Im3 Flashcards
(39 cards)
Hereditary haemorrhagic telangiectasia (vs.) Ehlers–Danlos disease
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.
Thrombocytopenia
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
ITP
Idiopathic (Immune) thrombocytopenic purpura
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.
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).
Platelet function disorders
Platelet function disorders
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.
Haemophilia A
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.
Haemophilia B (Christmas disease)
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.
Von Willebrand disease
Von Willebrand disease
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.
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
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.
• 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
Venous thromboembolic
disease
⦿ 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).
Risk factors for venous thromboembolism.
. 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
Once a diagnosis of DVT or PE is made, or strongly suspected
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.
Antithrombin deficiency
Protein C and S deficiencies
Factor V Leiden
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.
Antiphospholipid syndrome
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.
DIC
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.
TTP
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.
Anticoagulant and antithrombotic therapy
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.
Anemias
In general
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.
Anemia
Classification
Dx
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.
IDA
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.
Megaloblastic anaemia
Precious anaemia
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
Anaemia of chronic disease
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.
Primary idiopathic acquired aplastic anaemia
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
HA
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
Red cell membrane defects Hereditary spherocytosis
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.
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Red cell enzymopathies Glucose-6-phosphate dehydrogenase deficiency
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.
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