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

Haemophilia B is a bleeding disorder caused by a deficiency of clotting factor IX. It is the second commonest form of haemophilia, and is rarer than haemophilia A. Haemophilia B tends to be similar to haemophilia A but less severe. The two disorders can only be distinguished by specific coagulation factor assays.

The incidence is one-fifth of that of haemophilia A. Laboratory findings demonstrate prolonged APTT, normal PT and low factor IX.
Haemophilia B inherited in an X-linked recessive fashion, affecting males born to carrier mothers.
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.

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.

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.

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.

Neutropenia is defined as a total neutrophil count of < 2.0 x 109/l.
It can be caused by:
Viral infections
Collagen disease e.g. SLE and RA
Chemotherapy and radiotherapy
Hypersplenism
Marrow infiltration
Vitamin and folate deficiency
Drug reactions
Drugs that cause neutropenia include flecainide, phenytoin, carbimazole, indomethacin and co-trimoxazole.

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. Typical 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.

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.

TRALI (Transfusion Related Acute Lung Injury) is a clinical syndrome with abrupt onset of non-cardiogenic pulmonary oedema within 6 hours of transfusion not explained by another risk factor. Associated with the presence of antibodies in the donor blood to recipient leukocyte antigens. patients present with dyspnoea, hypertension, hypotension, acute leukopenia.

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 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.

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.

Features of intravascular haemolysis include:haemoglobinaemia, methaemalbuminaemia, haemoglobinuria (dark urine) and haemosiderinuria

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.

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.

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.

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

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.

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.

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.

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)

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.

The presence of Reed-Sternberg cells is pathognomonic for Hodgkin’s Lymphoma, which is a disease-causing neoplastic transformation of lymphocytes. There is a bimodal age distribution with peaks in the 20s and 60s. Patients typically present with enlarged, rubbery, non-tender lymph nodes. Symptoms such as fever, night sweats and weight loss may be present.

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.

Multiple myeloma most commonly presents with bone pain, especially in the back and ribs.

In non-Hodgkin’s lymphoma, Reed-Sternberg cells are not present.

Acute lymphoblastic leukaemia will present with features of anaemia, thrombocytopenia and leukopenia.

The most common symptoms of chronic lymphocytic leukaemia are fatigue, night sweats and low-grade fever.

The most common cause of microcytic anaemia and of any anaemia worldwide is iron deficiency anaemia.