thalassaemia major and megaloblastic anaemia.
- Erythropoietin (EPO) is a hormone which controls erythropoiesis. It is produced in the kidneys (90%) and liver (10%)
Hemoglobin
Hemoglobin performs the main functions of red cells - carrying O2/CO2. Hemoglobin synthesis coccurs in the mitochondria of the developing red cell. Vitamin B6 is a coenzyme for the rate-limiting step of synthesis.
ANAEMIA
Anaemia is present when there is a decrease in Hb in the blood below the reference level for the age and sex of the individual. There are various types of anaemia, classified by MCV. The three major types are:
- Hypochromic microcytic with a low MCV
- Normochromic normocytic with a normal MCV
- Macrocytic with a high MCV
Symptoms (all nonspecific): fatigue, headaches, faintness, breathlessness, angina, intermittent claudication, palpitations
Signs: pallor, tachycardia, systolic flow murmur, cardiac failure
Specific signs:
- Koilonychia - spoon-shaped nails seen in longstanding iron deficiency anemia
- Jaundice - hemolytic anemia
- Bone deformities - thalassaemia major
- Leg ulcers - sickle cell disease
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| Koilonychia = indented spoon shaped nail |
MICROCYTIC ANEMIA
Iron deficiency is the most common cause of anemia in the world, affecting 30% of the worlds population. Although iron is abundant, most is in the insoluble ferric (Fe3+) form which has poor bioavailability. Ferrous (Fe2+) is more readily absorbed. The other causes of a microcytic anemia are anemia of chronic disease, sideroblastic anemia and thalassaemia. In thalassaemia there is a defect in globin synthesis, in contrast to the other three causes of microcytic anemia where the defect is in the synthesis of haem.
Iron
Dietary haem iron is more rapidly absorbed than non haem iron derived from vegetable and grain. Most haem is absorbed in the proximal intestine. The haem transporter HCP1 (haem carrier pritein 1) has been identified and found to be highly expressed in the duodenum. It is upregulated 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 the ferrous form by a brush border ferriductase. Iron stored as ferritin will be lost into the gut lumen when the mucosal cells are shed; this regulates iron balance.
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. Hepcidin 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. Therefore high levels of hepcidin via inflammatory cytokines will destroy ferroportin and limit iron absorption, and low levels of hepcidin will encourage iron absorption.
Hereditary haemochromatosis; deficiency of hepcidin would lead to less ferroportin being bound --> more iron will be released into plasma.
Beta-thalassaemia; downregulation of hepcidin and upregulation of ferroportin.
About two third of the total body iron is in the circulation as hemoglobin. Iron is stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells. About two-third of this is stored as ferritin and one-third as haemosiderin in normal idividuals.
Hereditary haemochromatosis; deficiency of hepcidin would lead to less ferroportin being bound --> more iron will be released into plasma.
Beta-thalassaemia; downregulation of hepcidin and upregulation of ferroportin.
About two third of the total body iron is in the circulation as hemoglobin. Iron is stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells. About two-third of this is stored as ferritin and one-third as haemosiderin in normal idividuals.
- Ferritin is a water-soluble complex of iron and protein.
- Hemosiderin is an insoluble iron-protein complex found in macrophages in the bone marrow, liver and spleen.
Iron deficiency
Iron deficiency anemia is caused by:
- Blood loss
- Increased demands such as growth and pregnancy
- Decreased absorption (post-gasterectomy)
- Poor intake.
A common cause of iron deficiency worldwide is blood loss from the GI resulting from parasites such as hookworm infestation.
Clinical features (longstanding anemia)
Clinical features (longstanding anemia)
- Brittle nails
- Spoon-shaped nails (Koilonychia)
- Atrophy of the papillae of the tongue
- Angular stomatitis
- Brittle hair
- A syndrome of dysphagia and glossitis (Plummer-Vinson or Paterson-Brown-Kelly syndrome)
Differential diagnosis
The presence of anaemia with microctyosis (MCV<80fL) and hypochromia does not necessarily indicate iron deficiency. The most common other causes are thalassaemia, sideroblastic anaemia and anemia 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. Oral iron is all that is required in most cases. The best preparation is ferrous sulphate - 200mg 3x day. The commenest causes of failure to respond to oral iron are:
- Lack of compliance.
- Continuing hemorrhage
- Incorrect diagnosis e.g. thalassaemia trait
Parenteral iron can be given by slow intravenous infusion of low-molecular-weight iron dextran, iron sucrose, ferric carboxymaltose, iron isomaltoside 1000.
Anemia of chronic disease
One of the most common types of anaemia occuring in patients with chronic infections such as tuberculosis, chronic inflammatory disease such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyalgia rheumatica and malignant disease. There is decreased release of iron from the bone marrow to developing erythroblasts and inadequate eythropoietin response to the anaemia, and decreased red cell survival.
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. 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 in Perls' reaction. A structural defect in ALA synthase, the pyridoxine dependent enzyme responsible for the first step in haem synthesis has been identified in one form of inherited sideroblastic anaemia. Sideroblastic anaemias can be inherited as an X-linked disease transmitted by females. Acquired causes include myelodysplasia, myeloproliferative disorders, myeloid leukemia, drugs, alcohol misuse and lead toxicity.
Treatment
Some patients respond when drugs or alcohol are withdrawn. In occasional cases there is response to pyridoxine. Treatment with folic acid may be required to treat accompanying folate deficiency.
NORMOCYTIC ANAEMIA
Normocytic, normochromic anaemia is seen in anaemia of chronic disease in some endocrine disorders and in some haematological disorders. In addition this type of anaemia is seen acutely following blood loss.
MACROCYTIC ANAEMIAS
Megablastic anaemia
Megablastic anaemia is characterized by the presence in the bone marrow of erythroblasts with delayed nuclear maturation because of defective DNA synthesis (megablasts). Megablasts are large and have large immature nuclei. Megaloblastic changes occur in:
Hereditary haemorrhagic telangiectasia is a rare disorder with autosomal dominant inheritance. Mutations occur in genes that encode components of the TGF-beta signaling pathway that is involved in blood vessel development. Dilation of capillaries and small arterioles produces characteristic small red spots that blanch on pressure in the skin and mucous membranes.
Easy bruising syndrome is a common benign disorder occurring in otherwise healthy women. It is characterized by bruises on the arms, legs, trunk with minor trauma, possibly because of skin vessel fragility.
Senile purpura and purpura due to steroids are both due to atrophy of vascular supporting tissue.
Henoch-Schonlein purpura is a type III hypersensitivity (immune complex) reaction that is often preceded by an acute upper respiratory tract infection
PLATELET DISORDERS
Thrombocytopenia
Thrombocytopenia is caused by reduced platelet production in the bone marrow, excessive peripheral destruction of platelets or sequestration in an enlarged spleen. Specific tests may be useful to confirm the presence of conditions such as paroxysmal nocturnal haemoglobinuria (PNH) or systemic lupus erythematous (SLE). Treating underlying disease is enough by high risk bleeding platelet transfusion is indicated.
Immune thrombocytopenia Purpura
Thrombocytopenia is due to immune destruction of platelets. The antibodies found have specificity for platelet membrane glycoprotein IIb/IIA and/or Ib.
ITP in children occurs most commonly in age group 2-6 years. IPS has an acute onset with mucocutaneous bleeding and there may be a history of recent viral infection, including varicella zoster or measles.
ITP in adults. The presentation is usually less acute than in children. ITP is characteristically seen in women and maybe associated with other autoimmune disorders such as SLE, thyroid disease and autoimmune haemolytic anaemia (Evans' syndrome). It is also seen in CLL and HIV.
Clinical features. Easy bruising, purpura, epistaxis and menorrhagia are common. Physical examination is normal except for evidence of bleeding
Investigation. The only count abnormalities is thrombocytopenia. Normal or increased numbers of megakaryocytes are found in bone marrow.
Treatment
Children usually don't require treatment. Where this is necessary, corticosteroids, intravenous immunoglobulin and anti-D are effective.
Adults with platelets count >30x10^9/L generally require no treatment unless they are about to undergo a surgical procedure. First-line therapy consists of oral corticosteroids. Intravenous immunoglobulin is effective. Second-line therapy involves splenectomy, to which the majority of patients respond. Third-line therapy includes high dose corticosteroid, intravenous immunoglobulin, anti-D, vinca alkaloids, danazol, immunosuppressive agents, combination chemotherapy and mycophenolate mofetil.
Thrombotic thrombocytopenia purpura (TTP)
TTP arises due to endothelial damage and microvascular thrombosis. This occurs due to a reduction in ADAMTS-13 a protease which is normally responsible for regulating the size of von Willebrand factor (vWF) Reduction in ADAMTS-13 results in multiorgan microthrombi. In congenital cases the the deficiency is due to mutations in the ADAMTS-13 gene. Secondary causes of acute TTP include pregnancy, oral contraceptives, SLE, infection and drug treatment.
Treatment consists of plasma exchange, it provides a source of ADAMTS-13. Pulsed intravenous methylprednisolone is given acutely as is increasingly rituximab as a primary treatment of choice. Disease activity is monitored by measuring the platelet count and serum LDH.
Platelet function disorders
Platelet function disorders are usually associated with excessive bruising and bleeding and in some of the acquired forms, with thrombosis. The platelet count is normal or increased and the bleeding time is prolonged.
Thrombocytosis
The platelet count may rise above 400x10^9/L as a result of:
Essential thrombocythaemia. Myeloproliferative disorder and other myeloproliferative conditions such as polythemia vera (PV), myelofibrosis and chronic myeloid leukaemia (CML) may also be associated with high platelet count.
A persistently elevated platelet count can lead to arterial or venous thrombosis
INHERITED COAGULATION DISORDERS
Haemophilia A is due to a lack of factor VIII. It is inherited as an X-linked disorder. Bleeding is treated by administration of factor VIII concentrate by intravenous infusion to achieve normalization of levels. Factor VIII has a half-life of 12h and therefore must be administered at least twice a daily. Complications. Up to 30% of people with severe haemophilia will, during their lifetime, develop antibodies to factor VIII that inhibit its action. Such inhibitors usually develop after the first few treatment doses of factor VIII. Recombinant factor VIIa at very high 'pharmacological' levels can bypass factor IX/VIII activity and is an effective treatment in more than 80% of bleeding episodes in patients with high levels of inhibitor antibodies. The long-term aim of management is to eradicate the inhibitory antibody. This is done using immune tolerance induction strategies, sometimes using additional immunosuppression and immunoabsorption.
Haemophilia B (Christmas disease)
Haemiphilia B is caused by a deficiency of factor IX. The inheritance and clinical features are identical to haemophilia A. It is treated with factor IX concentrate and prophylactic doses given twice a day.
Von Willebrand's Disease (VWD)
In WVD there is defective platelets function as well as factor VIII deficiency and both are due to a deficiency or abnormality of vWF. vWF plays a role in platelet adhesion to damaged subendothelium as well as stabilizing factor VIII in plasma.
ACQUIRED COAGULATION DISORDERS
Vitamin K deficiency
Vitamin K is necessary for carboxylation of glutamic acid residues on coagulation factors II, VII, IX, X and on proteins C and S. Without it these factors cannot bind calcium.
Deficiency of vitamin K may be due to:
Liver disease
Liver disease may result in a number of defects in haemostasis:
The presence of anaemia with microctyosis (MCV<80fL) and hypochromia does not necessarily indicate iron deficiency. The most common other causes are thalassaemia, sideroblastic anaemia and anemia 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. Oral iron is all that is required in most cases. The best preparation is ferrous sulphate - 200mg 3x day. The commenest causes of failure to respond to oral iron are:
- Lack of compliance.
- Continuing hemorrhage
- Incorrect diagnosis e.g. thalassaemia trait
Parenteral iron can be given by slow intravenous infusion of low-molecular-weight iron dextran, iron sucrose, ferric carboxymaltose, iron isomaltoside 1000.
Anemia of chronic disease
One of the most common types of anaemia occuring in patients with chronic infections such as tuberculosis, chronic inflammatory disease such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyalgia rheumatica and malignant disease. There is decreased release of iron from the bone marrow to developing erythroblasts and inadequate eythropoietin response to the anaemia, and decreased red cell survival.
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. 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 in Perls' reaction. A structural defect in ALA synthase, the pyridoxine dependent enzyme responsible for the first step in haem synthesis has been identified in one form of inherited sideroblastic anaemia. Sideroblastic anaemias can be inherited as an X-linked disease transmitted by females. Acquired causes include myelodysplasia, myeloproliferative disorders, myeloid leukemia, drugs, alcohol misuse and lead toxicity.
Treatment
Some patients respond when drugs or alcohol are withdrawn. In occasional cases there is response to pyridoxine. Treatment with folic acid may be required to treat accompanying folate deficiency.
NORMOCYTIC ANAEMIA
Normocytic, normochromic anaemia is seen in anaemia of chronic disease in some endocrine disorders and in some haematological disorders. In addition this type of anaemia is seen acutely following blood loss.
MACROCYTIC ANAEMIAS
Megablastic anaemia
Megablastic anaemia is characterized by the presence in the bone marrow of erythroblasts with delayed nuclear maturation because of defective DNA synthesis (megablasts). Megablasts are large and have large immature nuclei. Megaloblastic changes occur in:
- Vitamin B12 deficiency and abnormal vitamin B12 metabolism
- Folic acid deficiency or abnormal folate metabolism
- Defects of DNA synthesis
- Myelodysplasia due to dyserythropoiesis
Haematological findings
- Anaemia may be present. The MCV is characteristically >96 fL.
- If severe, there may be leucopenia and thrombocytopenia
Biochemical basis of megaloblastic anaemia
The key biochemical problem common to both vitamin B12 and folate deficiency is block in DNA synthesis owing to an inability to methylate deoxyuridine monophosphate to deoxythymidine monophosphate, which is then used to build DNA. The methyl group is supplied by the folate coenzyme, methylene tetrahydrofolate (Methylene FH4).
Deficiency of folate reduces the supply of methylene FH4; deficiency of vitamin B12 also reduces its supply by slowing demethylation of methyltetrahydrofolate (methyl FH4) and preventing cells receiving FH4 for synthesis of methylene tetrahydrofolaye polyglutamate.
Other congential and acquired forms of megaloblastic anaemia are due to interference with purine or pyrimidine synthesis causing an inhibition in DNA synthesis.
Vitamin B12
Vitamin B12 is synthesized by certain microorganisms and humans are dependent on animal sources. It is found in meat, fish, eggs and milk. An adults has storage of vit B12 in the liver. It takes about 2 years or more after absorptive failure before B12 deficiency develops.
The main function of B12 is the methylation of homocysteins to methionine with the demthylation of methyl FH4 to FH4.
Absorption and transport
Vitamin B12 is liberated from protein complexes in food by gastric enzymes and then binds to a vitamin B12 binding proteins (R binder). VitB12 is released from R binder by pancreatic enzyme and then becomes bound to intrinsic factor. Intrinsic factor is a glycoprotein secreted by gastric parietal cells along with H+. Intrinsic factor combines with vitB12 and carries it to specific receptors on the surface of the mucosa of the ileum. VitB12 enters the ileal cells and intrinsic factor remains in the lumen and is excreted.
Pernicious anaemia
Pernicious anaemia (PA) is an autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in the gastric mucosa with the consequent failure of intrinsic factor production and vit B12 malabsorption.
Clinical features
The onset of PA is insidious with progressively increasing symptoms of anaemia. Patients are sometimes said to have a lemon-yellow colour owing to a combination of pallor and mild jaundice caused by excess breakdown of hemoglobin. A red sote tongue (glossitis and angular stomatitis are sometimes present.
The classical neurological features are those of a polyneuropathy progressively involving the peripheral nerves and columns of the spinal cord. Patients present with symmetrical paraesthesiae in the fingers and toes, early loss of vibration sense and proprioception and progressive weakness and ataxia. The neurological changes, if left untreated for a long time, can be irreversible. Paraplegia may result. Dementia, psychiatric problems, hallucinations, delusions and optic atrophy may occur from vitB12 deficiency.
APLASTIC ANEMIA
Aplastic anaemia is defined as pancytopenia with hypocellularity (aplasia) of the bone marrow; there are no leukaemic, cancerous or other abnormal cells in the peripheral blood or bone marrow. Aplastic anaemia is due to a 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.
Causes
Immune mechanisms are probably responsible for most cases of idiopathic acquired aplastic anaemia and play a part in at least persistance of many secondary cases. Activated cytotoxic T cells in blood and bone marrow are responsible for the bone marrow failure. Many cytotoxic drugs may cause marrow aplasia, however some individuals develop aplasia due to sensitivity to non-cytotoxic drugs such as gold, ribavirin, chlorpromazine.
Fanconi's anaemia is inherited as an autosomal recessive and is associated with skeletal, skin, eye, renal and CNS abnormalities.
Clinical features
Clinical features manifestations of marrow failure from any cause are anemia, bleeding and infection. Bleeding is often the predominant initial presentation of aplastic anaemia with bruising with minimal trauma or blood blisters in the mouth. Physical findings include ecchymoses, bleeding gums and epistaxis.
Investigation
VASCULAR DISORDERSThe key biochemical problem common to both vitamin B12 and folate deficiency is block in DNA synthesis owing to an inability to methylate deoxyuridine monophosphate to deoxythymidine monophosphate, which is then used to build DNA. The methyl group is supplied by the folate coenzyme, methylene tetrahydrofolate (Methylene FH4).
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| Role of vitamin B12 and folate in DNA synthesis |
Other congential and acquired forms of megaloblastic anaemia are due to interference with purine or pyrimidine synthesis causing an inhibition in DNA synthesis.
Vitamin B12
Vitamin B12 is synthesized by certain microorganisms and humans are dependent on animal sources. It is found in meat, fish, eggs and milk. An adults has storage of vit B12 in the liver. It takes about 2 years or more after absorptive failure before B12 deficiency develops.
The main function of B12 is the methylation of homocysteins to methionine with the demthylation of methyl FH4 to FH4.
Absorption and transport
Vitamin B12 is liberated from protein complexes in food by gastric enzymes and then binds to a vitamin B12 binding proteins (R binder). VitB12 is released from R binder by pancreatic enzyme and then becomes bound to intrinsic factor. Intrinsic factor is a glycoprotein secreted by gastric parietal cells along with H+. Intrinsic factor combines with vitB12 and carries it to specific receptors on the surface of the mucosa of the ileum. VitB12 enters the ileal cells and intrinsic factor remains in the lumen and is excreted.
Pernicious anaemia
Pernicious anaemia (PA) is an autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in the gastric mucosa with the consequent failure of intrinsic factor production and vit B12 malabsorption.
Clinical features
The onset of PA is insidious with progressively increasing symptoms of anaemia. Patients are sometimes said to have a lemon-yellow colour owing to a combination of pallor and mild jaundice caused by excess breakdown of hemoglobin. A red sote tongue (glossitis and angular stomatitis are sometimes present.
The classical neurological features are those of a polyneuropathy progressively involving the peripheral nerves and columns of the spinal cord. Patients present with symmetrical paraesthesiae in the fingers and toes, early loss of vibration sense and proprioception and progressive weakness and ataxia. The neurological changes, if left untreated for a long time, can be irreversible. Paraplegia may result. Dementia, psychiatric problems, hallucinations, delusions and optic atrophy may occur from vitB12 deficiency.
APLASTIC ANEMIA
Aplastic anaemia is defined as pancytopenia with hypocellularity (aplasia) of the bone marrow; there are no leukaemic, cancerous or other abnormal cells in the peripheral blood or bone marrow. Aplastic anaemia is due to a 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.
Causes
Immune mechanisms are probably responsible for most cases of idiopathic acquired aplastic anaemia and play a part in at least persistance of many secondary cases. Activated cytotoxic T cells in blood and bone marrow are responsible for the bone marrow failure. Many cytotoxic drugs may cause marrow aplasia, however some individuals develop aplasia due to sensitivity to non-cytotoxic drugs such as gold, ribavirin, chlorpromazine.
Fanconi's anaemia is inherited as an autosomal recessive and is associated with skeletal, skin, eye, renal and CNS abnormalities.
Clinical features
Clinical features manifestations of marrow failure from any cause are anemia, bleeding and infection. Bleeding is often the predominant initial presentation of aplastic anaemia with bruising with minimal trauma or blood blisters in the mouth. Physical findings include ecchymoses, bleeding gums and epistaxis.
Investigation
- Pancytopenia
- The virtual absence of reticulocytes
- A hypocellular or aplastic bone marrow with increased fat spaces
Treatment and prognosis
The treatment of aplastic anaemia depends on providing supportive care while awaiting bone marrow recovery and specific treatment to accelerate marrow recovery. Supportive care includes broad spectrum antibiotic, transfusions of red cells/platelets.
Bone marrow transplatation is the treament of choice for patients under the age 40 with HLA identical sibling donor.
Immunosuppresive therapy (antithymocyte globulin & ciclosporin) is recommend for:
Immunosuppresive therapy (antithymocyte globulin & ciclosporin) is recommend for:
- Patients with severe disease over the age 14
- Younger patients with severe disease without an HLA identical sibling donor
- Patients who are transfusion dependent
Adult pure red cell aplasia is associated with a thymoma in 5-15% of cases and thymectomy occasionaly induces a remission.
HAEMOLYTIC ANEMIAS
Haemolytic anaemias are caused by increased destruction of red cells. The red cell normally survives about 120 days. Shortening of red cell survival does not always cause anaemia as there is a compensatory increase in red cell production by the bone marrow. If the red cell loss can be contained within the marrow's capacity for increased output, then a haemolytic state can exist without anaemia. The bone marrow can increase its output by 6-8x by increasing the proportion of cells committed to erythropoiesis - erythroid hyperplasia. In addition immature red cells (reticulocytes) are released prematurely.
INHERITED HAEMOLYTIC ANAEMIA
How Hereditary Spherocytosis Causes Anemia door mednotez
Hereditary spherocytosis (HS)
HS is the most common inherited haemolytic anaemia in northern europeans, affecting 1 in 5000. It is inherited in a autosomal dominant matter. 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
- Jaundice
- Anaemia
- Splenomegaly
- Ulcers on the leg
- Pigment gallstones
Investigation
- Anaemia
- Blood film shows spherocytes and reticulocytes
- Raised serum bilirubin and urinary urobilinogen
- Osmotic fragility
- Coombs' test
Treatment
Splenectomy is indicated in hereditary spherocytosis to relieve symptoms due to anaemia or splenomegaly, reverse growth failure and prevent recurrent gallstones. Splenectomy should be preceded by appropriate immunization and followed by lifelong penicillin prophylaxis. In addition there is also some evidence that there us a significant risk of adverse arterial and venous thromboembolic events after splenectomy performed for hereditary spherocytosis.
Hereditary elliptocytosis
This disorder of the red cell membrane is inherited in an autosomal dominant manner and has a prevalence of 1 in 2500 caucasians. The red cells are elliptical due to deficiencies of protein 4.1 or the spectrin/actin/4.1 complex which leads to weakness of the horizontal protein interation and to the membrane defect. Only a minority of patients have anaemia and on;y occasional patients require splenectomy.
Hereditary stomatocytosis
Stomatocytes are red cells in which the pale central area appears slik-like. Their presence in large numbers may occur in a hereditary haemolytic anaemia associated with a membrane defect, but excess alcohol intake is also a common cause. Splenectomy is contradicted as it may result in fatal thromboembolic events.
β-Thalassemia
In homozygous β-thalassemia either no normal β chains are produced or β-chain production is very reduced. There is an excess of alpha chains, which precipitate in erythroblasts and red cells causing ineffective erythropoiesis and haemolysis. In heterozygous β-thalassaemia there is usually symptom less microcytosis with or without mild anaemia.
Clinical syndromes
Clinically β thalassaemias can be divided into the following:
- Thalassaemia minor (or trait) the symptomless heterzygous carrier state
- Thalassaemia intermedia, a moderate anaemia, not requiring regular transfusion
- Thalassaemia major, severe anaemia requiring regular transfusion
Thalassaemia minor (trait)
Anaemia is mild or absent. The red cells are hypochromic and microcytic with a low MCV and MCH, and it maybe confused with iron deficiency but easily distinguished as in thalassaemia trait the serum ferritin and the iron stores are normal.
Thalassaemia intermedia
Patients may have splenomegaly and bone deformaties. Recurrent leg ulcers, gallstones and infections are also seem\n.
Thalassaemia major (Cooley's anaemia)
Presentation:
- Failure to thrive and recurrent bacterial infection
- Severe anaemia from 3-6 months when the switch from gamma to β chain production should normally occur
- Extramedullary haemopoiesis that soom leads to hepatosplenomegaly and bone expansion giving rise to the classical thalassaemic facies
Skull X-rays in these children show the characteristic "hair on end" appearance as a result of expansion of bone marrow into cortical bone. The expansion of the bone marrow is also shown in an X-ray if the hand.
Management:
The aims of the treament are ti suppress ineffective erythopoiesis, prevent bone deformaties and allow normal activity and development.
- Long-term folic acid supplement
- Regular transfusion
- Splenectomy is transfusion requirement increase
- Monitoring of iron overload due to transfusion and using iron-chelating agents (desferrioxamine) as necessary.
- Bone marrow transplantation (HLA matched sibling)
- Prenatal gene therapy
α-Thalassaemia
Sickle cell anemia door mednotez
Sickle syndromes
Sickle cell haemoglobulin (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 heterzygous state (sickle cell trait, HbAS) only one chromosome carries the gene. 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 precipitated by infection, dehydration, cold, acidosis or hypoxia.
Sickle cell anaemia
Vaso-occlusive crises
An early presentation may be acute pain in the hands and feet (dactylitis) owing to vaso-occulusion of the small vessels. Severe pain in other bones occurs in older children/adults. Fever often accompanies the pain.
Pulmonary hypertension
Pulmonary hypertension occurs in 30-40% of sickle cell anaemia patient.
Hyperhaemolytic paradigm (HHP): 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
The acute chest syndrome is caused by infection, fat embolism from necrotic bone marrow or pulmonary infarction due to sequestration of sickle cells. It comprises shortness of breath, chest pain, hypoxia and new chest X-ray change due to consolidation
Anaemia
Chronic haemolysis produces a stable haemoglobin level but an acute fall can occur owing to:
- Splenic sequestration
- Bone marrow aplasia
- Further haemolysis due to drugs, acute infection or associated G6PD deficiency
Splenic sequestration
Vaso-occulusion produces an acute painful enlargement of the spleen. There is splenic pooling of red cells and hypovolaemia, leading in some to circulatory collapse and death. The latter eventually leads to a fibrotic nonfunctioning spleen.
Bone marrow aplasia
This most commonly occurs following an infection with erythrovirus B19, which invades proliferating erythroid progenitors.
Long-term problems
Investigations
- Blood count. The level of Hb is in 60-80 g/L with a high reticulocyte count (10-20%)
- Blood films - hyposplenism and sickling
- Sickle solubility test
- Hb electrophoresis
Management
Acute painful attacks require supportive therapy with intravenous fluids and adequate analgesia. O2 and antibiotics are only given in specifically indicated. Crises require strong narcotic analgesia. Morphine is the drug of choice.
Prophylaxis with penicillin 500MG daily and vaccination with polyvalent pneumococcal and haemophilus influenzae type B vaccine. Folic acid is given to all patients with haemolysis.
Hydrocycarbamide (hydroxyurea) is the first drug which has been widely used as therapy for sickle cell anaemia. It acts by increasing HbF concentration.
INHERITED HAEMOLYTIC ANAEMIA
How Hereditary Spherocytosis Causes Anemia door mednotez
Hereditary spherocytosis (HS)
HS is the most common inherited haemolytic anaemia in northern europeans, affecting 1 in 5000. It is inherited in a autosomal dominant matter. 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
- Jaundice
- Anaemia
- Splenomegaly
- Ulcers on the leg
- Pigment gallstones
Investigation
- Anaemia
- Blood film shows spherocytes and reticulocytes
- Raised serum bilirubin and urinary urobilinogen
- Osmotic fragility
- Coombs' test
Treatment
Splenectomy is indicated in hereditary spherocytosis to relieve symptoms due to anaemia or splenomegaly, reverse growth failure and prevent recurrent gallstones. Splenectomy should be preceded by appropriate immunization and followed by lifelong penicillin prophylaxis. In addition there is also some evidence that there us a significant risk of adverse arterial and venous thromboembolic events after splenectomy performed for hereditary spherocytosis.
Hereditary elliptocytosis
This disorder of the red cell membrane is inherited in an autosomal dominant manner and has a prevalence of 1 in 2500 caucasians. The red cells are elliptical due to deficiencies of protein 4.1 or the spectrin/actin/4.1 complex which leads to weakness of the horizontal protein interation and to the membrane defect. Only a minority of patients have anaemia and on;y occasional patients require splenectomy.
Hereditary stomatocytosis
Stomatocytes are red cells in which the pale central area appears slik-like. Their presence in large numbers may occur in a hereditary haemolytic anaemia associated with a membrane defect, but excess alcohol intake is also a common cause. Splenectomy is contradicted as it may result in fatal thromboembolic events.
β-Thalassemia
In homozygous β-thalassemia either no normal β chains are produced or β-chain production is very reduced. There is an excess of alpha chains, which precipitate in erythroblasts and red cells causing ineffective erythropoiesis and haemolysis. In heterozygous β-thalassaemia there is usually symptom less microcytosis with or without mild anaemia.
Clinical syndromes
Clinically β thalassaemias can be divided into the following:
- Thalassaemia minor (or trait) the symptomless heterzygous carrier state
- Thalassaemia intermedia, a moderate anaemia, not requiring regular transfusion
- Thalassaemia major, severe anaemia requiring regular transfusion
Thalassaemia minor (trait)
Anaemia is mild or absent. The red cells are hypochromic and microcytic with a low MCV and MCH, and it maybe confused with iron deficiency but easily distinguished as in thalassaemia trait the serum ferritin and the iron stores are normal.
Thalassaemia intermedia
Patients may have splenomegaly and bone deformaties. Recurrent leg ulcers, gallstones and infections are also seem\n.
Thalassaemia major (Cooley's anaemia)
Presentation:
- Failure to thrive and recurrent bacterial infection
- Severe anaemia from 3-6 months when the switch from gamma to β chain production should normally occur
- Extramedullary haemopoiesis that soom leads to hepatosplenomegaly and bone expansion giving rise to the classical thalassaemic facies
Skull X-rays in these children show the characteristic "hair on end" appearance as a result of expansion of bone marrow into cortical bone. The expansion of the bone marrow is also shown in an X-ray if the hand.
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| "Hair on end" |
The aims of the treament are ti suppress ineffective erythopoiesis, prevent bone deformaties and allow normal activity and development.
- Long-term folic acid supplement
- Regular transfusion
- Splenectomy is transfusion requirement increase
- Monitoring of iron overload due to transfusion and using iron-chelating agents (desferrioxamine) as necessary.
- Bone marrow transplantation (HLA matched sibling)
- Prenatal gene therapy
α-Thalassaemia
- Four-gene deletion: there is no α-chain synthesis and only Hb-Barts is present. Hb barts cannot carry oxygen and incompatible with life. Infants are either stillborn at 28-40 weeks or die very shortly after birth. They are pale, oedamatous and have enormous liver and spleen - hydrops fetails.
- 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 microcytosis with or without mild anaemia
- One-gene deletion; the blood picture is usually normal
Sickle cell anemia door mednotez
Sickle syndromes
Sickle cell haemoglobulin (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 heterzygous state (sickle cell trait, HbAS) only one chromosome carries the gene. 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 precipitated by infection, dehydration, cold, acidosis or hypoxia.
Sickle cell anaemia
Vaso-occlusive crises
An early presentation may be acute pain in the hands and feet (dactylitis) owing to vaso-occulusion of the small vessels. Severe pain in other bones occurs in older children/adults. Fever often accompanies the pain.
Pulmonary hypertension
Pulmonary hypertension occurs in 30-40% of sickle cell anaemia patient.
Hyperhaemolytic paradigm (HHP): 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
The acute chest syndrome is caused by infection, fat embolism from necrotic bone marrow or pulmonary infarction due to sequestration of sickle cells. It comprises shortness of breath, chest pain, hypoxia and new chest X-ray change due to consolidation
Anaemia
Chronic haemolysis produces a stable haemoglobin level but an acute fall can occur owing to:
- Splenic sequestration
- Bone marrow aplasia
- Further haemolysis due to drugs, acute infection or associated G6PD deficiency
Splenic sequestration
Vaso-occulusion produces an acute painful enlargement of the spleen. There is splenic pooling of red cells and hypovolaemia, leading in some to circulatory collapse and death. The latter eventually leads to a fibrotic nonfunctioning spleen.
Bone marrow aplasia
This most commonly occurs following an infection with erythrovirus B19, which invades proliferating erythroid progenitors.
Long-term problems
- Growth and development. Patients remain below the normal height. There is often delayed sexsual maturation - hormone therapy.
- Bones are a common site for vaso-occlusive episodes, leading to chronic infarcts. Avascular necrosis of the hipes, shoulder, hands, feet occur. Osteomyelitis is common, caused by S.aureus, S. pneumoniae and salmonella.
- Infections
- Leg ulcers
- Cardiac problems - cardiomegaly, arrhythmias, iron overload cardiomyopathy
- Neurological complications - transient ischemic attacks, fits, cerebral infarction, cerebral haemorrhage and coma
- Cholelithiasis - pigment stones
- Liver - hepatomegaly, liver dyfunction caused by trapping of sickle cells
- Renal - chronic tubulointerstitial nephritis
- Priapism, treatment is with an alpha-adrenergic blocking drug, analgesia and hydration.
- Eye - retinopathy, vitreous hemorrhage and retinal detachment.
- Pregnancy. Impaired placental blood flow causes spontaneous abortion, intrauterine growth retardation, pre-eclampsia and fetal death.
Investigations
- Blood count. The level of Hb is in 60-80 g/L with a high reticulocyte count (10-20%)
- Blood films - hyposplenism and sickling
- Sickle solubility test
- Hb electrophoresis
Management
Acute painful attacks require supportive therapy with intravenous fluids and adequate analgesia. O2 and antibiotics are only given in specifically indicated. Crises require strong narcotic analgesia. Morphine is the drug of choice.
Prophylaxis with penicillin 500MG daily and vaccination with polyvalent pneumococcal and haemophilus influenzae type B vaccine. Folic acid is given to all patients with haemolysis.
Hydrocycarbamide (hydroxyurea) is the first drug which has been widely used as therapy for sickle cell anaemia. It acts by increasing HbF concentration.
Hereditary haemorrhagic telangiectasia is a rare disorder with autosomal dominant inheritance. Mutations occur in genes that encode components of the TGF-beta signaling pathway that is involved in blood vessel development. Dilation of capillaries and small arterioles produces characteristic small red spots that blanch on pressure in the skin and mucous membranes.
Easy bruising syndrome is a common benign disorder occurring in otherwise healthy women. It is characterized by bruises on the arms, legs, trunk with minor trauma, possibly because of skin vessel fragility.
Senile purpura and purpura due to steroids are both due to atrophy of vascular supporting tissue.
Henoch-Schonlein purpura is a type III hypersensitivity (immune complex) reaction that is often preceded by an acute upper respiratory tract infection
PLATELET DISORDERS
Thrombocytopenia
Thrombocytopenia is caused by reduced platelet production in the bone marrow, excessive peripheral destruction of platelets or sequestration in an enlarged spleen. Specific tests may be useful to confirm the presence of conditions such as paroxysmal nocturnal haemoglobinuria (PNH) or systemic lupus erythematous (SLE). Treating underlying disease is enough by high risk bleeding platelet transfusion is indicated.
Immune thrombocytopenia Purpura
Thrombocytopenia is due to immune destruction of platelets. The antibodies found have specificity for platelet membrane glycoprotein IIb/IIA and/or Ib.
ITP in children occurs most commonly in age group 2-6 years. IPS has an acute onset with mucocutaneous bleeding and there may be a history of recent viral infection, including varicella zoster or measles.
ITP in adults. The presentation is usually less acute than in children. ITP is characteristically seen in women and maybe associated with other autoimmune disorders such as SLE, thyroid disease and autoimmune haemolytic anaemia (Evans' syndrome). It is also seen in CLL and HIV.
Clinical features. Easy bruising, purpura, epistaxis and menorrhagia are common. Physical examination is normal except for evidence of bleeding
Investigation. The only count abnormalities is thrombocytopenia. Normal or increased numbers of megakaryocytes are found in bone marrow.
Treatment
Children usually don't require treatment. Where this is necessary, corticosteroids, intravenous immunoglobulin and anti-D are effective.
Adults with platelets count >30x10^9/L generally require no treatment unless they are about to undergo a surgical procedure. First-line therapy consists of oral corticosteroids. Intravenous immunoglobulin is effective. Second-line therapy involves splenectomy, to which the majority of patients respond. Third-line therapy includes high dose corticosteroid, intravenous immunoglobulin, anti-D, vinca alkaloids, danazol, immunosuppressive agents, combination chemotherapy and mycophenolate mofetil.
Thrombotic thrombocytopenia purpura (TTP)
TTP arises due to endothelial damage and microvascular thrombosis. This occurs due to a reduction in ADAMTS-13 a protease which is normally responsible for regulating the size of von Willebrand factor (vWF) Reduction in ADAMTS-13 results in multiorgan microthrombi. In congenital cases the the deficiency is due to mutations in the ADAMTS-13 gene. Secondary causes of acute TTP include pregnancy, oral contraceptives, SLE, infection and drug treatment.
Treatment consists of plasma exchange, it provides a source of ADAMTS-13. Pulsed intravenous methylprednisolone is given acutely as is increasingly rituximab as a primary treatment of choice. Disease activity is monitored by measuring the platelet count and serum LDH.
Platelet function disorders
Platelet function disorders are usually associated with excessive bruising and bleeding and in some of the acquired forms, with thrombosis. The platelet count is normal or increased and the bleeding time is prolonged.
Thrombocytosis
The platelet count may rise above 400x10^9/L as a result of:
- Splenectomy
- Malignant disease
- Inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease
- Major surgery and post haemorrhage
- Myeloproliferative disorders
- Iron deficiency
Essential thrombocythaemia. Myeloproliferative disorder and other myeloproliferative conditions such as polythemia vera (PV), myelofibrosis and chronic myeloid leukaemia (CML) may also be associated with high platelet count.
A persistently elevated platelet count can lead to arterial or venous thrombosis
INHERITED COAGULATION DISORDERS
Haemophilia A is due to a lack of factor VIII. It is inherited as an X-linked disorder. Bleeding is treated by administration of factor VIII concentrate by intravenous infusion to achieve normalization of levels. Factor VIII has a half-life of 12h and therefore must be administered at least twice a daily. Complications. Up to 30% of people with severe haemophilia will, during their lifetime, develop antibodies to factor VIII that inhibit its action. Such inhibitors usually develop after the first few treatment doses of factor VIII. Recombinant factor VIIa at very high 'pharmacological' levels can bypass factor IX/VIII activity and is an effective treatment in more than 80% of bleeding episodes in patients with high levels of inhibitor antibodies. The long-term aim of management is to eradicate the inhibitory antibody. This is done using immune tolerance induction strategies, sometimes using additional immunosuppression and immunoabsorption.
Haemophilia B (Christmas disease)
Haemiphilia B is caused by a deficiency of factor IX. The inheritance and clinical features are identical to haemophilia A. It is treated with factor IX concentrate and prophylactic doses given twice a day.
Von Willebrand's Disease (VWD)
In WVD there is defective platelets function as well as factor VIII deficiency and both are due to a deficiency or abnormality of vWF. vWF plays a role in platelet adhesion to damaged subendothelium as well as stabilizing factor VIII in plasma.
ACQUIRED COAGULATION DISORDERS
Vitamin K deficiency
Vitamin K is necessary for carboxylation of glutamic acid residues on coagulation factors II, VII, IX, X and on proteins C and S. Without it these factors cannot bind calcium.
Deficiency of vitamin K may be due to:
- Inadequate stores e.g. malnutrition
- Malabsorption of vitamin K
- Oral anticoagulant drugs which are vitamin K antagonists
Liver disease
Liver disease may result in a number of defects in haemostasis:
- Vitamin K deficiency - intrahepatic or extrahepatic cholestasis.
- Reduced systhesis. Reduced synthesis of coagulation factors c\may be result of severe hepatocellular damage.
- Thrombocytopenia - hypersplenism due to splenomegaly associated with portal hypertension or from folic acid deficiency
- Disseminated intravascular coagulation occurs in acute liver failure.
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