Haematological disease

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8 Haematological disease

Questions

What is favism?

What is the haemoglobin content of reticulocytes and how can this be measured or determined?

We are told that an erythrocyte sedimentation rate (ESR) above 100mm/h has a limited differential diagnosis, mainly vasculitis, malignancy and granulomatous diseases. Could you explain whether that applies to an ESR after one hour or two?

What causes a raised erythrocyte sedimentation rate (ESR)?

What are the causes of very raised erythrocyte sedimentation rate (ESR)? I mean an ESR < 100mm/h. Is this test diagnostic in any disease besides polymyalgia rheumatica and giant cell arteritis?

1. Does the erythrocyte sedimentation rate (ESR) rise with age?

2. Can an ESR of 50mm/h in an 80-year-old female with no evidence of systemic disease be considered normal?

1. What is a ‘normal’ erythrocyte sedimentation rate (ESR)? Is the equation of a normal ESR = age – 10, correct?

2. Would a normal ESR exclude a vasculitic cause in the case of stroke?

In which conditions is C-reactive protein (CRP) more informative than the erythrocyte sedimentation rate (ESR)?

What is the management of an isolated high ferritin (without any signs, symptoms or changes in the other blood investigations)?

Is the mean corpuscular volume (MCV) useful? What is the RDW and when is it used?

What is the significance of renal disease with respect to anaemia, if any?

Can anaemia be a differentiating point between muscle wasting and cachexia owing to another systemic disorder?

Anaemia of chronic disease does not respond to iron therapy, but there are trials studying the use of iron and erythropoietin (EPO). Could you tell me where to find more detailed information about these trials, and whether there have since been any further developments?

Is the deoxyuridine test helpful?

The Schilling test is very rarely performed. Why is this?

There is no extramedullary haematopoiesis in aplastic anaemia, why?

Why is the anaemia in aplastic anaemia, macrocytic?

Is vitamin B₁₂ absorbed passively from the jejunum?

What role does ‘R’ binder play in the absorption of vitamin B₁₂?

In pernicious anaemia, investigation of the serum shows an elevated level of gastrin. Why is it so?

1. Please explain the term Coombs’ positive (direct and indirect) and negative haemolytic anaemia.

2. What are the principles of the Coombs’ test?

How often is Aldomet (alpha methyldopa) associated with autoimmune haemolytic anaemia or hepatitis? Is a normal person, with a positive Coombs’ test owing to previous treatment with this drug, safe to donate blood?

What is the mechanism of priapism in sickle-cell anaemia?

Is sickle-cell disease associated with any of the glomerular disorders?

What is the acute chest syndrome?

Patients with thalassaemia intermedia have recurrent leg ulcers and recurrent infections. What is the mechanism of this?

What is the mechanism of iron absorption from iron polymaltose complex and carbonyl iron?

Iron overload in patients with thalassaemia major should be checked by measuring the serum ferritin and hepatic iron stores. How are the hepatic iron stores measured? By liver biopsy? And does not the measurement of serum ferritin suffice?

In the investigation for paroxysmal nocturnal haemoglobinuria (PNH), are the sucrose haemolysis test and Ham’s acid serum test commonly done? What are the principles behind these tests?

Why isn’t the blood of polycythaemia vera patients, after repeated phlebotomies, used for transfusion purposes? Although it is a premalignant condition, the red cells do not contain a nucleus and thus transfusion of only pure red blood cells (RBCs) would be a great benefit.

What investigations are necessary to exclude secondary polycythaemia?

What is the management plan in a patient with secondary polycythaemia presenting with transient ischaemic attacks (TIA)?

Why do patients with polycythaemia vera have a tendency to bleed, even though 50% of them have an elevated platelet count?

In hyposplenic patients, what precautions are necessary for patients who intend to travel to Saudi Arabia for the Haj?

What is the mechanism of development of splenomegaly in chronic leukaemia?

In idiopathic thrombocytopenic purpura (ITP), thrombocytes are mainly destroyed in the spleen owing to an immune mechanism. Why, therefore, is there no splenic enlargement as there is with other diseases?

Where exactly is the Traub’s space? How exact is the percussion of the Traub’s space as a sign indicating the size of the spleen?

Can you please tell me the indications and complications of blood transfusion.

Several times I have read the phrase ‘white blood cells elevated with a left shift’. I am wondering what ‘left shift’ or ‘left deviation’ stands for.

What is the clear definition of ‘bleeding time’ and ‘clotting time’? And what are the applied differences between them?

What is the meaning of the international normalized ratio (INR) blood test?

What is the cause of moderate thrombocytopenia in Bernard-Soulier syndrome? It is a qualitative defect not a quantitative platelet disorder.

What is new about thrombopoietin?

What is the rationale behind the use of desmopressin in bleeding disorders?

What effect does the contraceptive pill have on the blood fibrinogen level and on blood coagulability?

Does standard (unfractionated) heparin in doses of 10000-15000 units/day need monitoring?

Is there an antidote for low-molecular-weight heparin (LMWH)? Can Enoxaprin be used?

1. What is the mechanism of the action of aprotinin?

2. What is the therapeutic window for aprotinin?

3. In a case of haemorrhagic stroke, how many days should aprotinin be prescribed for and what is the recommended dosage?

My question is, what are thrombophilia scan tests? Can we use these in patients on anticoagulant therapy?

In thromboembolic disorders, how is clopidogrel superior to aspirin?

What are the definitions for prothrombin time (PT) and partial thromboplastin time (PTT), and how are they different?

1. Why, in chronic disease anaemia, are serum iron and the total iron-binding capacity (TIBC) low?

2. Why, in sideroblastic anaemia with increased levels of serum iron, is the TIBC normal?

What is the red cell distribution width (RDW) value above which anisocytosis can be diagnosed?

Is anisocytosis diagnostic of iron deficiency anaemia?

In the case of a patient who has been treated with streptokinase and has bleeding complications in the form of haematemesis, haemoptysis or similar, how can the effect of streptokinase on the coagulation system be reversed, and can tranexamic acid help?

We know that salmonella infection is a common complication in patients with sickle cell anaemia. Is this true for patients with thalassaemia major and, if so, why?

This is caused by the ingestion of fava beans. It can produce an acute haemolysis in patients with glucose-6-phosphate deficiency (G6PD). Others can enjoy the beans!

The reticulocyte is a young erythrocyte without a nucleus. Over 90% of the reticulocyte’s protein is haemoglobin. It is not normally measured.

It applies to the ESR after 1 hour.

A raised ESR is due to a rise in the large plasma proteins (e.g. fibrinogen or immunoglobulins). These proteins cause rouleaux formation when the cells clump together like a stack of coins and therefore fall more rapidly in a tube.

A very high ESR occurs with myeloma and sometimes with malignancies where there is an increase in the plasma concentration of immunoglo- bulins. It can also occur in inflammatory conditions, e.g. rheumatoid arthritis and inflammatory bowel disease (IBD). It is never diagnostic but sometimes adds strong support to the clinical picture, e.g. polymyalgia, giant cell arteritis, rheumatic fever. Its main use is in monitoring the response to treatment, e.g. when using steroids for IBD, a fall in the ESR indicates a good response.

1. There is a progressive rise with age. For example, in men aged 61-70 years the ESR is about 14; over 70, it is about 30. Women have slightly higher levels: aged 61-70 years the ESR is 20 and, over 70 it is 35.

2. An ESR of 50mm/h is therefore abnormal in an 80-year-old but it is not usually worth pursuing beyond simple investigation (e.g. blood count). Do remember the various ways polymyalgia rheumatica can present, e.g. tiredness, loss of weight and often without the characteristic pain. It responds dramatically to steroids.

1. Up to 20mm in 1 hour. The equation is not helpful.

2. This makes it very unlikely but not impossible.

CRP follows the clinical state of the patient much more closely in many inflammatory conditions, e.g. Crohn’s disease. It is unaffected by anaemia. The CRP does not rise in systemic lupus erythematosus but the ESR does.

Ferritin is an acute-phase protein and therefore will go up in inflammation, malignant disease or with acute liver necrosis. A high serum ferritin not associated with any of these should be investigated for possible hereditary haemochromatosis. Sending blood for genetic analysis of the HFE gene is now the best way to make this diagnosis.

The MCV (normal range 80-96fL) is useful in diagnosing the type of anaemia. A reading of 80 would suggest microcytic anaemia and 96fL, macrocytic anaemia. The RDW (red blood cell distribution width) is the ratio of the width of the red cell over the MCV. It helps in the diagnosis of microcytosis but not macrocytosis. In a patient with anaemia, a raised RDW would favour iron deficiency and a normal RDW, thalassaemia.

Anaemia is common in chronic kidney disease. The anaemia is often the normochromic, normocytic anaemia of chronic disease. The major cause of anaemia is a relative deficiency of erythropoietin. Other causes include bone marrow toxins, haemolysis, deficiency of haematinic factors (K&C 7e, p. 628).

Recombinant human erythropoietin is effective treatment in these cases; remember to replenish iron stores to optimize therapy.

Not really; anaemia can occur with cachexia associated with cancer and can also occur with muscle wasting associated with polymyositis.

The statement is correct, the anaemia does not respond to iron therapy alone. EPO is used in anaemia of chronic disease, e.g. rheumatoid arthritis, chronic kidney disease. The response can be dramatic so that iron must be made available, otherwise iron deficiency will occur.

Further reading

Remuzzi G, Inglefinger JR (2006) Correction of anemia – payoffs and problems. New England Journal of Medicine355; 2144-2146.

The problem with this test is that it needs a bone marrow sample. It is useful, however, because it gives a rapid result for vitamin B₁₂ and folate status, whereas the blood tests take more time. It is not used very often (K&C 7e, p. 398).

Because radiolabelled vitamin B₁₂ is now unavailable in the UK.

In aplastic anaemia there is damage to the stem cells, due to a number of causes including viruses and radiation. Damaged stem cells mean no haematopoiesis of any sort.

In aplastic anaemia there are few red cells and the anaemia is usually normocytic. It can occasionally be macrocytic as the abnormal red cells can be big.

Yes. Patients with pernicious anaemia who have no intrinsic factor can still be treated with vitamin B₁₂ orally by giving large amounts (2mg per day), which are absorbed passively in the jejunum. There is a specific transport mechanism for vitamin B₁₂ in the ileum, which requires intrinsic factor as a cofactor.

Vitamin B₁₂ is liberated from protein complexes in food by gastric enzymes and then bound to ‘R’ binder (a B₁₂ binding protein) from the saliva. This is similar to transcobalamin that is found in plasma. The bound B₁₂ is released by pancreatic enzymes and then becomes bound to intrinsic factor for absorption.

In pernicious anaemia, there is atrophy of parietal cells and therefore no acid is produced. The gastrin level is raised as there is no negative feedback.

1. In the direct Coombs’ test, the patient’s red cells are sensitized in vivo; the test is positive if agglutination occurs on the addition of antihuman globulin. In the indirect Coombs’ test, normal red cells are sensitized in vitro by incubation with the patient’s serum and again will be positive if there is agglutination on the addition of antihuman globulin.

2. The Coombs’ test detects autoantibody on the surface of the patient’s red cells.

Twenty per cent of patients develop a positive Coombs’ test with methyldopa but haemolytic anaemia is rare. Your normal person with previous drug treatment would not be able to donate blood because of problems with cross-matching and interference with agglutination tests. Hepatitis is rare.

Veno-occlusion is the easy answer but the mechanism of priapism is not clearly understood in sickle-cell disease.

Yes; focal glomerulosclerosis leads to chronic kidney disease.

This describes the pulmonary complications that occur in sickle-cell disease. These include pneumonia, thrombosis causing infarctions in the chest or bone marrow and embolism due to fat. It occurs in about 30-50% of patients with sickle-cell disease and is the commonest acute problem in the chest.

The mechanism is unclear but hypoxia due to anaemia has been suggested. Many are traumatic.

These compounds will be broken down in the intestine. Ferrous iron is absorbed in the duodenum initially by attaching to a protein divalent metal transporter, which transports Fe² into the cell where it is transported across the cell to reach the plasma or stored as ferritin (see reference). These compounds are, however, often passed intact beyond the point of iron absorption, the first part of the duodenum. Always prescribe simple iron preparations, e.g. ferrous sulphate.

Further reading

Fleming RE, Bacon BR (2005) Orchestration of Iron Homeostasis. New England Journal of Medicine 352: 1741-1744.

Iron stores have traditionally been assessed on liver biopsy – grams of iron per dry weight of liver. Magnetic resonance imaging is now the best technique. Measurement of serum ferritin will, however, suffice when monitoring treatment.

Osmotic damage does not occur when normal red cells are exposed to isotonic sucrose. The low ionic strength of the solution enhances the binding of the complement components to the red cell membrane. PNH cells develop membrane defects and sucrose molecules enter the red cell, producing osmotic lysis; 5% lysis is positive. In the Ham test, PNH red cells are significantly lysed when exposed to acidified serum (1% is positive). However, both these tests have now been replaced by flow cytometric analysis of red cells with anti-CD55 and anti-CD59 antibodies to the protein involved in the destruction of red cells by activated complement.

Polycythaemia vera is a clonal cell disorder in which 5% of patients develop acute myeloid leukaemia. It is thus thought to be unwise to use this for blood transfusion. Red cells do not contain nuclei but even pure red cell concentrates still contain a few leukocytes that of course do contain nuclei.

Further reading

Campbell PJ, Green AR (2006) The Myeloproliferative disorders. New England Journal of Medicine 355; 2452-2466.

The secondary causes can sometimes be excluded with a history and examination. A renal ultrasound, an arterial PO₂ and carboxyhaemoglobin levels will exclude most causes of secondary polycythaemia.

Treatment of the cause if possible; venesection may help. Aspirin 75mg daily should be given.

Platelets show a functional defect and haemorrhage causes death in 5% of patients.

These patients should already have had pneumococcal and meningococcal group C vaccines. They should receive, in addition, the meningococcal polysaccharide vaccine (A, C, W, Y types).

Further reading

Gardner P (2006) Prevention of meningococcal disease. New England Journal of Medicine 355: 1466-1473.

The splenomegaly is due to a combination of extramedullary haemopoiesis and infiltration of the spleen with neutrophils.

There is no explanation as to why the spleen remains the normal size. Presumably platelet destruction can occur without enlargement.

The area of resonance overlying the gas bubble in the left lateral hemithorax. Its size and localization depend on the contents and position of the stomach. It is displaced downwards by an enlarged spleen. Compared with ultrasound scanning in one study, the sign was 62% sensitive and 72% specific.

The main indication for blood transfusion is hypovolaemia due to loss of blood. The complications of blood transfusion are several (K&C 7e, p. 425) and include immunological causes (red cell and leucocyte incompatibility, anaphylactic reactions, graft versus host) and non-immunological (infection transmission, volume overload, thrombophlebitis). An avoidable cause is the transfusion of the wrong unit of blood.

A blood film shows a shift to the left if there are relatively more young polymorphonuclear leucocytes present than normal. These young cells have more band forms within them, and in addition there are sometimes myelocytes present; for example this occurs in acute infection.

The bleeding time measures platelet plug formation in vivo. Platelet function defects and low platelet numbers (80 10⁹L) result in an increased bleeding time. Activated whole blood clotting time has been replaced by activated partial thromboplastin time (APTT), which is also known as the partial thromboplastin time with kaolin (PTTK) as a measure of clotting.

The INR is the ratio of the patient’s prothrombin time (PT) to a normal control when using the international reference preparation. PT tests are therefore standardized, whichever laboratory is used.

The cause of the moderate thrombocytopenia in Bernard-Soulier syndrome is unclear. It is possibly related to ineffective or decreased thrombopoiesis.

Thrombopoietin is a regulator of platelet function. Its clinical use is in cancer chemotherapy, both for solid tumours and for acute leukaemia, hopefully avoiding platelet transfusion. It was also used in idiopathic autoimmune thrombocytopenia as second line therapy but Romiplostim, a similar protein, is now used.

Desmopressin is used in von Willebrand’s disease to release von Willebrand factor from the endothelium. In platelet function disorders it might have an effect on platelet function. In haemophilia A, desmopressin produces a transient rise in factor VIII and is useful for treating bleeding episodes in mild haemophilia and as a prophylaxis before minor surgery.

Factors V, VIII, X and fibrinogen levels are increased by ethinylestradiol, which can enhance thrombosis.

Unfractionated heparin should always be monitored with activated partial thromboplastin time (APTT) to ensure adequacy of effect. The dose of 10000-15000 units will not be dangerous but might well be ineffective.

Antidotes are not usually required for LMWH. Protamine (if used) is less effective than as an antidote against standard heparin. In patients at risk of bleeding, give LMWH twice daily instead of once. Enoxaparin is a LMWH.

1. Aprotinin inhibits the activation of plasminogen to plasmin. It also inhibits kallikrein. These actions mean that aprotinin has an antifibrinolytic effect as well as inhibiting coagulation.

2. Aprotinin is given intravenously every hour in open heart surgery to reduce bleeding.

3. It is not recommended for haemorrhagic stroke.

You cannot do thrombophilia scan tests on patients on anticoagulants.

The thrombophilia tests are full blood count and coagulation screen, which will detect erythrocytosis, thrombocytosis and dysfibrinogenaemia and the possible presence of a lupus anticoagulant. Specific tests include; assay for antithrombin, protein C and S, molecular testing for factor V Leiden and for anticardiolipin antibodies.

A number of studies have shown some slight benefit of clopidogrel over aspirin but with more bleeding, and it is more expensive. The question asks how is it superior? This is unclear, but is possibly due to a different site of action. Aspirin inhibits the enzyme cyclo-oxygenase (COX), resulting in reduced action of thromboxane A₂ (TXA₂). Clopidogrel affects the adenosine diphosphate (ADP) activation of the glycoprotein 11b/111a complex.

The prothrombin time is prolonged with abnormalities of coagulation factors VII, X, V, II or I, liver disease or if the patient is on warfarin. The activated partial thromboplastin time (APTT) is prolonged with abnormalities of factors XII, XI, IX, X, V, II or I (not factor VII).

1. The bone marrow contains iron but this is not released into the serum. The TIBC is low, as are levels of many circulating proteins. The mechanisms of these effects are unclear but are probably mediated by inflammatory cytokines.

2. In sideroblastic anaemia the TIBC might be high or normal, but not low.

No; anisocytosis just means that the red cells are of different size on a blood film. This can occur with iron deficiency but also, for example, with thalassaemia.

Stop the streptokinase immediately. Fresh frozen plasma and cryoprecipitate should also be given. Antiproteolytic agents such as tranexamic acid can be tried. No treatment is, however, very effective and if the bleeding is significant, the mortality is high.

Salmonella infection does occur but much less commonly than in sickle disease. The explanation is probably splenic dysfunction.

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