Thalassaemias are a group of genetic disorders characterised by decreased production of either alpha or beta chains of haemoglobin (Hb). Beta thalassaemia trait is an autosomal recessive condition in which a disproportionate hypochromic, microcytic anaemia occurs—microcytosis is disproportionate to the Hb level. It is usually asymptomatic.

Microcytic anaemia in a female should raise the possibility of either gastrointestinal blood loss or menorrhagia. However, there is no history to suggest this in the aforementioned patient. This, combined with characteristic disproportionate microcytosis and raised HbA2 levels ( >3.5%), point towards beta thalassaemia trait.

Basophilic stippling is also seen in lead poisoning but the raised HbA2 levels cannot be explained in such a case.

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)

Hb S is the most common type of abnormal haemoglobin and the basis of sickle cell trait and sickle cell anaemia. It differs from normal adult haemoglobin (called haemoglobin A—Hb A) only by a single amino acid substitution due to point mutation—a valine replacing a glutamine in the sixth position of the beta chain of globin. Hb S molecules polymerize in hypoxic and acidic environments, imparting a sickle shape to the RBCs. Hb S molecules are less negatively charged than Hb A (due to the loss of glutamine) and have a lower affinity for oxygen (right shift of the oxygen-dissociation curve).

Warfarin inhibits the vitamin K-dependent procoagulants II, VII, IX, and X as well as anticoagulant protein C and S. It is highly protein-bound and can be displaced by a wide variety of drugs. It has a half-life of 36–48 hours.

Bleeding is the major side effect. Easy bruising, as seen in this case, is commonly seen in patients of warfarin overdose. Grossly prolonged PT and lesser increase in APTT may be seen in such cases.

Hypogammaglobulinemia is a complication of chronic lymphocytic leukaemia (CLL) that leads to recurrent infections.

CLL is a type of cancer caused by monoclonal proliferation of well-differentiated lymphocytes, typically B cells (99%). Onset of the disease is usually asymptomatic and later constitutes anorexia, weight loss, bleeding, and recurrent infections. Lymphadenopathy is more marked in CLL than in chronic myelogenous leukaemia (CML).

Investigations to diagnose CLL include blood film and immunophenotyping. Smudge cells (also known as smear cells) seen on the blood film point towards CLL. Complications of the disease include hypogammaglobulinemia leading to recurrent infections, autoimmune haemolytic anaemia in 10–15% of the patients, and transformation to high-grade lymphoma (Richter’s transformation).

5–15% of the cases of polycythaemia vera progress to myelofibrosis or acute myeloid leukaemia (AML).

Polycythaemia vera (PV), also known as polycythaemia rubra vera, is a myeloproliferative disorder caused by clonal proliferation of marrow stem cells leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has peak incidence in the sixth decade of life, with typical features including hyperviscosity, pruritus, splenomegaly, haemorrhage (secondary to abnormal platelet function), and plethoric appearance.

Some management options of PV include lose-dose aspirin, venesection (first-line treatment), hydroxyurea (slightly increased risk of secondary leukaemia), and radioactive phosphorus (P-32) therapy.

In PV, thrombotic events are a significant cause of morbidity and mortality. 5–15% of the cases progress to myelofibrosis or AML. The risk of having AML is increased with chemotherapy treatment.

Poor prognostic factors for breast cancer include:
1. Young age (<40 years)
2. Premenopausal at the time of diagnosis
3. Increased tumour size
4. High-grade tumour
5. Oestrogen and progesterone receptor-negative tumour
6. Positive lymph node status

Urinary porphobilinogen is increased between attacks of acute intermittent porphyria (AIP) and even more so, between acute attacks.

AIP is a rare autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem. This results in the toxic accumulation of delta-aminolaevulinic acid and porphobilinogen.

Abdominal and neuropsychiatric symptoms are characteristic of AIP especially in people between the ages of 20–40 years. The disease is more common in females than in males (5:1). Major signs and symptoms of AIP include abdominal pain, vomiting, motor neuropathy, hypertension, tachycardia, and depression.

Diagnosis:
1. Urine turns deep red on standing (classical picture of AIP)
2. Raised urinary porphobilinogen (elevated between attacks and to a greater extent, between acute attacks)
3. Raised serum levels of delta-aminolaevulinic acid and porphobilinogen
4. Assay of red blood cells for porphobilinogen deaminase

Vitamin B12 is mostly used in the body for the development of red blood cells and maintenance of the nervous system. It is actively absorbed in the terminal ileum after binding to the intrinsic factor (IF) which is secreted from the parietal cells of stomach. Moreover, a small amount is also passively absorbed without being bound to IF.

Vitamin B12 deficiency is characterised by sore tongue and mouth, mood disturbances, ataxia, and macrocytic anaemia. Its causes include poor diet, impaired absorption (due to disorders of terminal ileum), pernicious anaemia, and post-gastrectomy. While managing this condition, if the person is also deficient in folic acid, then it is important to treat the B12 deficiency first in order to avoid precipitating subacute combined degeneration of the cord.

The direct Coombs test will specifically confirm immune-mediated haemolysis occurring post-transfusion in the aforementioned case.

There are two types of Coombs test used in immunohematology and immunology:

1. Direct Coombs test—It confirms autoimmune haemolytic anaemia by detecting antibodies or complement proteins attached to the surface of red blood cells.

2. Indirect Coombs test—It is used in prenatal testing of pregnant women and in testing prior to a blood transfusion. It detects antibodies floating freely in the blood, against foreign red blood cells.

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.

Monoclonal gammopathy of undetermined significance (MGUS)—also known as benign paraproteinemia and monoclonal gammopathy—is a pre-malignant condition not necessarily leading to its malignant form—multiple myeloma. MGUS causes increase of a serum monoclonal protein (M protein). It is not associated with ostealgia or increased risk of infections. It is often mistaken for multiple myeloma, differing from the latter in, no immunosuppression, anaemia, hypercalcaemia, lytic bone lesions, or renal failure; normal levels of beta-2 microglobulin; and stable lower levels of paraproteinemia.

Deletion of part of chromosome 5 or 7 is a poor prognostic feature for acute myeloid leukaemia (AML).

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:
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.

The patient is displaying signs and symptoms of hyperviscosity syndrome, secondary to the Waldenström’s macroglobulinemia. Treatment of choice is plasmapheresis.

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.

Generally, underlying causes of confusion need to be looked for and treated as appropriate, for example, hypercalcaemia, infection, urinary retention, and medication. If specific treatments fail, the following may be tried:

1. First choice: haloperidol
2. Other options: chlorpromazine, levomepromazine

In the terminal phase of the illness, agitation or restlessness is best treated with midazolam.

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).

The patient has paroxysmal nocturnal haemoglobinuria (PNH). The classic sign of the disease is red discolouration of the urine due to the presence of haemoglobin and hemosiderin from the breakdown of red blood cells. As the urine is more concentrated in the morning, this is when the colour is most pronounced.

PNH is an acquired clonal disorder of haematopoietic stem cells, characterised by variable combinations of intravascular haemolysis, thrombosis, and bone marrow failure. Diagnosis is made by flow cytometric evaluation of blood, which confirms the CD55 and CD59 deficiencies and deficiency of expression of other GPI-linked proteins. This test is replacing older complement-based assays such as the Ham test and sucrose lysis test.

Out of the aforementioned markers, low corrected calcium is the only biochemistry result consistent with the diagnosis. All of the other markers are elevated in TLS.

TLS is a potentially fatal condition occurring as a complication during the treatment of high-grade lymphomas and leukaemias. It occurs from the simultaneous breakdown (lysis) of the tumour cells and subsequent release of chemicals into the bloodstream. This leads to hyperkalaemia and hyperphosphatemia in the presence of hyponatraemia. As phosphate precipitates calcium, the serum concentration of calcium becomes low. TLS can occur in the absence of chemotherapy, but it is usually triggered by the introduction of combination chemotherapy. Awareness of the condition is critical for its prophylactic management.

Patients at high risk of TLS should be given IV rasburicase or IV allopurinol immediately prior to and during the first few days of chemotherapy. Rasburicase is a recombinant version of urate oxidase which is an enzyme that metabolizes uric acid to allantoin. Allantoin is much more water soluble than uric acid and is therefore more easily excreted by the kidneys. Patients in lower-risk groups
should be given oral allopurinol during cycles of chemotherapy in an attempt to avoid the condition.

TLS is graded according to the Cairo-Bishop scoring system as:
1. Laboratory tumour lysis syndrome
2. Clinical tumour lysis syndrome

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.

Cryoglobulinemia may be caused by paraprotein bands such as those seen in Waldenström’s macroglobulinemia and multiple myeloma (MM). Meltzer’s triad of arthralgia, weakness, and palpable purpura are common to all types of cryoglobulinemia—as are membranoproliferative glomerulonephritis and low C4 levels. Raynaud’s phenomenon, however, occurs only in type 1 cryoglobulinemia, and its presence can be helpful in ascertaining the underlying cause.

Cryoglobulinemia is a condition in which the blood contains large amounts of pathological cold-sensitive antibodies called cryoglobulins—proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. One-third of the cases are idiopathic.

There are three types of cryoglobulinemia:
1. Type I (25%):
Monoclonal—IgG or IgM
Associated with multiple myeloma (MM), Waldenström’s macroglobulinemia

2. Type II (25%):
Mixed monoclonal and polyclonal—usually with rheumatoid factor (RF)
Associated with hepatitis C, rheumatoid arthritis (RA), Sjogren’s syndrome

3. Type III (50%):
Polyclonal—usually with RF
Associated with rheumatoid arthritis, Sjogren’s syndrome

Investigation results for cryoglobulinemia show low complement (especially C4) and high ESR. Treatment options include immunosuppression and plasmapheresis.

An MRI whole spine should be performed in a patient suspected of spinal metastasis which can occur before developing metastatic spinal cord compression. This patient has renal cell carcinoma, which readily metastasises to the bones and also has progressive back pain. He, therefore, needs urgent imaging of his spine before any neurological compromise develops. MRI whole spine is preferable because patients with spinal metastasis often have metastases at multiple levels within the spine. Plain radiographs and CT scans should not be performed as they have a lower sensitivity for revealing lesions and cannot exclude cord compression.

In general, imaging should be performed within one week if symptoms suspicious of spinal metastasis without neurological symptoms are present. If there are symptoms suggestive of malignant spinal cord compression, then imaging should be done within 24 hours.

The signs and symptoms of spinal metastases include:
1. Unrelenting lumbar back pain
2. Thoracic or cervical back pain
3. Pain associated with tenderness and worsens with sneezing, coughing, or straining
4. Nocturnal pain

Aprepitant is an anti-emetic which blocks the neurokinin 1 (NK1) receptor and acts as a substance P antagonist. It is licensed for chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting.

Nausea and vomiting are the common side effects of chemotherapy. Risk factors for the development of these symptoms include age<50 years, anxiety, concurrent use of opioids, and the type of chemotherapy administered.

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.

The patient is on stage IV according to the Ann Arbor staging system for Hodgkin lymphoma (HL). The disease has spread beyond the lymph nodes into the liver (involvement of extra lymphatic organ).

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.

Staging of HL is done according to the Ann Arbor staging system:
Stage
I: Single lymph node region (I) or one extra lymphatic site (IE)

II: Two or more lymph node regions on same side of the diaphragm (II) or local extra lymphatic extension plus one or more lymph node regions on same side of the diaphragm (IIE)

III: Lymph node regions on both sides of the diaphragm (III) which may be accompanied by local extra lymphatic extension (IIIE)

IV: Diffuse involvement of one or more extra lymphatic organs or sites

Suffix
A: No B symptoms

B: Presence of at least one of the following: unexplained weight loss >10% baseline during 6 months before staging; recurrent unexplained fever >38°C; recurrent night sweats

The patient has spinal cord compression until proven otherwise. Urgent assessment is required.

Spinal cord compression is an oncological emergency and affects up to 5% of cancer patients. Extradural compression accounts for the majority of cases, usually due to vertebral body metastases. One of the most common causes of spinal cord compression is osteoarthritis. It is also more commonly seen in patients with lung, breast, or prostate cancer.

Clinical features include:
1. Back pain: the earliest and most common symptom, may worsen on lying down or coughing
2. Lower limb weakness
3. Sensory changes: sensory loss and numbness
4. Neurological signs: depending on the level of the lesion.
Lesions above L1 usually result in upper motor neurone signs in the legs. Lesions below L1 usually cause lower motor neurone signs in the legs and perianal numbness. Tendon reflexes are increased below the level of the lesion and absent at the level of the lesion.

Management options are:
1. High-dose oral dexamethasone
2. Urgent MRI for consideration of radiotherapy or surgery

The combination of frequent infections, eczema, and thrombocytopaenia are characteristic of Wiskott-Aldrich syndrome, which is due to an abnormality in the WASP gene. It is an X-linked recessive disorder that causes primary immunodeficiency owing to a combined B- and T-cell dysfunction.

The other listed options are:
1. PKD1: polycystic kidney disease
2. CFTR: cystic fibrosis
3. HFE1: haemochromatosis
4. RET: multiple endocrine neoplasia, Hirschsprung’s disease

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.

All of the aforementioned listed tumours, except brain tumours, can metastasise to lungs and produce the typical CXR picture consisting of hilar lymphadenopathy with either diffuse multinodular shadows resembling miliary disease or multiple large well-defined masses (canon balls). Occasionally, cavitation or calcification may also be seen.

Most brain tumours, however, do not metastasise. Some, derived form neural elements, do so but in these cases, intraparenchymal metastases generally precede distant haematogenous spread.

This is a picture of bone marrow failure secondary to acute myeloid leukaemia (AML). 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:
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.

Other listed options are ruled out because:
1. Von Willebrand disease: may present with epistaxis and bleeding gums in severe cases but rarely with abnormalities on blood results.

2. Acute lymphoblastic leukaemia: mostly seen in children.

3. Lymphoma: usually presents with rubbery enlargement of lymph nodes.

4. Warfarin overdose: no bilobed large mononuclear cells seen on blood film.

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.