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.

Rasburicase is a recombinant version of urate oxidase which is an enzyme that metabolizes uric acid to allantoin.

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. 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. 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

Diagnosis of multiple myeloma (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

The cytotoxic drug bleomycin can cause bleomycin-induced pneumonitis (BIP). It usually occurs during chemotherapy but can also occur up to six months post-therapy.

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.

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.

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

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. For patients at low risk of these symptoms, drugs such as metoclopramide may be used. For high-risk patients, however, 5-HT3 receptor antagonists such as ondansetron are often effective, especially if combined with dexamethasone.

Neutrophilia is also commonly associated with polycythaemia vera.

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.

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).

Haemophilia B (Christmas disease), is the deficiency of clotting factor IX and is inherited in an X-linked recessive pattern. The factor IX level dictates the disease severity and established arthropathy is usually seen in those with severe disease.

The aforementioned patient’s history and presentation is consistent with the development of hemarthrosis. Joint aspiration is not recommended. The treatment, therefore, should be intravenous replacement of the deficient clotting factor with plasma-derived factor IX concentrate.

The other listed options are ruled out because:
1. Joint aspiration is not preferred over the administration of clotting factor as the first step of management.
2. DDAVP (desmopressin) can increase factor VIII levels transiently in those with mild haemophilia A and is useful prior to minor surgical procedures in such patients.
3. Cryoprecipitate is rich in fibrinogen, factor VIII, and von Willebrand factor and is used in the treatment of haemophilia A.

This is a classical picture of graft versus host disease (GVHD) following bone marrow transplant. Acute GVHD occurs in the first 100 days post transplant with chronic GVHD occurring 100-300 days after transplant. GVHD is graded according to the Seattle system, and each organ involved is scored (skin, liver, and gut).

The standard initial treatment in the acute setting is high-dose methylprednisolone started immediately. If there is no response, a more intensive immunosuppressive agent such as alemtuzumab or antilymphocyte globulin is needed.

Prostate cancer is the most common primary tumour that metastasises to the bone.

Most common tumours causing bone metastasis (in descending order):
1. Prostate (32%)
2. Breast (22%)
3. Kidneys (16%)
4. Lungs
5. Thyroid

Most common sites of bone metastasis (in descending order):
1. Spine
2. Pelvis
3. Ribs
4. Skull
5. Long bones

Bombesin is a tumour marker elevated in small cell lung carcinomas, as well as in gastric carcinomas and retinoblastomas.

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)

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 prognosis of breast cancer depends chiefly on the extent of nodal metastases.

The breast cancer TNM staging system is the most common way that doctors use to stage breast cancer. TNM stands for Tumour, Node, Metastasis. The results are combined to determine the stage of cancer for each person. There are five stages: stage 0 (zero), which is non-invasive ductal carcinoma in situ (DCIS), and stages I through IV (1 through 4), which are used for invasive breast cancer.

Staging can be clinical or pathological. Clinical staging is based on the results of tests done before surgery, which may include physical examinations, mammogram, ultrasound, and MRI scans. Pathologic staging is based on what is found during surgery to remove breast tissue and lymph nodes. In general, pathological staging provides the most information to determine a patient’s prognosis.

Immune thrombocytopenic purpura (ITP) refers to thrombocytopaenia occurring in the absence of toxic exposure or other diseases associated with low platelets and involves IgG-type antibodies. It is characterised by normal or increased marrow megakaryocytes, shortened platelet survival, and the absence of splenomegaly. Autoimmune haemolytic anaemia (AIHA) occurs commonly in association with ITP. Leukemic transformation, however, does not occur in ITP.

In neonatal ITP, IgG antibodies are passively transferred across the placenta. The infant platelet count may be normal at birth but decreases within 12–24 hours. It is rarely severe enough to induce bleeding diathesis in the infant.

Sickle cell anaemia is characterised by periods of good health with intervening crises. One of the main types is aplastic crisis characterised by a sudden fall in haemoglobin without marked reticulocytosis (3%—in this case—is just above the normal range). It usually occurs secondary to parvovirus infection.

The other main types of sickle cell crises are thrombotic crisis (painful or vaso-occlusive crisis), sequestration crisis, and haemolytic crisis. Thrombotic crisis is precipitated by infection, dehydration, alcohol, change in temperature, and deoxygenation. Sequestration crisis is characterised by acute chest syndrome (i.e. fever, dyspnoea, chest/rib pain, low pO2, and pulmonary infiltrates). In haemolytic crisis, fall in haemoglobin occurs secondary to haemolysis. It is a rare type of sickle cell crises.

Gram-staining of the blood cultures of this patient will show gram-positive cocci. Gram-negative bacilli used to be the most common pathogen isolated in neutropenic sepsis, but currently, the most common pathogens are gram-positive organisms. Staphylococcus epidermidis is the most frequent causative agent, and following this are other staphylococci and streptococci species.

Neutropenic sepsis is a relatively common complication of cancer therapy—usually chemotherapy. It most commonly occurs 7-14 days after the treatment and is usually defined as a neutrophil count of <0.5 x 10^9/L in a patient undergoing anticancer treatment and who has either a temperature higher than 38°C or has other features consistent with clinically significant sepsis. Management approach includes starting empirical antibiotic therapy (piperacillin with tazobactam—Tazocin) immediately. Following this initial treatment, the patient is usually assessed by a specialist and risk-stratified to see if outpatient treatment may be possible. However, if the patient remains febrile and unwell after 48 hours, an alternative antibiotic such as meropenem is often prescribed with or without vancomycin. If patient is still not responding after 4-6 days, then an antifungal, such as amphotericin B, is started after carrying out investigations (e.g. HRCT and Aspergillus PCR) to determine the likelihood of systemic fungal infection.

Rasburicase should be given prior to chemotherapy in order to reduce the risk of tumour lysis syndrome (TLS). Rasburicase is a recombinant version of urate oxidase which is an enzyme that metabolizes uric acid to allantoin. Allantoin is 5–10 times more soluble than uric acid, hence, renal excretion is more effective.

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. 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.

Burkitt lymphoma is a high-grade B-cell neoplasm. There are two major forms:
1. Endemic (African) form: typically involves maxilla or mandible.
2. Sporadic form: abdominal (e.g. ileocaecal) tumours are the most common form. More common in patients with HIV.

Burkitt lymphoma is associated with the c-myc gene translocation, usually t(8;14). The Epstein-Barr virus (EBV) is strongly implicated in development of the African form of Burkitt lymphoma and to a lesser extent, the sporadic form.

Management of the lymphoma is with chemotherapy. This tends to produce a rapid response which may cause TLS.

This patient is having vaso-occlusive event/crisis (thrombotic crisis) which is a type of sickle cell crisis. It may be associated with ostealgia.

There is no evidence of an aplastic crisis in this case as the haemoglobin level is reasonable with a good reticulocyte count. Conversely, the haemoglobin is not low enough and reticulocyte count and bilirubin are not high enough for a haemolytic crisis.

Sickle cell anaemia is characterised by periods of good health with intervening crises. The four main types of sickle cell crises are thrombotic crisis (painful or vaso-occlusive crisis), sequestration crisis, aplastic crisis, and haemolytic crisis.

Thrombotic crisis is precipitated by infection, dehydration, alcohol, change in temperature, and deoxygenation. Sequestration crisis is characterised by acute chest syndrome (i.e. fever, dyspnoea, chest/rib pain, low pO2, and pulmonary infiltrates). Aplastic crisis is characterised by a sudden fall in haemoglobin without marked reticulocytosis. It usually occurs secondary to parvovirus infection. In haemolytic crisis, a fall in haemoglobin occurs secondary to haemolysis. It is a rare type of sickle cell crisis.

Tumour lysis syndrome (TLS), triggered by the introduction of chemotherapy, has resulted in the aforementioned symptoms in this patient.

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. 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.

Rasburicase should be given prior to chemotherapy in order to reduce the risk of tumour lysis syndrome (TLS). Rasburicase is a recombinant version of urate oxidase which is an enzyme that metabolizes uric acid to allantoin. Allantoin is 5–10 times more soluble than uric acid, hence, renal excretion is more effective.

Burkitt lymphoma is a high-grade B-cell neoplasm. There are two major forms:
1. Endemic (African) form: typically involves maxilla or mandible.
2. Sporadic form: abdominal (e.g. ileocaecal) tumours are the most common form. More common in patients with HIV.

Burkitt lymphoma is associated with the c-myc gene translocation, usually t(8;14). The Epstein-Barr virus (EBV) is strongly implicated in development of the African form of Burkitt lymphoma and to a lesser extent, the sporadic form.

Management of the lymphoma is with chemotherapy. This tends to produce a rapid response which may cause TLS.

Superior vena cava (SVC) obstruction is an oncological emergency caused by compression of the SVC and is most commonly associated with lung cancer.

Some causes of the condition include:
1. Common malignancies: non small cell lung cancer, lymphoma
2. Other malignancies: metastatic seminoma, Kaposi’s sarcoma, breast cancer
3. Aortic aneurysm
4. Mediastinal fibrosis

Clinical features of SVC obstruction include:
1. Dyspnoea: most common
2. Swelling of the face, neck, and arms: conjunctival and periorbital oedema may be seen
3. Headache: often worse in the morning
4. Visual disturbances
5. Pulseless jugular venous distension

Management options are:
1. General: dexamethasone, balloon venoplasty, stenting
2. Small cell lung cancer: chemotherapy and radiotherapy
3. Non small cell lung cancer: radiotherapy

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.

Exposure to aniline dyes is a risk factor for transitional cell carcinoma. Aniline dyes are used in dyestuffs and pigment manufacturing.

The other aforementioned options are ruled out because:
1. Feed production may expose to aflatoxin (hepatocellular carcinoma).

2. Being a military personnel may expose to mustard gas (lung cancer).

3. Rubber industry may expose to nitrosamines (oesophageal and gastric cancer).

4. Refrigerant production before 1974 may expose to vinyl chloride (hepatic angiosarcoma).

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

Liver cirrhosis is not associated with hyposplenism.

Hyposplenism is caused by a variety of conditions. These are:
1. Splenectomy
2. Sickle cell anaemia
3. Coeliac disease, dermatitis herpetiformis
4. Graves’ disease
5. Systemic lupus erythematosus (SLE)

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 patient has acute promyelocytic leukaemia (APML) with associated disseminated intravascular coagulation (DIC). Although
the platelet count is high, platelet function is ineffective.

Patients may present, as in this case, with severe bleeding, and the most appropriate emergency treatment would be administration of fresh frozen plasma (FFP).

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.

Leukemoid reaction has a high LAP score.

Leukemoid reaction refers to leucocytosis occurring as a physiological response to stress or infection which may be mistaken for leukaemia, especially chronic myeloid leukaemia (CML). Leucocytosis occurs, initially, because of accelerated release of cells from the bone marrow and is associated with increased count of more immature neutrophils in the blood (left-shift). In order to differentiate, LAP score is used. Leukocytic alkaline phosphatase (ALP) activity is high in a leukemoid reaction but low in CML.

LAP score is high in:
1. Leukemoid reaction
2. Infections
3. Myelofibrosis
4. Polycythaemia rubra vera
5. Steroids, Cushing’s syndrome
6. Pregnancy, oral contraceptive pill

LAP score is low in:
1. CML
2. Pernicious anaemia
3. Paroxysmal nocturnal haemoglobinuria (PNH)
4. Infectious mononucleosis

CXR, blood, and urine tests should be carried out initially to exclude an underlying malignancy. If these are normal, a CT scan of abdomen and pelvis should be arranged as the patient’s age is >40 years. Antiphospholipid antibodies should also be checked for the first unprovoked DVT/PE. There is no history, however, to support an inherited thrombophilia.

The National Institute for Health and Care Excellence (NICE) published guidelines in 2012 for the investigation and management of DVT. If a patient is suspected of having DVT, a two-level DVT Wells score should be used:

DVT likely: 2 points or more
DVT unlikely: 1 point or less

This system of points is based on the following clinical features:
1. Active cancer (treatment ongoing, within six months, or palliative)—1
2. Paralysis, paresis, or recent plaster immobilisation of the lower extremities—1
3. Recently bedridden for three days or more, or major surgery within 12 weeks requiring general or regional anaesthesia—1
4. Localised tenderness along the distribution of the deep venous system—1
5. Entire leg swollen—1
6. Calf swelling at least three cms larger than the asymptomatic side—1
7. Pitting oedema confined to the symptomatic leg—1
8. Collateral superficial veins (non-varicose)—1
9. Previously documented DVT—1
10. An alternative diagnosis is at least as likely as DVT—2

If two points or more—DVT is ‘likely’
If one point or less—DVT is ‘unlikely’

Management

1. LMWH or fondaparinux should be given initially after a DVT is diagnosed.
2. A vitamin K antagonist such as warfarin should be given within 24 hours of the diagnosis.
3. LMWH or fondaparinux should be continued for at least five days or until the international normalised ratio (INR) is 2.0 or above for at least 24 hours. LMWH or fondaparinux is given at the same time as warfarin until the INR is in the therapeutic range.
4. Warfarin should be continued for at least three months. At three months, clinicians should assess the risks and benefits of extending the treatment.
5. Consider extending warfarin beyond three months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding. This essentially means that if there is no obvious cause or provoking factor (surgery, trauma, significant immobility, etc.), it may be implied that the patient has a tendency to thrombose and should be given treatment longer than the normal of three months. In practice, most clinicians give six months of warfarin for patients with an unprovoked DVT/PE.
6. For patients with active cancer, LMWH should be used for six months.

As both malignancy and thrombophilia are obvious risk factors for DVT, therefore, all patients with unprovoked DVT/PE who are not already known to have cancer should undergo the following investigations:
1. Physical examination (guided by the patient’s full history)
2. Chest X-ray
3. Blood tests (full blood count, serum calcium, and liver function tests) and urinalysis
4. Testing for antiphospholipid antibodies
5. Testing for hereditary thrombophilia in patients who have had unprovoked DVT/PE and have a first-degree relative who has a history of DVT/PE.

B2-microglobulin is a useful marker of prognosis in multiple myeloma (MM). Raised levels imply a poorer prognosis. Low levels of albumin are also associated with a poor prognosis.

Night sweats are a B symptom in Hodgkin lymphoma (HL) and imply a poor prognosis.

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—poor prognosis.

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 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.

The diagnosis of Hodgkin disease requires the identification of Reed-Sternberg cells in a characteristic cellular background. The normal cell of origin for the Reed-Sternberg cells remains unclear, with the predominance of evidence indicating a B or T lymphocyte.

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.

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 weight loss and lethargy; monoclonal IgM paraproteinemia; hyperviscosity syndrome leading to bilateral central retinal vein occlusion (CRVO) and hence, visual disturbances; hepatosplenomegaly and lymphadenopathy; and cryoglobulinemia. It is not, however, associated with bone pain.

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

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.

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.

Cisplatin is a cytotoxic agent that acts by causing cross-linking in DNA. Its adverse effects include ototoxicity, peripheral neuropathy, hypomagnesaemia, etc.

The causative cytotoxic agents acting through the other aforementioned MOAs are as follows:

1. Doxorubicin: Stabilizes DNA topoisomerase II complex and inhibits DNA and RNA synthesis.

2. Hydroxyurea (hydroxycarbamide): Inhibits ribonucleotide reductase, decreasing DNA synthesis.

3. Mercaptopurine (6-MP): Purine analogue that is activated by HGPRTase, decreasing purine synthesis.

4. Vincristine, vinblastine: Inhibits formation of microtubules.

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. Around 10% of patients eventually develop myeloma over 10 years, with 50% at 15 years. MGUS causes paraproteinemia and is usually asymptomatic. 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, normal levels of beta-2 microglobulin, and stable lower levels of paraproteinemia.

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.

In patients with factor V Leiden, inactivation of the active factor V (a clotting factor) by active protein C occurs 10x more slowly than normal. Therefore, this condition is also called activated protein C resistance.

Factor V Leiden is the most commonly inherited thrombophilia, being present in around 5% of the UK’s population. It occurs due to gain-of-function mutation in the Factor V Leiden protein.

Gamma delta T cells are of low abundance in the body, are found in the gut mucosa, skin, lungs and uterus, and are involved in the initiation and propagation of immune responses. Their ligands are not known in detail, but the gamma delta T cell receptors recognise intact proteins rather than MHC-presented peptides. Like alpha beta T cells, they develop in the thymus.

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 has Meigs syndrome. Meigs syndrome is defined as a triad of benign ovarian tumour with ascites and pleural effusion that resolves after resection of the tumour. Ovarian fibromas constitute the majority of the benign tumours seen in Meigs syndrome.

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 is a typical picture of acute chest syndrome (ACS). According to the British Committee for Standards in Haematology (BCSH), ACS is defined as ‘an acute illness characterised by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray’. ACS occurs in sequestration crisis, which is one of the four main types of crises occurring in sickle cell disease.

The fundamentals of initial management are as follows:
1. Oxygen therapy to maintain saturation >95%
2. Intravenous fluids to ensure euvolemia
3. Adequate pain relief
4. Incentive spirometry in all patients presenting with rib or chest pain
5. Antibiotics with cover for atypical organisms
6. Bronchodilators if asthma co-exists with acute chest syndrome, or if there is an evidence of acute bronchospasm on auscultation
7. Early consultation with the critical care team and haematology department

A senior haematologist then makes a decision as to whether a simple or exchange transfusion is necessary in order to achieve a target Hb of 10.0–11.0g/dL in either instance.

Sickle Cell Crises:
Sickle cell anaemia is characterised by periods of good health with intervening crises:
1. Sequestration crisis: acute chest syndrome (i.e. fever, dyspnoea, chest/rib pain, low pO2, and pulmonary infiltrates)

2. Thrombotic (painful or vaso-occlusive) crisis: precipitated by infection, dehydration, and deoxygenation

3. Aplastic crisis: sudden fall in haemoglobin without marked reticulocytosis, usually occurring secondary to parvovirus infection

4. Haemolytic crisis: fall in haemoglobin secondary to haemolysis, rare type of sickle cell crises