Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder in which there is a deficiency of the enzyme G6PD. This causes instability of red blood cell membranes under oxidative stress leading to haemolysis.Triggers include: 1) Fava beans2) Sulphonamides3) Primaquine4) Anti-TB drugs5) Infections Most individuals will be asymptomatic until exposed to one of the triggers listed above. It is the commonest human enzyme defect and affects males more than females because of the X-linked inheritance pattern. The use of penicillins and cephalosporins is generally safe.

Haemophilia A is the most common of the hereditary clotting factor deficiencies. The inheritance is sex-linked but up to one-third of patients have no family history and these cases result from recent mutation. The vast majority of cases are inherited in an X-linked recessive fashion, affecting males born to carrier mothers. Females born to affected fathers can also, rarely, be affected due to homozygosity for the gene, where there is marriage to close relatives. The defect is an absence or low level of plasma factor VIII. The APTT is prolonged but the PT is normal. Recurrent painful haemarthroses and muscle haematomas dominate the clinical course of severely affected patients and if inadequately treated, lead to progressive joint deformity and disability. Local pressure can cause entrapment neuropathy or ischaemic necrosis. Prolonged bleeding occurs after dental extractions or post-trauma. Spontaneous haematuria and gastrointestinal haemorrhage may occur. The clinical severity of the disease correlates inversely with the factor VIII level. Operative and post-traumatic haemorrhage are life-threatening both in severely and mildly affected patients.

Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the bone marrow and is the most common malignancy of childhood. The incidence of ALL is highest at 3 – 7 years, with 75% of cases occurring before the age of 6. There is a secondary rise after the age of 40 years. 85% of cases are of B-cell lineage and have an equal sex incidence; there is a male predominance for the 15% of T-cell lineage.

98% of cases of myeloma occur over the age of 40 years with a peak incidence between 65 and 70 years. The disease is twice as common in black individuals compared to those of white or Asian origin. Laboratory findings include presence of a paraprotein in serum/urine (the paraprotein is IgG in 60% of cases, IgA in 20% and light chain only in almost all the rest) and marked Rouleaux formation on blood film. There is no cure for myeloma. The overall median survival is now 7-10 years and in younger (less than 50 years) patients it can be over 10 years.

Dipyridamole inhibits both the reuptake of adenosine and phosphodiesterase, preventing the degradation of cAMP and thus blocking the platelet aggregation response to ADP.

Chronic myeloid leukaemia (CML) is a clonal disorder of a pluripotent stem cell. The disease accounts for around 15% of leukaemias and may occur at any age. The diagnosis of CML is rarely difficult and is assisted by the characteristic presence of the Philadelphia (ph) chromosome. This disease occurs in either sex, most frequently between the ages of 40 and 60 years. In up to 50% of cases the diagnosis is made incidentally from a routine blood count. Leucocytosis is the main feature, with a complete spectrum of myeloid cells seen in the peripheral blood. The levels of neutrophils and myelocytes exceed those of blast cells and promyelocytes.Increased circulating basophils are a characteristic feature. Normochromic normocytic anaemia is usual. Platelet count may be increased (most frequently), normal or decreased. The clinical outlook is very good and 90% of patients can expect long-term control of disease.

Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the growth stage to the mitosis stage. This leads to continuing cell growth without division, which presents as macrocytosis, with an increase in mean corpuscular volume (MCV). The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency.Folate is an essential vitamin found in most foods, especially liver, green vegetables and yeast. The normal daily diet contains 200 – 250 μg, of which about 50% is absorbed. Daily adult requirements are about 100 μg. Absorption of folate is principally from the duodenum and jejunum. Stores of folate are normally only adequate for 4 months and so features of deficiency may be apparent after this time.

Dietary iron may be in the form of haem or non-haem iron. Haem iron is degraded after absorption through the cell surface to release Fe2+. Most non-haem iron is in the form Fe3+, which is reduced at the luminal surface to the more soluble Fe2+, facilitated by hydrochloric acid in gastric secretions (and enhanced by ascorbic acid). Fe2+is taken across the enterocyte apical membrane by the divalent metal transporter (DMT1). In the enterocyte, Fe2+is then either stored in enterocyte epithelial cells as ferritin, or released into portal plasma via the molecule ferroportin at the basolateral membrane.

Non-Hodgkin’s Lymphoma (NHL) causes neoplastic transformation of both B cell (85%) and T cell (15%) lines. The most common presentation is with enlarged, rubbery, painless lymph nodes. The patient may also have B symptoms which consist of night sweats, weight loss and fevers. Multiple myeloma most commonly presents with bone pain, especially in the back and ribs. The presence of Reed-Sternberg cells characterises Hodgkin’s lymphoma. Acute lymphoblastic leukaemia will present with features of anaemia, thrombocytopenia and leukopenia. The most common symptoms of chronic lymphocytic leukaemia are fatigue, night sweats and low-grade fever.The peak incidence of NHL is in the 50-70 years age group, it affects men and women equally, but affects the Caucasian population more commonly than black and Asian ethnic groups.The following are recognised risk factors for NHL:Chromosomal translocations and molecular rearrangementsEpstein-Barr virus infectionHuman T-cell leukaemia virus type-1 (HTLV-1)Hepatitis CCongenital and acquired immunodeficiency statesAutoimmune disorders, e.g. Sjogren’s syndrome and Hashimoto’s thyroiditis

Multiple myeloma is a clonal abnormality affecting plasma cells in which there is an overproduction of functionless immunoglobulins. The most common patient complaint is bone pain, especially in the back and ribs. Anaemia and renal failure are common, along with hypercalcemia. Hypercalcemia may lead to an altered mental status, as in this case. Chronic lymphocytic leukaemia occurs due to the overproduction of lymphocytes, usually B cells. CLL may present with an asymptomatic elevation of B cells. Patients are generally more than 50 years old and present with non-specific fatigue and weight loss symptoms.There is no history of alcohol abuse in this case. Furthermore, patients with a history of alcohol abuse may have signs of liver failure, which are not present here. Metastatic prostate cancer would most often cause lower backache as it metastasises first to the lumbar spine via the vertebral venous plexus. A patient with Vitamin B12 deficiency would have anaemia, megaloblastic, hypersegmented neutrophils, and signs of peripheral neuropathy.

Beta thalassemia is caused by mutations in one or both of the beta globin genes. Alpha thalassemia is caused by a deletion or mutation (less commonly) in one or more of the four alpha globin gene copies. β-thalassaemia is more common in the Mediterranean region while α-thalassaemia is more common in the Far East.

A history of stroke and poor nutritional status points towards a nutritional deficiency as the most likely cause of her symptoms. The examination would differentiate between Vitamin B12 and Folic acid deficiency as in the former. The patient has a beefy red tongue and symptoms indicating peripheral nervous system involvement or subacute combined spinal cord degeneration. The patient may also have a lemon-yellow skin colour, loss of proprioception and vibratory sense and oral ulceration. Investigations in B12 deficiency can reveal the following:1. Macrocytic anaemia2. Neutropoenia3. Thrombocytopaenia4. Blood film: anisocytosis, poikilocytosis5. Low serum B126. Raised serum bilirubin (haemolysis)7. Intrinsic factor antibodies8. Positive Schilling test

All the Haemophilia’s have an X-linked recessive inheritance pattern, so they only manifest in male patients. Diseases with a mitochondrial inheritance pattern include MELAS syndrome, Leigh syndrome, LHON and MERRF syndrome. Autosomal dominant disorders include Huntingdon disease and Marfan syndrome. X-linked dominant diseases include Fragile X syndrome. Autosomal recessive diseases include cystic fibrosis and sickle cell disease.

Bence Jones proteins are monoclonal immunoglobulin light chains found in urine (and plasma) of some patients with myeloma. Because of their relatively small size, light chains are readily excreted into the urine. The presence of significant amounts of Bence Jones proteins in urine is indicative of malignant B cell proliferation.

Glanzmann’s thromboasthenia is a rare platelet disorder in which platelets contain defective or low levels of glycoprotein IIb/IIIa.

Lymphomas are a group of diseases caused by malignant lymphocytes that accumulate in lymph nodes and other lymphoid tissue and cause the characteristic clinical feature of lymphadenopathy. The major subdivision of lymphomas is into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) and this is based on the histological presence of Reed-Sternberg cells present in HL. Hodgkin lymphoma can present at any age but is rare in children and has a peak incidence in young adults. There is an almost 2 : 1 male predominance. Most patients present with painless, asymmetrical, firm and discrete enlargement of superficial lymph nodes. Cervical nodes are involved in 60-70% of cases, axillary nodes in 10-15% and inguinal nodes in 6-12%. Modest splenomegaly occurs during the course of the disease in 50% of patients; the liver may also be enlarged. Bone marrow failure involvement is unusual in early disease. The prognosis depends on age, stage and histology, but overall approximately 85% of patients are cured. Alcohol‐induced pain and pruritus are two well‐known but rare symptoms in HL.

Non-Hodgkin’s lymphoma (NHL) refers to a group of lymphoproliferative malignancies (about 85% of B-cell and 15% of T or NK (natural killer) cell origin) with different behavioural patterns and treatment responses. This group of malignancies encompasses all types of lymphoma without Reed-Sternberg cells being present. The Reed-Sternberg cell is classically seen in Hodgkin’s lymphoma.NHL is five times as common as Hodgkin’s lymphoma. The peak incidence of NHL is in the 50-70 years age group, it affects men and women equally, but affects the Caucasian population more commonly than black and Asian ethnic groups.The following are recognised risk factors for NHL:Chromosomal translocations and molecular rearrangementsEpstein-Barr virus infectionHuman T-cell leukaemia virus type-1 (HTLV-1)Hepatitis CCongenital and acquired immunodeficiency statesAutoimmune disorders, e.g. Sjogren’s syndrome and Hashimoto’s thyroiditisThe most common clinical features at presentation are:Lymphadenopathy (typically asymmetrical and painless)Weight lossFatigueNight sweatsHepatosplenomegalyFor clinical purposes, NHL is divided into three groups: indolent, high-grade, and lymphoblastic.Indolent (low-grade) NHL:The cells are relatively matureDisease follows an indolent course without treatmentOften acceptable to follow a ‘watch and wait’ strategyLocal radiotherapy often effectiveRelatively good prognosis with median survival of 10 yearsHigh-grade NHL:Cells are immatureDisease progresses rapidly without treatmentSignificant number of patients can be cured with intensive combination chemotherapy regimensApproximately 40% cure rateLymphoblastic NHL:Cells are very immature and have a propensity to involve the CNSTreatment and progression are similar to that of acute lymphoblastic leukaemia (ALL)

Acute ITP is most common in children. In approximately 75% of cases, the episode follows vaccination or infection such as chicken pox or glandular fever. Most cases are caused by non-specific immune complex attachment to platelets. Acute ITP usually has a very sudden onset and the symptoms usually disappear in less than 6 months (often within a few weeks). It is usually a self-limiting condition and over 80% of children recover without treatment; in 5 – 10% of cases a chronic form of the disease develops.

Febrile transfusion reactions presents with an unexpected temperature rise (≥ 38ºC or ≥ 1ºC above baseline, if baseline ≥ 37ºC) during or shortly after transfusion. It is usually an isolated finding and the fever is accompanied by chills and malaise occasionally.Allergic reaction is commonly caused by foreign plasma proteins but may be due to anti-IgA. Allergic type reactions usually present with urticaria, pruritus, hives. Associations include laryngeal oedema or bronchospasm.Acute haemolytic reaction aka immediate haemolytic transfusion reaction presents with fever, chills, pain at transfusion site, nausea, vomiting, dark urine and feeling of ‘impending doom’. Often, it occurs due to ABO incompatibility.Transfusion-associated circulatory overload (TACO) presents as acute or worsening respiratory distress within 6 hours of transfusion of a large volume of blood. It is common in patients with diminished cardiac reserve or chronic anaemia. Elderly patients, infants and severely anaemic patients are particularly susceptible. Clinical features of TACO include: Acute respiratory distress, Tachycardia, Hypertension, Acute/worsening pulmonary oedema on chest X-ray. The BNP is usually raised to at least 1.5 times the pre-transfusion baseline.Transfusion-related lung injury (TRALI) is a form of acute respiratory distress caused by the donor plasma containing antibodies against the patient’s leukocytes. It is defined as hypoxia and bilateral pulmonary oedema that occurs within 6 hours of a transfusion in the absence of other causes of acute lung injury. Clinical features include Breathlessness, cough, frothy sputum, hypertension or hypotension, hypoxia and fever. Chest X-ray shows multiple perihilar nodules with infiltration of the lower lung fields.

Abciximab, eptifibatide and tirofiban are GPIIb/IIIa inhibitors, inhibiting platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive molecules.

Myelodysplastic syndromes are a group of clonal haematopoietic disorders which are characterised by anaemia, leukopenia and thrombocytopenia. Patients will complain of fatigue, symptoms of thrombocytopenia such as nosebleeds and easy bleeding and a history of repeated infections due to low white blood cells (especially Neutrophils). In Chronic lymphocytic leukaemia production of hematopoietic cells goes on for a longer time. Folate and B12 deficiency would result in hypersegmented neutrophils and a raised MCV. Iron deficiency anaemia would not cause neutropenia or thrombocytopenia.

Non-specific signs of anaemia include: 1. pallor of mucous membranes or nail beds (if Hb < 90 g/L), 2. tachycardia3. bounding pulse4. wide pulse pressure5. flow murmurs 6. cardiomegaly 7. signs of congestive cardiac failure (in severe cases)

Paroxysmal nocturnal haemoglobinuria is an acquired genetic disorder that causes a decrease in red blood cells due to a membrane defect that allows increased complement binding to RBCs, causing haemolysis. Patients complain of dark-coloured urine first in the morning due to haemoglobinuria secondary to lysis of red blood cells overnight. Thrombosis occurs, which affects hepatic, abdominal, cerebral and subdermal veins. Thrombosis of hepatic veins can lead to Budd-Chiari syndrome, thrombosis of subdermal veins can lead to painful nodules on the skin, and thrombosis of cerebral vessels can lead to stroke. The presence of dark urine in the morning only and at no other time differentiates this condition from other conditions.Multiple myeloma would present with bone pain, signs of radiculopathy if there were nerve root compression and a history of repeated infections. Patients with Non-Hodgkin Lymphoma would complain of enlarged lymph nodes, fatigue, fever, weight loss and a history of repeated infections. Acute lymphoblastic leukaemia presents more commonly in children than in adults. The patient would complain of bone pain, and on examination, there would be hepatosplenomegaly.

Immunodeficiency is present in all patients with chronic lymphocytic leukaemia (CLL), though it is often mild and not clinically significant. Infections are the leading cause of death in 25-50 percent of CLL patients, with respiratory tract, skin, and urinary tract infections being the most common.Hypogammaglobulinemia is the most common cause of immunodeficiency in CLL patients, accounting for about 85 percent of all cases.

Aspirin irreversibly inhibits cyclooxygenase and blocks the platelet production of thromboxane A2 (TXA2), thus inhibiting platelet aggregation.

A total neutrophil count of greater than 7.5 x 109/L is called neutrophilia. Typhoid fever usually causes leukopenia or neutropenia. Both localised and generalised bacterial infections can cause neutrophilia. Metabolic disorders such as – gout- eclampsia- uraemia can also cause neutrophilia. Acute neutrophilia, in which immature neutrophils can be seen, is referred to as a left shift and can be seen in conditions such as appendicitis.

Features include: AnaemiaJaundice (caused by unconjugated bilirubin in plasma, bilirubin is absent from urine)Pigment gallstonesSplenomegalyAnkle ulcersExpansion of marrow with, in children, bone expansion e.g. frontal bossing in beta-thalassaemia majorAplastic crisis caused by parvovirus

Signs and symptoms of Sickle cell disease(SCD):Acute and chronic pain: The most common clinical manifestation of SCD is vaso-occlusive crisis; pain crises are the most distinguishing clinical feature of SCDBone pain: Often seen in long bones of extremities, primarily due to bone marrow infarctionAnaemia: Universally present, chronic, and haemolytic in natureAplastic crisis: Serious complication due to infection with parvovirus B19 (B19V)Splenic sequestration: Characterized by the onset of life-threatening anaemia with rapid enlargement of the spleen and high reticulocyte countInfection: Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae; adult infections are predominantly with gram-negative organisms, especially SalmonellaGrowth retardation, delayed sexual maturation, being underweightHand-foot syndrome: This is a dactylitis presenting as bilateral painful and swollen hands and/or feet in childrenAcute chest syndrome: Young children present with chest pain, fever, cough, tachypnoea, leucocytosis, and pulmonary infiltrates in the upper lobes; adults are usually afebrile, dyspnoeic with severe chest pain, with multilobar/lower lobe diseasePulmonary hypertension: Increasingly recognized as a serious complication of SCDAvascular necrosis of the femoral or humeral head: Due to vascular occlusionCentral nervous system (CNS) involvement: Most severe manifestation is strokeOphthalmologic involvement: Ptosis, retinal vascular changes, proliferative retinitisCardiac involvement: Dilation of both ventricles and the left atriumGastrointestinal involvement: Cholelithiasis is common in children; liver may become involvedGenitourinary involvement: Kidneys lose concentrating capacity; priapism is a well-recognized complication of SCDDermatologic involvement: Leg ulcers are a chronic painful problem

Delayed haemolytic transfusion reactions (DHTRs) commonly occurs 4-8 days after blood transfusion, but can occur up to a month after. Signs and symptoms include jaundice, fever, an inadequate rise in PCV, reticulocytosis, a positive antibody screen and a positive Direct Antiglobulin Test (Coombs test). DHTRs usually have a benign course and require no treatment but sometimes, life-threatening haemolysis with severe anaemia and renal failure can occur so haemoglobin levels and renal function should be monitored.Acute haemolytic reaction aka immediate haemolytic transfusion reaction presents with fever, chills, pain at transfusion site, nausea, vomiting, dark urine and feeling of ‘impending doom’. Often, it occurs due to ABO incompatibility.Febrile transfusion reaction presents with a 1 degree rise in temperature from baseline during transfusion. Patient may have chills and malaise. It is the most common transfusion reaction (1 in 8 transfusions) and is usually caused by cytokines released from leukocytes in transfused red cell or platelet components.Transfusion-associated circulatory overload (TACO) presents as acute or worsening respiratory distress within 6 hours of transfusion of a large volume of blood. It is common in patients with diminished cardiac reserve or chronic anaemia. Elderly patients, infants and severely anaemic patients are particularly susceptible. Clinical features of TACO include: Acute respiratory distress, Tachycardia, Hypertension, Acute/worsening pulmonary oedema on chest X-ray. The BNP is usually raised to at least 1.5 times the pre-transfusion baseline.Graft versus host disease(GVHD) is an immune mediated condition that arises from a complex interaction between donor and recipients adaptive immunity. It presents as dermatitis, hepatitis and enteritis developing within 100 days after stem cell or bone marrow transplant.

Megaloblastic anaemia occurs when there is inhibition of DNA synthesis as red blood cells are produced. Impairment of DNA synthesis causes the cell cycle to be unable to progress from the growth stage to the mitosis stage. As a result, there is continuous cell growth without division, with an increase in mean corpuscular volume (MCV), which presents as macrocytosis. The most common cause of this defect in red cell DNA synthesis is hypovitaminosis, in particular, vitamin B12 deficiency or folate deficiency.Folate is an essential vitamin that can be found in most foods, and is highest in liver, green vegetables and yeast. 200 – 250 μg is found in the normal daily diet, and about 50% is absorbed. The daily adult requirement is about 100 μg and its absorption is principally from the duodenum and jejunum. Folate stores are normally only adequate for 4 months and so clinical features of folate deficiency usually become evident after this time.