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.

Chronic myeloid leukaemia is most common in middle-aged and elderly people. It is responsible for 20% of all leukemias. The majority of CML patients experience fatigue, weight loss, and excessive sweating.

The Philadelphia chromosome is found in over 90% of CML cases. A balanced translocation between chromosomes 9 and 22 is known as the Philadelphia chromosome.

Because white cells produce a B12 binding protein, serum B12 levels in CML are typically high.

In CML, the neutrophil alkaline phosphatase score is usually low.

Almost all patients with CML eventually progress to blast crisis, though this can take up to ten years. If any of the following features are present in a CML patient, a blast crisis is diagnosed:
In the blood or bone marrow, there are more than 20% myeloblasts or lymphoblasts.
On a bone marrow biopsy, large clusters of blasts were discovered.

CML can be treated with tyrosine kinase inhibitors like imatinib and dasatinib if a chloroma (a solid tumour made up of myeloblasts that grows outside of the bone marrow) is present.

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.

Bacterial infections are common in the following situations:

Platelet transfusions are associated with a higher risk of bacterial infection (as platelets are stored at room temperature)
Immersion in a water bath thawed previously frozen components.
Components of red blood cells that have been stored for several weeks
Gram-positive and Gram-negative bacteria have both been linked to transfusion-transmitted bacterial infection, but Gram-negative bacteria are linked to a higher rate of morbidity and mortality.
Yersinia enterocolitica is the most common bacterial organism linked to transfusion-transmitted bacterial infection. This organism can multiply at low temperatures while also utilising iron as a nutrient. As a result, it’s well-suited to proliferating in blood banks.

The following are some of the most common clinical signs and symptoms of a bacterial infection transmitted through a blood transfusion. These symptoms usually appear shortly after the transfusion begins:
Fever is very high.
Rigours and chills
Vomiting and nausea
Tachycardia
Hypotension
Collapse of the circulatory system

If a bacterial infection from a transfusion is suspected, the transfusion should be stopped right away. Blood cultures and a Gram stain should be requested, as well as broad-spectrum antibiotics. In addition, the blood pack should be returned to the blood bank for an urgent culture and Gram-stain.

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.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer that primarily affects children. ALL is most common between the ages of 2 and 4, and it is uncommon in adults.

The clinical and laboratory findings, in this case, support a diagnosis of polycythaemia vera. A plethoric appearance, lethargy, splenomegaly and itching are common in this disease. Patients may also have gouty arthritis, Budd-Chiari syndrome, erythromelalgia, stroke, myocardial infarction or DVT. The average age for diagnosis of Polycythaemia Vera is 65-74 years. It is a haematological malignancy in which there is overproduction of all three cell lines. Venesection is the treatment of choice as it would cause a decrease in the number of red blood cells within the body.

Erythropoietin is given in patients with chronic renal failure as they lack this hormone. Administration of erythropoietin in such patients causes stimulation of the bone marrow to produce red blood cells.

Desferrioxamine is a chelating agent for iron and is given to patients with iron overload due to repeated blood transfusions, e.g. in thalassemia patients.

Penicillamine is a chelating agent for Copper, given as treatment in Wilson’s disease.

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.

Lymphoma is a cancer of the lymphatic system, which is part of the body’s germ-fighting network. They are a group of diseases that are caused by malignant lymphocytes. These malignant cells accumulate in lymph nodes and other lymphoid tissue, giving rise to the characteristic clinical feature of lymphadenopathy.
They can be subdivided into Hodgkin lymphoma (HL) which are characterised by the presence of Reed-Sternberg cells, and non-Hodgkin lymphoma (NHL).
Characteristics of HL include:
1. can present at any age but is rare in children and has a peak incidence in young adults,
2. almost 2:1 male predominance.
3. presents with painless, asymmetrical, firm and discrete enlargement of superficial lymph nodes.
4. cervical node involvement in 60-70% of cases,
5. axillary node involvement in 10-15%
6. inguinal node involvement in 6-12%.
7. modest splenomegaly during the course of the disease in 50% of patients
8. may occasionally have liver enlargement
9. bone marrow failure involvement is unusual in early disease.
Approximately 85% of patients are cured, but the prognosis depends on age, stage and histology.
Two well‐known but rare symptoms in HL are alcohol‐induced pain and pruritus.

Raised platelet levels have emerged as a cancer risk marker, according to a large population-based study published in 2017(link is external). According to the study, 12 percent of men and 6% of women with thrombocytosis were diagnosed with cancer within a year. These figures increased to 18% in men and 10% in women if a second platelet count was taken within 6 months of the first and showed an increased or stable elevated platelet count.

The researchers discovered that thrombocytosis linked to cancer is most common in colorectal and lung cancers, and it is linked to a worse prognosis. Furthermore, one-third of the cancer patients in the study had no other symptoms that would have prompted an immediate cancer referral.

The exact mechanism by which these cancers cause thrombocytosis is unknown, but one theory proposes the existence of pathogenic feedback loops between malignant cells and platelets, with a reciprocal interaction between tumour growth and metastasis, as well as thrombocytosis and platelet activation. Another hypothesis is that thrombocytosis occurs independently of cancer but aids in its spread and progression.

The findings show that routinely testing for thrombocytosis could cut the time it takes to diagnose colorectal and lung cancer by at least two months. In the UK, this could result in around 5500 earlier cancer diagnoses per year.

Because the positive predictive value of thrombocytosis in middle age for cancer (10%) is higher than the positive predictive value for a woman in her 50s presenting with a new breast lump (8.5%), this is clearly an important research paper that should be used to adjust future clinical practise. The current NICE guidelines predate these new research findings, so we’ll have to wait and see how they affect cancer referral guidelines in the UK.

Because there are so many possible cancers associated with thrombocytosis, the treating clinician should take a thorough history and perform a thorough clinical examination if a patient is diagnosed with it. Further investigation and the most appropriate referral route should be aided by this information.

It’s worth noting that the patients in the study had their blood tests done for a medical reason rather than as a random screening test.

If there are no other symptoms to guide investigation and referral (one-third of the patients in the study had no other symptoms), keep in mind that the two most common cancers encountered were colorectal and lung cancer, so a chest X-ray and a faecal immunochemical test (FIT) for faecal blood may be reasonable initial investigations.

The LDH level is usually markedly increased in severe megaloblastic anaemia. Reticulocyte counts are inappropriately low, representing a lack of production of RBCs due to massive intramedullary haemolysis. These findings are characteristics of ineffective haematopoiesis that occurs in megaloblastic anaemia as well as in other disorders such as thalassemia major.
The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells. To a lesser extent, RNA and protein synthesis are impaired. Unbalanced cell growth and impaired cell division occur since nuclear maturation is arrested. More mature RBC precursors are destroyed in the bone marrow prior to entering the bloodstream (intramedullary haemolysis).

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 beans
2) Sulphonamides
3) Primaquine
4) Anti-TB drugs
5) 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.

A total neutrophil count of less than 2 x 109/L is defined as neutropenia. It can be caused by the following:
1. viral infections
2. SLE
3. RA
4. hypersplenism
5. chemo- and radiotherapy
6. vitamin B12 and folate deficiency
7. drug reactions

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 rearrangements
Epstein-Barr virus infection
Human T-cell leukaemia virus type-1 (HTLV-1)
Hepatitis C
Congenital and acquired immunodeficiency states
Autoimmune disorders, e.g. Sjogren’s syndrome and Hashimoto’s thyroiditis
The most common clinical features at presentation are:
Lymphadenopathy (typically asymmetrical and painless)
Weight loss
Fatigue
Night sweats
Hepatosplenomegaly
For clinical purposes, NHL is divided into three groups: indolent, high-grade, and lymphoblastic.
Indolent (low-grade) NHL:
The cells are relatively mature
Disease follows an indolent course without treatment
Often acceptable to follow a ‘watch and wait’ strategy
Local radiotherapy often effective
Relatively good prognosis with median survival of 10 years
High-grade NHL:
Cells are immature
Disease progresses rapidly without treatment
Significant number of patients can be cured with intensive combination chemotherapy regimens
Approximately 40% cure rate
Lymphoblastic NHL:
Cells are very immature and have a propensity to involve the CNS
Treatment and progression are similar to that of acute lymphoblastic leukaemia (ALL)

Laboratory findings typically show (although this varies depending on VWD type):
Abnormal PFA-100 test
Low factor VIII levels (if low a factor VIII/VWF binding assay is performed)
Prolonged APTT (or normal)
Normal PT
Low VWF levels
Defective platelet aggregation
Normal platelet count

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.

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

CML is a myeloproliferative disorder characterised by an abnormal pluripotent haemopoietic stem cell. A cytogenetic abnormality known as the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22, causes more than 80% of cases of CML.

CML is a disease that develops slowly over several years. This is known as the ‘chronic stage.’ This stage is usually asymptomatic, and 90 percent of patients are diagnosed at this point, with the disease being discovered frequently as a result of a routine blood test. During this stage, the bone marrow contains less than 10% immature white cells (blasts).

When CML cells expand, symptoms typically begin to appear. The ‘accelerated stage’ is what it’s called. Approximately 10% of people are diagnosed at this point. During this stage, between 10% and 30% of blood cells in the bone marrow are blasts. During this stage, common clinical features include:
Fatigue and exhaustion
Night sweats and fever
Distension of the abdomen
Pain in the left upper quadrant (splenic infarction)
Splenomegaly (commonest examination finding)
Hepatomegaly
Bruising is simple.
Gout is a type of arthritis that affects (rapid cell turnover)
Hyperviscosity is a condition in which the viscosity of (CVA, priapism)
A small percentage of patients experience a ‘blast crisis’ (blast stage). More than 30% of the blood cells in the bone marrow are immature blast cells at this stage. Patients with severe constitutional symptoms (fever, weight loss, bone pain), infections, and bleeding diathesis typically present at this stage.

In CML, laboratory findings include:
White cell count is abnormally high (often greater than 100 x 109/l).
Increased number of immature leukocytes causes a left shift.
Anaemia that is mild to moderately normochromic and normocytic.
Platelets can be low, normal, or elevated, and the Philadelphia chromosome can be found in > 80% of patients.
Serum uric acid and ALP levels are frequently elevated.
Tyrosine kinase inhibitors (TKIs), such as imatinib and dasatinib, are the current mainstay of CML treatment.
Allogenic bone marrow transplantation is now only used in cases where TKIs have failed to work.

Blood loss from the gastrointestinal (GI) tract is the most common cause of iron deficiency anaemia in adult men and postmenopausal women.

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.

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.

Deficiency of Factor IX causes Haemophilia B, and like the other Haemophilia’s, it has an X-linked recessive pattern of inheritance, affecting males born to carrier mothers.

Haemophilia B is the second commonest form of haemophilia and is rarer than haemophilia A. Haemophilia B is similar to haemophilia A but is less severe. You can distinguish the two disorders by specific coagulation factor assays.

The incidence of Haemophilia B is one-fifth of that of haemophilia A.

In laboratory findings, you get prolonged APTT, normal PT and low factor IX for Haemophilia B.

There is also a variation called Leyden, in which factor IX levels are below 1% until puberty, when they rise, potentially reaching as high as 40-60% of normal. This is thought to be due to the effects of testosterone at puberty.

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.

Features of sickle cell disease include:
Anaemia (symptoms are usually mild because the O2 dissociation curve of Hb S is shifted to the right)
Vaso-occlusive crisis
Visceral sequestration crisis
Aplastic crisisIncreased susceptibility to infection
Other clinical features: Pigment gallstones with cholecystitis
Chronic leg ulcers
Avascular necrosis of the femoral and humeral heads or other bones
Cardiomyopathy
Pulmonary hypertension
Proliferative retinopathy
Priapism
Renal papillary necrosis
Stroke

Polycythaemia vera (PCV), which is also referred to as polycythaemia rubra vera, is a clonal haematological malignancy in which the bone marrow produces too many red blood cells. It may also result in the overproduction of white blood cells and platelets. It is most commonly seen in the elderly and the mean age at diagnosis is 65-74 years.
Patients can be completely asymptomatic and it is often discovered as an incidental finding on a routine blood count. Approximately 1/3 of patients present with symptoms due to thrombosis, of these 3/4 have arterial thrombosis and 1/4 venous thrombosis. Features include stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.
The other clinical features of PCV include:
Plethoric appearance
Lethargy and tiredness
Splenomegaly (common)
Pruritis (in 40% – particularly after exposure to hot water)
Headaches, dizziness and sweating (in 30%)
Gouty arthritis (in 20%)
Budd-Chiari syndrome (in 5-10%)
Erythromyalgia (in <5% – burning pain and red/blue discolouration of hands and feet)
Increased incidence of peptic ulcer disease (possibly related to increased histamine release from mast cells)
The diagnosis of PCV requires two major criteria and one minor criterion, or the first major criterion and two minor criteria:
Major criteria:
HB > 18.5 g/dl in men, 16.5 g/dl in women
Elevated red cell mass > 25% above mean normal predicted value
Presence of JAK2 mutation

Minor criteria:
Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic and megakaryocytic proliferation
Serum erythropoietin level below normal range
Endogenous erythroid colony formation in vitro
The main aim of treatment is to normalize the full blood count and prevent complications such as thrombosis. Venesection is the treatment of choice but hydroxyurea can also be used to help control thrombocytosis.

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.

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 anaemia
2. Neutropoenia
3. Thrombocytopaenia
4. Blood film: anisocytosis, poikilocytosis
5. Low serum B12
6. Raised serum bilirubin (haemolysis)
7. Intrinsic factor antibodies
8. Positive Schilling test

ALL affects children predominantly.

The CNS is commonly involved in ALL.

The Philadelphia chromosome is present in 25% of adult ALL and 5% of childhood ALL cases.

The cure rate in children is approximately 80% in children and 50% in adults.

ALL is classified into 3 groups using the French-American-British (FAB) classification:
ALL-L1: small uniform cells
ALL-L2: large varied cells
ALL-L3: large varied cells with vacuoles.

CLL (chronic lymphocytic leukaemia) is the most common type of chronic lymphoid leukaemia, with a peak incidence between the ages of 60 and 80. It is the most common type of leukaemia in Europe and the United States, but it is less common elsewhere.

The CLL tumour cell is a mature B-cell with low immunoglobulin surface expression (IgM or IgD). The average age at diagnosis is 72 years, with only 15% of cases occurring before the age of 50.

The male-to-female ratio is about 2:1. Over 80% of cases are identified by the results of a routine blood test, which is usually performed for another reason.

Lymphocytic anaemia, thrombocytopenia, and normochromic normocytic anaemia are common laboratory findings. Aspiration of bone marrow reveals up to 95% lymphocytic replacement of normal marrow elements.

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. 85% of cases are of B-cell lineage. Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. There is great variation in the chance of individual patients achieving a long-term cure based on a number of biological variables. Approximately 25% of children relapse after first-line therapy and need further treatment but overall 90% of children can expect to be cured. The cure rate in adults drops significantly to less than 5% over the age of 70 years.

A serious complication in sickle cell disease (SCD) is the aplastic crisis. This may be caused by infection with Parvovirus B-19 (B19V). This virus causes fifth disease, a normally benign childhood disorder associated with fever, malaise, and a mild rash. This virus infects RBC progenitors in bone marrow, resulting in impaired cell division for a few days.
Healthy people experience, at most, a slight drop in hematocrit, since the half-life of normal erythrocytes in the circulation is 40-60 days. In people with SCD, however, the RBC lifespan is greatly shortened (usually 10-20 days), and a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

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

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.

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

Features include:
Anaemia
Jaundice (caused by unconjugated bilirubin in plasma, bilirubin is absent from urine)
Pigment gallstones
Splenomegaly
Ankle ulcers
Expansion of marrow with, in children, bone expansion e.g. frontal bossing in beta-thalassaemia major
Aplastic 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 SCD
Bone pain: Often seen in long bones of extremities, primarily due to bone marrow infarction
Anaemia: Universally present, chronic, and haemolytic in nature
Aplastic 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 count
Infection: Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae; adult infections are predominantly with gram-negative organisms, especially Salmonella
Growth retardation, delayed sexual maturation, being underweight
Hand-foot syndrome: This is a dactylitis presenting as bilateral painful and swollen hands and/or feet in children
Acute 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 disease
Pulmonary hypertension: Increasingly recognized as a serious complication of SCD
Avascular necrosis of the femoral or humeral head: Due to vascular occlusion
Central nervous system (CNS) involvement: Most severe manifestation is stroke
Ophthalmologic involvement: Ptosis, retinal vascular changes, proliferative retinitis
Cardiac involvement: Dilation of both ventricles and the left atrium
Gastrointestinal involvement: Cholelithiasis is common in children; liver may become involved
Genitourinary involvement: Kidneys lose concentrating capacity; priapism is a well-recognized complication of SCD
Dermatologic involvement: Leg ulcers are a chronic painful problem

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults and becomes increasingly common with age, with a median onset of 65 years. It forms only a minor fraction (10 – 15%) of childhood leukaemia. The clinical features of AML typically presents with clinical features secondary to leukaemic infiltration of bone marrow and extramedullary sites:
Anaemia (lethargy, pallor and breathlessness)
Thrombocytopaenia (petechiae, bruising, epistaxis, haemorrhage) – often profound
Neutropenia (infections)
Hepatosplenomegaly
Gingival infiltration
Central nervous system involvement in AML is uncommon.
Leukaemia cutis is the infiltration of neoplastic leukocytes in the skin. It occurs in approximately 10% of patients with AML.Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. The total white cell count is usually increased and blood film examination typically shows a variable number of blast cells. The bone marrow is hypercellular and typically contains many blast cells.. The prognosis for patients with AML has been improving steadily, particularly for those under 60 years of age, and approximately one-third of patients of this group can expect to achieve long-term cure. For the elderly, the situation is poor and less than 10% of those over 70 years of age achieve long-term remission.
CML is commonly associated with the Philadelphia chromosome. The Philadelphia chromosome is present in only 1% of adults AML cases.
Lymphadenopathy is rare in AML.

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.

Clinical features of haemolytic anaemia include:
Anaemia
Jaundice (caused by unconjugated bilirubin in plasma, bilirubin is absent from urine)
Pigment gallstones
Splenomegaly
Ankle ulcers
Expansion of marrow with, in children, bone expansion e.g. frontal bossing in beta-thalassaemia major
Aplastic crisis caused by parvovirus

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.

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

A diagnosis of Haemophilia is supported in this patient by the family history and the presence of hemarthrosis-both characteristics of Haemophilia. Haemophilia A is caused by Factor VIII deficiency, leading to impaired coagulation. This disease typically presents after six months when the child starts crawling.

Von Willebrand disease presents with nosebleeds and hematomas. Idiopathic thrombocytopenic purpura presents with bruises that resemble a rash.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency presents with haemolytic anaemia induced by specific drugs or foods.

Factor V Leiden mutation causes blood clotting rather than bleeding.

Hodgkin’s lymphoma is a malignant tumour of the lymphatic system that is characterised histologically by the presence of Reed-Sternberg cells (multinucleated giant cells). The peak incidence is in young adults aged 20-35, and there is a slight male predominance.

The following are recognised risk factors for Hodgkin’s lymphoma:
Male gender
Age 20-35
Positive family history
Epstein-Barr virus infection
Immunosuppression including HIV infection
Prolonged use of human growth hormone
Most patients present with an enlarged, but otherwise asymptomatic lymph node. The most commonly affected lymph nodes are in the supraclavicular and lower cervical areas. Other common clinical features include shortness of breath and chest discomfort secondary to mediastinal mass. Mediastinal masses are sometimes discovered as incidental findings on routine chest X-rays. Approximately 30% of patients with Hodgkin’s lymphoma develop splenomegaly.
‘B’ symptoms occur in approximately 25% of patients. The ‘B’ symptoms of Hodgkin’s lymphoma are:
Fever (>38ºC)
Night sweats
Weight loss (>10% over 6 months)
Pain after alcohol consumption is a pathognomonic sign of Hodgkin’s lymphoma, it is, however, not a ‘B’ symptom. It is rare though, only occurring in 2-3% of patients with Hodgkin’s lymphoma.

The Ann Arbour clinical staging is as follows:
Stage I: one involved lymph node group
Stage II two involved lymph node groups on one side of the diaphragm
Stage III: lymph node groups involved on both sides of the diaphragm
Stage IV: Involvement of extra-nodal tissues, such as the liver or bone marrow
Diagnosis is made by lymph node biopsy, which should be taken from a sufficiently large specimen or excisional biopsy, as opposed to a fine needle biopsy. The Reed-Sternberg cell is the most useful diagnostic feature. This is a giant cell with twin mirror-image nuclei and prominent ‘owl’s eye’ nucleoli.
The Reed-Sternberg cell of Hodgkin’s Lymphoma
Histological typing depends upon the other cells within the diseased tissue. Nodular sclerosing is the most common type of Hodgkin’s lymphoma. Lymphocyte-depleted and lymphocyte-predominant are rare subtypes.
The majority of cases can be successfully treated, and unlike many other malignancies even if the first-line treatment fails, a cure can often be achieved with second-line therapies. Stage 1 Hodgkin’s lymphoma is usually treated with radiotherapy alone, but more advanced stages require combination chemotherapy. In localised disease treated with irradiation, there is a 5-year survival rate of greater than 80%. In disseminated disease treated with chemotherapy, the 5-year survival falls to around 50%. Overall, a 5-year survival of >70% should be achieved.

Myeloma laboratory findings include:
– The presence of a paraprotein in serum or urine (the paraprotein is IgG in 60 percent of cases, IgA in 20 percent, and light chain only in almost all the rest),
– Increased serum immunoglobulin-free light chain proteins generated by plasma cells but not coupled with heavy chains 
– Reduced IgG, IgA, and IgM levels in the blood (immune paresis)
– Anaemia, whether normochromic, normocytic, or macrocytic. 
– On a blood film, a Rouleaux formation has been marked.
– In advanced illness, neutropenia and thrombocytopenia are common.
– ESR is high.
– Plasma cells in the bone marrow are overabundant, typically in aberrant forms. – Hypercalcemia
– Creatinine levels are high.
– Serum albumin levels are low in advanced illness.
60 percent of patients have osteolytic lesions, osteoporosis, or pathological fractures.

Chronic ITP is a relatively common disorder. The highest incidence is in women aged 15 – 50 years. It is the most common cause of thrombocytopaenia without anaemia or neutropaenia. It is usually idiopathic but it may been seen in association with other conditions. Platelet autoantibodies (usually IgG) result in the premature removal of platelets from the circulation by macrophages of the reticuloendothelial system. In many causes the antibody is directed against the glycoprotein IIb/IIIa or Ib complex. The normal platelet lifespan of 10 days is reduced to a few hours. Total megakaryocyte mass and platelet turnover are increased to approximately five times normal. Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged.  In fact, an enlarged spleen should lead to a search for other possible causes for the thrombocytopenia.

Anaemia of chronic disease is one of the most common causes of normocytic anaemia. The anaemia is usually mild (Hb > 90 g/L) and non-progressive. Anaemia of chronic disease is usually associated with low serum iron, low transferrin saturation, and a low total iron binding capacity (TIBC) with normal or raised ferritin which differentiates it from iron deficiency anaemia.

Sickling of red blood cells can lead to several different clinical syndromes. If the sickling occurs in the corpora cavernosa, it can lead to a sustained, painful erection of the penis, referred to as priapism. One of the complications is long-term impotence. It is important to seek a urological opinion immediately in this case, but in the interim, treat with perineal ice packs and walk up and down the stairs.

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.

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.

Acute lymphoblastic leukaemia (ALL) is a clonal (malignant) bone marrow disorder in which early lymphoid precursors multiply and replace the marrow’s normal hematopoietic cells. ALL is most common between the ages of 3 and 7, with 75 percent of cases occurring before the age of 6.

DIC is characterised by a widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets. This may occur as a consequence of many disorders that release procoagulant material into the circulation or cause widespread endothelial damage or platelet aggregation. Increased activity of thrombin in the circulation overwhelms its normal rate of removal by natural anticoagulants. In addition to causing increased deposition of fibrin in the microcirculation and widespread platelet aggregation to the vessels, intravascular thrombin formation interferes with fibrin polymerisation. Intense fibrinolysis is stimulated by thrombi on vascular walls and the release of fibrin degradation products again interferes with fibrin polymerisation. The combined action of thrombin and plasmin causes depletion of fibrinogen and all coagulation factors, compounded by thrombocytopaenia caused by platelet consumption.

Beta-thalassaemia major is caused by a complete or almost complete failure of β-globin chain synthesis, severe imbalance of α:β-chains with deposition of α-chains in erythroblasts, ineffective erythropoiesis and extramedullary haemopoiesis. The severe anaemia becomes apparent at 3 – 6 months when the switch from γ-chain to β-chain synthesis normally occurs. Beta-thalassaemia minor is a variable syndrome, milder than thalassaemia major, with later onset and characterised by moderate hypochromic microcytic anaemia with raised haemoglobin A2. Beta-thalassaemia trait is characterised by mild hypochromic, microcytic anaemia with raised red cell count and raised haemoglobin A2.

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.

Bone pain, pathologic fractures, weakness, anaemia, infection, hypercalcemia, spinal cord compression, and renal failure are all signs and symptoms of multiple myeloma (MM). The patient’s condition matched the signs and symptoms of myeloma.

Causes of intravascular haemolysis:
Haemolytic transfusion reactions
G6PD deficiency
Red cell fragmentation syndromes
Some severe autoimmune haemolytic anaemias
Some drug-and infection-induced haemolytic anaemias
Paroxysmal nocturnal haemoglobinuria

Blood transfusion can be a life-saving treatment with significant clinical benefits, but it also comes with a number of risks and potential complications, including:
Immunological side effects
Errors in administration (episodes of ‘wrong blood’)
Viruses and Infections (bacterial, viral, possibly prion)
Immunodilution

A culture of better safety procedures as well as steps to reduce the use of transfusion has emerged as a result of growing awareness of avoidable risk and improved reporting systems. Transfusion errors, on the other hand, continue to occur, and some serious adverse reactions go unreported.

Transfusion-associated graft-vs-host disease (TA-GVHD) is a rare blood transfusion complication that causes fever, rash, and diarrhoea 1-4 weeks after the transfusion. Pancytopenia and liver function abnormalities are common laboratory findings.

TA-GVHD, unlike GVHD following allogeneic marrow transplantation, causes profound marrow aplasia with a mortality rate of >90%. Survival is uncommon, with death occurring within 1-3 weeks of the onset of symptoms.

Because of immunodeficiency, severe immunosuppression, or shared HLA antigens, viable T lymphocytes in blood components are transfused, engraft, and react against the recipient’s tissues, and the recipient is unable to reject the donor lymphocytes.
The following is a list of the most common transfusion reactions and complications:

1) Reaction to a febrile transfusion
The temperature rises by one degree from the baseline. Chills and malaise are also possible symptoms.
The most common response (1 in 8 transfusions).
Cytokines from leukocytes in transfused red cell or platelet components are usually to blame.
Only supportive. The use of paracetamol is beneficial.

2) Acute haemolytic reaction is a type of haemolytic reaction that occurs when the
Fever, chills, pain at the transfusion site, nausea, vomiting, and dark urine are all symptoms of a transfusion reaction.
Early on, many people report a sense of ‘impending doom.’
The most serious reaction. ABO incompatibility is frequently caused by a clerical error.
STOP THE TRANSFUSION OF INFORMATION. IV fluids should be given. It’s possible that diuretics will be required.

3) Haemolytic reaction that is delayed
It usually happens 4 to 8 days after a blood transfusion.
Fever, anaemia, jaundice, and haemoglobinuria are all symptoms that the patient has.
Positive Coombs test for direct antiglobulin.
Because of the low titre antibody, it is difficult to detect in a cross-match, and it is unable to cause lysis at the time of transfusion.
The majority of delayed haemolytic reactions are harmless and do not require treatment.
Anaemia and renal function should be monitored and treated as needed.

4) Reaction to allergens
Foreign plasma proteins are usually to blame, but anti-IgA could also be to blame.
Urticaria, pruritus, and hives are typical allergic reactions. It’s possible that it’s linked to laryngeal oedema or bronchospasm.
Anaphylaxis is a rare occurrence.
Antihistamines can be used to treat allergic reactions symptomatically. It is not necessary to stop transfusions.
If the patient develops anaphylaxis, the transfusion should be stopped and the patient should be given adrenaline and treated according to the ALS protocol.

5) TRALI (Transfusion Related Acute Lung Injury)
Within 6 hours of transfusion, there was a sudden onset of non-cardiogenic pulmonary oedema.
It’s linked to the presence of antibodies to recipient leukocyte antigens in the donor blood.
The most common cause of death from transfusion reactions is this.
STOP THE TRANSFUSION OF INFORMATION. Oxygen should be given to the patient. Around 75% of patients will require aggressive respiratory support.
The use of diuretics should be avoided.

6) TACO (Transfusion Associated Circulatory Overload)
Acute or worsening respiratory distress within 6 hours of a large blood transfusion. Fluid overload and pulmonary and peripheral oedema can be seen. Rapid blood pressure rises are common. BNP is usually 1.5 times higher than it was before the transfusion. It is most common in the elderly and those who have chronic anaemia.

Blood transfusions should be given slowly, over the course of 3-4 hours.

The history of nosebleeds and fatigue, and gingival hyperplasia presents a typical picture of acute myeloid leukaemia. Leukemic infiltrates within the gingiva cause hypertrophy and distinguish this condition from other types of leukaemia. The fatigue is secondary to anaemia, while the nosebleeds are caused by thrombocytopenia secondary to leukemic infiltration of bone marrow. Patients may also report frequent infections secondary to neutropenia and hepatosplenomegaly.

Features include:
– severe anaemia (becoming apparent at 3 – 6 months when the switch from gamma-chain to beta-chain production takes place)
– failure to thrive
– hepatosplenomegaly (due to excessive red cell destruction, extramedullary haemopoiesis and later due to transfusion related iron overload)
– expansion of bones (due to marrow hyperplasia, resulting in bossing of the skull and cortical thinning with tendency to fracture)
– increased susceptibility to infections (due to anaemia, iron overload, transfusion and splenectomy)
– osteoporosis
– hyperbilirubinaemia and gallstones
– hyperuricaemia and gout
– other features of haemolytic anaemia
– liver damage and other features of iron overload

The collection of abnormalities found in these patients is referred to as a hyposplenic film.
The following features can be seen on hyposplenic blood films:
Howell-Jolly bodies
Heinz’s bodies
Target cells
RBCs with nuclei on occasion
Lymphocytosis
Macrocytosis
Acanthocytes
Teardrop cells, also known as dacrocytes, are named for their teardrop-shaped shape.

Dacrocytosis is a condition in which a large number of these cells are present. Myelofibrosis and beta thalassemia major both have dacrocytes, but hyposplenism does not.

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