	Aetiology	Examples
Primary	Myeloproliferative disorder	Polycythaemia rubra vera (PRV)
Secondary	Appropriately increased Epo due to tissue hypoxia Inappropriately increased Epo	High altitude Lung disease Cyanotic heart disease Renal disease (hydronephrosis, cysts, carcinoma) Other tumours (e.g. hepatoma, bronchogenic carcinoma, cerebellar haemangioblastoma)

Relative polycythaemia with a reduction in plasma volume: Usually a consequence of dehydration, diuretic use or alcohol consumption.

LYMPHADENOPATHY

Enlarged lymph nodes may be an indicator of haematological disease but can also occur in reaction to infection or inflammation (Box 14.2). Reactive nodes usually expand rapidly and are painful, whereas those due to haematological disease are frequently painless and may be generalised. Initial investigations in lymphadenopathy should include:

• FBC (to detect neutrophilia in infection or evidence of haematological disease).

• CXR (to detect mediastinal lymphadenopathy).

If the findings suggest malignancy, lymph node biopsy is required.

SPLENOMEGALY

Causes of splenic enlargement are listed in Box 14.3.

• Massive splenomegaly occurs in chronic myeloid leukaemia, myelofibrosis, malaria and leishmaniasis.

• Hepatosplenomegaly is more suggestive of lympho- or myeloproliferative disease or liver disease.

• The presence of lymphadenopathy makes a diagnosis of lymphoproliferative disease more likely.

An enlarged spleen may cause abdominal discomfort; splenic infarction causes severe pain radiating to the shoulder tip. In rare cases, spontaneous or traumatic rupture may occur.

• USS or CT will detect splenomegaly, and will also allow imaging of the liver and abdominal lymph nodes.

• FBC, blood film examination and CXR are required in all patients.

• Further investigations may include lymph node biopsy and bone marrow examination.

BLEEDING

Normal haemostasis

Haemostasis depends upon interactions between the vessel wall, platelets and clotting factors. In the initial primary phase, the damaged vessel constricts and platelets aggregate to form a plug. This is followed by activation of the coagulation cascade, resulting in the formation of a cross-linked fibrin clot (Fig. 14.1). Clotting factors are synthesised by the liver and several are dependent on vitamin K for their activation; activated factors are designated by the suffix ‘a’. The extrinsic pathway is the main physiological mechanism in vivo.

Fig. 14.1 Normal haemostatic mechanisms: clotting factors of the intrinsic and extrinsic pathways. The reactions of IXa/VIIIa and Xa/Va (in the boxes) take place on the platelet surface. The dotted lines represent positive feedback effects from small amounts of thrombin.

Excessive coagulation is prevented by natural inhibitors of the clotting system. Antithrombin is a protein with inhibitory activity against thrombin and factor Xa. Its inhibitory activity is markedly increased by heparin. Protein C inactivates factors Va and VIIIa; protein S is a co-factor for protein C. Any reduction in the function of these inhibitors results in a tendency to thrombosis.

Examination

Check for:

• Bruising.

• Purpura.

• Telangiectasia on lips (indicates hereditary haemorrhagic telangiectasia).

• Swollen joints/haemarthrosis.

• Hepatomegaly.

• Splenomegaly.

THROMBOCYTOPENIA (LOW PLATELETS)

Causes of thrombocytopenia are listed in Box 14.4. Purpura, bruising and spontaneous oral, nasal, GI or GU bleeding may occur but not usually until the platelet count falls below 30 × 10⁹/l. Blood film may be diagnostic (e.g. acute leukaemia). Bone marrow examination may reveal:

• A reduced number of megakaryocytes (platelet precursors) in cases of decreased platelet formation (e.g. hypoplastic anaemia).

• An increased number of megakaryocytes indicating excessive platelet destruction (e.g. idiopathic thrombocytopenic purpura).

THROMBOCYTOSIS (HIGH PLATELETS)

The platelet count may be raised as part of the inflammatory response (reactive thrombocytosis), as with infection, malignancy or GI bleeding. Alternatively, it may be a feature of myeloproliferative disorders such as primary thrombocythaemia, PRV and chronic myeloid leukaemia.

VENOUS THROMBOSIS

Deep venous thrombosis (DVT) must be excluded in patients presenting with unilateral leg-swelling. Other causes include a calf haematoma, cellulitis and a ruptured Baker’s cyst (which normally occurs in rheumatoid arthritis of the knee). Bilateral leg-swelling may result from extensive proximal DVT extending into the inferior vena cava, impaired venous or lymphatic return due to obstruction in the pelvis, right-sided heart failure and hypoalbuminaemia.

Using the patient’s symptoms, the probability of DVT can be established using the Well’s score (Box 14.5). Those with a medium or high risk should undergo further investigation.

14.5 PROCEDURE FOR PREDICTING THE PRE-TEST PROBABILITY OF DVT

Clinical characteristic	Score
Active cancer (patient receiving treatment for cancer within the previous 6 mths or currently receiving palliative treatment)	1
Paralysis, paresis or recent plaster immobilisation of the lower extremities	1
Recently bedridden for 3 days or more, or major surgery within the previous 12 wks requiring general or regional anaesthesia	1
Localised tenderness along the distribution of the deep venous system	1
Entire leg swollen	1
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity)	1
Pitting oedema confined to the symptomatic leg	1
Collateral superficial veins (non-varicose)	1
Previously documented DVT	1
Alternative diagnosis at least as likely as DVT	− 2
Clinical probability	Total score
DVT unlikely	<2
DVT likely	≥2

USS is a reliable, non-invasive method of demonstrating thrombus between the popliteal fossa and the inguinal ligament, but venography remains the most accurate and reliable way of demonstrating DVT. For those with a low Well’s score, plasma D-dimer level should be measured; if low, DVT is excluded, but if raised, USS or venography is required.

ELEVATED MARKERS OF INFLAMMATION (Box 14.6)

BLOOD PRODUCTS AND TRANSFUSION

BLOOD PRODUCTS

Transfusion may be needed in patients with deficiency of a certain blood constituent. Blood products are obtained from donations by healthy individuals. Every blood donation must be reliably tested to exclude those containing transmissible agents. In the developed world, this includes:

• Hepatitis B.

• Hepatitis C.

• HIV.

• Human T lymphotrophic virus (HTLV).

In the UK, in order to minimise the risk of passing on variant Creutzfeldt–Jakob disease (vCJD, p. 674), all blood components are processed to remove white cells, and in addition transfusion recipients are not subsequently accepted as blood donors.

Red cell concentrate: Used to increase red cell mass in patients with anaemia and in acute blood loss. Red cell components must be compatible with the patient’s ABO blood group.

Platelet concentrate: Used to treat and prevent bleeding due to thrombocytopenia.

Fresh frozen plasma (FFP): Used to replace coagulation factors.

Cryoprecipitate: Obtained from plasma and contains proteins including fibrinogen, factor VIII and von Willebrand factor (vWF). It is used to replace fibrinogen.

Coagulation factor concentrates factor VIII and IX: Used for the treatment of conditions such as haemophilia and von Willebrand disease. Recombinant substitutes are preferred as they avoid infection risk.

I.V. immunoglobulin: Used to prevent infection in patients with hypogammaglobulinaemia. It is also used in idiopathic thrombocytopenic purpura and Guillain–Barré syndrome.

RED CELL COMPATIBILITY

There are four different ABO groups, determined by whether or not an individual’s red cells express A or B antigens. Healthy individuals have antibodies directed against the A or B antigens that are not expressed on their own cells (Box 14.7). If red cells of an incompatible ABO group are transfused, the patient’s antibodies bind to the transfused cells leading to red cell haemolysis. This is the main cause of an acute transfusion reaction, and can lead to disseminated intravascular coagulation (DIC), renal failure and death.

14.7 THE ABO SYSTEM

Blood group	Red cell A or B antigens	Antibodies in plasma
O	None	Anti-A and anti-B
A	A	Anti-B
B	B	Anti-A
AB	A and B	None

About 15% of Caucasians lack the Rhesus D (RhD) red cell antigen (‘Rhesus-negative’). IgG antibodies to RhD-positive red cells are produced if such cells enter the circulation of an RhD-negative individual via fetomaternal haemorrhage during pregnancy. During a subsequent pregnancy with an RhD-positive fetus, these antibodies can cross the placenta and cause haemolytic disease of the newborn and severe neurological damage. Administration of anti-RhD immunoglobulin (anti-D) after delivery blocks the immune response to the RhD antigen and prevents the development of Rhesus antibodies in RhD-negative women.

SAFE TRANSFUSION PROCEDURES

Red cells from the patient’s blood sample are tested to determine the ABO and RhD type. The patient’s plasma is tested to detect any red cell antibodies that could haemolyse transfused red cells. The transfusion laboratory will then perform either a ‘type and screen’ (‘group and save’) or a cross-match. In the type and screen procedure, the patient’s sample is held in the laboratory and compatible blood can be prepared within 15 mins if required. Cross-matching involves allocating specific red cell units to a particular patient for transfusion.

It is essential to ensure that no ABO-incompatible red cell transfusion is ever given. Most incompatible transfusions result from:

• Mistakes in taking and labelling the blood sample for pre-transfusion testing.

• Failure to perform standard checks before infusion to ensure the correct pack has been selected for the patient.

ADVERSE EFFECTS OF TRANSFUSION

• A temperature rise of <1.5°C in an otherwise well patient indicates a febrile non-haemolytic transfusion reaction. Paracetamol should be administered and the transfusion rate slowed.

• A mild allergic reaction is characterised by urticaria; it is treated with an antihistamine (e.g. chlorphenamine 10 mg i.v.) and by slowing the transfusion rate.

• In severe reactions (bronchospasm, angioedema, hypotension) the transfusion should be stopped and any unused units returned to the blood bank. The patient should be treated with oxygen, i.v. chlorphenamine, nebulised salbutamol and, in hypotensive patients, i.m. adrenaline (epinephrine, 0.5 ml of 1 in 1000).

• ABO incompatibility causes red cell haemolysis leading to fever, rigors, tachycardia, hypotension, chest and abdominal pain, and shortness of breath. The transfusion must be stopped immediately and any unused blood returned to the blood bank. An i.v. saline infusion should be commenced to maintain an adequate urine output, and DIC should be treated with appropriate blood components.

• Formerly, viral infections were transmitted by blood transfusion; however, testing of blood donations (see above) has dramatically reduced the incidence of such infections in the developed world. Transmission of malaria or Chagas disease by transfusion occasionally occurs in endemic areas.

• Fluid overload is treated by stopping the transfusion and administering oxygen and i.v. furosemide.

ANAEMIAS

Around 30% of the world population is anaemic; iron deficiency is the cause in half of these.

IRON DEFICIENCY ANAEMIA

Causes of iron deficiency include:

Blood loss: The most common explanation in men and post-menopausal women is GI blood loss. This may result from gastric or colorectal malignancy, peptic ulceration, inflammatory bowel disease, diverticulitis and angiodysplasia. GI bleeding may be exacerbated by the use of aspirin or NSAIDs. In younger women, menstrual bleeding and pregnancy often contribute to iron deficiency.

Malabsorption: Gastric acid is required to release iron from food and helps keep it in the soluble ferrous (Fe²+) state. Hypochlorhydria due to proton pump inhibitor (PPI) treatment or previous gastric surgery may contribute to deficiency. Iron is absorbed actively in the upper small intestine and absorption can be affected by coeliac disease.

Physiological demands: Increased demands for iron during puberty and pregnancy can lead to deficiency.

Management

Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron supplementation (ferrous sulphate 200 mg 8-hourly for 3–6 mths) is appropriate, together with treatment of the underlying cause. The Hb should rise by 10 g/l every 7–10 days.

MEGALOBLASTIC ANAEMIA

This results from deficiency of vitamin B₁₂ or folic acid, both of which are required for DNA synthesis. Deficiency leads to red cells with arrested nuclear maturation but normal cytoplasmic development within the bone marrow (megaloblasts). There is a macrocytic anaemia with an MCV often >120 fl, and mature red cells are commonly oval in shape. Involvement of white cells and platelets can lead to neutrophils with hypersegmented nuclei and, in severe cases, pancytopenia. Bone marrow examination reveals hypercellularity and megaloblastic changes.

VITAMIN B₁₂

The average diet contains well in excess of the 1 μg daily requirement of vitamin B₁₂, mainly in meat, eggs and milk. In the stomach, gastric enzymes release vitamin B₁₂ from food and it binds to a carrier protein called R protein. The gastric parietal cells produce intrinsic factor, a vitamin B₁₂-binding protein. As gastric emptying occurs, vitamin B₁₂ released from the diet switches from the R protein to intrinsic factor. B₁₂ is absorbed in the terminal ileum and is transported in plasma bound to transcobalamin II, a transport protein produced by the liver. The liver stores enough B₁₂ for 3 yrs, and deficiency therefore takes many years to become manifest even if all dietary intake is stopped.

Vitamin B₁₂ deficiency can result in neurological disease including peripheral neuropathy and subacute combined degeneration of the cord. The latter involves the posterior columns (resulting in diminished vibration sense and proprioception leading to sensory ataxia) and corticospinal tracts (resulting in upper motor neuron signs). Dementia and optic atrophy can also occur.

Causes of vitamin B₁₂ deficiency

Dietary deficiency: This only occurs in strict vegans.

Gastric factors: Gastric surgery (including gastrectomy) can result in B₁₂ deficiency due to impaired secretion of gastric acid and intrinsic factor.

Pernicious anaemia: This is an autoimmune disorder characterised by atrophy of the gastric mucosa. Loss of the parietal cells causes intrinsic factor deficiency leading to B₁₂ malabsorption. Pernicious anaemia has an average age of onset of 60 yrs, and is associated with other autoimmune conditions including Hashimoto’s thyroiditis, Graves’ disease, vitiligo and Addison’s disease. Antiparietal cell antibodies are present in 90% of cases and antibodies to intrinsic factor in 60%.

Small bowel factors: Terminal ileal disease (e.g. Crohn’s disease) and ileal resection result in vitamin B₁₂ malabsorption. Motility disorders can result in bacterial overgrowth and the resulting competition for free vitamin B₁₂ can result in deficiency.

It is possible to distinguish B₁₂ deficiency due to pernicious anaemia from that due to intestinal problems with a two-part Schilling test, although this is rarely performed in practice (Fig. 14.2).

Fig. 14.2 The two-part Schilling test in the diagnosis of the cause of vitamin B12 deficiency.

Tags: Davidsons Essentials of Medicine

Apr 3, 2017 | Posted by admin in GENERAL & FAMILY MEDICINE | Comments Off

Infective	Bacterial, e.g. streptococcal, TB Viral, e.g. Epstein–Barr, HIV Protozoal, e.g. toxoplasmosis Fungal, e.g. histoplasmosis
Neoplastic	Primary, e.g. lymphomas, leukaemias Secondary, e.g. lung, breast, thyroid, stomach
Inflammatory	Connective tissue disorders, e.g. rheumatoid arthritis, SLE Sarcoidosis
Miscellaneous	Amyloidosis

Congestive	Portal hypertension, e.g. cirrhosis, portal vein thrombosis Cardiac, e.g. congestive cardiac failure
Infective	Bacterial, e.g. endocarditis, septicaemia, TB Viral, e.g. hepatitis, Epstein–Barr Protozoal, e.g. malaria, leishmaniasis (kala-azar) Fungal, e.g. histoplasmosis
Inflammatory/granulomatous disorders	e.g. Felty’s syndrome, SLE, sarcoidosis
Haematological	Red cell disorders, e.g. megaloblastic anaemia, haemoglobinopathies Autoimmune haemolytic anaemias Myeloproliferative disorders, e.g. chronic myeloid leukaemia, myelofibrosis, PRV, essential thrombocythaemia Neoplastic, e.g. leukaemias, lymphomas

Marrow disorders	Hypoplasia Infiltration, e.g. leukaemia, myeloma, carcinoma, myelofibrosis Vitamin B₁₂/folate deficiency
Increased platelet consumption	Disseminated intravascular coagulation (DIC) Idiopathic thrombocytopenic purpura (ITP) Infections, e.g. Epstein–Barr virus, Gram-negative septicaemia Hypersplenism Thrombotic thrombocytopenic purpura Liver disease Connective tissue diseases, e.g. SLE

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Blood disorders

ELEVATED MARKERS OF INFLAMMATION (Box 14.6)

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