chapter 22 Blood
INTRODUCTION AND OVERVIEW
In recent years, patients with haematological conditions may have been treated with new therapies, including immunotherapy (e.g. rituximab for non-Hodgkin’s lymphomas) or molecularly targeted therapies (‘designer drugs’ or ‘magic bullets’ such as imatinib mesylate for chronic myeloid leukaemia (CML)).1 The impact of these new therapies and the rapidly changing treatment of blood cancers is discussed.
ANAEMIA AND HAEMATINIC DEFICIENCY STATES
Symptoms that are often present, and may alert you to the presence of anaemia, include:
The history, in a simplified clinical approach, should focus on:
In the patient without obvious cause, anaemia itself is best regarded as a symptom, not a diagnosis.
Microcytic anaemia results mostly from iron deficiency, anaemia of chronic disease or thalassaemia/haemoglobinopathy. The most common causes of macrocytic anaemia are alcohol, pregnancy, and vitamin B12 and folate deficiency (Table 22.1).
TABLE 22.1 Red cell size as a pointer to the likely cause of anaemia
Microcytic | Normocytic | Macrocytic |
---|---|---|
Iron deficiency | Chronic disease* | Pregnancy |
Chronic disease* | Combined haematinic deficiencies | Reticulocytosis |
Thalassaemias & haemoglobinopathies | Renal failure | |
Sideroblastic anaemia | Liver disease | Myeloma |
Alcohol | ||
Drugs (chemotherapy) | ||
Hypothyroidism |
* Anaemia of chronic disease can cause normocytic or microcytic anaemia.
When the bone marrow responds to an insult such as haemorrhage or haemolysis with a brisk increase in reticulocytes (immature red cell forms), they can increase the MCV. For example, a reticulocytosis of over 10% may bring the MCV up to 105 fL (normal range: approx. 80–100). Rarer causes include hypothyroidism, myeloma and many chemotherapy drugs.
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.
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
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.
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.
It follows that treatment of ITP and AIHA is aimed at:
IMMUNE-MEDIATED THROMBOCYTOPENIA
Therapeutics
Splenectomy is effective in about 50–75% of cases of chronic refractory ITP or AIHA. Other indications include diagnostic splenectomy (rare, for suspected primary splenic lymphoma), symptomatic hereditary spherocytosis, Gaucher’s disease, Felty’s syndrome, and after traumatic or spontaneous splenic rupture. Electively, it can be done laparoscopically, which is far less invasive and traumatic for the patient, who can often go home by the second postoperative day. (Much smaller incisions are made; the splenic pedicle is clamped and the spleen enclosed in a plastic bag; the organ is then mulched to a deformable state and passed out through one of the small incisions.) Recent guidelines for the management of splenectomised patients are provided in Box 22.1.7
COAGULATION DISORDERS
The modern understanding of haemostasis describes a primary phase and a secondary phase. The actions of blood vessels and platelets constitute the primary phase. In response to injury, blood vessels constrict. Platelets, in response to newly exposed collagen, ADP and adrenaline, undergo the shape change reaction, rather like inflating an inverted rubber glove. Thus, previously hidden, or cryptic, molecules are exposed on the platelet surface, allowing interaction principally with von Willebrand factor (vWf). Platelets can now bind to injured endothelium (adhesion) and each other (aggregation), leading to a ‘stacks on the mill’ aggregation of platelets, and thrombus formation.
The coagulation protein reactions constitute the second phase of haemostasis. This generates fibrin in high local concentration at the site of injury or thrombosis, in effect ‘throwing a net’ over the platelet aggregate, anchoring it in place. These protein reactions occur as a sequence of macromolecular aggregates (not a ‘cascade’, Fig 22.6), mediated on the platelet surface, at the site of injury. In the current view, tissue factor has a crucial role as the initiator of haemostasis, down both the intrinsic and the extrinsic pathways (see below). The last step involves the conversion of fibrinogen to fibrin (factors I and Ia respectively) by thrombin (also called factor IIa). Fibrinogen’s shape becomes linear and it spontaneously polymerises (side-to-side and end-to-end, making D-dimers) to create the fibrin net. Finally, this fibrin mesh is stabilised by cross-linkage with factor XIII.
The endothelial cell has a key role in locally regulating pro-coagulant and anti-coagulant proteins, to allow a thrombus to form where needed, but inhibit propagation too widely. There are complex local mechanisms controlling levels of required proteins, cofactors and substrates in these reactions. Ex vivo testing of plasma cannot accurately reflect these events in the body.
Causes of a bleeding diathesis (referring here to mild or asymptomatic) are listed in Table 22.2. Congenital causes include mild phenotypes of the classic bleeding disorders, haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency) and von Willebrand’s disease, and rarer deficiencies of other clotting factors.
INVESTIGATING THE PATIENT WITH EASY BRUISING
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.
DISORDERS OF PLATELET NUMBER AND FUNCTION
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.
COAGULATION PROFILE TESTS AND ASSOCIATED DISORDERS
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
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