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.

The aPTT time is the most effective way to evaluate the intrinsic pathway of the clotting cascade. If the aPTT time is prolonged, it may indicate haemophilia or the use of heparin.

To assess the extrinsic pathway, the prothrombin time (PT) is the preferred measurement.

The thrombin time is a test that evaluates the formation of fibrin from fibrinogen in plasma. It can be prolonged by heparin, fibrin degradation products, and fibrinogen deficiency.

A 50:50 mixing study is utilized to determine whether a prolonged PT or aPTT is caused by a factor deficiency or a factor inhibitor.

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).

GVHD occurs when T cells from the donor tissue attack the recipient’s cells. This often manifests as skin and gastrointestinal symptoms in a host who lacks T cells, following a bone marrow or stem cell transplant. The immune response is initiated by donor CD4+ T cells recognizing the recipient’s MHC II as foreign, while donor CD8+ T cells cause tissue damage.

Understanding Graft Versus Host Disease

Graft versus host disease (GVHD) is a complication that can occur after bone marrow or solid organ transplantation. It happens when the T cells in the donor tissue attack the recipient’s cells. This is different from transplant rejection, where the recipient’s immune cells attack the donor tissue. GVHD is diagnosed using the Billingham criteria, which require that the transplanted tissue contains functioning immune cells, the donor and recipient are immunologically different, and the recipient is immunocompromised.

The incidence of GVHD varies, but it can occur in up to 50% of patients who receive allogeneic bone marrow transplants. Risk factors include poorly matched donor and recipient, the type of conditioning used before transplantation, gender disparity between donor and recipient, and the source of the graft.

Acute and chronic GVHD are considered separate syndromes. Acute GVHD typically occurs within 100 days of transplantation and affects the skin, liver, and gastrointestinal tract. Chronic GVHD may occur after acute disease or arise de novo and has a more varied clinical picture.

Diagnosis of GVHD is largely clinical and based on the exclusion of other pathology. Signs and symptoms of acute GVHD include a painful rash, jaundice, diarrhea, nausea, vomiting, and fever. Chronic GVHD can affect the skin, eyes, gastrointestinal tract, and lungs.

Treatment of GVHD involves immunosuppression and supportive measures. Intravenous steroids are the mainstay of treatment for severe cases of acute GVHD, while extended courses of steroid therapy are often needed in chronic GVHD. Second-line therapies include anti-TNF, mTOR inhibitors, and extracorporeal photopheresis. Topical steroid therapy may be sufficient in mild disease with limited cutaneous involvement. However, excessive immunosuppression may increase the risk of infection and limit the beneficial graft-versus-tumor effect of the transplant.

The para-aortic nodes receive lymphatic drainage from the ovary through the gonadal vessels.

Lymphatic Drainage of Female Reproductive Organs

The lymphatic drainage of the female reproductive organs is a complex system that involves multiple nodal stations. The ovaries drain to the para-aortic lymphatics via the gonadal vessels. The uterine fundus has a lymphatic drainage that runs with the ovarian vessels and may thus drain to the para-aortic nodes. Some drainage may also pass along the round ligament to the inguinal nodes. The body of the uterus drains through lymphatics contained within the broad ligament to the iliac lymph nodes. The cervix drains into three potential nodal stations; laterally through the broad ligament to the external iliac nodes, along the lymphatics of the uterosacral fold to the presacral nodes and posterolaterally along lymphatics lying alongside the uterine vessels to the internal iliac nodes. Understanding the lymphatic drainage of the female reproductive organs is important for the diagnosis and treatment of gynecological cancers.

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.

Cytarabine is a medication used in chemotherapy to treat acute myeloid leukaemia (AML). It works by interfering with DNA synthesis during the S-phase of the cell cycle and inhibiting DNA polymerase.

Allopurinol is a medication that inhibits xanthine oxidase, which prevents the production of uric acid. It is commonly used to treat gout, but can also be used to prevent hyperuricaemia in high-grade lymphoma and leukaemia before chemotherapy treatment.

Methotrexate works by inhibiting dihydrofolate reductase and thymidylate synthesis. It is used to treat rheumatoid arthritis and various types of cancer.

Ondansetron is an anti-emetic medication that is used to prevent nausea during chemotherapy treatment. It works by selectively blocking serotonin receptors (5-HT3) in the chemoreceptor trigger zone (CTZ) of the medulla.

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.

The ovarian vessels directly branch from the aorta to supply ovarian tumours. Meanwhile, the internal and external iliac nodes are responsible for draining the cervix.

Para-aortic Lymphadenopathy and its Association with Metastasis

Para-aortic lymphadenopathy is a condition where the lymph nodes located near the aorta become enlarged due to the spread of cancer cells. This condition is commonly associated with the metastasis of cancer cells from various organs, including the testis, ovary, and uterine fundus. In these cases, the cancer cells spread to the para-aortic lymph nodes at an early stage of the disease.

However, it is important to note that para-aortic nodal disease may also occur as a result of cancer cells spreading from other organs. In these cases, the para-aortic nodal disease represents a much later stage of the disease, as other nodal stations are involved earlier.

Overall, para-aortic lymphadenopathy is a significant concern for individuals with cancer, as it can indicate the spread of cancer cells to other parts of the body. Early detection and treatment of para-aortic nodal disease can improve the chances of successful treatment and recovery.

The Factor V Leiden mutation causes activated protein C resistance, resulting in excess clotting due to inefficient inactivation of factor V. This is the correct answer.

Antiphospholipid antibodies binding to plasma membranes is not the correct answer as it is a mechanism of blood clot formation in antiphospholipid syndrome (APS).

High levels of platelets in the blood is also not the correct answer as it is not implicated in Factor V Leiden. Thrombocytosis, or high levels of platelets, can lead to clots but is not related to this mutation.

Low levels of factor V in the blood is also not the correct answer as factor V deficiency is a rare inherited bleeding disorder, not a clotting disorder. It is a form of haemophilia.

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

Lymphomas and their Staging

Malignancies that arise from lymphocytes can spread to different lymph node groups due to their ability to retain adhesion and signalling receptors. Lymphomas can present at various sites, including bone marrow, gut, and spleen, as normal trafficking of lymphoid cells occurs through these places. Interestingly, higher-grade lymphomas are easier to cure than lower grade lymphomas, despite initially being associated with a higher mortality rate. On the other hand, low-grade lymphomas may not require immediate treatment, but the disease progresses over time, leading to a poorer prognosis.

To diagnose lymphoma, a biopsy of the affected area, such as a lymph node or bone marrow, is necessary. The Ann Arbor staging system is used to stage lymphomas, with Stage I indicating disease in a single lymph node group and Stage IV indicating extra-nodal involvement other than the spleen. The addition of a ‘B’ signifies the presence of ‘B’ symptoms, which are associated with a poorer prognosis for each disease stage.

From the examination findings, it is evident that the disease is present on both sides of the diaphragm, indicating at least Stage III lymphoma. the staging of lymphomas is crucial in determining the appropriate treatment plan and predicting the patient’s prognosis.

Leukaemia is a type of cancer that affects the blood and bone marrow. There are two main types of leukaemia: acute and chronic. Acute leukaemia progresses quickly and requires immediate treatment, while chronic leukaemia progresses more slowly and may not require treatment for some time.

There are also different subtypes of leukaemia based on the type of blood cell affected. Acute lymphocytic leukaemia is the most common type of leukaemia in children, while acute myeloid leukaemia is less common. In adults, chronic lymphocytic leukaemia is the most common type, followed by chronic myeloid leukaemia and acute myeloid leukaemia.

Understanding Chronic Lymphocytic Leukaemia: Symptoms and Diagnosis

Chronic lymphocytic leukaemia (CLL) is a type of cancer that affects the blood and bone marrow. It is caused by the abnormal growth of B-cells, a type of white blood cell. CLL is the most common form of leukaemia in adults and is often asymptomatic, meaning it may be discovered incidentally during routine blood tests. However, some patients may experience symptoms such as weight loss, anorexia, bleeding, infections, and lymphadenopathy.

To diagnose CLL, doctors typically perform a full blood count to check for lymphocytosis, a condition where there is an abnormally high number of lymphocytes in the blood. Patients may also have anaemia or thrombocytopenia, which can occur due to bone marrow replacement or autoimmune hemolytic anaemia. A blood film may also be taken to look for smudge cells, which are abnormal lymphocytes that appear broken or fragmented.

The key investigation for CLL diagnosis is immunophenotyping, which involves using a panel of antibodies specific for CD5, CD19, CD20, and CD23. This test helps to identify the type of lymphocyte involved in the cancer and can confirm the diagnosis of CLL. With early detection and proper treatment, patients with CLL can manage their symptoms and improve their quality of life.

Parotid Mass and Facial Nerve Involvement

Swelling over the angle of the mandible is a common site for a parotid mass. The majority of these masses are benign, with pleomorphic adenomas being the most common type. However, Warthin’s tumour is also a possibility. Malignancy is indicated when there is involvement of the facial nerve, which is a feature found in malignant parotid tumours. Bilateral facial nerve involvement with bilateral parotid swelling may be indicative of sarcoidosis. Parotitis, on the other hand, causes painful acute swelling over the parotid gland with redness. Bell’s palsy is a benign and often temporary paralysis of the facial nerve, which is usually preceded by a viral infection that causes inflammation and paralysis.

The lumbar lymph nodes, also referred to as the para-aortic lymph nodes, receive drainage from the ovary.

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.

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.

If a patient has a history of gastrectomy and is experiencing macrocytic anaemia, it is likely that they are suffering from B12 deficiency.

Vitamin B12 is essential for the development of red blood cells and the maintenance of the nervous system. It is absorbed through the binding of intrinsic factor, which is secreted by parietal cells in the stomach, and actively absorbed in the terminal ileum. A deficiency in vitamin B12 can be caused by pernicious anaemia, post gastrectomy, a vegan or poor diet, disorders or surgery of the terminal ileum, Crohn’s disease, or metformin use.

Symptoms of vitamin B12 deficiency include macrocytic anaemia, a sore tongue and mouth, neurological symptoms, and neuropsychiatric symptoms such as mood disturbances. The dorsal column is usually affected first, leading to joint position and vibration issues before distal paraesthesia.

Management of vitamin B12 deficiency involves administering 1 mg of IM hydroxocobalamin three times a week for two weeks, followed by once every three months if there is no neurological involvement. If a patient is also deficient in folic acid, it is important to treat the B12 deficiency first to avoid subacute combined degeneration of the cord.

The correct answer is T lymphocytes, as the thymus plays a role in their maturation. DiGeorge syndrome is caused by a microdeletion on chromosome 22, resulting in the failure of development of the third and fourth pharyngeal arches. The syndrome is characterized by cardiac abnormalities, abnormal facies, thymus aplasia, cleft palate, and hypoparathyroidism, which can be remembered with the acronym CATCH.

The Thymus Gland: Development, Structure, and Function

The thymus gland is an encapsulated organ that develops from the third and fourth pharyngeal pouches. It descends to the anterior superior mediastinum and is subdivided into lobules, each consisting of a cortex and a medulla. The cortex is made up of tightly packed lymphocytes, while the medulla is mostly composed of epithelial cells. Hassall’s corpuscles, which are concentrically arranged medullary epithelial cells that may surround a keratinized center, are also present.

The inferior parathyroid glands, which also develop from the third pharyngeal pouch, may be located with the thymus gland. The thymus gland’s arterial supply comes from the internal mammary artery or pericardiophrenic arteries, while its venous drainage is to the left brachiocephalic vein. The thymus gland plays a crucial role in the development and maturation of T-cells, which are essential for the immune system’s proper functioning.

The primary cause of vitamin B12 deficiency is pernicious anaemia. This condition occurs when the stomach lining is destroyed by autoimmune factors, leading to reduced production of intrinsic factor. Intrinsic factor is responsible for binding B12 in the gut, and without it, B12 absorption is impaired. This can result in a deficiency of vitamin B12 and macrocytic anaemia, as well as neurological symptoms due to damage to spinal cord myelination.

While a strict vegan diet and alcoholism can also lead to B12 deficiency, they are not the most common causes.

Microcytic sideroblastic anaemia, on the other hand, is caused by lead poisoning, which impairs haem production.

Vitamin B12 is essential for the development of red blood cells and the maintenance of the nervous system. It is absorbed through the binding of intrinsic factor, which is secreted by parietal cells in the stomach, and actively absorbed in the terminal ileum. A deficiency in vitamin B12 can be caused by pernicious anaemia, post gastrectomy, a vegan or poor diet, disorders or surgery of the terminal ileum, Crohn’s disease, or metformin use.

Symptoms of vitamin B12 deficiency include macrocytic anaemia, a sore tongue and mouth, neurological symptoms, and neuropsychiatric symptoms such as mood disturbances. The dorsal column is usually affected first, leading to joint position and vibration issues before distal paraesthesia.

Management of vitamin B12 deficiency involves administering 1 mg of IM hydroxocobalamin three times a week for two weeks, followed by once every three months if there is no neurological involvement. If a patient is also deficient in folic acid, it is important to treat the B12 deficiency first to avoid subacute combined degeneration of the cord.

Vincristine inhibits the formation of microtubules, which are essential for separating chromosomes during cell division. This mechanism is also shared by paclitaxel, a member of the taxane family. Alkylating agents, such as cyclophosphamide, disrupt the double helix of DNA by adding an alkyl group to guanine bases. Methotrexate inhibits dihydrofolate reductase, an enzyme that supports folate in DNA synthesis. Pyrimidine antagonists, like cytarabine, prevent the use of pyrimidines in DNA synthesis.

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.

The presence of necrosis in a tumour may indicate that it has become too large for its blood supply, suggesting a high grade tumour. However, when grading breast cancer using the Bloom-Richardson model, nuclear features such as mitoses, coarse chromatin, and pleomorphism are given more weight. The formation of tubular structures is a key indicator of the level of differentiation, with well differentiated tumours showing the presence of tubules.

Tumour Grading and Differentiation

Tumours can be classified based on their degree of differentiation, mitotic activity, and other characteristics. The grading system ranges from grade 1, which is the most differentiated, to grade 3 or 4, which is the least. The evaluation is subjective, but generally, high-grade tumours indicate a poor prognosis or rapid growth.

Glandular epithelium tumours tend to form acinar structures with a central lumen. Well-differentiated tumours exhibit excellent acinar formation, while poorly differentiated tumours appear as clumps of cells around a desmoplastic stroma. Some tumours produce mucous without acinar formation, and these are referred to as mucinous adenocarcinomas. Squamous cell tumours produce structures resembling epithelial cell components, and well-differentiated tumours may also produce keratin, depending on the tissue of origin.

The submandibular lymph nodes are the primary drainage site for the mid-portion of the tongue. Subsequently, the lymphatic fluid will spread to the deep cervical lymph nodes.

Lymphatic Drainage of the Tongue

The lymphatic drainage of the tongue varies depending on the location of the tumour. The anterior two-thirds of the tongue have minimal communication of lymphatics across the midline, resulting in metastasis to the ipsilateral nodes being more common. On the other hand, the posterior third of the tongue has communicating networks, leading to early bilateral nodal metastases being more common in this area.

The tip of the tongue drains to the submental nodes and then to the deep cervical nodes, while the mid portion of the tongue drains to the submandibular nodes and then to the deep cervical nodes. If mid tongue tumours are laterally located, they will usually drain to the ipsilateral deep cervical nodes. However, those from more central regions may have bilateral deep cervical nodal involvement. Understanding the lymphatic drainage of the tongue is crucial in determining the spread of tumours and planning appropriate treatment.

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.

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

GVHD is a condition where T cells from the donor tissue (the graft) attack healthy cells in the recipient (the host). This can occur after a haematopoietic cell transplantation and is diagnosed based on symptoms such as fever, rash, and gastrointestinal issues. Antigen-presenting cells activate the donor T cells, but do not attack host cells. B cells, host T cells, and mast cells do not contribute to the attack on host tissue in GVHD.

Understanding Graft Versus Host Disease

Graft versus host disease (GVHD) is a complication that can occur after bone marrow or solid organ transplantation. It happens when the T cells in the donor tissue attack the recipient’s cells. This is different from transplant rejection, where the recipient’s immune cells attack the donor tissue. GVHD is diagnosed using the Billingham criteria, which require that the transplanted tissue contains functioning immune cells, the donor and recipient are immunologically different, and the recipient is immunocompromised.

The incidence of GVHD varies, but it can occur in up to 50% of patients who receive allogeneic bone marrow transplants. Risk factors include poorly matched donor and recipient, the type of conditioning used before transplantation, gender disparity between donor and recipient, and the source of the graft.

Acute and chronic GVHD are considered separate syndromes. Acute GVHD typically occurs within 100 days of transplantation and affects the skin, liver, and gastrointestinal tract. Chronic GVHD may occur after acute disease or arise de novo and has a more varied clinical picture.

Diagnosis of GVHD is largely clinical and based on the exclusion of other pathology. Signs and symptoms of acute GVHD include a painful rash, jaundice, diarrhea, nausea, vomiting, and fever. Chronic GVHD can affect the skin, eyes, gastrointestinal tract, and lungs.

Treatment of GVHD involves immunosuppression and supportive measures. Intravenous steroids are the mainstay of treatment for severe cases of acute GVHD, while extended courses of steroid therapy are often needed in chronic GVHD. Second-line therapies include anti-TNF, mTOR inhibitors, and extracorporeal photopheresis. Topical steroid therapy may be sufficient in mild disease with limited cutaneous involvement. However, excessive immunosuppression may increase the risk of infection and limit the beneficial graft-versus-tumor effect of the transplant.

Apixaban is a medication that directly inhibits factor Xa, which is responsible for the conversion of prothrombin to thrombin in the coagulation cascade. It is used as prophylaxis against embolic events in patients with atrial fibrillation, who are at increased risk due to blood pooling in the atria and potential clot formation. Unlike heparin, which activates antithrombin III to reduce blood clotting, apixaban works independently of antithrombin III. It also does not directly inhibit thrombin, which is the mechanism of action of dabigatran. Antiplatelets, such as aspirin and clopidogrel, work to decrease platelet activation and aggregation, but are not recommended for reducing the risks of embolic events in AF. Apixaban also does not inhibit vitamin K, which is the mechanism of action of warfarin.

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.

What is the blood group that can be given to anyone regardless of their blood type?

Blood Products and Cell Saver Devices

Blood products are essential in various medical procedures, especially in cases where patients require transfusions due to anaemia or bleeding. Packed red cells, platelet-rich plasma, platelet concentrate, fresh frozen plasma, and cryoprecipitate are some of the commonly used whole blood fractions. Fresh frozen plasma is usually administered to patients with clotting deficiencies, while cryoprecipitate is a rich source of Factor VIII and fibrinogen. Cross-matching is necessary for all blood products, and cell saver devices are used to collect and re-infuse a patient’s own blood lost during surgery.

Cell saver devices come in two types, those that wash the blood cells before re-infusion and those that do not. The former is more expensive and complicated to operate but reduces the risk of re-infusing contaminated blood. The latter avoids the use of donor blood and may be acceptable to Jehovah’s witnesses. However, it is contraindicated in malignant diseases due to the risk of facilitating disease dissemination.

In some surgical patients, the use of warfarin can pose specific problems and may require the use of specialised blood products. Warfarin reversal can be achieved through the administration of vitamin K, fresh frozen plasma, or human prothrombin complex. Fresh frozen plasma is used less commonly now as a first-line warfarin reversal, and human prothrombin complex is preferred due to its rapid action. However, it should be given with vitamin K as factor 6 has a short half-life.

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).

Aplastic anemia is a condition where there is a shortage of blood cells from all types of progenitor lines. It is most commonly seen in individuals between the ages of 15 to 25 and those over 60.

The causes of aplastic anemia can be attributed to various factors such as infections (including Epstein-Barr), toxic exposure (such as benzene and radiation), idiopathic, and rarely hereditary.

Haematopoietic stem cells in the bone marrow generate immune cells. These cells produce two main types of progenitors, myeloid and lymphoid progenitor cells, which give rise to all immune cells.

Myeloid progenitor cells give rise to 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.

Aplastic anaemia is a condition characterized by a decrease in the number of blood cells due to a poorly functioning bone marrow. It is most commonly seen in individuals around the age of 30 and is marked by a reduction in red blood cells, white blood cells, and platelets. While lymphocytes may be relatively spared, the overall effect is a condition known as pancytopenia. In some cases, aplastic anaemia may be the first sign of acute lymphoblastic or myeloid leukaemia. A small number of patients may later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia.

The causes of aplastic anaemia can be idiopathic, meaning that they are unknown, or they can be linked to congenital conditions such as Fanconi anaemia or dyskeratosis congenita. Certain drugs, such as cytotoxics, chloramphenicol, sulphonamides, phenytoin, and gold, as well as toxins like benzene, can also cause aplastic anaemia. Infections such as parvovirus and hepatitis, as well as exposure to radiation, can also contribute to the development of this condition.

The presence of factor V Leiden mutation leads to resistance to activated protein C.

The most probable cause of the patient’s recurrent DVTs and family history of thrombo-embolic events is factor V Leiden, which is the most common inherited thrombophilia. This mutation results in activated protein C resistance, as activated factor V is not inactivated as efficiently by protein C.

Antiphospholipid syndrome is an acquired thrombophilia that can cause both arterial and venous thromboses, and may present with thrombocytopenia. However, the patient’s positive family history and normal full blood count make this diagnosis less likely than factor V Leiden.

Protein C deficiency, protein S deficiency, and antithrombin III deficiency are all inherited thrombophilias, but they are less prevalent in the population compared to factor V Leiden. Therefore, they are less likely to be the underlying cause of the patient’s symptoms.

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

Multiple Myeloma and Carpal Tunnel Syndrome

Multiple myeloma (MM) is a condition that results in the increased production of amyloid light chains, which can deposit in various organs, including the narrow carpal tunnel. This deposition can cause carpal tunnel syndrome, which is characterized by median nerve neuropathy. MM is caused by the clonal proliferation of monoclonal antibodies, which can lead to increased plasma volume and free light chains in the blood. These free light chains can then be processed into insoluble fibrillation proteins and deposited in various tissues throughout the body, resulting in amyloid deposits.

It is important to note the ALARM signs and symptoms in the clinical history, such as unexplained weight loss and night sweats, which can indicate malignancy. In this case, MM and prostatic carcinoma are the two most likely options. However, the absence of urinary symptoms in this patient makes MM more likely. It is important to consider that an elderly gentleman presenting with low back pain could suggest secondary metastases to axial vertebral bone from primary prostatic carcinoma and should be high up on the list of differentials.

In summary, carpal tunnel syndrome can be a result of amyloid deposition in the carpal tunnel due to MM. It is important to consider the ALARM signs and symptoms in the clinical history to determine the likelihood of malignancy, and to consider other potential causes of symptoms such as vertebral compression fracture.

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.

Cholestatic jaundice and prolonged antibiotic therapy can lead to a deficiency in vitamin K.

Abnormal coagulation can be caused by various factors such as heparin, warfarin, disseminated intravascular coagulation (DIC), and liver disease. Heparin prevents the activation of factors 2, 9, 10, and 11, while warfarin affects the synthesis of factors 2, 7, 9, and 10. DIC affects factors 1, 2, 5, 8, and 11, and liver disease affects factors 1, 2, 5, 7, 9, 10, and 11.

When interpreting blood clotting test results, different disorders can be identified based on the levels of activated partial thromboplastin time (APTT), prothrombin time (PT), and bleeding time. Haemophilia is characterized by increased APTT levels, normal PT levels, and normal bleeding time. On the other hand, von Willebrand’s disease is characterized by increased APTT levels, normal PT levels, and increased bleeding time. Lastly, vitamin K deficiency is characterized by increased APTT and PT levels, and normal bleeding time. Proper interpretation of these results is crucial in diagnosing and treating coagulation disorders.