Microcytic	Normocytic	Macrocytic
Iron deficiency	Chronic disease^*	Pregnancy
Chronic disease^*	Combined haematinic deficiencies	Reticulocytosis
Thalassaemias & haemoglobinopathies	Renal failure	Megaloblastosis Vitamin B₁₂/folate deficiency

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.

The diagnosis may be more difficult in those with a normocytic anaemia; in this situation, review of the blood film can be diagnostic. Such red cell changes include:

• increased numbers of spherocytes (small, rounded red cells without central pallor), which indicate immune-mediated haemolytic anaemia

• fragmented red cells with so-called ‘helmet cells’ (think of an American GI’s helmet), seen in syndromes such as glomerulonephritis, malignant hypertension, disseminated intravascular coagulation and the rare thrombotic thrombocytopenic purpura

• nucleated red cells, coupled with markedly left-shifted granulocytes, which define leuco-erythroblastic change that implies marrow invasion (metastatic cancer) or compromise (extreme sepsis). A leuco-erythroblastic blood film without a known cause warrants immediate referral to a haematologist and consideration of marrow biopsy for occult cancer.

Where the cause of anaemia is still obscure, it may be appropriate to proceed to referral for further investigation, including a bone marrow biopsy; generally, if this is contemplated, the focus has shifted to the possibility of intrinsic marrow disorders such as myelodysplastic syndrome. The biopsy is taken from the posterior iliac crest and includes: an aspirate, to look at cellular morphology; a bone marrow core or trephine biopsy, which gives a better indication of the overall cellularity and the presence of the occult malignancy; and cytogenetic examination, which often gives the best yield for diagnosing early myelodysplastic syndrome. A sample is also frequently collected for flow cytometry to quantify blast cells (acute leukaemia), plasma cells (myeloma) or lymphoid cells (lymphoma). Bone marrow biopsy is best performed at a specialised centre, to allow optimum specimen collection and handling.

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:

• reducing antibody production with immune suppression, such as corticosteroids or rituximab (a more elegant way of inhibiting antibody production without systemic steroid side effects)

• ‘mopping up’ circulating antibody, which is thought to be one mechanism of efficacy of intravenous immunoglobulin or intragam, as well as saturation of the Fc receptors of the macrophages lining the splenic sinusoids, or

• removing the location of cellular removal (i.e. splenectomy).

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.

Therapeutics

Steroids (e.g. prednisolone 1 mg/kg/day) remain the first line of therapy in all patients. Intragam (IVIg) can be given if the response is inadequate, partly to shorten the length of time spent in hospital. Once a response is achieved, steroids can be weaned. Should relapse occur, options now include further steroids, rituximab and/or splenectomy. Thrombopoietin receptor agonists, including romiplostim (a platelet lineage equivalent of erythropoietin), show promising results and may eventually reduce the need for splenectomy.

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

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!)

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.

FIGURE 22.5 Immune thrombocytopenia: A ×250; B ×1000; C ×200; D ×1600

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.

FIGURE 22.6 Coagulation cascade; a denotes activated factor. Ca: calcium; PL: phospholipid

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.

Defects in the primary phase usually manifest with mucosal-style bleeding, such as epistaxis, menorrhagia, petechial rashes, haematuria and blood blisters in the oral mucosa. Mild von Willebrand’s disease is the classic example. Defects in the secondary phase of haemostasis, including haemophilia, mostly lead to deep tissue bleeding with haematomas and haemarthroses.

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.

TABLE 22.2 A guide to bleeding diagnoses and typical coagulation test results

Liver disease, warfarin overdose and vitamin K deficiency (secondary to antibiotic use) are the more common acquired causes. Haemophilia can be acquired; this is an acquired antibody that binds to factor VIII or IX, resulting in plasma clearance and functional deficiency. Antibodies to other plasma proteins are called inhibitors of coagulation; the lupus anticoagulant is one example. Low-grade disseminated intravascular coagulation (DIC) occurs in some cancers, mostly adenocarcinomas. Purpura simplex is a diagnosis of exclusion in women with increased bruising linked to their menstrual cycle. In the absence of abnormal coagulation times, it is not clinically significant.

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:

• mild deficiency states

• mild von Willebrand’s disease

• platelet dysfunction syndromes

• acquired inhibitors to anticoagulant proteins; factor XIII deficiency

• rare fibrinolytic disorders

• vasculopathies

• corticosteroids, like old age (and scurvy!), lead to small vessel fragility, and secondary purpura and ecchymoses.

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.

INTEGRATIVE MEDICINE IN BLEEDING DISORDERS

Aspirin, antiplatelet drugs (clopidogrel), NSAIDs and herbal supplements, notably gingko, garlic, ginger and ginseng, all reduce platelet function.

VENOUS THROMBOEMBOLIC DISEASE

Venous thromboembolism (VTE) remains the most common preventable cause of hospital death, and the management of newly diagnosed cases has shifted to the GP in recent years.

CAUSES AND DIAGNOSIS

Thrombosis occurs with perturbations of Virchoff’s triad of intrinsic properties of the blood favouring thrombosis, vascular injury and stasis. The thrombophilias are a group of inherited and acquired measurable abnormalities of the blood associated with increased VTE risk. These can be distinguished from the hypercoagulable states (discussed below). Examples of vascular injury include trauma and venous cannulation. Immobility, left ventricular dysfunction, atrial fibrillation and venous insufficiency may all contribute to stasis.

Hypercoagulable states (Fig 22.7) refer to clinical settings associated with increased thrombosis risk:

• postoperative status

• prolonged immobility during travel (‘economy class syndrome’).

FIGURE 22.7 Hypercoagulable states and thrombosis risk. * Prevalence unknown. † includes acquired defects. AT: antithrombin III; FV: factor V; PC: protein C; PS: protein S

The diagnosis of VTE is notoriously prone to false-negative clinical examination. Tests should be used and interpreted in the light of clinical suspicion. Undue credence is given by many clinicians to the D-dimer test. A positive result is not helpful: there are many things that can cause it to be elevated, and in a hospital ward or emergency room population, specificity is very low. However, a negative result (normal titre) in an outpatient with a low possibility of thrombosis helps to exclude recent VTE. Ultrasound examination results are operator-dependent; venography is still the gold standard in clinical trials. CT pulmonary angiogram (CTPA) and/or ventilation-perfusion (VQ) scanning remain important in diagnosing pulmonary embolism (PE).

TREATMENT

Treatment is usually with heparin in some form, and warfarin. The two can often be started together. Unfractionated heparin (MW 15,000 Dalton), first isolated from ox liver in 1916, has marked variation in effect, partly due to its high negative charge and non-specific binding to a variety of plasma proteins, and to unpredictable antiplatelet effects. It is fully and rapidly reversible with protamine and is best reserved for patients who must be anticoagulated but who are at high risk of bleeding. Heparin is also preferred over LMWH in the treatment of major or life-threatening pulmonary embolism (PE), but lesser PE can be safely treated with LMWH.

If heparin is used, a baseline APTT should be raised two-fold over baseline within 8–24 hours, to reduce the chance of VTE progression.^12,¹³ Monitoring of the APTT is required.

Low molecular weight heparins have a molecular weight of 4000–7000 Dalton, greater predictability in effect, longer half-life, greater specificity of action (inhibition of activated factor Xa and IIa, i.e. thrombin), and better correlation of effect with body weight. A Cochrane review concluded that once-daily treatment for deep vein thrombosis (DVT) and sub-massive PE at home with LMWH is safer than with heparin.¹⁴ Levels may accumulate in renal failure or be low in the very obese. Reversibility with protamine is incomplete. Monitoring is not usually needed, but can be achieved by measuring anti-factor Xa activity in, for example, those with renal insufficiency or the very obese.

Warfarin was discovered in rotten hay when a herd of cattle bled to death at the Wisconsin Agricultural Research Facility (WARF) in 1936—hence its name. There is marked inter-individual variation in dose (doses vary between 1 and 15 mg daily) and the effect of any dose is maximal 36 hours later—so be aware that, when adjusting the dose, it is in response to today’s blood test and the day before yesterday’s dose. Many patients are tested too frequently and dose-adjusted too often for the pharmacokinetics of the drug. It is still often poorly prescribed, especivally initially and later, when over-confidence can occur in either patient or physician.

The international normalised ratio (INR) is a mathematical manipulation of the prothrombin time to equalise different laboratories and reagents, such that the patient can be advised that, ‘An INR of 2.0 means your blood is taking twice as long to clot as someone not taking warfarin; and any laboratory the world over would get a similar result’. The INR has been a meaningful advance for those who travel while taking warfarin.

Five milligrams daily will achieve therapeutic levels in 80% within 4 days.¹⁵

When starting a patient on warfarin, be satisfied that they will be able to comply, and check other drugs and supplements, noting any that may be likely to affect the INR and/or be stopped (e.g. antibiotics). Ensure that the patient has a monitoring book; explain the meaning of the INR result and the risks of over-dosage. Explain the role of diet (capsicum and alfalfa have high doses of the antagonist vitamin K, but the dose can be adjusted according to usual diet) and alcohol (maximum two standard drinks in any one sitting; some say none at all). Many patients ultimately require a dose between discrete daily doses, and patients should have a monitoring book with allocated spaces for each day of the week so that, in long-term patients, the weekly rather than the daily dose can be changed.

Antiplatelet agents should be used with great caution with warfarin, especially aspirin and clopidogrel, with a half-life of 10 days (in terms of antiplatelet effects) compared with 2 days for NSAIDs.

The duration of anticoagulation for a DVT should be at least 3 months.¹⁶ A meta-analysis found that recurrence is 40% less with 12–24 weeks of anticoagulation after unprovoked DVT, than with 3–6 weeks, without increased risk of major bleeding.¹⁷ For ‘provoked’ (e.g. associated with a venous catheter, or injury) and calf vein DVT, some say a shorter course can be given. With the latter, a repeat ultrasound at 10 days to exclude more proximal extension and higher risk of PE may be worthwhile.¹⁸ For superficial vein thrombosis and thrombophlebitis, topical hyaluronidase and aspirin are more appropriate therapy. For a PE, anticoagulation is usually for 6–12 months.

For a second confirmed episode of VTE, lifelong anticoagulation should be strongly considered.¹⁹ The intensity of anticoagulation with warfarin (target INR) is 2.0–3.0 in all circumstances, save one: mechanical left-sided cardiac valves require anticoagulation to an intensity of INR 3.0–4.5. See Table 22.3 for guidelines on target and duration of therapy, based on published Australian recommendations.²⁰

TABLE 22.3 Anticoagulation recommendations after VTE

	Intensity (target INR)
All patients, except …	2.0–3.0
Mechanical heart valves (caged ball, caged disc)	3.0–4.5

	Duration (risk stratification)
First episode	3 months
First episode, provoked (e.g. venous catheter) or calf vein DVT	6–12 weeks
First episode, permanent risk factors	3–6 months, consider indefinite
Two episodes	Indefinite

There has been much interest in warfarin pharmacogenomics. CYPC29 polymorphisms are seen in 1% of the population, in whom a lower dose of warfarin may be needed and there is higher risk of bleeding. Conversely, VKORC1 refers to genetic variations of the vitamin K epoxide reductase subunit 1 gene; they are rare and associated with clotting factor deficiencies and warfarin resistance. The value of screening the population is debated.²¹

Ultimately, the decision to anticoagulate must be a clinical one, weighing up the potential benefits and risks in any one case. The decision should be re-evaluated periodically; the risk of major bleeding with warfarin rises to over 5% in the over-75 years age bracket and, for example, this may swing the cost-benefit equation against continuing warfarin in an elderly patient with atrial fibrillation and declining ability to comply.

Warfarin reversal can be achieved with vitamin K, fresh frozen plasma or Prothrombinex®, depending upon urgency (see Baker et al 2004 ²² for guidelines). Prothrombinex® contains concentrates of factors II, VII and IX; although it is recommended that cryoprecipitate or fresh frozen plasma (FFP) be given as well, to supply factor X, it might not be needed.²³

PREVENTION OF VTE

Primary prevention, using either low-dose heparin or LMWH, is recommended by most authorities perioperatively in all patients for some forms of surgery (such as orthopaedics) and in hospitalised or critically ill patients (Table 22.4).

TABLE 22.4 High-risk groups

Indication	Medication	Duration
Orthopaedic surgery (total hip, total knee, hip fracture)	LMWH + GCS/IPC	35 days
Major abdominal surgery and age > 40	LMWH + GCS/IPC	Until discharge or 28 days if high risk
Acute medical illness requiring immobility, with other risk factors	LMWH	Until ambulant
Pregnancy and postpartum with other risk factor	LMWH	During pregnancy and 4–6 weeks post-partum
Travel over 8 hours	LMWH Compression stockings, adequate hydration, movement, avoid alcohol, no restrictive clothing

24 hours before flight, again just before flying and 24 hours later

GCS: graduated compression stockings; IPC: intermittent pneumatic compression; LMWH: low molecular weight heparin.

Secondary prevention measures should be applied equally to those with a prior episode of VTE, a thrombophilic state (see below) or both.^22,²⁴ Long-haul travel (in planes, cars and trains for longer than 8 hours) is associated with a small absolute increase in thrombosis, possibly as little as one per two million arriving passengers over the subsequent 30 days.²⁵ Recommended measures include wearing loose clothing, drinking plenty of fluids, frequent calf muscle contraction and, for those at higher risk (past VTE, thrombophilia), fitted compression stockings and LMWH immediately pre-travel (repeating the dose 24 hours later).

Aspirin is not an effective thromboprophylactic in this setting.²⁴ Travel within 3 weeks of a VTE or high-risk event (e.g. surgery) is best avoided, even for those on warfarin. In cancer patients, VTE is best treated indefinitely with LMWH, not warfarin, as recurrence is halved.²⁶

HYPERCOAGULABLE STATES AND THROMBOPHILIA

Hypercoagulable states refer to clinical settings associated with increased thrombosis risk: pregnancy, malignancy, sepsis, oestrogen therapy, postoperative status and prolonged immobility during travel (‘economy class syndrome’). Thrombophilia is a growing list of measurable inherited and acquired disorders that predispose an individual to thrombosis to varying degrees (Table 22.5). There is much debate over who to screen, but probably the indications include younger VTE patients (< 40 years); those with unprovoked ‘atypical’ VTE; those with VTE in an unusual site such as cerebral, renal, hepatic or mesenteric veins; those with a strong family history; and perhaps those in whom elective pro-thrombotic therapy is contemplated. Patients should be assessed individually, as the familial predispositions tend to ‘run true’ in kindreds, and family history is important.

TABLE 22.5 Frequency and effect (increased thrombosis risk) of selected thrombophilias ²⁷

Syndrome	Frequency in Caucasian population	Prothrombotic effect
Congenital
Factor V Leiden	3–5%	× 3–7^*
Anti-thrombin III deficiency	< 1%	× 10
Protein C deficiency	< 1%	× 10
Protein S deficiency	< 1%	× 10
Prothrombin 20210A mutation	3%	× 3
Hyperhomocysteinaemia	5% have level > 18 μmol/L	mild
Acquired
Lupus anticoagulant	Rare	× 10

* Homozygotes, however, have a 30-fold increased risk.

Inherited thrombophilias include:

• factor V Leiden mutation

• antithrombin

• protein C and protein S deficiency

• prothrombin gene mutation.

The most common inherited thrombophilia in Caucasians is factor V Leiden, with an incidence of around 3–5%, associated with a three- to seven-fold increased risk.

However, the diagnosis of thrombophilia has little impact on the management of the individual patient. Asymptomatic thrombophilic patients should be advised to avoid oestrogens and consider prophylactic measures for long-haul plane travel or surgery.

Thrombophilic individuals after one episode of VTE are at only a modestly increased risk of a second DVT, compared with others who have had a VTE episode.^28,²⁹ Anticoagulation should be at the usual level and duration. Exceptions include homozygosity for factor V Leiden and those with two thrombophilic states, which confer a much higher thrombosis risk. Such individuals should be reviewed by a haematologist, and lifelong therapy offered.

EXOGENOUS OESTROGEN

Oestrogen is pro-thrombotic in a dose-dependent way, mostly through lowering proteins C and S. Advising women with a history of DVT, or those found to have a thrombophilia state, and who want to take oestrogen for contraception or as hormone replacement therapy (HRT), is particularly difficult. All alternative forms of contraception or menopause management should be discussed. Once again, individual assessment of risk, including assessment of provoked or unprovoked VTE, and family history, are important.

Screening all women contemplating HRT for a thrombophilic state is not feasible, and this raises a dilemma. A meta-analysis of 81 studies concluded that screening of all women is impractical and not cost-effective, whereas screening of higher-risk groups based on individual assessment of risk is.³⁰

For thrombophilic or post-VTE women, other forms of contraception should be encouraged. There is no evidence that progesterone alone is pro-thrombotic. Some women find menopausal symptoms so bad that they will take HRT against haematological advice. Some find symptom relief with phyto-oestrogens and other treatments (see Ch 53, Menopause). Transcutaneous oestrogen patches, due to first-pass metabolism, are less thrombogenic.^31,³² The French ESTHER study performed a multi-centre case-control study of 271 consecutive cases of VTE among postmenopausal women aged 45–70 years and 610 controls (426 hospital controls, 184 community controls) matched for centre, age and admission date. After adjustment for potential confounding factors, the odds ratios (ORs) for VTE in current users of oral and transdermal oestrogen compared with non-users were 4.2 (95% CI 1.5–11.6) and 0.9 (95% CI 0.4–2.1), respectively.³¹ These findings suggest that transdermal oestrogen may not be thrombogenic at all.

MALIGNANT HAEMATOLOGY

After an infection, the white cell count rises, sometimes with the platelet count, and then falls to the same premorbid level. Thus, marrow haemopoietic tissue, some 5 kg scattered around the long and flat bones of the body, behaves in a coordinated way, as a single organ. Moreover, it is subject to the same pathological processes as other organs. For historical reasons, the terminology is different. Table 22.6 shows how haematological terms correspond conceptually to the more familiar terms aplasia, dysplasia, hyperplasia and neoplasia in the spectrum of primary bone marrow pathologies. On the deficit side, complete loss of marrow or marrow function is called aplastic anaemia (a better term would be aplastic pancytopenia). Hypoplasia of the marrow usually maps to the myelodysplastic syndromes. In contrast, hyperplastic disorders of the marrow are referred to as the myeloproliferative syndromes. Neoplasia of the marrow stem cell is acute leukaemia.

TABLE 22.6 Overview of myeloid pathology

Symptoms in patients with haematological malignancies can be considered negative or positive.

Negative symptoms arise from marrow hypofunction, manifesting with:

• symptomatic anaemia

• infection—for example, a common presentation of acute leukaemia is recurrent sore throat

• bleeding—due to lack of red cells, white cells or platelets respectively.

Positive symptoms are a characteristic complex arising from increased levels of cytokines liberated by white blood and immune cells, such as tumour necrosis factor, interleukin-1, IL-3 and IL-6. These cause the classic ‘B’ symptoms of:

• unintentional weight loss (> 10%)

• fevers (> 38.5°C on two occasions without cause) and drenching night sweats

• fatigue, and spontaneous cigarette, alcohol or meat intolerance—may occur, as with any malignancy

• itch—common in Hodgkin’s lymphoma, T-cell non-Hodgkin’s lymphomas and some of the myeloproliferative disorders; it may be provoked by exercise or hot water

• bone pain—can mimic acute back pain; is often felt in the back, pelvis and thighs

• very high white cell counts—may cause leucostasis, manifesting as pseudo-strokes, dyspnoea, angina and even priapism.

Physical examination should include assessment of all peripheral lymph node stations, including visualising the tonsils and palpating the epitrochlear and popliteal lymph nodes; plus a careful check for splenomegaly; and gently testing for bone tenderness over the sternum.

Often the first indication is, of course, the blood count. The more of the three blood cell lineages that are numerically abnormal, the more likely there is to be primary marrow pathology, such as myelodysplasia or acute leukaemia. For example, isolated thrombocytopenia of 3 × 10⁹/L in a young adult is probably ITP; but if the Hb is 90 g/L and the neutrophils 1.1 × 10⁹/L, then more-sinister pathology is likely.

In those with suspected haematological malignancy, referral should be made urgently for haematological assessment. It is very helpful to perform FBC, U&E, liver function tests, serum LDH, blood film, uric acid, serum calcium and possibly flow cytometry of peripheral blood lymphocytes; chest X-ray and CT scans of thorax and abdomen are always appropriate in those with suspected lymphoma.

A brief summary of the main haematological cancers now follows.

CHRONIC MYELOID LEUKAEMIA

Chronic myeloid leukaemia (CML) (Fig 22.8) is a misnomer, as it is really a myeloproliferative pre-leukaemia, albeit one that had a 100% risk of progression to acute leukaemia before effective therapies were available. It has a unique triphasic natural history, from chronic phase, to accelerated and, finally, transformed CML. Patients may present late in the chronic phase, with a white cell count as high as 600,000 × 10¹²/L. Fatigue, moderate or massive splenomegaly, early satiety, night sweats and weight loss are classic symptoms. Increasingly the diagnosis is made in asymptomatic patients as an incidental finding—at a health or insurance check, for example.

FIGURE 22.8 Chronic myeloid leukaemia

Treatment has changed from busulphan in the 1970s, to interferon in the 1980s, to the astonishing success of imatinib mesylate in the early 2000s. This has provided proof-of-concept that the molecular biology revolution can deliver to the clinic. Imatinib is the first widely used drug targeted at a pathological molecule—that is, BCR-ABL, a tyrosine kinase, generated by the famous Philadelphia chromosome (translocation 9;22). The full story has been told recently elsewhere.¹ For many with CML, lifelong disease control with tyrosine kinase inhibitors, such as imatinib and its successors, appears probable, after our first 10 years’ experience at least; bone marrow transplantation, although still the only cure, is reserved for those with accelerated or transformed disease, which remains much feared.

CHRONIC LYMPHOCYTIC LEUKAEMIA

Rather than abnormal cell growth, chronic lymphocytic leukaemia (CLL) (Fig 22.9) is characterised by the accumulation over time of lymphocytes in the bloodstream, lymph glands and/or bone marrow, or combinations thereof. Again, increasingly the diagnosis is made incidentally. The diagnostic test is no longer the bone marrow biopsy. Peripheral blood flow cytometry is easier and gives a pathognomic result, although the marrow often shows unexpectedly high numbers of CLL cells, and this may influence clinical decision-making. Treatment is indicated for symptomatic disease, bulky or disfiguring lymphadenopathy, or cytopenia. Most haematologists recommend treatment when the lymphocyte count hits 100 × 10¹²/L, for at this level, the other triggers for treatment usually soon follow.

FIGURE 22.9 Chronic lymphocytic leukaemia

The treatment paradigm has shifted from oral chlorambucil to more aggressive combination chemotherapy, with good evidence that this confers better survival and longer remissions.³³

For many newly diagnosed patients, treatment is not immediately indicated. Nevertheless, all patients should be referred for haematological review, even if asymptomatic, as the immediate implications for health include advice to start antibiotics promptly for suspected bacterial infection, to take measures to reduce solar skin damage and to assess for complications. As with any B-cell tumour, hypogammaglobulinaemia may occur (IgG < 2 g/L). Other complications include increased second cancers including skin and other cancers, autoimmune haemolytic anaemia in up to 20% of cases, and Richter’s transformation, a rare progression to aggressive non-Hodgkin’s lymphoma.

ACUTE LEUKAEMIA

When the term leukaemia was coined, in the nineteenth century, it referred to an excess of white cells in the bloodstream. Those with normal-appearing white cells lived longer (hence chronic leukaemia), whereas those with abnormal, or blast, cells, died rapidly, and so this was called acute leukaemia. We now recognise acute leukaemia (Fig 22.10) as a cancer of the bone marrow stem cell. The modern definition is: more than 20% blast cells in the marrow. (Less than 2% blast cells is normal; 5–20% blast cells characterises myelodysplasia.) Acute lymphoblastic leukaemia (ALL) is seven times more common than acute myeloid leukaemia (AML) in children; the ratio is reversed in adults.

FIGURE 22.10 Acute monoblastic leukaemia. A High white cell counts due to circulating monoblasts; B Bone marrow aspirate packed with monoblasts (C) and showing few granulocytic elements; D Rare granulocytes show the blue reaction product from the combined esterase reaction while the rest show orange-brown; E Biopsy sample is unusually packed with sheets of monoblasts with fine nuclear chromatin and abundant pink cytoplasm

The history is typically of two or more infections in the previous 3 months, or increasing bone pain; rarer presentations include DIC, priapism and meningism. Usually there is pancytopenia (i.e. neutropenia, anaemia, thrombocytopenia), in which the neutropenia may or may not be masked by a high blast cell count. Thus, the white cell count in acute leukaemia can be high, normal or low, depending upon the readiness of the blast cells to leave the marrow compartment for the bloodstream. Bone marrow biopsy remains essential for medico-legal and prognostic reasons, even if the diagnosis is evident in the blood film.

It is good practice to refrain from giving the diagnosis to the patient until the bone marrow biopsy is done. Obviously, patients will need to be told ‘there is concern over a possible bone marrow disorder’ to explain the prompt contact and recommendation to attend hospital.

The diagnosis of acute leukaemia is a medical emergency. In some forms, notably acute promyelocytic leukaemia (APML), prompt institution of appropriate therapy can be life-saving. Patients should be managed at a centre with expertise.

Therapeutics

Curative management of acute leukaemia requires 3 or 4 months of intensive chemotherapy in or near hospital. In ALL, the central nervous system is recognised as a possible sanctuary site for future relapse, and chemotherapy or adjunctive radiotherapy is given accordingly. Some 80% of patients achieve an initial response or remission; the problem then is keeping it. Paediatric ALL has cure rates approaching 90%, a great success story. Present cure rates in adults rest at 40% for AML and 25% for ALL. There are better results with some subtypes, including AML with certain karyotypic abnormalities and APML. Bone marrow transplantation is offered to selected patients in first remission as the best chance of cure, and has become less dangerous with improvements in tissue typing, viral and fungal antibiotics and supportive care for graft versus host disease. For the very elderly, a palliative chemotherapy approach may give surprising longevity (over a year) with good quality of life.

MYELODYSPLASIA

The myelodysplastic syndromes occur mostly in the elderly. Causes include prior chemotherapy and/or radiotherapy. Characteristically there are low peripheral blood counts, leading to negative symptoms of marrow failure. The cells look abnormal in the bone marrow biopsy (Fig 22.11). It is a morphogical diagnosis. Abnormal marrow cytogenetics are found in up 60% of cases, and there is a 20–80% risk of progression to acute leukaemia.

FIGURE 22.11 Characteristic forms of myelodysplasia: A Nucleated red cell progenitors with multi-lobed or multiple nuclei; B Ringed sideroblasts—erythroid progenitors with iron-laden mitochondria seen stained with Prussian blue; C Pseudo-Pelger-Hüet cells (top and bottom)—neutrophils with only two nuclear lobes instead of the normal three or four; D Megakaryocytes with multiple nucleii instead of normal single, multi-lobed nucleus

Therapeutics

Treatment is supportive, with blood and platelet transfusions, and growth factor injections; some will respond to erythropoietin. New therapies are in clinical trials worldwide. Quality of life is usually poor once transfusion dependence reaches every 3 weeks or less. Iron overload can occur rapidly.

MYELOPROLIFERATIVE DISORDERS

Symptoms common to all these diseases include:

Very high platelet counts can lead to burning pain of the extremities (often in individual digits)—that is, erythromelalgia.

High haemoglobin levels may cause facial plethora, conjunctival injection and gritty eyes. A patient with an elevated haemoglobin may have plasma volume contraction (Gaisbock’s syndrome, associated with diuretic and tobacco use), secondary polycythaemia (to chronic hypoxia from cardiorespiratory disease) or true polycythaemia rubra vera (PRV). Rarer causes of secondary polycythaemia include various erythropoietin-secreting tumours.

The clinical approach should therefore cover prescribed and other drug history, exercise tolerance, and careful physical examination of the cardiac and respiratory systems. Two-thirds of PRV patients have splenomegaly.

Cellular morphology in the blood film is generally normal, with a raised peripheral blood cell count along one or other cell lineage: the red cells in PRV, the platelets in essential thrombocythaemia (ET), and the granulocytes in CML. In myelofibrosis, the peripheral blood is often leuco-erythroblastic and there are increased marrow stromal cells and collagen deposition in the marrow. Very high haemoglobin levels (e.g. > 20 g/L) are a haematological emergency due to high risk of stroke, and urgent referral for therapeutic venesection is recommended. The risk of progression to acute leukaemia in these myeloproliferative disorders (except CML) is 5–15%.

The recent description of an acquired mutation of the JAK2 kinase gene in the MPS has revolutionised the diagnosis.³⁴ It is positive in 95% of those with PRV and 50% of those with ET. Previously, nuclear medicine scans and bone marrow biopsy were needed to diagnose PRV and ET respectively. Now, screening for the JAK2 kinase mutation is diagnostic in most cases (now readily available in many countries) and it is an appropriate step for the GP to perform prior to referral.

Therapeutics

Although the lifespan for most is near normal, management of these patients is complex, and options include hydroxyurea, interferon, anagrelide and venesection (PRV only). Low-dose aspirin is also given to many patients, to reduce the risk of thrombosis. New drugs targeting the JAK2 kinase mutation are in clinical trials in the United States and elsewhere, with encouraging early results.

LYMPHOMA

Lymphoma (Fig 22.12) is cancer of the immune system, and this in part explains the difficulty in classification over many years. Modern understanding of the immune system only began with the identification of B- and T-lymphocytes around 1970. Seeing lymphomas in this way also explains their heterogeneity, as there are many types of lymphocytes, with specialised roles and organ sites. Nevertheless, some broad generalisations can be made.

• Lymphoma can occur anywhere in the body. Rarer locations for lymphomas include the skin, central nervous system and testes.

• Generally, there is a lump. This is because lymphoma is a cancer of a committed lymphopoietic progenitor, and these are cells programmed to grow in lumps—unlike marrow stem cells in leukaemia. Lymphadenopathy from lymphoma is rarely painful and may fluctuate in size.

• In Hodgkin’s lymphoma, 90% of cases arise in lymph glands (‘nodal disease’); in non-Hodgkin’s lymphoma (NHL), 40% of cases are extra-nodal and sites include mucosal associated lymphoid tissue (MALT) lymphomas of the stomach, and cutaneous mycosis fungoides.

• Eighty per cent of lymphomas are of B-cell origin. T-cell lymphomas tend to be slower growing but more resistant to therapy.

• Fine needle aspiration (FNA) biopsy is inadequate for accurate lymphoma diagnosis. Core or open biopsy is mandatory.

• Surgery is never curative. Lymphoma is not a surgical disease. Patients presenting with imminent or completed bowel obstruction are an exception.

• Some 10–20% of lymphoma cases have marrow involvement, and marrow biopsy should be included in staging tests, as well as serum lactate dehydrogenase (LDH), uric acid, flow cytometry, FBC, urea and electrolytes, CT and PET scanning.

• In NHL, smaller tumour cells and follicular (once called ‘nodular’) growth patterns are mostly associated with a better prognosis. There are exceptions (e.g. mantle cell lymphoma, where the cells are small, but the prognosis is poor).

FIGURE 22.12 Lymphoma

Therapeutics

Lymphoma management is complex and changing.³⁵ Multidisciplinary care, as for many solid tumours, is increasingly used, principally with consolidative radiotherapy. In aggressive NHL, cure rates are high (around 70%). Randomised, controlled clinical trials have generally shown no benefit for more intensive regimens or for up-front bone marrow transplantation for aggressive NHL. Instead, cure rates improved in B-cell lymphomas with the addition of rituximab to the familiar CHOP regimen (R-CHOP). This is a humanised antibody to CD20, a pan-B-cell antigen found on most B-lymphoma cell types; it seems to work essentially by ‘lighting up’ the B-cells for the patient’s own T-cells to kill. Rituximab has rewritten the NHL landscape and represents an advance that proved elusive with intensified chemotherapy. Very high-grade lymphomas are treated essentially as for acute leukaemia.

Cases of follicular, or low-grade, NHL often present beyond stage II and are rarely curable with radiotherapy. Worldwide, with evidence that the addition of rituximab improves survival, the treatment paradigm has shifted to a more aggressive approach, also using R-CHOP, followed by maintenance rituximab, after which fully 80% can expect a remission lasting 4 years.³⁶

Hodgkin’s lymphoma, now recognised as a B-cell tumour although lacking the usual B-cell surface antigens, has a cure rate of around 85–90%, mostly with the relatively non-toxic regimen of ABVD. Nevertheless, using a prognostic scoring system,³⁷ cases at high risk of relapse can be identified and should be treated with a more intensive approach, such as BEACOPP or variants.

Relapses of many kinds of lymphomas are best managed with an autologous stem cell transplant in suitable patients, and this may require planning in the initial phases of treatment, to collect marrow stem cells before they are depleted by chemotherapy.

INVESTIGATION OF A PATIENT WITH LYMPHADENOPATHY

Lymph nodal enlargement of greater than 1 cm persisting for more than 4 weeks in an adult may warrant further investigation. Referral to a haematologist prior to surgical referral is recommended. It is reasonable for the GP also to organise FBC, U&E, serum LDH, chest X-ray and FNA. If the last suggests a lymphoma, CT scanning of the chest and abdomen are helpful.

However, open biopsy will still be necessary to provide tissue for the large battery of tests in modern histopathology to grade a lymphoma. There are often up to 12 different immuno-histochemical stains, plus fluorescence in situ hybridisation, flow cytometry of cell suspensions and molecular work-up of tumour cell DNA. Lymphoma work-up in a larger pathology laboratory with an interest in lymphoma diagnosis will reclassify about 1 in 20 cases, leading to possible changes in treatment.³⁸^–⁴⁰

MULTIPLE MYELOMA

Multiple myeloma (Fig 22.13) is not a tumour of bone, as the name suggests. Rather, it is a tumour of antibody-secreting (into the plasma, hence ‘plasma cells’) immune cells that reside in the marrow. It is an insidious process of unknown cause, and the diagnosis may easily be missed for several years. These cells can erode bone, and crowd out the normal production of blood cells, and the protein they secrete can induce renal failure. Classic presentations are covered by the CRAB acronym: hypercalcaemia, renal failure, anaemia and bone pain or fractures. It may mimic osteoporotic spinal fractures. Rarer presentations include neutropenia or other cytopenia, hyperviscosity syndrome (headaches, blurred vision, dyspnoea and organ dysfunction), pyrexia of unknown origin and splenomegaly. Physical examination has little diagnostic value.

FIGURE 22.13 Myeloma

Screening is best done with a full blood count and film (background protein staining may be noticed in the haematology laboratory), a serum QEPP and serum free light chain (SFLC) assay. Until recently, a urinary QEPP was also required to exclude myeloma, because in some 20% of cases, the plasma cells secrete light chains only. These are small molecules that spill over from the bloodstream into the urine, leading to a negative serum QEPP, and positive urinary light chain (Bence-Jones) proteins. Light chains do not give a positive result on dipstick protein analysis. Most laboratories now perform, or have access to, the SFLC, which will detect light chains in serum at low levels (mg/L rather than g/L), and urine collection is no longer needed. A skeletal survey is more sensitive than a nucleotide bone scan for lytic lesions.

Therapeutics

Treatment is indicated for those with symptoms, high tumour burden or evidence of end-organ damage, such as lytic lesions or fractures, anaemia or renal failure. Components of treatment include chemotherapy, radiotherapy and bisphosphonates. Management of myeloma is also complex and rapidly changing—the past 15 years or so have seen the introduction of autologous stem cell transplantation, thalidomide, bortezomib and lenalidomide, all effective and capable of improving survival.⁴¹ Thus, for many, myeloma can be brought into remission for periods lasting several years at a time between lines of therapy and a more optimistic message can and should be given to myeloma patients. Oral or IV bisphosphonate therapy reduces bony adverse events by some 40%; recently, a rare complication, osteonecrosis of the jaw, has been recognised.⁴²

INTEGRATIVE MANAGEMENT OF BLOOD CANCERS

The GP has a responsibility to be well informed about the adjunctive treatments that may be of benefit to patients in alleviating side effects of cancer treatments and enhancing the patient’s ability to cope with the disease and its treatment. There is also a valuable role for adjunctive therapies in rehabilitation after treatment with surgery, chemotherapy or radiotherapy (see Ch 24, Cancer).

Surveys in all developed countries consistently report that around 80% of cancer patients turn to complementary and alternative medicine (CAM). Ignoring this is dangerous (the risk of herb–drug interactions) and, at worst, humiliating for patients, who are, after all, trying to be proactive about their health.

Cancer patients have traditionally been advised by medical experts to stay away from the many self-cures, unproven remedies, fad diets and dietary supplements, sometimes but not always for good reason. These are a vulnerable patient group, and unfounded, frequently expensive, promises of cure are all too seductive. Moreover, many cancer patients will be deluged with well-meaning advice, and need help to react appropriately.

Encouraging the patient to develop a personal approach to their illness can be very empowering for them, and can improve compliance with mainstream treatment.⁴³ The patient must be involved in treatment and have the chance to buy into the therapeutic decisions, rather than having assumptions made and choice removed. There is good (level 2) evidence that lifestyle interventions can alleviate or reduce cancer symptoms and treatment side effects. This has recently been reviewed.⁴⁴ A number of these interventions are now discussed here.

Lifestyle

Exercise

Perhaps the best single lifestyle intervention before, during and after cancer is exercise. It has been shown to have primary cancer preventive effect in the Californian teachers’ study, in which women who exercised (very hard, it must be said) reduced their breast cancer risk by 20%.⁴⁵ Secondary cancer preventive benefit has been suggested in the setting of colorectal cancer,^46,⁴⁷ breast cancer and prostate cancer. Exercise promotes immune cell function and changes circulating white cell and lymphocyte subsets. Chemotherapy causes muscle catabolism and widespread loss of muscle mass; this may be potentiated by steroid myopathy. Resistance training in various muscle groups is more likely to help retain muscle mass, and reduce fatigue, than is mild aerobic exercise such as walking.⁴⁸ High-intensity exercise is inappropriate, if not impossible, during chemotherapy, and a rough rule of thumb is: never exercise so hard that you can’t complete a sentence.