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.

During or shortly after transfusion, febrile transfusion reactions, also known as non-haemolytic transfusion reactions, present with an unexpected temperature rise (38oC or 1oC above baseline, if baseline is 37oC). This is usually a one-off occurrence. The fever is sometimes accompanied by chills.The most common type of transfusion reaction is febrile transfusion reactions, which occur in about 1 in every 8 transfusions.The most common event leading to symptoms of febrile transfusion reactions is cytokine accumulation during storage of cellular components (especially platelet units). White cells secrete cytokines, and pre-storage leucodepletion has reduced this risk.Recipient antibodies (raised as a result of previous transfusions or pregnancies) reacting to donor human leukocyte antigen (HLA) or other antigens can also cause febrile transfusion reactions. Donor lymphocytes, granulocytes, and platelets all contain these antigens.Treatment is reassuring. Other causes should be ruled out, and antipyretics like paracetamol can help with fever relief. If another cause of fever is suspected, the transfusion should be stopped; however, if other causes of fever have been ruled out, it can be restarted at a slower rate.

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.

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 exhaustionNight sweats and feverDistension of the abdomenPain in the left upper quadrant (splenic infarction)Splenomegaly (commonest examination finding)HepatomegalyBruising 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.

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.

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.

Features include: AnaemiaJaundice (caused by unconjugated bilirubin in plasma, bilirubin is absent from urine)Pigment gallstonesSplenomegalyAnkle ulcersExpansion of marrow with, in children, bone expansion e.g. frontal bossing in beta-thalassaemia majorAplastic crisis caused by parvovirus

Acute haemolytic transfusion reactions present with: Feeling of ‘impending doom’ as the earliest symptom, fever and chills, pain and warmth at transfusion site, nausea and vomiting, back, joint, and chest pain. Transfusion should be stopped immediately and IV fluid (usually normal saline) administered.Supportive measures and paracetamol can be given since patient has fever but it is not the immediate first step.

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

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.

ALL is the most common leukaemia in children, with a peak incidence between the ages of 2 and 5.ALL has a wide range of clinical symptoms, but many children present with an acute illness that resembles coryza or a viral infection. ALL also has the following features:Weakness and sluggishness all overMuscle, joint, and bone pain that isn’t specificAnaemiaPetechiae and unexplained bruisingOedemaLymphadenopathyHepatosplenomegalyThe following are typical features of a full blood count in patients with ALL:Anaemia (normocytic or macrocytic)Leukopenia affects about half of the patients (WCC 4 x 109/l).Around 25% of patients have leucocytosis (WCC > 10 x 109/l).Around 25% of patients have hyperleukocytosis (WCC > 50 x 109/l).Thrombocytopaenia

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

A total neutrophil count of less than 2 x 109/L is defined as neutropenia. It can be caused by the following:1. viral infections2. SLE3. RA4. hypersplenism5. chemo- and radiotherapy6. vitamin B12 and folate deficiency7. drug reactions

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.

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.

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.

Acute ITP is most common in children. In approximately 75% of cases, the episode follows vaccination or infection such as chicken pox or glandular fever. Most cases are caused by non-specific immune complex attachment to platelets. Acute ITP usually has a very sudden onset and the symptoms usually disappear in less than 6 months (often within a few weeks). It is usually a self-limiting condition and over 80% of children recover without treatment; in 5 – 10% of cases a chronic form of the disease develops.

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.

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

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.

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.

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.

Acute lymphocytic leukaemia (ALL) is more common in children than chronic leukaemias, which generally occur in adults. Bone marrow failure occurs early on in the course of the disease in acute leukaemias, and there is the massive proliferation of undifferentiated cells with functioning cells being crowded out. Hepatosplenomegaly occurs in both acute and chronic forms of leukaemia and is not a differentiating feature.

98% of cases of myeloma occur over the age of 40 years with a peak incidence between 65 and 70 years. The disease is twice as common in black individuals compared to those of white or Asian origin. Laboratory findings include presence of a paraprotein in serum/urine (the paraprotein is IgG in 60% of cases, IgA in 20% and light chain only in almost all the rest) and marked Rouleaux formation on blood film. There is no cure for myeloma. The overall median survival is now 7-10 years and in younger (less than 50 years) patients it can be over 10 years.

Features may include:Normochromic normocytic anaemia is most common; bone marrow failure involvement is unusual in early disease, but if it occurs bone marrow failure may develop with leucoerythroblastic anaemiaOne-third of patients have a neutrophilia; eosinophilia is frequentAdvanced disease is associated with lymphopenia and loss of cell-mediated immunityPlatelet count is normal or increased in early disease and reduced in later stagesESR and CRP are usually raised (ESR is useful in monitoring disease progress)Serum LDH is raised initially in 30-40% of casesDiagnosis is made by histological examination of an excised lymph nodeThe distinctive multinucleate polypoid RS cell is central to the diagnosis of the four classic types of HL (95% of cases)

Anaemia is defined as a reduction in haemoglobin concentration below the normal range for the age and sex of the individual. Children tend to have lower haemoglobin than adults, and women tend to have lower haemoglobin than men. Anaemia may occur from an actual reduction in total circulating haemoglobin mass, or with an increase in plasma volume e.g. in pregnancy, causing a dilutional anaemia. After acute major blood loss, anaemia is not immediately apparent because total blood volume is reduced and it takes up to a day for plasma volume to be replaced and hence the degree of anaemia to become apparent. The initial clinical features in acute haemorrhage are therefore a result of reduction in blood volume rather than that of anaemia. When anaemia develops slowly, the associated symptoms are often very mild as the body has time to adapt to the fall in haemoglobin. This involves mechanisms such as an increase in red cell 2,3 -diphosphoglycerate (2,3 – DPG), which shifts the oxygen dissociation curve to the right, allowing enhanced delivery of O2 to the tissues, and an increase in stroke volume and heart rate.

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 weeksGram-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 chillsVomiting and nauseaTachycardiaHypotensionCollapse of the circulatory systemIf 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.

Factor V Leiden gene mutation is the most common inherited cause of an increased risk of venous thrombosis. Activated protein C normally breaks down activated factor V and so should slow the clotting reaction and prolong the APTT, but a mutation in the factor V gene makes factor V less susceptible to cleavage by activated protein C, resulting in increased levels of activated factor V.Heterozygotes for factor V Leiden are at an approximately five- to eight- fold increased risk of venous thrombosis compared to the general population (but only 10% of carriers will develop thrombosis in their lifetime). Homozygotes have a 30 – 140-fold increased risk. The incidence of factor V Leiden in patients with venous thrombosis is approximately 20 – 40%. It does not increase the risk of arterial thrombosis.

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 annual incidence of Hodgkin’s lymphoma in the UK is approximately 3 per 100,000 per year. 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 genderAge 20-35Positive family historyEpstein-Barr virus infectionImmunosuppression including HIV infectionProlonged use of human growth hormoneMost 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 sweatsWeight 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 groupStage II two involved lymph node groups on one side of the diaphragmStage III: lymph node groups involved on both sides of the diaphragmStage IV: Involvement of extra-nodal tissues, such as the liver or bone marrowDiagnosis 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 LymphomaHistological 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.

The release of cytokines from Reed-Sternberg cells can cause fever in patients with Hodgkin lymphoma, which increases and decreases in a cyclical pattern of 1 to 2 weeks. This is called Pel-Ebstein or Ebstein-Cardarelli fever, specifically seen in Hodgkin lymphoma. The fever is always high grade and can reach 40 degrees or higher.Cyclical fever in other conditions is common but is not termed as Pel-Ebstein fever. This term is reserved only with Hodgkin lymphoma.