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Question 1

Hereditary haemorrhagic telangiectasia (vs.) Ehlers–Danlos disease

Answer 1

Hereditary haemorrhagic telangiectasia transmitted as an autosomal dominant trait.

Telangiectasia and small aneurysms are found on the fingertips, face and tongue, and in the nasal passages, lung and gastrointestinal tract. A significant proportion of these patients develop larger pulmonary arteriovenous malformations (PAVMs). Patients present either with recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastrointestinal bleeding.

Local cautery or laser therapy may prevent single lesions from bleeding. A variety of medical therapies have been tried but none has been found to be universally effective.

Ehlers–Danlos disease rare autosomal dominant disorder.

caused by a defect in type 3 collagen that results in fragile blood vessels and organ membranes, leading to bleeding and organ rupture. Classical joint hypermobility.

Scurvy Vitamin C deficiency affects the normal synthesis of collagen and results in a bleeding disorder characterised by perifollicular and petechial haemorrhage, bruising and subperiosteal bleeding. The key to diagnosis is the dietary history.

Question 2

Thrombocytopenia

Answer 2

Thrombocytopenia

A reduced platelet count may arise by one of two mechanisms:

• decreased or abnormal production

• increased consumption following release into the circulation Spontaneous bleeding does not usually occur until the platelet count falls below 20 × 109/L, unless their function is also compromised. Purpura and spontaneous bruising are characteristic but there may also be oral, nasal, gastrointestinal or genitourinary bleeding. Severe thrombocytopenia (< 10 × 109/L) may result in retinal haemorrhage and potentially fatal intracranial bleeding, but this is rare. Causes of thrombocytopenia

Failure of platelet production Cytotoxic drugs Radiotherapy Aplastic anaemia Leukaemia Myelodysplastic syndromes Myelofibrosis Marrow infiltration (e.g. carcinoma, lymphoma) Multiple myeloma Megaloblastic anaemia HIV infection Increased consumption of platelets Associated with systemic lupus erythematosus Infections: Helicobacter pylori, HIV Drug-induced, e.g. heparin Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Abnormal distribution of platelets Splenomegaly

Question 3

ITP

Answer 3

Idiopathic (Immune) thrombocytopenic purpura

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Platelet autoantibodies, result in the premature removal of platelets from the circulation by macrophages of the reticuloendothelial system, especially the spleen.

In many cases, the antibody is directed against the glycoprotein (GP) IIb/IIIa or Ib complex. The normal lifespan of a platelet is 10 days, but in ITP this is reduced to a few hours.

some cases occur in isolation while others are associated with underlying immune dysregulation in conditions such as connective tissue diseases, HIV infection, B-cell malignancies, pregnancy. 

Treatment with High-dose intravenous immunoglobulin therapy This is able to produce a rapid rise in platelet count in the majority of patients. It is particularly useful in patients with life threatening haemorrhage, in steroid-refractory ITP, prior to surgery.

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Clinical features The onset is often insidious with petechial haemorrhage, easy bruising and, in women, menorrhagia. Mucosal bleeding (e.g. epistaxes or gum bleeding) occurs in severe cases, but fortunately intracranial haemorrhage is rare.

Many patients with stable compensated ITP and a platelet count of more than 30 × 109/L do not require treatment to raise the platelet count, except at times of increased bleeding risk, such as surgery and biopsy. First-line therapy for patients with spontaneous bleeding is with high doses of glucocorticoids, either prednisolone (1 mg/kg daily) or dexamethasone (40 mg daily for 4 days).

Question 4

Platelet function disorders

Answer 4

Platelet function disorders

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Bleeding may result from congenital or acquired abnormalities of platelet function.

acquired disorders are iatrogenic, resulting from the use of aspirin, clopidogrel,dipyridamole to prevent arterial thrombosis.

Congenital abnormalities may be due to deficiency of the membrane glycoproteins, e.g. Glanzmann’s thrombasthenia (IIb/IIIa) or Bernard–Soulier syndrome (Ib), or due to the presence of defective platelet granules giving rise to storage pool disorders.

Question 5

Haemophilia A

Answer 5

Haemophilia A Factor VIII deficiency resulting in haemophilia. It is the most common congenital coagulation factor deficiency. has a half-life of about 12 hours. It is protected from proteolysis in the circulation by binding to von Willebrand factor (vWF).

As the factor VIII gene is on the X chromosome, haemophilia A is a sex-linked disorder. Thus all daughters of a patient with haemophilia are obligate carriers and they, in turn, have a 1 in 4 chance of each pregnancy resulting in the birth of an affected male baby, a normal male baby, a carrier female or a normal female. 

Although not common, spontaneous intracerebral haemorrhage occurs more frequently than in the general population and is an important cause of death in patients with severe disease.

Question 6

Haemophilia B (Christmas disease)

Answer 6

Haemophilia B (Christmas disease) The inheritance and clinical features of factor IX deficiency (Christmas disease, haemophilia B) are identical to those of haemophilia A,but is less common.

Laboratory findings 1 Prolongation of Activated partial thromboplastin time (APTT).

2 Factor VIII clotting assay for haemophillia A, factor IX clotting assay for haemophillia B. 

Most patients in developed countries attend specialized haemophilia centres where there is a multidisciplinary team dedicated to their care. Advances in prophylactic treatment to maintain prolonged elevation of factor VIII OR IX coagulant activity. Nevertheless, spontaneous and trauma-induced bleeding still occurs. This is treated with factor VIII OR IX replacement therapy.

Question 7

Von Willebrand disease

Answer 7

Von Willebrand disease

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In this disorder there is either a reduced level or abnormal function of VWF. VWD is the most common inherited bleeding disorder. Usually, the inheritance is autosomal dominant.

It promotes platelet adhesion to subendothelium and to each other at high shear rates and it is the carrier molecule for factor VIII, protecting it from premature destruction. 

Typically, there is mucous membrane bleeding (e.g. epistaxes, menorrhagia),

excessive blood loss from superficial cuts and abrasions, and operative and posttraumatic haemorrhage. The severity is variable in the different types. Haemarthroses and muscle haematomas. 

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Laboratory findings 1 The APTT may be prolonged.

2 VWF antigen levels are usually low.

Treatment Options are as follows:

1 Local measures and antifibrinolytic agent (e.g. Tranexamic acid for mild bleeding).

2 DDAVP infusion for those with mild to moderate VWD. This releases VWF from endothelial calls.

3 Recombinant VWF is available. Clinical assessment

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A careful clinical evaluation is the key to diagnosis of bleeding disorders . It is important to consider the following:

• Site of bleeding. Bleeding into muscle and joints, along with retroperitoneal and intracranial haemorrhage, indicates a likely defect in coagulation factors.

Purpura, epistaxis, gastrointestinal haemorrhage or menorrhagia is more likely to be due to thrombocytopenia, a platelet function disorder or von Willebrand disease.   

• Surgery. Dental extractions, circumcision are stressful tests of the haemostatic system.

• Family history.

• Drugs. Use of anticoagulant and fibrinolytic drugs must be elicited.

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• Duration of history. It may be possible to assess whether the disorder is congenital or acquired.

• Precipitating causes. Bleeding arising spontaneously indicates a more severe defect than bleeding that occurs only after trauma

Question 8

Venous thromboembolic
disease

Answer 8

⦿ For venous thrombosis, increased systemic coagulability and stasis are most important, with vessel wall damag. Stasis allows the completion of blood coagulation at the site of initiation of the thrombus.

⦿ While the most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) of the leg and/or pulmonary embolism, similar management principles apply to rarer manifestations such as jugular vein thrombosis, upper limb DVT, cerebral sinus thrombosis and intra-abdominal venous thrombosis (e.g. Budd–Chiari syndrome).

Question 9

Risk factors for venous thromboembolism.

Answer 9

. Increasing age
. Pregnancy and puerperium
.Prolonged immobility, e.g. long-haul travel . Obesity
. Trauma
. Surgery
. Indwelling venous devices
. Oestrogen related: combined oral contraceptive,hormone-replacement therapy, tamoxifen
. Chemotherapy and radiotherapy
. Heparins
. Antiphospholipid syndrome
. Cancer
. Myeloproliferative diseases
. Acute promyelocytic leukaemia
. Inflammatory states e.g. nephrotic syndrome, connective tissue disorders
. Stroke
.Thrombotic thrombocytopenic purpura . Congestive cardiac failure

Question 10

Once a diagnosis of DVT or PE is made, or strongly suspected

Answer 10

Once a diagnosis of DVT or PE is made, or strongly suspected, a rapidly acting anticoagulant should be started immediately.
⦿ warfarin is usually started at the same time as heparin(LMWH), or slightly later, but takes several days to produce an anticoagulant effect, hence the need for initial heparin in patients who are to receive warfarin.
⦿ LMWH should continue for at least five days and until the International Normalized Ratio (INR) has been greater than 2.0 for two consecutive days, when it is used in combination with warfarin.

⦿ Alternatively, patients may be treated with a DOAC. Rivaroxaban and apixaban may be used immediately from diagnosis without the need for LMWH, while the licences for dabigatran and edoxaban include initial treatment with LMWH for a minimum of 5 days before commencing the DOAC. ⦿ Patients with a provoked VTE in the presence of a temporary risk factor, which is then removed, can usually be treated for short periods ( 3 months) ⦿ If there are ongoing risk factors that cannot be alleviated, such as active cancer, long-term anticoagulation is usually recommended.

Question 11

Antithrombin deficiency

Protein C and S deficiencies

Factor V Leiden

Answer 11

Antithrombin deficiency
⦿ Antithrombin is a serpin (serine protease inhibitor) and its primary targets are thrombin, factor FXa and FIXa.
⦿ Antithrombin deficiency Inherited as autosomal dominant. There are recurrent venous thromboses, usually starting in early adult life, and arterial thrombi may occur.

Protein C and S deficiencies
⦿
Protein C and its co-factor protein S are vitamin K-dependent natural anticoagulants involved in switching off coagulation factor activation (factors Va and VIIIa) and thrombin generation.
Inherited deficiency of either protein C orS results in a prothrombotic state with a fivefold relative risk of VTE compared with the background population.
⦿

Factor V Leiden
⦿ This is the most common inherited cause of an increased risk of venous thrombosis.
There is failure of activated protein C (APC), so the phenotype is sometimes referred to as ‘activated protein C resistance’.
⦿ APC resistance is caused by a genetic polymorphism in the factor V gene, which makes factor V less susceptible to cleavage by APC.
⦿ Patients with factor V leiden mutation are at high risk of venous but not arterial thrombosis.

Question 12

Antiphospholipid syndrome

Answer 12

Antiphospholipid syndrome
⦿ The antiphospholipid syndrome (APS) can be defined as the occurrence of venous or arterial thrombosis and/or recurrent miscarriage in association with laboratory evidence of persistent antiphospholipid antibody.
⦿ The term antiphospholipid antibody encompasses both a lupus anticoagulant and an anticardiolipin antibody/ anti-β2-GP1; individuals may be positive for one, two or all three of these activities. It has been shown that patients who are ‘triple-positive’ have an increased likelihood of thrombotic events.

APS may present in isolation (primary APS) or in association with othor conditions most typically systemic lupus erythematosus (secondary APS), Rheumatoid arthritis, Behcet’s disease.
Clinical manifestations
• Adverse pregnancy outcome
Recurrent first trimester abortion (≥ 3)
Unexplained death of morphologically normal fetus after10
weeks’ gestation.
Severe early pre-eclampsia
• Venous thromboembolism
• Arterial thromboembolism
• Livedo reticularis, catastrophic APS, transverse myelitis, skin necrosis, chorea

management
⦿ Treatment is with anticoagulation. It is usual to maintain an international normalized ratio (INR) of between 2.0 and 3.0 with warfarin.
⦿ In women with obstetric presentations of APS, intervention with heparin and aspirin is almost routinely prescribed.

Question 13

DIC

Answer 13

Disseminated intravascular
coagulation
⦿ Disseminated intravascular coagulation (DIC) may complicate a range of illnesses . It is characterised by systemic activation of the pathways involved in coagulation and its regulation. This may result in the generation of intravascular fibrin clots causing multi-organ failure, with simultaneous coagulation factor and platelet consumption, causing bleeding.

  Underlying conditions  • Infection/sepsis • Trauma • Obstetric, e.g. amniotic fluid embolism, placental abruption, pre-eclampsia • Severe liver failure • Malignancy, e.g. solid tumours and leukaemias • Tissue destruction, e.g. pancreatitis, burns • Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas • Toxic/immunological, e.g. ABO incompatibility, snake bites.

Management
⦿ Measurement of coagulation times (APTT and PT), along with fibrinogen, platelet count and FDPs, helps in the assessment of prognosis and aids clinical decision-making with regard to both bleeding and thrombotic complications.
⦿ Therapy is primarily aimed at the underlying cause. Blood component therapy, such as fresh frozen plasma, cryoprecipitate and platelets, should be given if the patient is bleeding or to cover interventions with a high bleeding risk. Prophylactic doses of heparin should be given, unless there is a clear contraindication.

Question 14

TTP

Answer 14

Thrombotic
thrombocytopenic purpura
⦿ It is an acute autoimmune disorder mediated by antibodies against ADAMTS-13. This enzyme normally cleaves vWF multimers to produce normal functional units, and its deficiency results in large vWF multimers that cross-link platelets. The features are of microvascular occlusion by platelet thrombi affecting key organs, principally brain and kidneys.

⦿ TTP is characterised by • thrombocytopenia • microangiopathic haemolytic anaemia • neurological sequelae • fever • renal impairment. It is a rare disorder, which may occur alone or in association with drugs(ticlopidine,ciclosporin) , HIV and malignancy. It should be treated by emergency plasma exchange. Glucocorticoids, aspirin and rituximab also have a role in management.

Question 15

Anticoagulant and antithrombotic therapy

Answer 15

Anticoagulant and antithrombotic therapy
⦿ Heparins
⦿ an inhibitor of blood coagulation by potentiating
the activity of antithrombin.
⦿ LMWHs preferentially augment antithrombin activity against factor Xa.
⦿ LMWHs do not require monitoring of their anticoagulant effect
⦿ LMWHs have a half-life of around 4 hours when given subcutaneously, compared with 1 hour for UFH.
⦿ the risk of osteoporosis and heparin-induced thrombocytopenia is much lower for LMWH.

Heparin-induced thrombocytopenia
⦿ is a rare complication of heparin therapy, caused by induction of anti-heparin/PF4 antibodies that bind to and activate platelets via an Fc receptor.
⦿ This results in platelet activation and a prothrombotic state, with a paradoxical thrombocytopenia. HIT is more common in surgical than medical patients (especially cardiac and orthopaedic patients), with use of UFH rather than LMWH, and with higher doses of heparin.
⦿ Heparin therapy must be discontinued as soon as HIT is suspected, and an alternative anticoagulant that does not cross-react with the antibody should be substituted. Argatroban and danaparoid.

Coumarins
⦿ Although several coumarin anticoagulants are used around the world, warfarin is the most common.
⦿ Coumarins inhibit the vitamin K dependent factors II, VII, IX and X .
⦿ Warfarin anticoagulation typically takes more than 3–5 days to become established, even using loading doses.
⦿ The major problems with warfarin are:
• a narrow therapeutic window
• metabolism that is affected by many factors • numerous drug interactions.

Direct oral anticoagulants
⦿ DOACs are inhibitors of coagulation factors Xa or IIa (thrombin) and offer improvement over VKAs by virtue of:
⦿ ■■ Rapid onset of action.
⦿ ■■ No need for routine monitoring.
⦿ ■■ No food interactions.
⦿ ■■ Few drug interactions.

Question 16

Anemias
In general

Answer 16

Anemias

Definition Anemia is a blood disorder characterized by abnormally low levels of healthy red blood cells (RBCs) or reduced hemoglobin (Hgb), the iron-bearing protein in red blood cells that delivers oxygen to tissues throughout the body. Reduced blood cell volume (hematocrit) is also considered anemia.

The reduction of any or all of the three blood parameters reduces the oxygen-carrying capability of the blood, causing reduced oxygenation of body tissues, a condition called hypoxia.

Description All tissues in the human body need a regular supply of oxygen to stay healthy and perform their functions. RBCs contain Hgb, a protein pigment that allows the cells to carry oxygen (oxygenate) tissues throughout the body.

RBCs live about 120 days and are normally replaced in an orderly way by the bone marrow, spleen, and liver.

As RBCs break down, they release Hgb into the blood stream, which is normally filtered out by the kidneys and excreted. The iron released from the RBCs is returned to the bone marrow to help create new cells.

Anemia develops when either blood loss, a slow-down in the production of new RBCs (erythropoiesis), or an increase in red cell destruction (hemolysis) causes significant reductions in RBCs, Hgb, iron levels, and the essential delivery of oxygen to body tissues.

Anemia can be mild, moderate, or severe enough to lead to life-threatening complications.

More than 400 different types of anemia have been identified.

Many of them are rare.

Most are caused by ongoing or sudden blood loss.

Other causes include vitamin and mineral deficiencies, inherited conditions, and certain diseases that affect red cell production or destruction.

Question 17

Anemia
Classification
Dx

Answer 17

It can also be classified based on the size of red blood cells and amount of hemoglobin in each cell. If the cells are small, it is microcytic anemia.

If they are large, it is macrocytic anemia while if they are normal sized, it is normocytic anemia.

Hypochromic, microcytic anemia: is caused by an inadequate production of hemoglobin.  The most common causes of this type of anemia are iron deficiency and thalassemia

. Normocytic anemia: are associated with a systemic illness that impairs adequate marrow synthesis of RBCs.

Macrocytic anemia: are associated with vitamin B12 and folic acid deficiencies

Diagnosis in men is based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL), while in women, it must be less than 120 to 130 g/L (12 to 13 g/dL). Further testing is then required to determine the cause.

Question 18

IDA

Answer 18

Iron deficiency anaemia This occurs when iron losses or physiological requirements exceed absorption

Blood loss The most common explanation in men and postmenopausal women is gastrointestinal blood loss.

This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions.

Worldwide, hookworm and schistosomiasis are the most common causes of gut blood loss .

In women of child-bearing age: menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting

iron stores; in developed countries, one-third of premenopausal women have low iron stores but only 3% display iron-deficient haematopoiesis.

Very rarely, chronic haemoptysis or haematuria may cause iron deficiency.
Malabsorption A dietary assessment should be made in all patients to ascertain their iron intake. Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state Achlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery.

Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease

Physiological demands At times of rapid growth, such as infancy and puberty, iron requirements increase and may outstrip absorption.

In pregnancy, iron is diverted to the fetus, the placenta, and is lost with bleeding at labour.

Investigations Confirmation of iron deficiency Plasma ferritin is a measure of iron stores in tissues and is the best single test to confirm iron deficiency

a subnormal level is due to iron deficiency or, very rarely, hypothyroidism or vitamin C deficiency.

Ferritin levels can be raised in liver disease and in the acute phase response.

Plasma iron and total iron binding capacity (TIBC) are measures of iron availability; hence they are affected by many factors besides iron stores.

Investigation of the cause This will depend upon the age and sex of the patient, as well as the history and clinical findings. In men and in post-menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or radiological studies.

Serum antiendomysial or antitransglutaminase antibodies and possibly a duodenal biopsy are indicated to detect coeliac disease.

In the tropics, stool and urine should be examined for parasites

Management Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron replacement is appropriate.

Ferrous sulphate 200 mg 3 times daily is adequate and should be continued for 3–6 months to replete iron stores.

Many patients suffer gastrointestinal sideeffects with ferrous sulphate, including dyspepsia and altered bowel habit. When this occurs, reduction in dose to 200 mg twice daily or a switch to ferrous gluconate 300 mg twice daily or another alternative oral preparation should be tried.

Delayed-release preparations are not useful, since they release iron beyond the upper small intestine, where it cannot be absorbed.

The haemoglobin should rise by around 10 g/L every 7–10 days and a reticulocyte response will be evident within a week.

A failure to respond adequately may be due to non-compliance, continued blood loss, malabsorption or an incorrect diagnosis.,

Patients with malabsorption or chronic gut disease may need parenteral iron therapy. Previously, iron dextran or iron sucrose was used

but new preparations of iron isomaltose and iron carboxymaltose have fewer allergic effects and are preferred.

Question 19

Megaloblastic anaemia
Precious anaemia

Answer 19

Megaloblastic anaemia

This results from a deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism.

vitamin B12 a co-factor for, the generation of the essential amino acid methionine from homocysteine.

V1.0 Deficiency of either vitamin B12 or folate will therefore produce high plasma levels of homocysteine and impaired DNA synthesis.

V1.0 The megaloblastic changes are most evident in the early nucleated red cell precursors, and haemolysis within the marrow results in a raised bilirubin and lactate dehydrogenase (LDH), but without the reticulocytosis characteristic of other forms of haemolysis

V1.0 Iron stores are usually raised. The mature red cells are large and oval, and sometimes contain nuclear remnants.

The mature neutrophils show hypersegmentation of their nuclei, with cells having six or more nuclear lobes.

If severe, a pancytopenia may be present in the peripheral blood.

V1.0 Vitamin B12 deficiency, but not folate deficiency, is associated with neurological disease in up to 40% of cases, although advanced neurological disease due to B12 deficiency is now uncommon in the developed world.

V1.0 The main pathological finding is focal demyelination affecting the spinal cord, peripheral nerves, optic nerves and cerebrum.

The most common manifestations are sensory, with peripheral paraesthesiae and ataxia of gait.

V1.0 Clinical features of megaloblastic anaemia Symptoms

• Malaise (90%)

• Breathlessness (50%)

• Paraesthesiae (80%)

• Sore mouth (20%)

• Weight loss

• Impotence

• Poor memory

• Depression

• Personality change

• Hallucinations

• Visual disturbance

V1.0 Signs

• Smooth tongue

• Angular cheilosis

• Vitiligo

• Skin pigmentation

• Heart failure

• Pyrexia

V1.0 Vitamin B12

Vitamin B12 absorption The average daily diet contains 5–30 µg of vitamin B12, mainly in meat, fish, eggs and milk – well in excess of the 1 µg daily requirement.

In the stomach, gastric enzymes release vitamin B12 from food and at gastric pH it binds to a carrier protein termed R protein.

V1.0 Gastric parietal cells produce intrinsic factor, a vitamin B12- binding protein which optimally binds vitamin B12 at pH 8.

As gastric emptying occurs, pancreatic secretion raises the pH and vitamin B12 released from the diet switches from the R protein to intrinsic factor.

Bile also contains vitamin B12 which is available for reabsorption in the intestine.

V1.0 V1.0 The vitamin B12–intrinsic factor complex binds to specific receptors in the terminal ileum, and vitamin B12 is actively transported by the enterocytes to plasma, where it binds to transcobalamin II, a transport protein produced by the liver, which carries it to the tissues for utilisation.

V1.0 The liver stores enough vitamin B12 for 3 years and this, together with the enterohepatic circulation, means that vitamin B12 deficiency takes years to become manifest, even if all dietary intake is stopped or severe B12 malabsorption supervenes.

V1.0 Blood levels of vitamin B12 provide a reasonable indication of tissue stores and are usually diagnostic of deficiency.

V1.0 Causes of vitamin B12 deficiency

Dietary deficiency This only occurs in strict vegans but the onset of clinical features can occur at any age between 10 and 80 years.

V1.0 Gastric pathology

Release of vitamin B12 from the food requires normal gastric acid and enzyme secretion, and this is impaired by hypochlorhydria in elderly patients or following gastric surgery.

V1.0 V1.0 Pernicious anaemia

This is an organ-specific autoimmune disorder in which the gastric mucosa is atrophic, with loss of parietal cells causing intrinsic factor deficiency.

V1.0 It is more common in individuals with other autoimmune disease (Hashimoto’s thyroiditis, Graves’ disease, vitiligo, hypoparathyroidism or Addison’s disease or a family history of these or pernicious anaemia

V1.0 The finding of anti-intrinsic factor antibodies in the context of B12 deficiency is diagnostic of pernicious anaemia without further investigations.

V1.0 V1.0 V1.0 Small bowel pathology

V1.0 V1.0 Folate

Folate absorption Folates are produced by plants and bacteria; hence dietary leafy vegetables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal protein (liver, kidney) are a rich source. Total body stores of folate are small and deficiency can occur in a matter of weeks.

V1.0 Folate deficiency

The edentulous elderly or psychiatric patient is particularly susceptible to dietary deficiency and this is exacerbated in the presence of gut disease or malignancy.

V1.0 Pregnancy-induced folate deficiency is the most common cause of megaloblastosis worldwide and is more likely in the context of twin pregnancies, multiparity and hyperemesis gravidarum.

V1.0 Serum folate is very sensitive to dietary intake; a single folate-rich meal can normalise it in a patient with true folate deficiency, whereas anorexia, alcohol and anticonvulsant therapy can reduce it in the absence of megaloblastosis.

V1.0 For this reason, red cell folate levels are a more accurate indicator of folate stores and tissue folate deficiency

V1.0 V1.0 V1.0 V1.0 V1.0 V1.0 V1.0 Management of megaloblastic Anaemia

If a patient with a severe megaloblastic anaemia is very ill and treatment must be started before vitamin B12 and red cell folate results are available, that treatment should always include both folic acid and vitamin B12.

V1.0 The use of folic acid alone in the presence of vitamin B12 deficiency may result in worsening of neurological deficits

V1.0 Vitamin B12 deficiency

Vitamin B12 deficiency is treated with hydroxycobalamin 1000 µg IM for 6 doses 2 or 3 days apart, followed by maintenance therapy of 1000 µg every 3 months for life. The reticulocyte count will peak by the 5th–10th day after starting replacement therapy.

V1.0 The haemoglobin will rise by 10 g/L every week until normalised. The response of the marrow is associated with a fall in plasma potassium levels and rapid depletion of iron stores.

V1.0 If an initial response is not maintained and the blood film is dimorphic (i.e. shows a mixture of microcytic and macrocytic cells), the patient may need additional iron therapy.

A sensory neuropathy may take 6–12 months to correct; long-standing neurological damage may not improve

Folate deficiency

Oral folic acid 5 mg daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy.

Prophylactic folic acid in pregnancy prevents megaloblastosis in women at risk, and reduces the risk of fetal neural tube defects

Question 20

Anaemia of chronic disease

Answer 20

Anaemia of chronic disease

Anaemia of chronic disease (ACD) is a common type of anaemia, particularly in hospital populations. It occurs in the setting of chronic infection, chronic inflammation or neoplasia.

V1.0 The anaemia is not related to bleeding, haemolysis or marrow infiltration, is mild, with haemoglobin in the range of 85–115 g/L,

V1.0 and is usually associated with a normal MCV (normocytic, normochromic),though this may be reduced in long-standing inflammation.

V1.0 The serum iron is low but iron stores are normal or increased, as indicated by the ferritin or stainable marrow iron

V1.0 Pathogenesis

It has recently become clear that the key regulatory protein that accounts for the findings characteristic of ACD is hepcidin, which is produced by the liver . Hepcidin production is induced by proinflammatory cytokines, and thereby inhibiting the export of iron from these cells into the blood.

V1.0 The iron remains trapped inside the cells in the form of ferritin,levels of which are therefore normal or high in the face of significant anaemia.

Inhibition or blockade of hepcidin is a potential target for treatment of this form of anaemia.

V1.0 Diagnosis and management

It is often difficult to distinguish ACD associated with alow MCV from iron deficiency.

Examination of the marrow may ultimately be required to assess iron stores directly.

V1.0 A trial of oral iron can be given in difficult situations.

A positive response occurs in true iron deficiency but not in ACD.

Measures which reduce the severity of the underlying disorder generally help to improve the ACD

V1.0 Trials of higher-dose intravenous iron are under way to try to bypass the hepcidininduced blockade.

Question 21

Primary idiopathic acquired aplastic anaemia

Answer 21

Primary idiopathic acquired aplastic anaemia

is failure of the pluripotent stem cells, producing hypoplasia of the bone marrow with a pancytopenia in the blood.

V1.0 The diagnosis rests on exclusion of other causes of secondary aplastic anaemia and rare congenital causes, such as Fanconi’s anaemia

V1.0 Clinical features and investigations

Patients present with symptoms of bone marrow failure, usually anaemia or bleeding, and less commonly, infections.

An CBP demonstrates pancytopenia, low reticulocytes and often macrocytosis.

Bone marrow aspiration and trephine reveal hypocellularity.

V1.0 V1.0 V1.0 V1.0 Management

All patients will require blood product support and aggressive management of infection. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die,usually in the first year.

V1.0 The curative treatment for patients under 30 years of age with severe idiopathic aplastic anaemia is allogeneic HSCT if there is an available donor

V1.0 Those with a compatible sibling donor should proceed to transplantation as soon as possible; they have a 75–90% chance of long-term cure.

V1.0 In older patients, immunosuppressive therapy with ciclosporin and antithymocyte globulin gives 5-year survival rates of 75%.

V1.0 The thrombopoietin receptor agonist eltrombopag has produced trilineage responses in patients who fail IST ( immunosuppressive therapy ) and is licensed for this indication.

V1.0 V1.0

Question 22

HA

Answer 22

Haemolytic anaemia

Haemolysis indicates that there is shortening of the normal red cell lifespan of 120 days.

V1.0 The bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow, and releasing reticulocytes prematurely

V1.0 Anaemia only occurs if the rate of destruction exceeds this increased production rate .

V1.0 Red cell destruction overloads pathways for haemoglobin breakdown in the liver, causing a modest rise in unconjugated bilirubin in the blood and mild jaundice.

V1.0 Increased reabsorption of urobilinogen from the gut results in an increase in urinary urobilinogen . Red cell destruction releases LDH into the serum

V1.0 The bone marrow compensation results in a reticulocytosis, and sometimes nucleated red cell precursors appear in the blood.

V1.0 Increased proliferation of the bone marrow can result in a thrombocytosis, neutrophilia and, if marked, immature granulocytes in the blood, producing a leucoerythroblastic blood film.

V1.0 The appearances of the red cells may give an indication of the likely cause of the haemolysis:

V1.0 • Spherocytes are small, dark red cells which suggest autoimmune haemolysis or hereditary spherocytosis.

• Sickle cells suggest sickle-cell disease.

• Red cell fragments indicate microangiopathic haemolysis.

V1.0 The compensatory erythroid hyperplasia may give rise to folate deficiency, with megaloblastic blood features.

V1.0 Extravascular haemolysis

Physiological red cell destruction occurs in the reticuloendothelial cells in the liver or spleen, so avoiding free haemoglobin in the plasma.

In most haemolytic states, haemolysis is predominantly extravascular

V1.0 Intravascular haemolysis

Less commonly, red cell lysis occurs within the blood stream due to membrane damage by complement (ABO transfusion reactions, paroxysmal nocturnal haemoglobinuria),

V1.0 infections (malaria, Clostridium perfringens), mechanical trauma (heart valves, DIC) or oxidative damage (e.g. drugs such as dapsone and maloprim).

V1.0 V1.0 When intravascular red cell destruction occurs, free haemoglobin is released into the plasma. Free haemoglobin is toxic to cells and binding proteins have evolved to minimise this risk.

V1.0 If all the protective mechanisms are saturated, free haemoglobin may appear in the urine (haemoglobinuria). When fulminant, this gives rise to black urine, as in severe falciparum malaria infection

V1.0 Investigation results indicating active haemolysis Hallmarks of haemolysis

• ↓Haemoglobin

• ↑Unconjugated bilirubin

• ↑Lactate dehydrogenase

• ↑Reticulocytes

• ↑Urinary urobilinogen

V1.0 Additional features of intravascular haemolysis

• ↓Haptoglobin

• ↑Methaemalbumin

• Positive urinary haemosiderin

• Haemoglobinuria

Question 23

Red cell membrane defects Hereditary spherocytosis

Answer 23

Red cell membrane defects Hereditary spherocytosis

This is usually inherited as an autosomal dominant condition, although 25% of cases have no family history and represent new mutations. The incidence is approximately 1 : 5000 in developed countries

V1.0 V1.0 The most common abnormalities are deficiencies of beta spectrin or ankyrin The severity of spontaneous haemolysis varies. Most cases are associated with an asymptomatic compensated chronic haemolytic state with spherocytes present on the blood film, a reticulocytosis and mild hyperbilirubinaemia.

V1.0 Pigment gallstones are present in up to 50% of patients and may cause symptomatic cholecystitis.

V1.0 V1.0 The clinical course may be complicated by crises:

• A haemolytic crisis occurs when the severity of haemolysis increases; this is rare, and usually associated with infection.

V1.0 A megaloblastic crisis follows the development of folate deficiency; this may occur as a first presentation of the disease in pregnancy.

V1.0 An aplastic crisis occurs in association with parvovirus B19 infection

V1.0 Investigations

The patient and other family members should be screened for features of compensated haemolysis This may be all that is required to confirm the diagnosis. Haemoglobin levels are variable, depending on the degree of compensation.

V1.0 The blood film will show spherocytes but the direct Coombs test is negative, excluding immune haemolysis.

An osmotic fragility test may show increased sensitivity to lysis in hypotonic saline solutions but is limited by lack of sensitivity and specificity.

V1.0 Management

Folic acid prophylaxis, 5 mg daily, should be given for life.

Consideration may be given to splenectomy, which improves but does not normalise red cell survival.

V1.0 . Potential indications include moderate to severe haemolysis with complications (anaemia and gallstones), although splenectomy should be delayed until after 6 years of age in view of the risk of sepsis

V1.0 Hereditary elliptocytosis

This term refers to a heterogeneous group of disorders that produce an increase in elliptocytic red cells on the blood film and a variable degree of haemolysis.

V1.0 This is due to a functional abnormality of one or more anchor proteins in the red cell membrane, e.g. alpha spectrin or protein 4.1. Inheritance may be autosomal dominant or recessive.

V1.0 V1.0 V1.0

Question 24

Red cell enzymopathies Glucose-6-phosphate dehydrogenase deficiency

Answer 24

Red cell enzymopathies Glucose-6-phosphate dehydrogenase deficiency

The enzyme glucose-6-phosphate dehydrogenase (G6PD) is pivotal in the hexose monophosphate shunt pathway. Deficiencies result in the most common human enzymopathy, affecting 10% of the world’s population.

V1.0 The deficiency therefore affects males and rare homozygous females but it is carried by females.

V1.0 V1.0 Clinical features

• Acute drug-induced haemolysis to (e.g.): Analgesics: aspirin, phenacetin Antimalarials: primaquine, quinine, chloroquine, pyrimethamine Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin Miscellaneous: quinidine, probenecid, vitamin K, dapsone.

V1.0 • Favism, i.e. acute haemolysis after ingestion of broad beans (Vicia faba)

V1.0 V1.0 V1.0 G6PD level

• Can be indirectly assessed by screening methods which usually depend upon the decreased ability to reduce dyes

V1.0 • Care must be taken close to an acute haemolytic episode because reticulocytes may have higher enzyme levels and give rise to a false normal result.

V1.0 Management aims to stop any precipitant drugs and treat any underlying infection. Acute transfusion support may be life-saving.

V1.0 V1.0 V1.0

Question 25

Pyruvate kinase deficiency

Answer 25

Pyruvate kinase deficiency

This is the second most common red cell enzyme defect. It results in deficiency of ATP production and a chronic haemolytic anaemia.

It is inherited as an autosomal recessive trait.

Question 26

AIHA

Answer 26

Autoimmune haemolytic anaemia

This results from increased red cell destruction due to red cell autoantibodies.

The antibodies may be IgG or M, or more rarely IgE or A. If an antibody avidly fixes complement, it will cause intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular.

V1.0 Antibody-coated red cells lose membrane to macrophages in the spleen and hence spherocytes are present in the blood. The optimum temperature at which the antibody is active (thermal specificity) is used to classify immune haemolysis:

V1.0 V1.0 V1.0 • Warm antibodies bind best at 37°C and account for 80% of cases. The majority are IgG and often react against Rhesus antigens.

V1.0 *Primary (idiopathic) *Secondary (occurring in association with an underlying disorder such as SLE, lymphoma, chronic lymphocytic leukemia or after use of certain drugs)

V1.0 • Cold antibodies bind best at 4°C but can bind up to 37°C in some cases. They are usually IgM and bind complement. To be clinically relevant, they must act within the range of normal body temperatures. They account for the other 20% of cases.

V1.0 *Infections (especially mycoplasmal pneumonias or infectious mononucleosis)

*Lymphoproliferative disorders *Idiopathic

V1.0 Warm autoimmune haemolysis The incidence of warm autoimmune haemolysis is approximately 1/100 000 population per annum; it occurs at all ages but is more common in middle age and in females.

V1.0 Investigations There is evidence of haemolysis and spherocytes on the blood film. The diagnosis is confirmed by the direct Coombs or antiglobulin test

V1.0 The direct Coombs test can be negative in the presence of brisk haemolysis.

Around 10% of all warm autoimmune haemolytic anaemias are Coombs test-negative.

V1.0 Management If the haemolysis is secondary to an underlying cause, this must be treated and any implicated drugs stopped. It is usual to treat patients initially with prednisolone 1 mg/kg orally. A response is seen in 70–80% of cases but may take up to 3 weeks; a rise in haemoglobin will be matched by a fall in bilirubin, LDH and reticulocyte levels.

V1.0 Transfusion support may be required for lifethreatening problems, such as the development of heart failure or rapid unabated falls in haemoglobin.

The least incompatible blood should be used but this may still give rise to transfusion reactions or the development of alloantibodies.

V1.0 About two-thirds of patients respond to corticosteroid treatment.

In patients who relapse after corticosteroid cessation or who are refractory to corticosteroids, rituximab is usually used as a second-line drug.

V1.0 Other treatments include use of additional immunosuppressive drugs and/or splenectomy.

About one third to one half of patients have a sustained response after splenectomy.

In cases of fulminant hemolysis, high-dose pulse corticosteroids can be used.

V1.0 For less severe but uncontrolled hemolysis, immune globulin infusions have provided temporary control.

Long-term management with immunosuppressants (including cyclosporine) has been effective in patients in whom corticosteroids and splenectomy have been ineffective.

Question 27

Cold agglutinin disease

Answer 27

Cold agglutinin disease

This is due to antibodies, usually IgM, which bind to the red cells at low temperatures and cause them to agglutinate.

It may cause intravascular haemolysis if complement fixation occurs.

V1.0 Chronic cold agglutinin disease This affects elderly patients and may be associated with an underlying low-grade B cell lymphoma. It causes a low-grade intravascular haemolysis with cold, painful and often blue fingers, toes, ears or nose (so-called acrocyanosis).

Question 28

Paroxysmal cold hemoglobinuria

Answer 28

Paroxysmal cold hemoglobinuria

Paroxysmal cold hemoglobinuria (PCH; DonathLandsteiner syndrome) is a rare type of cold agglutinin disease. PCH is more common in children. Hemolysis results from exposure to cold, which may even be localized (eg, from drinking cold water, from washing hands in cold water). An IgG antibody binds to the P antigen on RBCs at low temperatures and causes intravascular hemolysis

V1.0 . It occurs most often after a nonspecific viral illness or in otherwise healthy patients, although it occurs in some patients with congenital or acquired syphilis..

V1.0 The severity and rapidity of development of the anemia varies and may be fulminant.

In children, this disease is often self-resolving

V1.0 TREATMENT OF COLD AGGLUTININ

Treatment is directed at any underlying lymphoma but if the disease is idiopathic, then patients must keep extremities warm, especially in winter.

V1.0 In many cases, avoidance of cold environments and other triggers of hemolysis may be all that is needed to prevent symptomatic anemia.

In cases associated with a lymphoproliferative disease, treatment is directed at the underlying disorder.

Rituximab is commonly used, and chemotherapy regimens used to treat B-cell cancers can be effective.

V1.0 In severe cases, plasmapheresis is an effective temporary treatment.

Transfusions should be given sparingly, with the blood warmed through an on-line warmer. Splenectomy is usually of no value. and

immunosuppressants have only modest effectiveness.

V1.0 Paroxysmal cold hemoglobinuria

In PCH, therapy consists of strict avoidance of exposure to cold. Immunosuppressants have been effective, but use should be restricted to patients with progressive or idiopathic cases.

Splenectomy is of no value.

Treatment of concomitant syphilis may cure PCH.

V1.0 V1.0

Question 29

Immune HEMOLYSIS Drug-Related

Answer 29

Immune HEMOLYSIS Drug-Related

• Immune Complex Mechanism

– Quinidine, Quinine, Isoniazid

• “Haptenic” Immune Mechanism

– Penicillins, Cephalosporins

• True Autoimmune Mechanism

– Methyldopa, L-DOPA, Procaineamide, Ibuprofen

Question 30

Non-immune haemolytic anaemia

Answer 30

Non-immune haemolytic anaemia

Physical trauma Physical disruption of red cells may occur in a number of conditions and is characterised by the presence of red cell fragments on the blood film and markers of intravascular haemolysis:

V1.0 • Mechanical heart valves.

• March haemoglobinuria. Vigorous exercise, such as prolonged marching or marathon running, can cause red cell damage in the capillaries in the feet.

V1.0 • Thermal injury. Severe burns cause thermal damage to red cells, characterised by fragmentation and the presence of microspherocytes in the blood.

V1.0 • Microangiopathic haemolytic anaemia. Fibrin deposition in capillaries can cause severe red cell disruption.

It may occur in a wide variety of conditions: disseminated carcinomatosis, malignant or pregnancy-induced hypertension, haemolytic uraemic syndrome thrombotic thrombocytopenic purpura and disseminated intravascular coagulation

V1.0 V1.0 Infection Plasmodium falciparum malaria Clostridium perfringens septicaemia

Chemicals or drugs Dapsone and sulfasalazine cause haemolysis Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis.

V1.0 V1.0 V1.0 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired, non-malignant clonal expansion of haematopoietic stem cells deficient in GPI-anchor protein; it results in intravascular haemolysis and anaemia because of increased sensitivity of red cells to lysis by complement

V1.0 . Episodes of intravascular haemolysis result in haemoglobinuria, most noticeable in early morning urine.

The disease is associated with an increased risk of venous thrombosis in unusual sites, such as the liver or abdomen.

V1.0 PNH is also associated with hypoplastic bone marrow failure, aplastic anaemia and myelodysplastic syndrome.

Management is supportive with transfusion and treatment of thrombosis.

Recently, the anti-complement C5 monoclonal antibody eculizumab was shown to be effective in reducing haemolysis

Question 31

Classification of leukaemia

Answer 31

Classification of leukaemia

⦿ The main classification is into four types: acute or chronic leukaemias, which are further subdivided into lymphoid or myeloid leukaemias.

⦿ Acute leukaemias are usually aggressive

diseases in which malignant transformation occurs in a haemopoietic stem cell or early progenitor. Acquired genetic damage results in an increased rate of proliferation, reduced apoptosis and a block in cellular differentiation. Together these events cause accumulation in the bone marrow of early haemopoietic cells known as blast cells. ⦿ The dominant clinical feature of acute

leukaemia is usually bone marrow failure caused by accumulation of blast cells, although organ infiltration also can occur. If untreated, acute leukaemias are usually rapidly fatal, although with modern treatments most younger patients are ultimately cured of their disease. ⦿ Acute leukaemia is normally defined as the presence of at least 20% of blast cells in the bone marrow or blood at clinical presentation.

⦿ it can be diagnosed with less than 20%

blasts if certain leukaemia-specific cytogenetic or molecular genetic abnormalities are present (promyelocytic leukaemia).

Question 32

AML

Answer 32

Acute myeloid leukaemia (AML)

⦿ AML is the most common form of acute leukaemia in adults and becomes increasingly common with age, with a median onset of 65 years. Clinical features

⦿ The clinical features of AML are dominated by

the pattern of bone marrow failure caused by the accumulation of malignant cells within marrow . Infections are frequent, and anaemia and thrombocytopenia are often profound. A bleeding tendency caused by thrombocytopenia and disseminated intravascular coagulation (DIC) is characteristic of the promyelocytic variant of AML. Tumour cells can infiltrate a variety of tissues. Gum hypertrophy and infiltration, skin involvement (leukaemia cutis) and central nervous system (CNS) involvement. Investigations

⦿ Haematological investigations reveal a

normochromic normocytic anaemia with thrombocytopenia in most cases. The total white cell count is usually increased, and blood film examination typically shows a variable numbers of blast cells.

⦿ The bone marrow is hypercellular and

typically contains many leukaemic blasts. Blast cells are characterized by morphology, immunological (flow cytometric) cytogenetic for confirming the diagnosis. ⦿ Tests for DIC are often positive in

patients with the promyelocytic variant of AML. Biochemical tests are performed as a baseline before treatment begins and may reveal raised uric acid or lactate dehydrogenase.

Question 33

ALL

Answer 33

Acute lymphoblastic leukaemia (ALL)

⦿ is caused by an accumulation of

lymphoblasts in the bone marrow and is the most common malignancy of childhood, although it can occur at any age.

⦿ The incidence of ALL is highest at 3–7

years, with 75% of cases occurring before the age of 6. There is a secondary incidence rise after the age of 40 years. B-cell lineage represents 85% of cases and these have an equal sex incidence; there is a male predominance for the 15% of T-cell ALL. Clinical features

⦿ Bone marrow failure

■■ Anaemia (pallor, lethargy and dyspnoea).

■■ Neutropenia (fever, malaise, features of infection).

■■ Thrombocytopenia (spontaneous bruises, purpura, bleeding gums and menorrhagia). ⦿ Organ infiltration ⦿ This can cause tender bones,

lymphadenopathy, moderate splenomegaly, hepatomegaly and meningeal syndrome (headache, nausea and vomiting, blurring of vision and diplopia). Fundal examination may reveal papilloedema and sometimes haemorrhage.

⦿ Less common manifestations include

testicular swelling or signs of mediastinal compression, which is more common in T-ALL. Investigations

⦿ Haematological investigations reveal

normochromic, normocytic anaemia with thrombocytopenia in most cases. The total white cell count may be decreased, normal or increased, sometimes to 200 × 109/L or more. The blood film typically shows a variable number of blast cells. The bone marrow is hypercellular with >20% leukaemic blasts. The blast cells are characterized by morphology, immunological tests and cytogenetic analysis. ⦿ Lumbar puncture for cerebrospinal fluid (CSF) examination is important in disease staging.

⦿ Biochemical tests may reveal a raised

serum uric acid, serum lactate dehydrogenase or, less commonly. Liver and renal function tests are performed as a baseline before treatment begins. Radiography may reveal a mediastinal mass caused by enlargement of the thymus and/or mediastinal lymph nodes characteristic of T-ALL. Management

⦿ Supportive therapy ⦿ Aggressive and potentially curative therapy,

which involves periods of severe bone marrow failure, would not be possible without appropriate supportive care. The following problems commonly arise.

⦿ Anaemia Anaemia is treated with red cell concentrate transfusions.

⦿ Bleeding Thrombocytopenic bleeding requires platelet transfusions, Recent trials have confirmed that in acute leukaemia prophylactic platelet transfusion should be given to maintain the platelet count above 10 × 109/L. ⦿

⦿

⦿

Infection Fever (> 38°C) lasting over 1 hour in a neutropenic patient indicates possible sepsis. Parenteral broad-spectrum antibiotic therapy is essential.

Metabolic problems Frequent monitoring of fluid balance and renal, hepatic and haemostatic function is necessary. Patients are often severely anorexic and diarrhoea is common as a consequence of the side-effects of therapy; they may find drinking difficult and hence require intravenous fluids and electrolytes.

Cellular breakdown during induction therapy(tumour lysis syndrome) causing hyperkalaemia, hyperuricaemia, hyperphosphataemia and hypocalcaemia. This may lead to renal failure.

Question 34

Specific ttt for LEUKAEMIA

Answer 34

Specific treatment

⦿ Remission iduction This is defined as less than 5% blasts in the bone marrow, normal or near-normal peripheral blood count and no other symptoms or signs of the disease.

⦿ Remission consolidation. If remission has

been achieved, residual disease is attacked by therapy during the consolidation phase.

⦿ Remission maintenance. If the patient is still in remission after the consolidation phase for ALL, a period of maintenance therapy is given. Specific therapy of AML ⦿ is determined by the age and performance

status of the patient, as well as the genetic

lesions within the tumour.

⦿ In younger patients, intensive

chemotherapy is usual. This is given in several blocks, each of approximately 1 week. The most frequently used drugs are cytosine arabinoside and daunorubicin . A standard induction regimen is 3 days of daunorubicin and 7 days of cytosine arabinoside (3+7). ⦿ ventoclax in combination with

chemotherapy shows promise for relapsed cases and in older patients as initial therapy with hypomethylating drugs.

⦿ APML has its own treatment protocol. ATRA therapy is given for this disease subtype and is combined initially with either arsenic trioxide or anthracycline. ⦿

Specific treatment for ALL

The factors that guide treatment include age, gender and white cell count at presentation. The initial response to therapy is also important.

⦿

⦿

remission induction is to rapidly kill most (>99%) of the tumour cells and get the patient into remission. Steroids,vincristine and asparaginase are the drugs usually used and they are very effective.

Consolidation These courses use high doses of multidrug chemotherapy in order to eliminate the disease or reduce the tumour burden to very low levels, Typical protocols involve the use of vincristine, cyclophosphamide, cytosine arabinoside,daunorubicin, etoposide or mercaptopurine, given as blocks in different combinations. ⦿ Central nervous system-directed therapy

Few of the drugs given systemically reach the CSF and specific treatment is required to prevent or treat CNS disease. Intrathecal methotrexate, cytosine arabinoside and corticosteroids are usually used.

⦿ Maintenance therapy with daily oral

mercaptopurine and once weekly oral methotrexate prevents late relapses.

⦿ Intravenous vincristine with a short course of oral corticosteroid is added at 3-monthly intervals. ⦿ Disease that relapses during treatment or

soon after the end of treatment carries a poor prognosis and is difficult to treat. The longer after the end of treatment that relapse occurs, the more likely it is that further treatment will be effective.

⦿ In patients with high-risk acute leukaemia,

allogeneic haematopoietic stem cell transplantation can improve 5-year survival from 20% to around 50%.

Question 35

Prognosis of LEUKAEMIA

Answer 35

Prognosis

⦿

⦿

The prognosis for patients with AML has been improving steadily, particularly for those under 60 years of age, and approximately one-third of this group can expect to achieve long-term cure. For the elderly the situation is poor, and less than 10% of those over 70 years of age achieve long-term remission.

For acute lymphoblastic leukaemia Approximately 25% of children relapse after first-line therapy and need further treatment, but overall 90% of children can expect to be cured. The cure rate in adults drops significantly to less than 5% over the age of 70years.

Question 36

CML

Answer 36

Chronic myeloid leukaemia
⦿ Chronic myeloid leukaemia (CML) is a myeloproliferative stem cell disorder resulting in proliferation of all haematopoietic lineages but manifesting predominantly in the granulocytic series.
⦿ a peak incidence at 55 years. accounts for 20% of all leukaemias.

⦿ The defining characteristic of CML is the chromosome abnormality known as the Philadelphia (Ph) chromosome. This is a shortened chromosome 22 resulting from a reciprocal translocation of material with chromosome 9.This results t(9;22) , as a result of which part of the oncogene ABL1 is moved to the BCR gene .
 
⦿ Symptoms related to hypermetabolism (e.g. weight loss,lassitude, anorexia or night sweats). Splenomegaly is nearly always present and may be massive splenic enlargement is associated with abdominal discomfort, pain or indigestion. Features of anaemia may include pallor, dyspnoea and tachycardia.

Natural history
⦿ The disease has three phases:
⦿ • A chronic phase, this phase has been prolonged to encompass a normal life expectancy in many patients.
⦿ • An accelerated phase (not always seen), in which disease control becomes more difficult.
⦿ • Blast crisis, in which the disease transforms into an acute leukaemia, either myeloblastic (70%) or lymphoblastic (30%), which is relatively refractory to treatment.

Laboratory findings
⦿ 1 Leucocytosis is the main feature and may reach levels greater than 200 × 109/L . A complete spectrum of myeloid cells is seen in the peripheral blood film. Myeloblasts usually constitute less than 10% of all white cells. Increased circulating basophils is a characteristic feature.
⦿ 2 Normochromic normocytic anaemia is usual.
⦿ 3 Platelet count may be increased (most frequently),
normal or decreased.
⦿ 4 Bone marrow should be obtained to confirm the diagnosis and phase of disease by morphology, chromosome analysis to demonstrate the presence of the Ph chromosome, and BCR ABL.
Management
⦿ Chronic phase
⦿ TKIs are the mainstay of the treatment of CML and
several different drugs are now available.
⦿ First-line therapy for patients with chronic phase CML is usually imatinib, nilotinib or dasatinib.
⦿ Most experience exists with imatinib, which is also the cheapest. Overall around 60% of patients given imatinib achieve an excellent response and remain on the drug longterm, whereas 40% proceed to a second-line agent due to intolerance or inadequate response.
⦿ Nilotinib and dasatinib achieve more rapid responses as first-line therapy and are therefore used first in some centres, although side-effects are somewhat more common.

⦿ Accelerated phase and blast crisis ⦿ Management is more difficult. For patients in accelerated phase, TKI therapy is indicated, most commonly with nilotinib or dasatinib. When blast transformation occurs, the type of blast cell should be determined. Second- or third-generation TKIs such as dasatinib are used in combination with chemotherapy to try and achieve remission. In younger and fitter patients an allogeneic HSCT is appropriate therapy if a return to chronic phase is achieved.

Question 37

CLL

Answer 37

Chronic lymphocytic
leukaemia
⦿ Chronic lymphocytic leukaemia (CLL) is the most common variety of leukaemia, accounting for 30% of cases. The male-to-female ratio is 2 : 1 and the median age at presentation is 65–70 years. CLL cells exhibit impaired apoptosis and a prolonged lifespan, and this is reflected in their accumulation in the blood, bone marrow, liver, spleen and lymph nodes.

⦿ Clinical features ⦿ The onset is usually insidious. Indeed, in around 70% of patients, the diagnosis is made incidentally on a routine FBC. Presenting problems may be anaemia, infections, painless lymphadenopathy, and systemic symptoms such as night sweats or weight loss.

Laboratory findings
⦿ The diagnosis is based on the peripheral blood findings of a mature lymphocytosis (> 5 × 109/L) with characteristic morphology and cell surface markers.
⦿ Normochromic normocytic anaemia is present in later stages as a result of marrow infiltration or hypersplenism.
⦿ Bone marrow aspiration shows lymphocytic replacement of normal marrow elements.

Management
⦿ It is difficult to cure CLL, Therefore, the approach to therapy is generally conservative, aiming for symptom control rather than a normal blood count.
⦿ Many patients will never need treatment. Treatment is required only if there is evidence of bone marrow failure, massive or progressive lymphadenopathy or splenomegaly, systemic symptoms such as weight loss or night sweats, a rapidly increasing lymphocyte count, autoimmune haemolytic anaemia or thrombocytopenia.

⦿ For patients who are under 70 years, fit, fludarabine in combination with the alkylating agent cyclophosphamide and the anti-CD20 monoclonal antibody rituximab (FCR) is standard care. For older, less fit patients, rituximab is combined with gentler chemotherapy: bendamustine or oral chlorambucil.
 
⦿ In recent years several new and highly effective therapies have emerged in the treatment of lymphoid disorders , They are used for treating relapsed, resistant patients, Ibrutinib is oral drug which inactivate BTK and lead to B-cell apoptosis.

Question 38

HL

Answer 38

⦿ Nodular lymphocyte predominant (LP) Hodgkin lymphoma does not show RS cells and has many features of non-Hodgkin lymphoma, the tumour cells being polylobated (‘popcorn’) B cells. It is usually treated like non-Hodgkin lymphomas. The prognosis is good.
⦿ There is no difference in the prognosis or management of the different subtypes of classical HL. Nodular sclerosis is the most frequent in Europe and the USA, whereas lymphocyte depleted is more common in developing countries and has a particularly strong association with EBV infection and malnutrition.

Investigations
⦿ 1 Normochromic normocytic anaemia is most common. One-third of patients have a neutrophilia; eosinophilia is frequent. Advanced disease is associated with lymphopenia.
⦿ 2 ESR and C-reactive protein are usually raised.
⦿ 3 Serum lactate dehydrogenase (LDH) is raised
initially in 30–40% of cases.
⦿ 4 Chest X-ray may show a mediastinal mass. CT
scan of chest, abdomen and pelvis permits staging.
⦿ 5Positron emission tomography (PET) scanning identifies nodes involved with HL, which are (FDG)-avid, and this allows more accurate staging and monitoring of response.
⦿ 6 Excisional Lymph node biopsy

Clinical staging
⦿ Selection of appropriate treatment depends on accurate staging of the extent of disease, Staging is performed by clinical examination together with combined (PET) and CT scans.

⦿ ⦿ ⦿
⦿ ⦿
Stage I indicates node involvement in one lymph node area.
Stage II indicates disease involving two or more lymph nodal areas confined to one side of the diaphragm.
Stage III indicates disease involving lymph nodes above and below the diaphragm. Splenic disease is included in stage III.
Stage IV indicates involvement outside the lymph node areas and refers to diffuse or disseminated disease in the bone marrow, liver and other extranodal sites.
The stage number in all cases is followed by the letter A or B, indicating the absence (A) or presence (B) of one or more of the following: unexplained fever above 38°C; night sweats; or loss of more than 10% of body weight within 6 months.

Treatment
⦿ Treatment is either with chemotherapy alone or a combination of chemotherapy with radiotherapy. The choice depends primarily on the stage, clinical state A or B.
⦿ Early-stage disease
⦿ The most widely used regimen is with courses of A (Adriamycin = Doxorubicin), B (Bleomycin), V (Vinblastine), D (Dacarbazine) (ABVD) chemotherapy followed by radiotherapy.

⦿ Advanced-stage disease ⦿ Cyclical chemotherapy is used for stage III and IV disease. Six courses of ABVD are most widely used. Escalated BEACOPP gives a higher complete remission rate at the expense of greater toxicity.
 
⦿ Because bleomycin causes pulmonary toxicity, there is interest in alternative agents that might offer comparable cure rates to ABVD or BEACOPP but with fewer adverse effects. Brentuximab vedotin is an antibody–drug conjugate directed against CD30 on the Reed–Sternberg cell surface.

Prognosis
⦿ The prognosis depends on age, stage and histology. Overall approximately 85% of patients are cured.
⦿ Patients who fail to respond to initial chemotherapy or relapse within a year of initial therapy have a poor prognosis but some may achieve long-term survival after autologous HSCT.

Question 39

NHL

Answer 39

⦿ The non-Hodgkin lymphomas (NHL) are a large group of clonal lymphoid tumours, about 85% of B cell and 15% of T or NK (natural killer) cell origin.
⦿ Their clinical presentation and natural history are much more variable than those of Hodgkin lymphoma. NHL are characterized by an irregular pattern of spread and a significant proportion of patients develop disease outside the lymph nodes.
⦿ The incidence of these tumours increases with age, to 62.8/million population per annum at age 75 years.

Low- versus high-grade NHL
⦿ NHL includes a diverse group of diseases that vary from highly proliferative and potentially rapidly fatal conditions to some very indolent and well-tolerated malignancies.
⦿ For many years, clinicians have subdivided lymphomas into ‘low-grade’ and ‘high-grade’ disease. This approach is valuable as, in general terms, the low-grade disorders are relatively indolent, respond well to chemotherapy or immunotherapy, and have a lengthy median survival but are very difficult to cure, whereas high-grade lymphomas are aggressive and need urgent treatment, but are more often curable.

Clinical features
⦿ The majority of patients present with asymmetrical painless enlargement of lymph nodes in one or more peripheral lymph node regions.
⦿ Fever, night sweats and weight loss can occur, but are less frequent than in Hodgkin lymphoma. Their presence is usually associated with more advanced, disseminated disease.
⦿ Sites of extranodal involvement include the bone marrow, gut, thyroid, lung, skin, testis, brain and, more rarely, bone.
⦿ Bone marrow involvement is more common in low-grade (50–60%) than high-grade (10%) disease.

Investigations
⦿ 1 In advanced disease with marrow involvement there may be anaemia, neutropenia or thrombocytopenia.
⦿ 2 Whole lymph node excisional biopsy, or more usually core needle (e.g. Trucut) biopsy of lymph node or of other involved tissue (e.g. bone marrow or extranodal tissue), is the definitive investigation .
⦿ 3 Trephine biopsy of marrow may be valuable in staging if risk of involvement is high.
⦿ 4 The serum lactate dehydrogenase (LDH) level is raised in rapidly proliferating and extensive disease.

Staging
⦿ The staging system is the same as that described for Hodgkin lymphoma,
⦿ Staging procedures usually include chest X-ray and PET/CT scanning.

Management
⦿ Low-grade NHL
⦿ Asymptomatic patients may not require therapy and are managed by ‘watching and waiting’. Indications for treatment include marked systemic symptoms, lymphadenopathy causing discomfort or disfigurement, bone marrow failure or compression syndromes.
⦿ • Radiotherapy. This can be used for localised stage I disease, which is rare.

⦿ The anti-CD20 antibody rituximab has been shown to induce durable clinical responses,and acts synergistically when given with chemotherapy cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) or bendamustine (R-bendamustine) is commonly used as first-line therapy. ⦿ Kinase inhibitors. Idelalisib and ibrutinib are approved for relapsed, a poor-prognosis lymphoma with low-grade histology but aggressive clinical behaviour. ⦿ Autologous HSCT can produce long remissions in patients with relapsed disease.
 
⦿ High-grade NHL ⦿ Patients with diffuse large B-cell NHL need treatment at initial presentation: ⦿ • Chemotherapy The majority (> 90%) are treated with intravenous combination chemotherapy, typically with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone). ⦿ • Monoclonal antibody therapy. When combined with CHOP chemotherapy, rituximab (R) increases the complete response rates and improves overall survival.
 
⦿ Radiotherapy is also indicated for a residual localised site of bulk disease after chemotherapy. ⦿ • HSCT. Autologous HSCT benefits patients with relapsed disease.

Prognosis
⦿ Low-grade NHL runs an indolent remitting and relapsing course, with an overall median survival of 12 years. Transformation to a high-grade NHL occurs in 3% per annum and is associated with poor survival.
⦿ For high-grade NHL, 5-year survival ranges from over 75% in those with low-risk scores to 25% in those with high-risk scores.
⦿ Relapse is associated with a poor response to further chemotherapy < 10% 5-year survival.