ANAEMIA OF CHRONIC DISEASE

The onset can be within 2 weeks of acute illness. The pathophysiology results in part from suboptimal erythropoietin activity, due to inhibition of gene expression by the inflammatory cytokines interleukin-1 and tumour necrosis factor. However, we now know that the principal mediator is hepcidin, which is synthesised in the liver, and this is upregulated by (other) inflammatory cytokines. High levels of hepcidin reduce iron absorption from the gut and inhibit iron release from macrophages. The net effect is that iron is unavailable for erythropoiesis.² The resulting anaemia can be normocytic or microcytic (25% of cases). In renal failure, lack of erythropoietin probably plays a larger part, and the anaemia can be profound, even with relatively mild renal insufficiency.

IRON DEFICIENCY ANAEMIA

In iron deficiency anaemia (Fig 22.1), the usual aetiology is negative iron balance, either from inadequate dietary intake or from gastrointestinal loss, menorrhagia or, more rarely, haemolysis. Iron deficiency is often symptomatic in the absence of anaemia. It can be associated with impaired mentation (‘thinking through a cloud of cotton wool’), excessive fatigue, restless legs, a mild subjective peripheral neuritis and the rare pica syndrome (the urge to eat bizarre foods such as plaster or ice in excessive amounts). The history should include careful assessment of dietary iron, blood loss with menses, and asking about possible melaena, and haematuria or haemoglobinuria with dark urine. Physical examination may reveal classic stigmata, including glossitis, angular cheilosis and koilonychia, but these may not be present even with severe deficiency.

FIGURE 22.1 Iron deficiency anaemia

The serum iron value gives no guide to bodily iron stores; it reflects only the state of iron transport in the body. The diagnosis is made if the ferritin is below the lower limit of the normal reference range in a given laboratory. This is a pathognomonic result. However, ferritin is also an acute phase reactant, and so, in the iron-deficient individual with an inflammatory process, it may be inappropriately normal. Ferritin is also raised by infection, iron overload and malignancy.

In the asymptomatic patient, test for faecal blood loss and consider panendoscopy. In men and postmenopausal women, iron deficiency usually signifies gastrointestinal blood loss.³

Absorption of dietary iron is best (around 20%) as haem iron from animal sources such as red meat, white meat and fish. Iron in the non-haem form is less well absorbed (< 5%), and is found in cereals, legumes, vegetables and nuts. Iron enhancers can improve non-haem iron absorption two- to three-fold, and include vitamin C (citrus, tomato and broccoli), animal protein and vitamin A (spreads, oils, dairy products). Oxalates in spinach, tannin in tea and phytates in certain foods are iron inhibitors; so, for example, spinach eaten with tomato or broccoli improves iron bio-availability.

Occasional patients are seen in whom dietary intake of iron is adequate and no ongoing source of blood or iron loss is identified. Recently described mutations of the TMPRSS6 gene leading to impaired iron absorption may explain why some patients are refractory to oral iron replacement therapy. However, it appears that patients with these mutations are rare.^4,5

Oral iron supplements are effective and well tolerated in about 80% of patients.⁶ Slow-release ferrous sulfate preparations are better tolerated than the iron salt, but rates of discontinuation in randomised trials are the same. Patients should be warned of possible constipation, and increased bloating, wind or flatulence, probably attributable to rapid bacterial overgrowth in the presence of increased available iron. Co-prescribing live culture yoghurts or probiotics may minimise this. Bowel motions will turn black (it is, however, a greenish-black, rather than the reddish-black of melaena). Oral iron should never be taken with tea (because of its tannin content), but rather with orange juice for its vitamin C content. Indeed, some iron formulations incorporate vitamin C. One tablet a day is usually enough; some patients tolerate two tablets daily without problems, but others find even one a day difficult. For these patients, taking the supplement with food may still provide enough iron to raise body stores. You will need to check the elemental iron equivalent in different supplements.

Some 20% of patients are genuinely intolerant of oral iron.⁶ It can lead to pseudo bowel obstruction and even surgical abdominal crises. For these patients, intravenous iron infusions are greatly preferable to intramuscular iron. The latter is poorly bio-available, and persists under the skin, leaving scarring and pigmentation. Whereas earlier IV preparations (iron dextran) were associated with cardiac arrhythmias, modern preparations (e.g. iron polymaltose, iron sucrose) have a far lower incidence of anaphylaxis and can be given rapidly without requiring electrocardiographic monitoring. This is best done in a specialised unit. Medical supervision should be on hand for the rare instance of anaphylaxis. Some patients experience arthralgia for 48 hours and this may require paracetamol. The response in many is gratifying, although it can take 2–6 weeks to become maximal. Thereafter, patients can be monitored with iron studies every 3 months, as many, but not all, will need further infusions in the future.

MEGALOBLASTIC ANAEMIA

A megaloblast is a morphologically abnormal red cell precursor with features of delayed nuclear maturation (Fig 22.2). The common causes are dietary vitamin B₁₂ or folate deficiency, some antimetabolite drugs and, infrequently, myelodysplasia with ‘megaloblastoid’ changes. In the history, check diet, drugs and past history of abdominal surgery or autoimmune disease. The physical examination may reveal evidence of dementia or loss of ankle reflexes and proprioception in the lower limbs. Vitamin B₁₂ deficiency anaemia can occur without the neurological deficits (subacute combined degeneration of the spinal cord, dementia) and vice versa.

FIGURE 22.2 Megaloblastic anaemia

Animal products (meat and dairy) are the only sources of vitamin B₁₂. Adequate absorption requires intact gastric mucosa, liberation of intrinsic factor and R binders, and small intestinal integrity. The modern diagnosis of pernicious anaemia has dispensed with the Schilling test and now relies upon direct measurement of intrinsic factor and gastric parietal cell auto-antibodies.

Folate deficiency is mostly seen with poor diet and alcoholism.

The combination of folate and iron deficiency is highly suggestive of coeliac disease.

Some medications inhibit dihydrofolate reductase and antagonise folate metabolism. Examples are trimethoprim, primethamine, phenytoin and methotrexate. Because both vitamin B₁₂ and folate are not injurious, therapeutic trials are a reasonable manoeuvre in cases where megaloblastic anaemia has been identified.

IMMUNE-MEDIATED CYTOPENIA

Whereas white cells (Fig 22.3) mostly leave the circulation to perform their various functions, red blood cells (Fig 22.4) and platelets are recycled. This recycling is one of the two functions of the spleen. The other function of the spleen is to act as a lymph gland for the bloodstream. Splenectomised patients are therefore at increased risk of septicaemia, with well-known encapsulated organisms including Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. Galen believed that the spleen was the ‘seat of the soul’. In evolutionary terms, the spleen was also the site of haematopoiesis, so it made sense to recycle blood cell components there.

FIGURE 22.3 White blood cells of a healthy person

FIGURE 22.4 Red blood cells of a healthy person

As red blood cells and platelets age, they accumulate molecules, mostly immunoglobulins, on their surface, with the antibody molecule stem (the Fc portion) protruding. In normal transit through the spleen, blood cells pass from the venous circulation into the splenic sinusoids, lined with macrophages. If the antibody density on the cell surface of the cell is high enough, the cell binds to the Fc receptors of macrophages, is removed from the circulation and its components recycled. In this way, normally senescent red cells and platelets are removed from circulation. However, in the presence of an anomalous autoimmune process, where an antibody (often post-infectious) cross-reacts with red cell or platelet cell surface antigens, younger cells rapidly acquire a density of antibodies that leads to premature removal. If the marrow response is overwhelmed, the resulting cytopenia is referred to as immune-mediated thrombocytopenia (ITP) or autoimmune haemolytic anaemia (AIHA). Red cell production can increase six-fold, which will compensate for red cell survival reduced from the normal 120 days to about 16, but not shorter.

It follows that treatment of ITP and AIHA is aimed at:

IMMUNE-MEDIATED THROMBOCYTOPENIA

Immune-mediated thrombocytopenia may present after recent viral illness or be apparently unprovoked. A range of drugs can cause ITP, including quinine, chemotherapy agents and methotrexate, valproic acid and interferon. The prognosis in children is good, with a self-limiting course being typical. Steroids can be given to hasten platelet count recovery. In adults, the natural history is unpredictable, and up to 40% may pursue a multiplying–relapsing course. Adult-onset ITP may be associated with chronic viral infections such as HIV, hepatitis B or hepatitis C, and also with autoimmune diseases such as systemic lupus erythematosus (SLE). Patients with bleeding, or platelet counts of less than 20 × 10⁹/L, should be referred urgently to a haematology centre.

INTEGRATIVE MEDICINE IN GENERAL HAEMATOLOGY

Simply put, there are no dietary ways to raise the white cell or platelet counts. Nor is there evidence to support the ‘blood group’ diet. (A Google search in May 2010 produced over 4 million hits!)

INVESTIGATING THE PATIENT WITH EASY BRUISING

Congenital disorders can manifest in adulthood, and acquired causes can appear in the elderly. Moreover, phenotypically mild bleeding problems may be very significant in the face of a major haemostatic challenge such as trauma or surgery. Patients who develop easy bruising or recurrent bleeding at any age should not be dismissed. Preoperative assessment may be another indication for investigation.

From the history, determine whether bleeding or bruising is longstanding or recent, and if it has been in pathological amounts. Endeavour to ascertain whether it has a mucosal (primary haemostasis defect, i.e. thrombocytopenia or platelet dysfunction) or deep-tissue pattern (defect implied in secondary haemostasis). Trauma, surgery, dental extractions and childbirth are all good in vivo tests of haemostasis. So, while many report heavy bleeding after dental extractions or childbirth, in only a few does this persist for more than a day and/or require transfusion.

Transfusion history, menses, family history and comorbidities such as liver disease or renal failure are all relevant.

Current drugs and complementary medicine use must be ascertained, including particularly aspirin, antiplatelet drugs (clopidogrel), NSAIDs and herbal supplements, notably gingko, garlic, ginger and ginseng. These all reduce platelet function. Commencing such medicines can be enough to unmask a hitherto hidden bleeding diathesis, especially mild von Willebrand’s disease. Drugs that cause thrombocytopenia are discussed below.

In the examination, the findings may point to a platelet-type bleeding defect or to a coagulation pathway problem with deep tissue bleeding. Look for bruises of differing ages, gum bleeding, haematuria and, possibly, fundoscopy for retinal haemorrhages. Tall stature, cardiac murmurs or loose skin could point to a collagen disorder, such as Marfan’s syndrome.

If the history and examination are worrying enough to warrant referral to a haematologist, it is appropriate to perform an initial FBC, Urea and electrolys (U&E), liver function tests, PT, APTT and TCT, as well as von Willebrand factor (vWf) assays and ABO blood typing.

Individuals with blood group O have 30% less vWf, although the clinical significance of this is doubtful. The results of these may help the haematologist proceed, after clinical review, to a subsequent round of tests if needed (discussed below).

DISORDERS OF PLATELET NUMBER AND FUNCTION

In the absence of any cause for platelet dysfunction, the risk of spontaneous bleeding corresponds to a platelet count of 20 × 10⁹/L or less. Patients with platelets < 50 × 10⁹/L should be referred urgently. Thrombocytopenia can be spurious, as in up to 1% of some populations, individuals form platelet clumps with EDTA, the most common sample tube anticoagulant. (The laboratory will request a citrate sample if this is suspected.) Partially clotted samples may also give a low platelet count.

Isolated thrombocytopenia is only rarely due to under-production (called ‘amegakaryocytic thrombocytopenia’), and far more commonly to platelet peripheral destruction from idiopathic immune mechanisms (ITP) or drug-associated. (Treatment of ITP is discussed under the cytopenias.)

Heparin and low molecular weight heparin (LMWH) are the most common drug cause of thrombocytopenia, referred to as the heparin-induced thrombocytopenia-thrombosis syndrome (HITTS). Classically, the platelet count starts halving daily 5–10 days after regular heparin or LMWH is commenced. The incidence is 1.5% and 1.2% of exposed individuals respectively in heparin-naive individuals.

Aggregates form that consist of drug, antibody (to complexes of heparin and platelet factor 4) and platelets; these can be life-, organ- and limb-threatening.

Referral to a haematologist is urgent, for accurate diagnosis and prompt treatment. This includes stopping heparin and, often, finding an alternative anticoagulant such as lepirudin or danaparoid.⁸ Re-exposure to heparin may induce an anamnestic response and a much more rapid fall in platelet count. This rapid-onset HITTS occurs mostly when the prior exposure was within the previous 3 months or, more typically, 30 days.

Other drugs causing thrombocytopenia include quinine (or quinidine), even in trace amounts in tonic water or angostura bitters; ranitidine, rifampicin, cotrimoxazole and others are rarer culprits.⁹ The full list is daunting, and any drug should be suspected.

Platelet function is affected in rare congenital syndromes including intrinsic platelet disorders, and collagen abnormalities like Ehlers-Danlos and Marfan’s syndromes, in some marrow disorders (e.g. myeloproliferative disease), in chronic liver and renal disease, and by many drugs as above.

COAGULATION PROFILE TESTS AND ASSOCIATED DISORDERS

The coagulation profile includes the prothrombin time (PT), the activated partial thromboplastin time (APTT), and sometimes the thrombin clotting time (TCT). The principle in all these tests is that factor levels of 30% or more give normal clotting times. Mild bleeding disorders (factor levels 30–50%) may give normal results, but a careful history may point to the need for factor assays when these are suspected.

The PT provides a measure of the extrinsic pathway. It measures functional tissue factor, factors VII, X, II (prothrombin) and fibrinogen. As factor VII has the shortest half-life of the plasma proteins targeted by warfarin, the PT is the best test to monitor warfarin. Causes of a long PT include warfarin, liver disease, vitamin K deficiency and factor VII deficiency.

The APTT measures the intrinsic pathway involving factors XII, XI, VIII, IX, X, prothrombin and fibrinogen. Causes of a long APTT include heparin, haemophilias, lupus anticoagulant and other inhibitors.

The PT and APTT are both long in liver disease, severe warfarin overdose, disseminated intravascular coagulopathy (DIC) and deficiencies of fibrinogen, thrombin and factors V and X.

The TCT is performed by measuring excess bovine thrombin to the sample, and the time taken to clot is proportional to the amount of functional fibrinogen present. Prolongation of the TCT is seen in afibrinogenaemia, hypofibrinogenaemia (e.g. DIC) and dysfibrinogenaemia (congenital, liver disease). Heparin, paraproteins and clot breakdown products can interfere with the TCT. As this is the final step in both pathways, if the TCT is prolonged, the other tests usually are as well.

There are recognised haemostatic defects that may be clinically significant, even if the coagulation profile is normal:

More-specific tests may be performed. The bleeding time is the only in vivo measure of primary haemostasis. Individual factor assays may be warranted by the clinical scenario, particularly to exclude mild bleeding disorders such as von Willebrand’s disease or similar. Tests of platelet function include platelet aggregometry.

Mild von Willebrand’s disease requires specifically assaying vWf. Various subtypes are recognised. Bleeding may manifest only after an antiplatelet agent is started, including some herbs as above. A distinction is increasingly being drawn between those with low vWf (30–50%) and those with mild von Willebrand’s disease (levels usually 10–30%).^10,11

Acquired inhibitors may manifest as a sudden onset of a bleeding diathesis in adults. Their detection relies upon demonstrating a prolonged APTT that fails to ameliorate after 50:50 pooling with normal plasma, which should normalise all clotting times (as all factor levels should be at least 50% or more). Repeating the test after a 2-hour incubation increases the sensitivity.

Diagnosing the lupus anticoagulant requires a battery of specialised tests, which should be positive on at least two occasions 3 months apart. If found, related autoantibodies should be checked, such as antiphospholipid and beta-2-glycoprotein I antibodies, plus tests for SLE.

In summary, a good history is the key to guide appropriate testing. When a mild bleeding diathesis is found, the implications of the diagnosis need to be explained, as well as any lifestyle and medication implications. A family study may be considered.