Hypersegmented neutrophils in the peripheral blood film is suggestive of megaloblastic changes in bone marrow.

Lead poisoning is characterised by abdominal pain, fatigue, constipation, peripheral neuropathy (mainly motor), and blue lines on gum margin in 20% of the adult patients (very rare in children).

For diagnosis, the level of lead in blood is usually considered with levels greater than 10 mcg/dL being significant. Furthermore, the blood film shows microcytic anaemia and basophilic stippling of red blood cells. Urinary coproporphyrin is increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased). Raised serum and urine levels of delta-aminolaevulinic acid may also be seen, making it sometimes difficult to differentiate from acute intermittent porphyria.

Patients with active cancer are at a continuous risk of having venous thromboembolism (VTE), such as DVT. Therefore, a six-month course of an anticoagulant such as LMWH is recommended. LMWH is the drug of choice since its side effects can be reversed and it can be stopped easily in case of a cancer-related bleed, for example, massive haemoptysis in a patient with lung cancer.

The patient is asymptomatic but matches the diagnostic criteria for multiple myeloma (MM). Therefore, the underlying diagnosis of this condition is smouldering multiple myeloma (SMM). SMM is an early precursor to MM. Its treatment is typically to watch and wait.

MM is a neoplasm of the bone marrow plasma cells. Peak incidence is in patients aged 60-70 years.

Clinical features of MM include:
1. Ostealgia, osteoporosis, pathological fractures (typically vertebral), and osteolytic lesions
2. Lethargy
3. Infections
4. Hypercalcaemia
5. Renal failure
6. Other features: amyloidosis e.g. macroglossia, carpal tunnel syndrome; neuropathy; hyperviscosity

Diagnosis of MM is based on the confirmation of (a) one major criterion and one minor criterion or (b) three minor criteria in an individual who has signs or symptoms of multiple myeloma.

Major criteria:
1. >30% plasma cells on bone marrow biopsy
2. Monoclonal band of paraprotein on electrophoresis: >35g/L for IgG, 20g/L for IgA, or >1g of light chains excreted in the urine per day

Minor criteria:
1. 10-30% plasma cells on bone marrow biopsy
2. Abnormal monoclonal band but levels less than listed above
3. Lytic bone lesions observed radiographically
4. Immunosuppression

NICE guidelines on hypercalcemia recommend that maintaining good hydration equals drinking 3-4 L of fluid/day, provided there are no contraindications. A low calcium diet is not necessary because intestinal absorption of calcium is reduced. The patient should avoid any other drugs or vitamins that could worsen the hypercalcemia. Mobilization is encouraged and any symptoms of hypercalcemia should be reported.

Individuals with thalassemia major usually develop symptoms within the first two years of life. These infants may fail to thrive and often have difficulty feeding, tire easily and suffer from severe anemia.

The infants may also suffer from diarrhea, irritability, recurrent episodes of fever, and other intestinal problems. These children have trouble gaining weight and growing at the rate expected for their age. Other complications include enlarged spleen, heart and liver and misshapen bones.

In many cases, the symptoms are severe enough to warrant regular blood transfusion to replenish the blood with healthy red blood cells. However, these regular transfusions can lead to a build up of iron in the blood that can damage the heart, liver and endocrine system and chelation therapy may be needed to remove this iron from the body.

Individuals with beta thalassemia trait usually have evidence of microcytosis and increased levels of hemoglobin A2. Hemoglobin F is sometimes elevated as well. Individuals with alpha thalassemia trait usually have evidence of microcytosis and normal levels of hemoglobin A2 and F.

In thalassemia major, the hemoglobin (Hb) level is usually less than 7 g/dl; the mean corpuscolar volume (MCV) less than 70 fl and the mean corpuscolar Hb (MCH) is over 20 pg.

In thalassemia intermedia, the hemoglobin level is between 7 and 10 g/dl; the MCV between 50 and 80 fl and MCH between 16 and 24 pg.

Thalassemia minor is characterized by a reduced MCV and MCH and an increased haemoglobin A2 level.

St John’s wort interferes with warfarin by increasing its breakdown and decreasing its effectiveness. This leads to the need for adjustment in the dose of warfarin and careful attention to monitoring if the patient decides to continue with the drug. Ideally, an alternative antidepressant should also be considered.

A grossly elevated APTT may be caused by heparin therapy, haemophilia, or antiphospholipid syndrome. A normal factor VIIIc activity, however, points towards the diagnosis of haemophilia B, which is the deficiency of factor IX in the blood.

Haemophilia is an X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to the deficiency of clotting factor VIII and is more common than haemophilia B, accounting for 90% of the cases. In haemophilia B (Christmas disease), there is a deficiency of clotting factor IX.

Characteristic features of haemophilia include hemarthrosis, haematomas, and prolonged bleeding following trauma or surgery. Coagulation profile of a haemophiliac person shows prolonged bleeding time, activated partial thromboplastin time (APTT), thrombin time (TT), but a normal prothrombin time (PT).

Diencephalon consists of four structures; thalamus, subthalamus, hypothalamus and epithalamus. The hypothalamus has a crucial role in controlling urinary frequency.

In hereditary non-polyposis colonic carcinoma (HNPCC), mutations in MSH2, MSH6, PMS2 or MLH1 genes are found.
Ataxia telangiectasia – ATM gene is affected.
Familial adenomatous polyposis – APC gene is affected.
Li-Fraumeni syndrome – mutation of the TP53 tumour suppressor gene. Neurofibromatosis – mutation in or a deletion of the NF1 gene

A translocation between chromosome 15 and 17 is seen in acute promyelocytic leukaemia (APL), which is known to carry a good prognosis.

Acute myeloid leukaemia (AML) is the acute expansion of the myeloid stem line, which may occur as a primary disease or follow the secondary transformation of a myeloproliferative disorder. It is more common over the age of 45 and is characterized by signs and symptoms largely related to bone marrow failure such as anaemia (pallor, lethargy), frequent infections due to neutropenia (although the total leucocyte count may be very high), thrombocytopaenia (bleeding), ostealgia, and splenomegaly. The disease has poor prognosis if:

The disease has poor prognosis if:
1. Age of the patient >60 years
2. >20% blasts seen after the first course of chemotherapy
3. Chromosomal aberration with deletion of part of chromosome 5 or 7.

APL is an aggressive form of AML. It is associated with t(15;17) and has a good prognosis. The general age of presentation is less than that in other types of AML (average age is 25 years old). On blood film, abundant Auer rods are seen with myeloperoxidase staining. Thrombocytopaenia or DIC is seen in patients presenting with this disease.

Red cell aplasia is commonly associated with thymomas.

Thymoma is the most common tumour of the anterior mediastinum and is usually detected between the sixth and seventh decades of life. It is associated with myasthenia gravis (30-40% of patients), red cell aplasia, and dermatomyositis. Compression of airway and cardiac tamponade are the common causes of death in thymoma.

Elevated haemoglobin A2 level is seen in beta thalassaemia trait, whereas, it is typically low in iron deficiency anaemia unless the patient has received a recent blood transfusion.

Low mean corpuscular volume (MCV) and reduced haematocrit (Ht) are encountered in both conditions. Peripheral blood smear is grossly abnormal in both beta thalassaemia and severe iron deficiency anaemia, showing bizarre morphology, target cells, and a small number of nucleated red blood cells.

Tumour marker CA 15-3 is mostly associated with breast cancer.

Tumour markers can be divided into:
1. Monoclonal antibodies
CA 125: Ovarian cancer, primary peritoneal cancer
CA 19-9: Pancreatic cancer
CA 15-3: Breast cancer

2. Tumour specific antigens
Prostate specific antigen (PSA): Prostatic carcinoma
Alpha-feto protein (AFP): Hepatocellular carcinoma, teratoma
Carcinoembryonic antigen (CEA): Colorectal cancer
S-100: Melanoma, schwannomas
Bombesin: Small cell lung carcinoma, gastric cancer

3. Enzymes
Alkaline phosphatase (ALP)
Neuron specific enolase (NSE)

4. Hormones
Calcitonin
Antidiuretic hormone (ADH)
Human chorionic gonadotropin (hCG)

This patient is a case of chronic myeloid leukaemia (CML) and should be started on imatinib as the first-line drug of choice.

This patient has leukopenia following chemotherapy and she is more prone to severe bacterial infections. Neutropenic sepsis is common among cancer patients and it is one of the main reasons for death amongst these patients. As the first line monotherapy for high-risk patients, Piperacillin-tazobactam, Cefepime, Meropenem and Imipenem-cilastatin can be started as they all have antipseudomonal activity.

A Coomb’s test should be performed to test for autoimmune haemolytic anaemia. Spherocytes and reticulocytes in the blood film are indications for haemolytic anaemia.

Progressive hoarseness of the voice is a very typical and early finding in people suspected to have squamous cell laryngeal cancer. Due to mechanical compression, patients might experience dysphagia as well as pain. The ‘lump in the throat sensation is not uncommon too. Haemoptysis might be present, together with respiratory symptoms such as dyspnoea. Other symptoms consist of constitutional complaints, such as weight loss or fatigue.

Haemochromatosis is an abnormally high rate of the production of haemoglobin. It is an autosomal recessive disease copied on chromosome 6. It is associated with hepatic disorders, cardiac diseases and skin pigmentation. It is treated by regular venesection.

Group AB donors are the universal donors of FFP. This is because they produce neither anti-A nor anti-B antigens in their plasma and are, therefore, compatible with all ABO groups.

The aforementioned patient’s blood group is B meaning, thereby, she naturally produces anti-A antigens in her plasma and would need to receive plasma that does not have anti-B antigens in it. Hence, she can only receive FFP from donors of group B or AB. Moreover, as she is of childbearing age, she must receive RhD negative blood in order to avoid problems with future pregnancies if her foetus would be RhD positive.

Philadelphia translocation, t(9;22), is a marker of poor prognosis in acute lymphoblastic leukaemia (ALL).

ALL is the malignancy of lymphoid progenitor cells affecting B or T cell lineage. This results in the arrest of lymphoid cell maturation and proliferation of immature blast cells (lymphoblasts), leading to bone marrow and tissue infiltration.

ALL is the most common type of childhood cancers. Its peak incidence is between two to three years of age.

Acute B lymphoblastic leukaemia (B-ALL) is the most common type of ALL, involving overproduction of B-cell lymphoblasts. It is manifested by low initial WCC and is associated with a good prognosis.

Poor prognostic factors for ALL include:
1. Pre-B cell or T-cell ALL (T-ALL)
2. Philadelphia translocation, t(9;22)
3. Age <2 years or >10 years
4. Male sex
5. CNS involvement
6. High initial WBC (e.g. >100 x 10^9/L)
7. non-Caucasian

The most common type of Hodgkin’s lymphoma (HL) is nodular sclerosing.

HL is a malignant proliferation of lymphocytes characterised by the presence of distinctive giant cells known as Reed-Sternberg cells. It has a bimodal age distribution being most common in the third and seventh decades of life.

According to the histological classification, there are four types of HL:

1. Nodular sclerosing: most common (around 70%), more common in women, associated with lacunar cells, good prognosis

2. Mixed cellularity: Around 20%, associated with a large number of Reed-Sternberg cells, good prognosis

3. Lymphocyte-predominant: Around 5%, Reed-Sternberg cells with nuclei surrounded by a clear space found, best prognosis

4. Lymphocyte-depleted: rare, worst prognosis

All of the aforementioned options may be important however cytogenetics, for detecting chromosomal abnormalities, is the single most important test to determine her disease prognosis.

Acute myeloid leukaemia (AML) is the acute expansion of the myeloid stem line, which may occur as a primary disease or follow the secondary transformation of a myeloproliferative disorder. It is more common over the age of 45 and is characterized by signs and symptoms largely related to bone marrow failure such as anaemia (pallor, lethargy), frequent infections due to neutropenia (although the total leucocyte count may be very high), thrombocytopaenia (bleeding), ostealgia, and splenomegaly.

The disease has a poor prognosis if:
1. Age of the patient >60 years
2. >20% blasts seen after the first course of chemotherapy
3. Chromosomal aberration with deletion of part of chromosome 5 or 7.

Acute promyelocytic leukaemia (APL) is an aggressive form of AML.

Cyclophosphamide is a cytotoxic alkylating agent that acts by causing cross-linking of DNA strands. Its major adverse effects include haemorrhagic cystitis, myelosuppression, and transitional cell carcinoma.

Cardiomyopathy is caused by doxorubicin and ototoxicity is caused by cisplatin. Alopecia and weight gain are associated with a variety of chemotherapeutic agents especially those that treat breast cancers (e.g. paclitaxel).

Mycoplasma infection causes cold autoimmune haemolytic anaemia (AIHA). The rest of the aforementioned options cause warm AIHA.

AIHA may be divided into ‘warm’ and ‘cold’ types, according to the temperature at which the antibodies best cause haemolysis. It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infection, or drugs.

1. Warm AIHA:
In warm AIHA, the antibody (usually IgG) causes haemolysis best at body temperature and tends to occur in extravascular sites, for example, spleen. Management options include steroids, immunosuppression, and splenectomy. It is caused by autoimmune diseases such as SLE (rarely causes mixed-type AIHA), cancers such as lymphomas and CLL, and drugs such as methyldopa.

2. Cold AIHA:
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4°C and occurs more commonly intravascularly. Features may include symptoms of Raynaud’s disease and acrocyanosis. Patients do not respond well to steroids. Cold AIHA is caused by cancers such as lymphomas, and infections such as mycoplasma and EBV.

The patient is most likely suffering from Waldenström’s macroglobulinemia in which IgM paraproteinemia is found. Hyperviscosity syndrome can occur in the patients accounting for 10-15% of the cases.

Waldenström’s macroglobulinemia (also called lymphoplasmacytic lymphoma) is an uncommon type of non-Hodgkin lymphoma seen in older people. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein. Its features include monoclonal IgM paraproteinemia; hyperviscosity syndrome leading to bilateral central retinal vein occlusion (CRVO) and hence, visual disturbances; weight loss and lethargy; hepatosplenomegaly and lymphadenopathy; and cryoglobulinemia. It is not, however, associated with bone pain.

Normal pO2 but decreased oxygen saturation is characteristic of methemoglobinemia.

Methemoglobinemia is a rare condition in which the haemoglobin iron is in oxidized or ferric state (Fe3+) and cannot reversibly bind oxygen. Normally, the conversion of ferrous form of iron (Fe2+) to its ferric form (Fe3+) is regulated by NADH methaemoglobin reductase, which results in the reduction of methaemoglobin to haemoglobin. Disruption in the enzyme leads to increased methaemoglobin in the blood. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxygen-haemoglobin dissociation curve is shifted to the left.

Methemoglobinemia can occur due to congenital or acquired causes. Congenital causes include haemoglobin variants such as HbM and HbH, and deficiency of NADH methaemoglobin reductase. Acquired causes are drugs (e.g. sulphonamides, nitrates, dapsone, sodium nitroprusside, and primaquine) and chemicals (such as aniline dyes).

The features of methemoglobinemia are cyanosis, dyspnoea, anxiety, headache, severe acidosis, arrhythmias, seizures, and loss of consciousness. Patients have normal pO2 but oxygen saturation is decreased. Moreover, presence of chocolate-brown coloured arterial blood (colour does not change with addition of O2) and brown urine also point towards the diagnosis of methemoglobinemia.

Good prognosis of chronic lymphocytic leukaemia (CLL) is associated with deletion of the long arm of chromosome 13 (del 13q). This is the most common abnormality, seen in around 50% of all CLL patients. Poor prognosis of the disease is related to deletion of part of the short arm of chromosome 17 (del 17p). This is seen in around 5-10% of the patients suffering from CLL.

Poor prognostic factors of CLL include:
1. Male sex
2. Age >70 years
3. Lymphocyte count >50
4. Prolymphocytes comprising more than 10% of blood lymphocytes
5. Lymphocyte doubling time <12 months
6. Raised LDH
7. CD38 expression positive

The diagnosis for the aforementioned case is thrombotic thrombocytopenic purpura (TTP). TTP is classically characterised as a pentad of thrombocytopaenia, microvascular haemolysis, fluctuating neurological signs, renal impairment, and fever.

The differential diagnosis for severe thrombocytopaenia is immune thrombocytopenic purpura (ITP). ITP is more common than TTP. However, a patient of ITP would not present with the range of symptoms seen in this scenario.

In TTP, there is deficiency of a protease which breaks down large multimers of von Willebrand factor. This leads to abnormally large and sticky multimers of von Willebrand factor which cause platelets to clump within the vessels.

Untreated TTP has a mortality rate of up to 90%. Therefore, rapid plasma exchange (PEX) may be a life-saving intervention. Platelet transfusion in TTP is only indicated if there is an ongoing life-threatening bleed. Intravenous methylprednisolone is indicated after treatment with PEX has been completed. There is no current role of intravenous immunoglobulin in the routine management of TTP. However, there have been reports of its successful use in PEX- and steroid-refractory cases. Intravenous argatroban is indicated in heparin-induced thrombocytopaenia (HIT), but there is no history of recent heparin administration or hospitalisation in this patient nor are the clinical signs consistent with HIT.

Management options for TTP include PEX as the treatment of choice. Steroids and immunosuppressants are also given. Antibiotics are not recommended as they may worsen the outcome of the disease. For cases resistant to PEX and pharmacologic therapy, vincristine is given.