Anaemia is one of the most common presenting complaints to general practice. One of several ways in which anaemias can be classified, is by red cell size. As such, anaemias can be said to be:

• Microcytic (small RBCs)
• Normocytic (RBC size within the normal range)
• Macrocytic (large RBCs) – see macrocytic anaemias

Differentiating the cause of microcytic anaemias is important because the treatments can be different. The most common cause of microcytic anaemia is iron deficiency anaemia – which itself can have many underlying causes – but it is also important to consider anaemia of chronic disease and the haemoglobinopathies – such as thalassaemia – especially in iron deficiency presenting in children.

Microcytic anaemia can be identified on blood film (looking at the red blood cells under the microscope) and noting the small size of the cells (more formally the low mean corpuscular volume or low MCV), as well as the hypochromia (reduced colouring – i.e. the cells appear more pale). See below the normal blood film (top) and microcytic anaemia of iron deficiency (bottom). Note that these images have different levels of magnification – and when measured the cells of microcytosis will always be smaller than those of a normal film.

History

• Diet history – particularly if diet is low in iron
  • In children – also ask about cow’s milk intake (should be <500mls per day)
  • Cow’s milk itself doesn’t cause iron deficiency, but children who drink more than 500mls / day tend to eat less food and thus are at risk of iron deficiency
  • Also – intake of java bean / broad beans – can precipitate haemolysis in G6PD deficiency
• Family history
  • Anaemia
  • Jaundice
  • Splenomegaly
• History of blood loss
  • Menorrhagia in females
  • GI bleeding – ask about stool colour, haemorrhoids
    • Be aware that the bleeding is often occult – consider faecal occult blood test

Examination

• Pallor
• Pale conjunctive
• Tachycardia
• SOB – especially on exertion
• Lethargy
• Poor concentration
• Weakness
• Heart failure
• Failure to thrive (in children)

Investigations

• FBC – Hb <90 g/L is particularly significant
  • Microcytosis (small RBCs)
• Iron studies
  • If normal, but patient has microcytic anaemia, request Hb electrophoresis
  • Elevated HbA2 >3.5% (+/- elevated HbF) suggests beta thalassaemia
  • Alpha thalassaemia requires genetic testing for diagnosis

Red flags

Consider urgent hospital admission for anybody with:

• Hb <70g/L (local policies may vary with a cut-off of 60-80g/L for transfusion)
• Tachycardia
• Murmur
• Signs of heart failure
  • Signs of haemolysis, dark urine, jaundice
• Co-existing thrmobocytopaenia or neutropenia
  • May indicate malignancy

Microcytic anaemia in children

• Occurs in 8% of all children in Australia
• The most common cause of anaemia in children
• The reference range for children is different from adults:
  • 2 months – 90 g/L
  • 2-6 months – 95 g/L
  • 6-24 months – 105 g/L
  • 2-11 years – 115 g/L
  • 12+ – 120g/L (female) and 130g/L (male)
• Differentials in children
  • Iron deficiency
  • Thalassaemia
  • G6PD deficiency

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
• Anaemia – RCH

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Deep Vein Thrombosis is exactly as its name suggests: a clot in the veins. They can occur in any vein, although they are much more likely in the veins of the pelvis and legs. If they occur in other locations (e.g. in the arm) they are often indicative of a more sinister underlying cause (e.g. clotting disorder, carcinoma, or an increased clotting risk of unknown cause) and are more likely to require life-long treatment / prevention. On their own, they are not particularly significant, however, they are dangerous because they can embolise, and cause a pulmonary embolism – these can be fatal.

Some studies suggest a ‘silent’ PE in up to 40% of DVT patients.

Aetiology

• Stasis/immobility – e.g. hospital bed, long flight
• Dehydration
• Oestrogen (pregnancy, and to a lesser extent, the COC pill)
• Genetic clotting defect (e.g. lack of protein C)
• Obesity (atherosclerosis)
• Age (old)
• Varicose veins
• Surgery
• Previous DVT/embolism
• Trauma
• Infection
• Malignancy

• Stasis
• Hypercoagulability
• Vessel wall injury

Signs & Symptoms

• Red, swollen leg (particularly calf)
• Tenderness
• Pitting oedema
• Fever

Diagnosis

• Score >3 – Treat as DVT – and also perform a compression USS to confirm
• Score 1-2 – Treat as DVT – and perform compression USS to confirm
• Score 0 – do a D-dimer test. If negative, then unlikely to be DVT. If positive, Treat as DVT, and perform compression USS.

Differentials

• Ruptured Baker’s cyst
• Cellulitis
• Lymphadenopathy

Pathology

• If they appear in a superficial vein, then they do not embolise, and can be left to resolve, you just have to raise the leg.

Investigations

• Venography – this is the gold standard test. A radio-opaque dye is injected into the foot, and then you can see if it is blocked off as it travels up the leg
• D-dimer – a negative test rules out DVT, but a positive test does not diagnose DVT. D-dimer is a breakdown product of fibrin, and can be released by many things, including MI, malignancy, pregnancy, inflammation, stroke, infarct, trauma, and is often raised post-operatively.
• Leg measurement – you should measure the diameter of the calf at the same point on each leg, usually 10cm below the tibial tuberosity. If the difference between legs is >3cm this is significant for DVT.
• USS – has about 90% sensitivity above the knee, but only 50% sensitivity for DVT below the knee. This is the test most often performed as it is cheap and reasonably reliable; and along with clinical factors, is all that is needed for diagnosis.

Treatment

LMWH – this is usually started as soon as the diagnosis is made, and is normally continued for a minimum of 5 days. It is usually stopped when the INR is in the target range (2-3)
Warfarin – also started at the same time as heparin, but warfarin actually increases coagulability in the first few days of use; hence the use of heparin initially. Warfarin is continued for:

• 6 months if it is the first DVT
• 3 months if it is the first DVT and occurred post operatively
• Indefinitely if it is a recurrent DVT or if there is a genetic clotting disorder, or if there are other large risk factors.

More Information

Virchow’s triad

• Stasis of blood flow
• Vessel wall injury
• Hypercoagulation 

Signs

• Calf – warmth, tenderness, swelling, eythema
• Mild fever
• Pitting oedema
• Horman’s sign – increased resistance/pain on forced foot dorsiflexion – however, you should NOT test for it as it can dislodge the clot! Also this is not diagnostic, as you can get it with other things as well.
• Well’s score
• Pain – find out where the pain will be for different clotting sites.

Differentials

• Cellulitis – this is normally really bright red, and really warm, and the leg will be tender.
• Ruptured Baker’s cyst – this is usually a result of pre-existing rheumatoid disease. The cyst is a protrusion of the synovium out of the knee joint, usually out of the back of the joint. It can burst and give you pain down the back of the leg, as the fluid leaks out of the cyst and flows down the back of the calf.
  • Note that both of these can co-exist with a DVT
• Superficial thrombophlebitis – this is basically thrombus and inflammation of the vein. It is often caused by a blood clot – and when it occurs in deep veins, it will probably be associated with DVT. However, when it occurs superficially, it is virtually never associated with DVT. You may be able to see the distended vein going all the way up the leg. It feels like rubber. it most commonly affects the saphenous vein, and is associated with varicosities. In these cases there may be a superficial clot secondary to the venous wall inflammation. Embolism does not occur from superficial thrombophlebitis. Treatment is generally with analgesics, rest, and elevation of the affected limb. Anticoagulants are not necessary.
• Injury – causing a muscle haematoma – if you give them heparin, and this will make the haematoma even worse. It can also cause rupture of the plantaris tendon.

• Note that this is different to the Well’s score for determining the seriousness of risk factors!
• These criteria are a clinical assessment of the situation to decide what management plan should be adopted.

• ≥3 points – very high probability. Treat as DVT and perform compression US to confirm
• 1-2 points – intermediate risk; treat as DVT and perform compression US to confirm
• 0 points – perform D-dimer in the hope of a negative result to fully rule out DVT. If test is positive, then treat as suspected DVT and perform compression US. If –negative then DVT can be confidently ruled out.

• Risk factors + alternative diagnosis – low risk
• Risk factors + no alternative diagnosis – high risk
• No risk factors + no alternative diagnosis – medium risk
• Clinical diagnosis alone is highly unreliable however – only 50% accurate! When this is combined with D-dimer, the accuracy is about 80%.
• Doppler ultrasound is about 90% reliable, but can only really detect clots above the knee. Below the knee, it is only about 70% reliable. Those below the knee will need to be detected with venography.
• Although venography is the gold standard, it is not used that often. Usually an ultrasound is done first. If this is negative it may be repeated in 1 week, or the patient may go for further tests, or a diagnosis may be made on clinical signs, and the patient put on anticoagulants.

Investigations

Coagulation investigations

• Bleeding time – this is the time it takes a small wound to stop bleeding. This can be tested by pricking the finger. The normal value is anywhere between 1-7 minutes.
• Coagulation time – a pretty inaccurate test, as there are many sources of error. You basically take a blood sample, and test how long it takes for a clot to form. It takes 3-15 minutes in a normal individual
• Prothrombin time (PT) – this gives an indication of the concentration of prothrombin in the blood. This is dependent on the factors produced in the liver. Heparin is monitored by the APPT, warfarin is monitored by the INR.
• INR – the internal normalised ratio. This is basically a comparison of the patients clotting ability compared to the ‘average’ of the population. It is a ratio of the patient’s PT to that of the average PT – and as a result, this test only looks at the extrinsic clotting pathway. You can use it to look at liver function, warfarin dose and vitamin K status.
  • This ISI is a different value for different drugs, but is normally between 1.0 and 2.0.

• APPT

D-dimer

• A negative value means there probably isn’t a clot
• A positive value DOES NOT MEAN there is a clot.

Venography

Venometer

Doppler USS

Fibrinogen testing

ECG

S1-Q3-T3 – commonly comes up in exams, but not often seen in clinical practice.

• S1 – increased S waves in lead I
• Q3 – increased Q waves in lead III
• T3 – inverted T waves in lead III

Prevention

• Stop the pill 4 weeks before a planned operation
• Mobilise early after the operation
• Heparin – 5000u/12hours may be given pre-operatively, as may enoxaparin (20mg/24hr) or dalteparin – these are LMWH’s, and are likely to cause less bleeding, and do not need monitoring – so in this situation are better than heparin for most patients.

Treatment

• 3 months if DVT was post-op
• 6 months if there was no cause for the DVT
• Lifelong if there is recurrent DVT or thrombophilia (genetic clotting defects)

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A swollen, tender, warm, red calf can be indicative of several conditions, one of which is Deep Vein Thrombosis (DVT).

Other differentials could include include cellulitis, muscle injury, achilles tendon rupture, phlegmasia and varicose eczema. Examining a swollen leg is a common OSCE station.

Introduction

• Introduce yourself
• Check you have the right patient
• Explain what you are going to do
• Gain consent
• Wash hands! 

Inspection

• Look around the bed for any mobility aids
• Look for signs of pregnancy
• Look for signs of any recent surgery or trauma
• Look for GTN spray (atherosclerotic disease – increase risk factor)
• Look for breathlessness – may be present if there is a secondary PE

Inspection of the legs

• Look for any obvious redness and swelling
• Look for varicose veins
• Look for missing digits
• Look for ulcers

Palpation

• Check the temperature of the legs at 3 different places. Compare the legs each time
• Check pulses
• Check for pitting oedema
• Check for tenderness – squeeze the patient’s leg around the ankle. Tell them what you are going to do first! Ask them if there is any pain, and look at their face! Repeat with the other leg
• Measure the diameter of the leg with a tape measure! Choose a point on the calf, and measure the same point on each leg. Usually this is 10cm below the tibial tuberosity.
• If there is a difference between the legs of >3cm then this is significant for DVT

Auscultation

• Listen at the lung bases – if PE is present, then there may be reduced breath sounds at the lung bases

Finishing off

Thank the patient, and tell them they can now cover up
Mention any further investigations:

• Well’s score – if this is low, do a D-dimer
• Bloods – U +E’s, clotting, FBC
• Duplex scanning – USS + Doppler
• Venogram

References

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• Factor XI deficiency: mainly found in Ashkenazi Jews, recessive inheritance. Homozygotes <5% levels of factor XI. Factor XI concentrate given.
• Factor VII deficiency: autosomal recessive, variable bleeding severity, risk of CNS haematoma. Diagnosis by factor VII assay, treatment with recombinant factor VII
• Factor V deficiency: treated with virally inactivated fresh frozen plasma
• Factor XIII deficiency: severe haemorrhagic tendency, poor healing (profuse bleeding from umbilical cord). Clots soluble in urea (failure of cross-linking). Factor XIII concentrate given.
• Fibrinogen: abnormalities may be quantitative (apofibrinogennaemia and hypofibrinogenaemia) or qualitative (dysfbrinogenaemia).
• Apofibrinogennaemia: autosomal recessive, failure to clot in any test of coagulation, severe bleeding tendency
• Dysfibrinogenaemia: rare group of autosomal dominant conditions, haemorrhagic or thrombotic states

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Von Willebrand’s Disease (vWD) is a type of haemophilia (clotting disorder). It is caused by deficiencies in a protein called von Willebrand factor (vWF), which helps to prolong the life of factor VIII in the clotting cascade. Most cases are relatively mild, and the vast majority probably go undiagnosed.

• Asymptomatic deficiencies affect 1% of general population
• Symptomatic disease affects 100 per million

von Willebrand’s disease is the most common inherited bleeding disorder (coagulopathy)

• Other examples include haemophilia A and haemophilia B
• Haemophilia A is caused by deficiencies in factor VIII itself
• Haemophilia B affects factor IX

It was first described in 1926 by Erik von Willebrand – working on remote islands between Sweden and Finland, as is also sometimes known as vascular haemophilia.

There are three types of vWD – types 1, 2 and 3.

Epidemiology

• Prevalence of 1-2% in the general population
• More common in females
• More common with blood type O
• Most patients have mild disease

Presentation

Variable – depends on the extent of the disease:

• Bleeding for mucosa
  • Epistaxis
  • Menorrhagia (consider vWD in women with menorrhagia and no identified gynaecological cause)
• Spontaneous bleeding
  • Including into joints or other internal organs
• Severe vWD: spontaneous mucosal bleeding, death secondary to massive GI haemorrhage

Pathology

vWD results from defects in von Willebrand factor – vWF

• vWF important in platelet adhesion and factor VIII transport
• vWF helps to attract circulating platelets to the site of bleeding
• It binds to factor VIII and prevents it being cleared from plasma
• You might want to brush on the clotting cascade!

Types of vWD

Type 1

• Decreased concentration of vWF
• 80% of cases of vWD
• Often autosomal dominant
• Levels of vWF can be measured – and disease severity correlates to levels – “quantitative deficiency“
• Normal lifespan
• Occasional easy bruising
• May have increased risk of bleeding after dental procedures and surgery

Type 2

• “Qualitative deficiency” – normal quantities if vWF produced – but it is defective
• Autosomal dominant or Autosomal recessive inheritance
• 20-30% of cases of vWD
• Subclassified according to the defect in the vWF:
  • 2a – lack of high molecular weight vWF
  • 2b – defective adhesion due to increased binding
  • 2m – decreased platelet dependent vWF function
  • 2n – failure to bind factor VIII
• Bleeding tendency varies depending on the type

Type 3

• Near complete absence of vWF
• 1-5% of cases
• Autosomal recessive inheritance
• Mimics haemophilia
• Severe mucosal bleeding
• May present with severe haemarthrosis (bleeding into the joints)

Investigations

Many patients with mild disease will go undiagnosed. Patients with abnormal bleeding will typically present as a result of their bleeding, and should be investigated.

• Blood count normal except for a moderate reduction in platelets in some with type 2
  • Most patients have normal platelet count
• APTT prolonged
• PT usually normal
• Diagnosis: quantitative immunoassay/functional assay of vWF, electrophoresis
  • Interpret vWF levels with blood group (usually lower in blood group O)
  • Will typically be reported as a qualitative or quantitative deficiency
• Factor VIII level
  • Usually low – vWF prolongs the life of factor VIII in the blood
• Offer screening to all first-degree relatives – regardless of their bleeding history

Management

• Avoid NSAIDs and anti platelet drugs
• Minor bleeds don’t require any specific treatment
• More severe bleeds may be treated with:
  • Local measures (pressure)
  • Tranexamic acid – can be given orally. Also available as a mouthwash, and IV infusion for severe cases
  • Desmopressin (DDAVP)
    • Used in severe bleeds
    • Can be given IV or intranasally
• Consider COCP in women with menorrhagia
• Factor VIII concentrates with vWF may be given
• Consider platelet infusion for patients who aren’t responsive to other treatment

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
• von Willebrand’s disease – patient.info

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• ≥3 points: High probability-treat as suspected DVT or perform compression US.
• 1-2 points: Intermediate probability-treat as suspected DVT and perform compression US.
• ≤0 points: Low probability of DVT-perform D-dimer test. If positive D-dimer then treat as suspected DVT and perform compression US. If negative D-dimer, DVT reliably excluded.

• ≥7 points: High probability
• 2.0-6.0 points: Intermediate probability
• 0-1 points: Low probability

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Iron studies are indicated in patients with anaemia, particularly those with microcytic anaemia.

They may also be indicated in microcytosis (without anaemia), general lethargy and tiredness and malnutrition.

Iron studies are particularly useful to distinguish iron-deficiency anaemia from other microcytic anaemias (usually anaemia of chronic disease, or rarely thalassaemia)

In many cases of iron deficiency anaemia, the diagnosis is straightforward, and can be made using a combination of history (blood loss, low iron in the diet, malabsoprtion, lack of risk factors for thalassaemia, lack of medical history indicating a chronic disorder ) and a full blood count (FBC) – which would show a macrocytic anaemia (↓Hb and ↓MCV).

This is fine in simple, straightforward, uncomplicated patients. Unfortunatly (for us as clinicians) in the real world, and particularly in hospital, nothing is straightforward, and many patients may have an underlying chronic disease.

Iron studies are most useful for patients with anaemia and a chronic disorder (most commonly chronic renal failure, but could be chronic infection, inflammation or a malignancy)

In these patients, ↓Hb and ↓MCV can occur either a result of iron deiciency or the anaemia of chronic disease, or thalassaemia and it is important to distinguish the two as the treatments differ.

Interpretation

So, its pretty straightforward, but something you’ll need to learn, so heres important bit:

	Iron def. anaemia	Anaemia of chronic disease	β-thalassaemia	Haemochromatosis
Serum Iron	↓	↓	↑ or	↑
TIBC – (Transferrin)	↑	↓		↓
Serum Ferritin	↓	↑ or	↑ or	↑↑
MCV	↓	↑ or	↑ or	↑↑

Key Points

• Both iron deficiency and anaemia of chronic disease with have low iron
• Iron deficiency anaemia will have high TIBC – this is because is iron deficiency anaemia, as iron stores are depleted, the body tries to compensate by increasing the serum’s ability to carry iron. In Anaemia of chronic disease, the low serum iron is a result of low TIBC.
• Iron deficiency will have low ferritin – ferritin is a measure of iron stores. In iron deficiency anaemia these are depleted. In anaemia of chronic disease, there is a not a problem with iron stores, but instead with iron utilisation / transfer, so ferritin levels will be normal or high.

*WARNING*
Iron levels are not a always a reliable indicator – iron is also an acute phase biochemical marker – and will rise with inflammation – like CRP or ESR.

• Take iron levels with a pinch of salt. Loads of things can alter serum iron levels:
  • False normal – if a patient is taking supplements
  • False low – acute or chronic inflammation, ongoing infection, post-operatively, malignancy, hypoalbuminaemia

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

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