Prognostic Factors in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow. The APML subtype of AML has a higher five-year survival rate of 70% compared to the average rate of 25%. However, it is a medical emergency upon presentation due to the risk of coagulopathy, tumor lysis, and life-threatening infections. Urgent treatment with ATRA chemotherapy is necessary. Younger patients tend to have a better prognosis and can tolerate intensive chemotherapy better. Certain cytogenetic changes, such as t(15;17) in APML and t(8;21) and inv(16), are associated with a favorable prognosis. However, complex cytogenetics are not. A performance status of 3, which indicates that an individual spends more than 50% of the day in bed, is not ideal for intensive chemotherapy. AML that arises from a pre-existing condition, such as a myeloproliferative neoplasm, has a worse prognosis than AML that arises de novo.

Overall, the prognostic factors in AML is crucial for determining the appropriate treatment plan and predicting outcomes.

Filgrastim is a medication that stimulates the growth of granulocytes and is commonly used to treat neutropenia. In the case of a patient with a history of fever, low blood pressure, and tachycardia, it is likely that they have developed sepsis, which is a common complication in patients receiving chemotherapy. The main treatment for sepsis is fluid resuscitation and broad-spectrum antibiotics. While filgrastim is not a direct treatment for sepsis, it can be used to address leukopenia caused by chemotherapy, aplastic anemia, and congenital neutropenia.

Darbepoetin is a medication that mimics the effects of erythropoietin and is commonly used to treat anemia, particularly in patients with renal failure.

Eltrombopag is a medication that activates the TPO receptor and is often used to treat autoimmune thrombocytopenia.

IFN-γ is a medication used to treat chronic granulomatous disease.

Granulocyte-Colony Stimulating Factors for Neutropenia

Granulocyte-colony stimulating factors (G-CSFs) are synthetic versions of a natural protein that stimulates the production of white blood cells called neutrophils. These drugs are used to increase neutrophil counts in patients who are neutropenic, meaning they have abnormally low levels of neutrophils. Neutropenia can occur as a side effect of chemotherapy or radiation therapy, or due to other factors such as infections or autoimmune disorders.

Recombinant human G-CSFs, such as filgrastim and perfilgrastim, are commonly used to treat neutropenia. These drugs work by stimulating the bone marrow to produce more neutrophils, which can help prevent infections and other complications associated with low white blood cell counts. G-CSFs are typically administered by injection, either subcutaneously or intravenously.

Overall, G-CSFs are an important tool in the management of neutropenia, particularly in patients undergoing chemotherapy or other treatments that can suppress the immune system. By boosting neutrophil production, these drugs can help reduce the risk of infections and improve outcomes for patients with compromised immune function.

The presence of a Factor V Leiden mutation can lead to activated protein C resistance, which is a common cause of thrombophilia. Budd-Chiari syndrome, characterized by abdominal pain, ascites, and hepatomegaly, may require a thrombophilia screen to identify potential causes. Antithrombin deficiency, caused by a mutation in the SERPINC1 gene, is another type of thrombophilia. Antiphospholipid syndrome, an immunological disorder that increases the risk of thrombosis, is not related to Factor V Leiden mutations. Protein C deficiency, caused by mutations in the PROC gene, is another type of thrombophilia.

Understanding Factor V Leiden

Factor V Leiden is a common inherited thrombophilia, affecting around 5% of the UK population. It is caused by a mutation in the Factor V Leiden protein, resulting in activated factor V being inactivated 10 times more slowly by activated protein C than normal. This leads to activated protein C resistance, which increases the risk of venous thrombosis. Heterozygotes have a 4-5 fold risk of venous thrombosis, while homozygotes have a 10 fold risk, although the prevalence of homozygotes is much lower at 0.05%.

Despite its prevalence, screening for Factor V Leiden is not recommended, even after a venous thromboembolism. This is because a previous thromboembolism itself is a risk factor for further events, and specific management should be based on this rather than the particular thrombophilia identified.

Other inherited thrombophilias include Prothrombin gene mutation, Protein C deficiency, Protein S deficiency, and Antithrombin III deficiency. The table below shows the prevalence and relative risk of venous thromboembolism for each of these conditions.

Overall, understanding Factor V Leiden and other inherited thrombophilias can help healthcare professionals identify individuals at higher risk of venous thrombosis and provide appropriate management to prevent future events.

Condition | Prevalence | Relative risk of VTE
— | — | —
Factor V Leiden (heterozygous) | 5% | 4
Factor V Leiden (homozygous) | 0.05% | 10
Prothrombin gene mutation (heterozygous) | 1.5% | 3
Protein C deficiency | 0.3% | 10
Protein S deficiency | 0.1% | 5-10
Antithrombin III deficiency | 0.02% | 10-20

The symptoms displayed by this individual suggest the presence of chronic myeloid leukemia (CML), which is identified by the Philadelphia chromosome. This chromosome results from a genetic abnormality where chromosome 9 and 22 exchange genetic material, leading to the formation of the BCR-ABL gene.

Understanding Chronic Myeloid Leukaemia and its Management

Chronic myeloid leukaemia (CML) is a type of cancer that affects the blood and bone marrow. It is characterized by the presence of the Philadelphia chromosome in more than 95% of patients. This chromosome is formed due to a translocation between chromosomes 9 and 22, resulting in the fusion of the ABL proto-oncogene and the BCR gene. The resulting BCR-ABL gene produces a fusion protein that has excessive tyrosine kinase activity.

CML typically affects individuals between the ages of 60-70 years and presents with symptoms such as anaemia, weight loss, sweating, and splenomegaly. The condition is also associated with an increase in granulocytes at different stages of maturation and thrombocytosis. In some cases, CML may undergo blast transformation, leading to acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL).

The management of CML involves various treatment options, including imatinib, which is considered the first-line treatment. Imatinib is an inhibitor of the tyrosine kinase associated with the BCR-ABL defect and has a very high response rate in chronic phase CML. Other treatment options include hydroxyurea, interferon-alpha, and allogenic bone marrow transplant. With proper management, individuals with CML can lead a normal life.

DIC is often associated with pregnancy complications such as placental abruption and shock, as well as bleeding from multiple sites and abnormal blood test results. Placenta praevia is characterized by painless vaginal bleeding, but when combined with other haematological results and occurring in a pregnant woman, it may indicate DIC rather than ITP. TTP typically presents with jaundice, low platelets, fever, renal complications, and CNS signs, which are not evident in this case, and clotting test results do not support this diagnosis. While von Willebrand’s disease can cause spontaneous bleeding, the platelet count is usually normal.

Disseminated Intravascular Coagulation: A Condition of Simultaneous Coagulation and Haemorrhage

Disseminated intravascular coagulation (DIC) is a medical condition characterized by simultaneous coagulation and haemorrhage. It is caused by the initial formation of thrombi that consume clotting factors and platelets, ultimately leading to bleeding. DIC can be caused by various factors such as infection, malignancy, trauma, liver disease, and obstetric complications.

Clinically, bleeding is usually the dominant feature of DIC, accompanied by bruising, ischaemia, and organ failure. Blood tests can reveal prolonged clotting times, thrombocytopenia, decreased fibrinogen, and increased fibrinogen degradation products. The treatment of DIC involves addressing the underlying cause and providing supportive management.

In summary, DIC is a serious medical condition that requires prompt diagnosis and management. It is important to identify the underlying cause and provide appropriate treatment to prevent further complications. With proper care and management, patients with DIC can recover and regain their health.

Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is a type of cancer that commonly affects children over the age of one. It occurs when a lymphocyte precursor, known as a ‘blast cell’, grows abnormally in the bone marrow, leading to a failure of normal blood cell production. This results in peripheral cytopenias, which can cause symptoms such as anaemia, recurrent infections, and purpura. While a raised peripheral white cell count may occur in severe or late-stage disease, it is not common.

Compared to other types of leukaemia and lymphoma, ALL is more likely to present with bone marrow failure symptoms. Acute myeloid leukaemia, for example, is more common in the elderly and presents with a raised peripheral white cell count. Burkitt lymphoma, on the other hand, is a high-grade non-Hodgkin lymphoma that typically presents with lymphadenopathy. Chronic lymphocytic leukaemia is also more common in the elderly and presents with a peripheral lymphocytosis. Langerhans histiocytosis, a condition that affects antigen-presenting cells, is more common in young children and often affects the skin or bones. While it can cause marrow failure, it is a rare occurrence.

In summary, ALL is a type of cancer that affects children and is caused by abnormal growth of blast cells in the bone marrow. It can cause symptoms of bone marrow failure, such as anaemia, recurrent infections, and purpura. While other types of leukaemia and lymphoma may present with different symptoms, ALL is more likely to present with bone marrow failure symptoms.

Mast cells originate from common myeloid progenitor cells.

Haematopoiesis: The Generation of Immune Cells

Haematopoiesis is the process by which immune cells are produced from haematopoietic stem cells in the bone marrow. These stem cells give rise to two main types of progenitor cells: myeloid and lymphoid progenitor cells. All immune cells are derived from these progenitor cells.

The myeloid progenitor cells generate cells such as macrophages/monocytes, dendritic cells, neutrophils, eosinophils, basophils, and mast cells. On the other hand, lymphoid progenitor cells give rise to T cells, NK cells, B cells, and dendritic cells.

This process is essential for the proper functioning of the immune system. Without haematopoiesis, the body would not be able to produce the necessary immune cells to fight off infections and diseases. Understanding haematopoiesis is crucial in developing treatments for diseases that affect the immune system.

Understanding Sickle-Cell Anaemia

Sickle-cell anaemia is a genetic disorder that occurs when an abnormal haemoglobin chain, known as HbS, is synthesized due to an autosomal recessive condition. This condition is more common in people of African descent, as the heterozygous condition offers some protection against malaria. In the UK, around 10% of Afro-Caribbean individuals are carriers of HbS. Symptoms in homozygotes typically do not develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

The pathophysiology of sickle-cell anaemia involves the substitution of the polar amino acid glutamate with the non-polar valine in each of the two beta chains (codon 6) of haemoglobin. This substitution decreases the water solubility of deoxy-Hb, causing HbS molecules to polymerize and sickle in the deoxygenated state. HbAS patients sickle at p02 2.5 – 4 kPa, while HbSS patients sickle at p02 5 – 6 kPa. Sickle cells are fragile and can cause haemolysis, block small blood vessels, and lead to infarction.

To diagnose sickle-cell anaemia, haemoglobin electrophoresis is the definitive test. It is essential to understand the pathophysiology and symptoms of sickle-cell anaemia to provide appropriate care and management for affected individuals.

The risk of venous thromboembolism is elevated in individuals with polycythaemia due to the abnormal overproduction of red blood cells, which leads to increased blood viscosity and slower flow rate, increasing the likelihood of clot formation. Conversely, low BMI does not increase the risk of VTE, while obesity is a known risk factor. Additionally, thrombophilia, not haemophilia, is a risk factor for VTE.

Risk Factors for Venous Thromboembolism

Venous thromboembolism (VTE) is a condition where blood clots form in the veins, which can lead to serious complications such as pulmonary embolism (PE). While some common predisposing factors include malignancy, pregnancy, and the period following an operation, there are many other factors that can increase the risk of VTE. These include underlying conditions such as heart failure, thrombophilia, and nephrotic syndrome, as well as medication use such as the combined oral contraceptive pill and antipsychotics. It is important to note that around 40% of patients diagnosed with a PE have no major risk factors. Therefore, it is crucial to be aware of all potential risk factors and take appropriate measures to prevent VTE.

Chronic Lymphocytic Leukaemia (CLL) Prognostic Indicators

Chronic lymphocytic leukaemia (CLL) is a type of cancer that affects the blood and bone marrow. Patients with CLL often have genetic mutations, with trisomy 12 being a bad prognostic indicator. ZAP-70, a tyrosine kinase involved in cell signalling, is also measured in CLL patients, and high expression is associated with a poor prognosis. On the other hand, lactate dehydrogenase (LDH) is a marker of tumour burden, and a normal level suggests less tumour bulk, which is a good prognostic marker.

Many patients with CLL may not require treatment and may die with the disease rather than from it. It is often diagnosed in asymptomatic patients who undergo blood tests for other reasons. Treating the disease too early may actually lead to a worse outcome than monitoring the patient initially. Therefore, patients who do not need to start treatment immediately have a more favourable outlook.

B cells in secondary lymphoid tissue undergo somatic hypermutation when they recognise an antigen. This process fine-tunes antibody specificity, and cells that have undergone somatic hypermutation are more mature. If CLL arises from one of these cells, it is associated with a more favourable prognosis. these prognostic indicators can help healthcare professionals determine the best course of treatment for patients with CLL.

Increased osteoclast activity in response to cytokines released by myeloma cells is the primary cause of hypercalcaemia in multiple myeloma, which typically affects individuals aged 60-70 years and presents with bone pain or pathological fractures from osteolytic lesions. Hypercalcaemia in kidney failure is associated with hyperphosphataemia and does not cause bone pain. Elevated calcitriol levels are linked to granulomatous disorders like sarcoidosis and tuberculosis, which do not typically cause bone pain. Rebound hypercalcaemia occurs after rhabdomyolysis, which usually results from a fall and long lie. Although primary hyperparathyroidism is a common cause of hypercalcaemia and can lead to bone pain or pathological fractures, it is not associated with anaemia.

Understanding Multiple Myeloma: Features and Investigations

Multiple myeloma is a type of cancer that affects the plasma cells in the bone marrow. It is most commonly found in patients aged 60-70 years. The disease is characterized by a range of symptoms, which can be remembered using the mnemonic CRABBI. These include hypercalcemia, renal damage, anemia, bleeding, bone lesions, and increased susceptibility to infection. Other features of multiple myeloma include amyloidosis, carpal tunnel syndrome, neuropathy, and hyperviscosity.

To diagnose multiple myeloma, a range of investigations are required. Blood tests can reveal anemia, renal failure, and hypercalcemia. Protein electrophoresis can detect raised levels of monoclonal IgA/IgG proteins in the serum, while bone marrow aspiration can confirm the diagnosis if the number of plasma cells is significantly raised. Imaging studies, such as whole-body MRI or X-rays, can be used to detect osteolytic lesions.

The diagnostic criteria for multiple myeloma require one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of the disease. Major criteria include the presence of plasmacytoma, 30% plasma cells in a bone marrow sample, or elevated levels of M protein in the blood or urine. Minor criteria include 10% to 30% plasma cells in a bone marrow sample, minor elevations in the level of M protein in the blood or urine, osteolytic lesions, or low levels of antibodies in the blood. Understanding the features and investigations of multiple myeloma is crucial for early detection and effective treatment.

Rectal cancer that occurs below the pectinate line is known to spread to the superficial inguinal lymph nodes. This is because the superficial inguinal nodes are responsible for draining the lymphatic system of the rectum below the pectinate line, as well as the lower limbs, scrotum/vulva.

It is important to note that the inferior mesenteric nodes are not involved in this process, as they primarily drain the hindgut structures from the transverse colon down to the rectum. Similarly, the internal iliac nodes are not involved, as they drain the inferior portion of the rectum, the anal canal superior to the pectinate line, and the pelvic viscera.

Para-aortic nodes are also not involved in the spread of rectal cancer below the pectinate line, as this portion of the rectum does not drain directly to these nodes. Instead, the testes/ovaries drain directly into the para-aortic nodes. Finally, popliteal nodes are not involved, as they only provide lymphatic drainage for the legs.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

The macroscopic features of this condition typically involve ulcers, fibrosis, and a granulomatous process. It is more commonly a primary occurrence rather than a consequence of acute inflammation.

Chronic inflammation can occur as a result of acute inflammation or as a primary process. There are three main processes that can lead to chronic inflammation: persisting infection with certain organisms, prolonged exposure to non-biodegradable substances, and autoimmune conditions involving antibodies formed against host antigens. Acute inflammation involves changes to existing vascular structure and increased permeability of endothelial cells, as well as infiltration of neutrophils. In contrast, chronic inflammation is characterized by angiogenesis and the predominance of macrophages, plasma cells, and lymphocytes. The process may resolve with suppuration, complete resolution, abscess formation, or progression to chronic inflammation. Healing by fibrosis is the main result of chronic inflammation. Granulomas, which consist of a microscopic aggregation of macrophages, are pathognomonic of chronic inflammation and can be found in conditions such as colonic Crohn’s disease. Growth factors released by activated macrophages, such as interferon and fibroblast growth factor, may have systemic features resulting in systemic symptoms and signs in individuals with long-standing chronic inflammation.

Schistocytes on a blood film are indicative of intravascular haemolysis, which is the most likely cause in this clinical scenario. The presence of a mid-line sternotomy scar, metallic click to the first heart sound, and warfarin prescription suggests a metal heart valve, which can cause sheering of red blood cells and subsequent intravascular haemolysis. Vasculitis, thrombotic thrombocytopenic purpura (TTP), and B12 deficiency are less likely causes in this case.

Pathological Red Cell Forms in Blood Films

Blood films are used to examine the morphology of red blood cells and identify any abnormalities. Pathological red cell forms are associated with various conditions and can provide important diagnostic information. Some of the common pathological red cell forms include target cells, tear-drop poikilocytes, spherocytes, basophilic stippling, Howell-Jolly bodies, Heinz bodies, schistocytes, pencil poikilocytes, burr cells (echinocytes), and acanthocytes.

Target cells are seen in conditions such as sickle-cell/thalassaemia, iron-deficiency anaemia, hyposplenism, and liver disease. Tear-drop poikilocytes are associated with myelofibrosis, while spherocytes are seen in hereditary spherocytosis and autoimmune hemolytic anaemia. Basophilic stippling is a characteristic feature of lead poisoning, thalassaemia, sideroblastic anaemia, and myelodysplasia. Howell-Jolly bodies are seen in hyposplenism, while Heinz bodies are associated with G6PD deficiency and alpha-thalassaemia. Schistocytes or ‘helmet cells’ are seen in conditions such as intravascular haemolysis, mechanical heart valve, and disseminated intravascular coagulation. Pencil poikilocytes are seen in iron deficiency anaemia, while burr cells (echinocytes) are associated with uraemia and pyruvate kinase deficiency. Acanthocytes are seen in abetalipoproteinemia.

In addition to these red cell forms, hypersegmented neutrophils are seen in megaloblastic anaemia. Identifying these pathological red cell forms in blood films can aid in the diagnosis and management of various conditions.

The superior mesenteric lymph nodes are responsible for draining the duodenum, which is the second section of the gastrointestinal system. This lymphatic drainage is important for staging gastrointestinal cancers, and is similar to the blood supply of the gut. While the coeliac lymph nodes drain the first part of the gastrointestinal system, the inferior mesenteric lymph nodes drain the third part, and the internal iliac lymph nodes drain the lower part of the rectum and some of the anal canal. The para-aortic lymph nodes are not involved in the drainage of the gastrointestinal system, but instead drain the genito-urinary system. It is important to understand the correct lymphatic drainage patterns for accurate cancer staging.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

The dimorphic blood film is a rare occurrence that can be seen in only a few medical conditions. One such condition is ACD, which is characterized by disordered iron metabolism, reduced erythropoietin response, and decreased erythropoiesis. However, the exact pathophysiology of ACD is not yet fully understood. In CRF, the problem is compounded by a reduction in EPO production and increased bleeding tendency.

Another cause of a microcytosis disproportionate to the degree of anemia is β-thalassemia trait. This condition is often mistaken for iron deficiency, but it does not respond to iron supplementation. Iron deficiency typically causes a hypochromic, microcytic anemia with some variation in red blood size, but not a dimorphic picture. However, partially treated iron deficiency anemia can lead to a dimorphic blood film.

In summary, the dimorphic blood film is a key feature that can be seen in only a limited number of medical conditions. The underlying causes of this condition is crucial for accurate diagnosis and appropriate treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic form of intrinsic hemolytic anemia that can present with symptoms such as hematuria, anemia, and venous thrombosis. The classic triad of PNH includes hemolytic anemia, pancytopenia, and venous thrombosis. The gold standard test for PNH is flow cytometry for CD59 and CD55, which shows a deficiency of these proteins on red and white blood cells.

A deficiency of C3 is a complement deficiency disorder that increases the risk of recurrent bacterial infections. While a deficiency of CD59 or CD55 may be present in this patient, PNH patients typically have a deficiency of both proteins. Terminal complement deficiency, indicated by a deficiency of complements forming the membrane attack membrane, confers a high risk of infection with Neisseria organisms. Eculizumab, a humanized monoclonal antibody, is approved for the treatment of PNH and works by inhibiting the terminal complement cascade.

Understanding Paroxysmal Nocturnal Haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a condition that causes the breakdown of haematological cells, mainly intravascular haemolysis. It is believed to be caused by a lack of glycoprotein glycosyl-phosphatidylinositol (GPI), which acts as an anchor that attaches surface proteins to the cell membrane. This leads to the improper binding of complement-regulating surface proteins, such as decay-accelerating factor (DAF), to the cell membrane. As a result, patients with PNH are more prone to venous thrombosis.

PNH can affect red blood cells, white blood cells, platelets, or stem cells, leading to pancytopenia. Patients may also experience haemoglobinuria, which is characterized by dark-coloured urine in the morning. Thrombosis, such as Budd-Chiari syndrome, is also a common feature of PNH. In some cases, patients may develop aplastic anaemia.

To diagnose PNH, flow cytometry of blood is used to detect low levels of CD59 and CD55. This has replaced Ham’s test as the gold standard investigation for PNH. Ham’s test involves acid-induced haemolysis, which normal red cells would not undergo.

Management of PNH involves blood product replacement, anticoagulation, and stem cell transplantation. Eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis. Understanding PNH is crucial in managing this condition and improving patient outcomes.

Ulcerative colitis, a type of inflammatory bowel disease characterized by bloody diarrhea, can be treated with various medications such as sulfasalazine, infliximab, 6-mercaptopurine, and in severe cases, a colectomy. 6-mercaptopurine is a purine analogue that is activated by HGPRTase, leading to decreased purine synthesis and reduced DNA synthesis. It is commonly used to treat non-malignant conditions like systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. On the other hand, 5-fluorouracil is a pyrimidine analogue that acts as an antimetabolite, interfering with DNA synthesis, and is used to treat colorectal and pancreatic cancer. Methotrexate, an antimetabolite that acts as a folic acid analogue, is widely used in many malignancies and non-malignant conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Bleomycin, doxorubicin, and daunorubicin cause free radical formation, leading to breaks in the DNA strand, while busulfan is an alkylating agent that causes cross-links in the DNA and is typically used to ablate a patient’s bone marrow before a bone marrow transplant.

Cytotoxic agents are drugs that are used to kill cancer cells. There are several types of cytotoxic agents, each with their own mechanism of action and potential adverse effects. Alkylating agents, such as cyclophosphamide, work by causing cross-linking in DNA. However, they can also cause haemorrhagic cystitis, myelosuppression, and transitional cell carcinoma. Cytotoxic antibiotics, like bleomycin and anthracyclines, degrade preformed DNA and stabilize DNA-topoisomerase II complex, respectively. However, they can also cause lung fibrosis and cardiomyopathy. Antimetabolites, such as methotrexate and fluorouracil, inhibit dihydrofolate reductase and thymidylate synthesis, respectively. However, they can also cause myelosuppression, mucositis, and liver or lung fibrosis. Drugs that act on microtubules, like vincristine and docetaxel, inhibit the formation of microtubules and prevent microtubule depolymerisation & disassembly, respectively. However, they can also cause peripheral neuropathy, myelosuppression, and paralytic ileus. Topoisomerase inhibitors, like irinotecan, inhibit topoisomerase I, which prevents relaxation of supercoiled DNA. However, they can also cause myelosuppression. Other cytotoxic drugs, such as cisplatin and hydroxyurea, cause cross-linking in DNA and inhibit ribonucleotide reductase, respectively. However, they can also cause ototoxicity, peripheral neuropathy, hypomagnesaemia, and myelosuppression.

Apixaban directly inhibits factor Xa, while bivalirudin and dabigatran directly inhibit thrombin. On the other hand, enoxaparin is a type of low molecular weight heparin that indirectly inhibits factor Xa by forming a complex with antithrombin III, leading to irreversible inactivation of factor Xa.

Direct oral anticoagulants (DOACs) are medications used to prevent stroke in non-valvular atrial fibrillation (AF), as well as for the prevention and treatment of venous thromboembolism (VTE). To be prescribed DOACs for stroke prevention, patients must have certain risk factors, such as a prior stroke or transient ischaemic attack, age 75 or older, hypertension, diabetes mellitus, or heart failure. There are four DOACs available, each with a different mechanism of action and method of excretion. Dabigatran is a direct thrombin inhibitor, while rivaroxaban, apixaban, and edoxaban are direct factor Xa inhibitors. The majority of DOACs are excreted either through the kidneys or the liver, with the exception of apixaban and edoxaban, which are excreted through the feces. Reversal agents are available for dabigatran and rivaroxaban, but not for apixaban or edoxaban.

The ideal blood type for the patient would be B rhesus negative, but it is not available. Among the available options, rhesus positive blood is not recommended for a woman of reproductive age as it may lead to haemolytic disease in newborns. A-type blood would also cause hemolysis in this patient. The only suitable option is O rhesus negative, which is the universal donor.

Blood product transfusion complications can be categorized into immunological, infective, and other complications. Immunological complications include acute haemolytic reactions, non-haemolytic febrile reactions, and allergic/anaphylaxis reactions. Infective complications may arise due to transmission of vCJD, although measures have been taken to minimize this risk. Other complications include transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), hyperkalaemia, iron overload, and clotting.

Non-haemolytic febrile reactions are thought to be caused by antibodies reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage. These reactions may occur in 1-2% of red cell transfusions and 10-30% of platelet transfusions. Minor allergic reactions may also occur due to foreign plasma proteins, while anaphylaxis may be caused by patients with IgA deficiency who have anti-IgA antibodies.

Acute haemolytic transfusion reaction is a serious complication that results from a mismatch of blood group (ABO) which causes massive intravascular haemolysis. Symptoms begin minutes after the transfusion is started and include a fever, abdominal and chest pain, agitation, and hypotension. Treatment should include immediate transfusion termination, generous fluid resuscitation with saline solution, and informing the lab. Complications include disseminated intravascular coagulation and renal failure.

TRALI is a rare but potentially fatal complication of blood transfusion that is characterized by the development of hypoxaemia/acute respiratory distress syndrome within 6 hours of transfusion. On the other hand, TACO is a relatively common reaction due to fluid overload resulting in pulmonary oedema. As well as features of pulmonary oedema, the patient may also be hypertensive, a key difference from patients with TRALI.

Free haemoglobin is bound by haptoglobin.

Copper is bound by ceruloplasmin.

Stored iron in the body is in the form of ferritin.

Free heme molecules are bound by hemopexin.

Laboratory Findings in Haematological Disease

Haptoglobin is a laboratory test that measures the level of a protein that binds to free haemoglobin. A decrease in haptoglobin levels is often associated with intravascular haemolysis, a condition where red blood cells are destroyed within blood vessels. On the other hand, an increase in mean corpuscular haemoglobin concentration (MCHC) is commonly seen in hereditary spherocytosis and autoimmune haemolytic anemia. In contrast, a decrease in MCHC is often observed in microcytic anaemia, which is commonly caused by iron deficiency. It is important to note that autoimmune haemolytic anemia is often associated with spherocytosis. These laboratory findings are commonly tested in haematological disease exams.

Sickle cell disease can be definitively diagnosed through haemoglobin electrophoresis. In the case of a patient experiencing an acute haemolytic episode due to sickle cell disease, normocytic anaemia with a high reticulocyte count and the presence of Howell jolly bodies indicate hyposplenism. A peripheral smear showing sickle cells is also highly indicative of sickle cell disease, which is an autosomal recessive condition that may be present in other family members.

The osmotic fragility test is used to diagnose hereditary spherocytosis by exposing red blood cells to varying osmolarity and observing their fragility. Plasma folate deficiency can lead to macrocytic anaemia, but this is not the case in sickle cell disease. Flow cytometry is not useful in diagnosing sickle cell disease, but it can be used to classify leukemias and diagnose paroxysmal nocturnal haemoglobinuria.

If an autoimmune cause is suspected, a Coombs test can be performed to confirm the pathogenesis, as in the case of haemolytic disease of the newborn. Haemoglobin electrophoresis is one of the definitive tests for diagnosing sickle cell trait and disease, as it shows a decrease in normal haemoglobin A and the presence of haemoglobin S. Genetic analysis can also confirm the diagnosis.

Understanding Sickle-Cell Anaemia

Sickle-cell anaemia is a genetic disorder that occurs when an abnormal haemoglobin chain, known as HbS, is synthesized due to an autosomal recessive condition. This condition is more common in people of African descent, as the heterozygous condition offers some protection against malaria. In the UK, around 10% of Afro-Caribbean individuals are carriers of HbS. Symptoms in homozygotes typically do not develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

The pathophysiology of sickle-cell anaemia involves the substitution of the polar amino acid glutamate with the non-polar valine in each of the two beta chains (codon 6) of haemoglobin. This substitution decreases the water solubility of deoxy-Hb, causing HbS molecules to polymerize and sickle in the deoxygenated state. HbAS patients sickle at p02 2.5 – 4 kPa, while HbSS patients sickle at p02 5 – 6 kPa. Sickle cells are fragile and can cause haemolysis, block small blood vessels, and lead to infarction.

To diagnose sickle-cell anaemia, haemoglobin electrophoresis is the definitive test. It is essential to understand the pathophysiology and symptoms of sickle-cell anaemia to provide appropriate care and management for affected individuals.

The patient’s CT scan showed lymphadenopathy in the superficial inguinal lymph nodes, which is expected as the infection is located in the perineum. The deep inguinal lymph nodes, which drain the glans penis and clitoris, are not the primary site for perineal drainage. The medial group of external iliac lymph nodes drain the urinary bladder, membranous aspect of the urethra, cervix, and upper part of the vagina, while the internal iliac lymph nodes drain the anal canal above the pectinate line, the lower part of the rectum, the cervix, and the inferior uterus. If there were retained products of conception in the uterus causing an infection or a type 4 perineal tear involving a substantial portion of the rectum, lymphadenopathy of the internal iliac lymph nodes may be seen on the CT scan. The para-aortic lymph nodes drain the ovaries, but this is not relevant to the patient’s case as there is no indication of an ovarian pathology.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

Causes of Generalised Lymphadenopathy

Generalised lymphadenopathy refers to the enlargement of multiple lymph nodes throughout the body. There are various causes of this condition, including infectious, neoplastic, and autoimmune conditions. Infectious causes include infectious mononucleosis, HIV, eczema with secondary infection, rubella, toxoplasmosis, CMV, tuberculosis, and roseola infantum. Neoplastic causes include leukaemia and lymphoma. Autoimmune conditions such as SLE and rheumatoid arthritis, graft versus host disease, and sarcoidosis can also cause generalised lymphadenopathy. Additionally, certain drugs like phenytoin and to a lesser extent allopurinol and isoniazid can also lead to this condition. It is important to identify the underlying cause of generalised lymphadenopathy to determine the appropriate treatment.

The clotting cascade is an example of a positive feedback mechanism, where the presence of clotting factors attracts further clotting factors until a functioning clot is formed. On the other hand, blood sugar, blood pressure, and cortisol are controlled via negative feedback mechanisms. When blood sugar rises, insulin is released to transport glucose into cells, lowering blood sugar. When BP is low, the RAAS is activated to increase BP through vasoconstriction and retention of salt and water. Cortisol is released in response to ACTH, which is inhibited by high levels of cortisol through negative feedback on the hypothalamus and anterior pituitary.

The Coagulation Cascade: Two Pathways to Fibrin Formation

The coagulation cascade is a complex process that leads to the formation of a blood clot. There are two pathways that can lead to fibrin formation: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway involves components that are already present in the blood and has a minor role in clotting. It is initiated by subendothelial damage, such as collagen, which leads to the formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and Factor 12. This complex activates Factor 11, which in turn activates Factor 9. Factor 9, along with its co-factor Factor 8a, forms the tenase complex, which activates Factor 10.

The extrinsic pathway, on the other hand, requires tissue factor released by damaged tissue. This pathway is initiated by tissue damage, which leads to the binding of Factor 7 to tissue factor. This complex activates Factor 9, which works with Factor 8 to activate Factor 10. Both pathways converge at the common pathway, where activated Factor 10 causes the conversion of prothrombin to thrombin. Thrombin hydrolyses fibrinogen peptide bonds to form fibrin and also activates factor 8 to form links between fibrin molecules.

Finally, fibrinolysis occurs, which is the process of clot resorption. Plasminogen is converted to plasmin to facilitate this process. It is important to note that certain factors are involved in both pathways, such as Factor 10, and that some factors are vitamin K dependent, such as Factors 2, 7, 9, and 10. The intrinsic pathway can be assessed by measuring the activated partial thromboplastin time (APTT), while the extrinsic pathway can be assessed by measuring the prothrombin time (PT).

CLL is linked to warm autoimmune haemolytic anaemia.

Complications of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a type of cancer that affects the blood and bone marrow. It can lead to various complications, including anaemia, hypogammaglobulinaemia, and warm autoimmune haemolytic anaemia. Patients with CLL may also experience recurrent infections due to their weakened immune system. However, one of the most severe complications of CLL is Richter’s transformation.

Richter’s transformation occurs when CLL cells transform into a high-grade, fast-growing non-Hodgkin’s lymphoma. This transformation can happen when the leukaemia cells enter the lymph nodes. Patients with Richter’s transformation often become unwell very suddenly and may experience symptoms such as lymph node swelling, fever without infection, weight loss, night sweats, nausea, and abdominal pain.

It is essential for patients with CLL to be aware of the potential complications and to seek medical attention if they experience any concerning symptoms. Regular check-ups and monitoring can also help detect any changes in the condition early on, allowing for prompt treatment and management.

Angiosarcoma of the liver is a tumor that is not commonly found. However, it has been associated with exposure to vinyl chloride, as seen in this instance. While current factories have taken measures to reduce exposure to this substance, this was not always the case.

Occupational cancers are responsible for 5.3% of cancer deaths, with men being more affected than women. The most common types of cancer in men include mesothelioma, bladder cancer, non-melanoma skin cancer, lung cancer, and sino-nasal cancer. Occupations that have a high risk of developing tumors include those in the construction industry, coal tar and pitch workers, miners, metalworkers, asbestos workers, and those in the rubber industry. Shift work has also been linked to breast cancer in women.

The latency period between exposure to carcinogens and the development of cancer is typically 15 years for solid tumors and 20 years for leukemia. Many occupational cancers are rare, such as sino-nasal cancer, which is linked to wood dust exposure and is not strongly associated with smoking. Another rare occupational tumor is angiosarcoma of the liver, which is linked to working with vinyl chloride. In non-occupational contexts, these tumors are extremely rare.

It is more probable for individuals with a history of colorectal cancer to develop a second colorectal cancer. However, the risk of developing other types of cancer is only slightly elevated and does not warrant screening.

Genetic Conditions and Their Association with Surgical Diseases

Li-Fraumeni Syndrome is an autosomal dominant genetic condition caused by mutations in the p53 tumour suppressor gene. Individuals with this syndrome have a high incidence of malignancies, particularly sarcomas and leukaemias. The diagnosis is made when an individual develops sarcoma under the age of 45 or when a first-degree relative is diagnosed with any cancer below the age of 45 and another family member develops malignancy under the age of 45 or sarcoma at any age.

BRCA 1 and 2 are genetic conditions carried on chromosome 17 and chromosome 13, respectively. These conditions are linked to developing breast cancer with a 60% risk and an associated risk of developing ovarian cancer with a 55% risk for BRCA 1 and 25% risk for BRCA 2. BRCA2 mutation is also associated with prostate cancer in men.

Lynch Syndrome is another autosomal dominant genetic condition that causes individuals to develop colonic cancer and endometrial cancer at a young age. 80% of affected individuals will get colonic and/or endometrial cancer. High-risk individuals may be identified using the Amsterdam criteria, which include three or more family members with a confirmed diagnosis of colorectal cancer, two successive affected generations, and one or more colon cancers diagnosed under the age of 50 years.

Gardners syndrome is an autosomal dominant familial colorectal polyposis that causes multiple colonic polyps. Extra colonic diseases include skull osteoma, thyroid cancer, and epidermoid cysts. Desmoid tumours are seen in 15% of individuals with this syndrome. Due to colonic polyps, most patients will undergo colectomy to reduce the risk of colorectal cancer. It is now considered a variant of familial adenomatous polyposis coli.

Overall, these genetic conditions have a significant association with surgical diseases, and early identification and management can help reduce the risk of malignancies and other associated conditions.

Understanding Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is a type of cancer that commonly affects children, accounting for 80% of childhood leukaemias. It is most prevalent in children aged 2-5 years, with boys being slightly more affected than girls. Symptoms of ALL can be divided into those caused by bone marrow failure, such as anaemia, neutropaenia, and thrombocytopenia, and other features like bone pain, splenomegaly, hepatomegaly, fever, and testicular swelling.

There are three types of ALL: common ALL, T-cell ALL, and B-cell ALL. Common ALL is the most common type, accounting for 75% of cases, and is characterized by the presence of CD10 and pre-B phenotype. T-cell ALL accounts for 20% of cases, while B-cell ALL accounts for only 5%.

Certain factors can affect the prognosis of ALL, including age, white blood cell count at diagnosis, T or B cell surface markers, race, and sex. Children under 2 years or over 10 years of age, those with a WBC count over 20 * 109/l at diagnosis, and those with T or B cell surface markers, non-Caucasian, and male sex have a poorer prognosis.

Understanding the different types and prognostic factors of ALL can help in the early detection and management of this cancer. It is important to seek medical attention if any of the symptoms mentioned above are present.

Guidelines for Red Blood Cell Transfusion

In 2015, NICE released guidelines for the use of blood products, specifically red blood cells. These guidelines recommend different transfusion thresholds for patients with and without acute coronary syndrome (ACS). For patients without ACS, the transfusion threshold is 70 g/L, while for those with ACS, it is 80 g/L. The target hemoglobin level after transfusion is 70-90 g/L for patients without ACS and 80-100 g/L for those with ACS. It is important to note that these thresholds should not be used for patients with ongoing major hemorrhage or those who require regular blood transfusions for chronic anemia.

When administering red blood cells, it is crucial to store them at 4°C prior to infusion. In non-urgent scenarios, a unit of RBC is typically transfused over a period of 90-120 minutes. By following these guidelines, healthcare professionals can ensure safe and effective transfusions for their patients.