Diseases of the blood and associated tissues are common both in community and hospital practice. They produce a remarkably diverse range of symptoms and signs. This heterogeneity is explained by the large number of different ways in which blood may malfunction and result in disease. Most simply, an individual may have a shortage of normal blood cells. The commonest of all haematological syndromes, anaemia, arises from a lack of normal circulating red cells. Underproduction or excessive destruction of white cells (leucopenia) or platelets (thrombocytopenia) also causes distinctive groups of symptoms and physical findings. Conversely, pathological overproduction of cells occurs in the myeloproliferative disorders.

Well-regulated haemostasis is crucial for health and both inadequate coagulation, such as in the inherited disorder haemophilia, and excessive coagulation, as occurs in thrombophilia, can have drastic consequences such as haemorrhage and thrombosis. Much of the clinical haematologist’s time is spent in managing malignant diseases of the bone marrow and lymphoid system, and these cancers have their own features. Leukaemias tend to lead to symptoms and signs because of the shortage of normal blood cells whereas lymphomas more often present with the consequences of direct tissue invasion, most commonly enlarged lymph nodes (lymphadenopathy). Both symptoms and signs may be produced by indirect mechanisms. In the malignant disease of plasma cells, myeloma, bone pain and fractures occur because of the secretion of tissue-damaging cytokines by the tumour cells.

A patient may have an isolated blood abnormality causing a predictable clinical presentation but, equally, they may have complex combinations of mechanisms. Patients with certain subtypes of acute myeloid leukaemia often have a shortage of all normal blood cells (pancytopenia) and a failure of haemostasis. Many patients with lymphoma have bone marrow infiltration by the tumour cells causing the symptoms and signs of blood cytopenia in addition to lymphadenopathy. It is important to understand not only the basic connection between blood abnormalities and clinical symptoms and signs (e.g. for anaemia) but also the characteristic clinical patterns of the major diseases of the blood (e.g. anaemia and bone pain in myeloma or anaemia and neurological signs in severe vitamin B12 deficiency).

The ‘haematological system’ can also become deranged in a very large number of non-blood disorders: an appreciation of this fact is important to properly interpret the symptoms and signs that result. The patient with iron deficiency anaemia may well present only with the symptoms of anaemia. Here, the diagnosis of anaemia is only the start, as a search for the underlying cause is crucial. If iron deficiency is confirmed with an appropriate laboratory test, then an exhaustive systemic enquiry and clinical examination is essential to elicit an occult site of bleeding. In this context, even the absence of clinical symptoms and signs of gastrointestinal pathology may not avoid the need for invasive investigation such as endoscopy. This scenario is a reminder that an understanding of the clinical presentation of the common abnormalities of the blood is necessary for general practice and is not confined to the management of rare blood diseases. The clinician who has grasped the significance of the symptoms and signs of iron deficiency anaemia is more likely to make the early diagnosis of otherwise asymptomatic colonic cancer.

One of the rewards of the practice of clinical haematology is the merging of the consulting room and the laboratory. Blood abnormalities first suspected during history taking and examination can be promptly confirmed with a relevant blood test, perhaps a full blood count or a coagulation screen. This chapter addresses the proper interviewing and physical examination of the patient but the role of careful selection of laboratory tests based on accurate clinical findings cannot be underestimated.




Presenting complaint



Anaemia is simply defined as a haemoglobin level below the accepted normal range. It is the commonest of all clinically significant blood abnormalities and has a large number of possible causes (Fig. 17.1). Symptoms result from the blood’s reduced oxygen carrying capacity leading to tissue hypoxia and the body’s attempts to compensate for this. Patients complain of fatigue and shortness of breath on exertion; the latter symptom may be ascribed to incipient cardiorespiratory failure. Cardiac overactivity causes palpitations and some also complain of tinnitus, dizziness and faintness. Other features include feelings of irritability, restlessness and insomnia. Severe anaemia will eventually lead to alarming symptoms such as dyspnoea at rest, syncope and visual disturbances.

In practice, the severity of symptoms is not only determined by the haemoglobin level. The rapid onset of anaemia will cause more profound upset than its insidious development where the affected person has more time to compensate physiologically and to adjust their lifestyle. Patients who are elderly or frail or who have co-existent heart disease are more vulnerable to the effects of anaemia. The exacerbation of angina is a concerning development.



There are five different types of white cell in the blood but in clinical practice, the two most significant forms of leucopenia are neutropenia and lymphopenia. These may be isolated or they may co-exist.

Neutrophils are phagocytes: they engulf and destroy foreign material and damaged cells. A shortage of neutrophils (neutropenia) may arise from underproduction or excess destruction. Whatever the mechanism, patients are at risk of infection and other insults. The likelihood of infection can be predicted by the degree of fall in the neutrophil count. Significant bacterial infections are commonly caused by Gram Positive cocci and also Gram-negative bacilli such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella and Proteus. Patients may present with fulminant life-threatening infection but early symptoms of neutropenic sepsis can be surprisingly subtle.

Lymphocytes are also essential for normal immunity:

  • B lymphocytes produce antibodies against a particular antigen (humoral immunity)
  • T lymphocytes interact with antigen-presenting cells in the genesis of the ‘cell-mediated response’.




In patients known to be at risk of neutropenia − this would include those on drugs known to be associated with agranulocytosis − complaints of general malaise or a persistent sore throat or mouth ulceration should prompt urgent investigation.


A shortage of lymphocytes (lymphopenia) can occur in various malignancies (e.g. lymphoma), in immune deficiency disorders (e.g. human immunodeficiency virus (HIV) infection) or associated with drug treatment or trauma. Patients with reduced humoral immunity, which can be quantitated by measuring immunoglobulin levels, often present with bacterial infections of the respiratory system, skin and urinary tract. Severe T cell depletion potentially leads to numerous unusual opportunistic infections, including those cause by viruses, fungi and Pneumocystis. Rather as with neutropenia, patients with lymphopenia may present with alarming symptoms of fulminant infection or with surprisingly low grade features. Vigilance is needed: in a patient with abnormal cell-mediated immunity, exertional dyspnoea may be the first sign of life-threatening Pneumocystis or cytomegalovirus-associated pneumonia.


Platelets are vital for normal haemostasis. Where there is either a reduced number of platelets (thrombocytopenia) or abnormal platelet function, there is the possibility of a haemorrhagic tendency. Characteristic symptoms include easy bruising and bleeding. There may be heavy periods (menorrhagia), nose bleeds (epistaxes), gum bleeding and excessive blood loss following dental extractions or other surgery. Bleeding from the gastrointestinal or urinary tract may occur but, even in severe thrombocytopenia, this is unusual in the absence of other pathology. Thankfully, cerebral haemorrhage is also a rare event but it must be considered in patients with low platelets who complain of headache or other neurological symptoms. The pattern of bleeding in platelet disorders is distinct from that seen in ‘coagulation disorders’.

Failure of coagulation

Formation of a normal clot depends not only on platelets but also on a coagulation component in which a fibrin scaffold (thrombus) is constructed around the platelet plug. Any deficiency in the ‘coagulation cascade’ − for instance, the deficiency of a single vital coagulation factor, as occurs in haemophilia − will lead to a tendency to bleed. Unlike thrombocytopenia, where oozing into skin and mucous membranes is the predominant problem, patients with abnormal coagulation are more likely to bleed spontaneously into joints (to form a haemarthrosis) and into muscles. They complain of local pain and loss of function. In some inherited or acquired bleeding disorders (e.g. von Willebrand’s disease or severe liver disease) there are deficiencies of both platelets and the coagulation cascade, and so there is a full range of haemorrhagic symptoms.


The clinical term ‘thrombophilia’ means a predisposition to thrombosis because of an enhanced coagulation mechanism. Many forms of the disease are inherited (e.g. factor V Leiden mutation) and venous thrombosis is the major risk. Affected people have an increased chance of deep vein thrombosis with the typical complaints of lower limb swelling and pain or associated pulmonary embolus. Thrombus may form in unusual sites: unilateral arm swelling suggests axillary vein occlusion. In acquired thrombophilia (e.g. antiphospholipid antibody syndrome) arterial thrombosis can also be a significant factor and patients present with the protean symptoms of myocardial or cerebral infarction.

Haematological malignancy

Haematological malignancy can lead to a very wide range of disease symptoms. Some of the commoner presenting symptoms may be divided into local and systemic subtypes.

Local symptoms

Patients with lymphoma often present with enlarging, non-tender lumps in the neck, axillae and groins because of infiltration of peripheral lymph nodes. Less commonly, bulky mediastinal or intra-abdominal nodes lead to local compression and respiratory and gastrointestinal symptoms. Oddly, pain is a relatively late manifestation of lymphoma. Similar symptoms may be experienced in chronic lymphocytic leukaemia. A large spleen, seen in both lymphoproliferative and myeloproliferative disorders, leads to a dragging uncomfortable sensation in the left abdomen and, if there is peri-capsular inflammation, a sharp localized pain exacerbated by movement and inspiration.

The characteristic presentation of myeloma is bone pain. This is often in the back − its relentless nature helps to differentiate it from the much more common pain of spinal degenerative disease. Rib pain is another clue. Symptoms such as paraesthesiae and loss of lower limb and bladder function are likely to herald spinal cord compression. Acute leukaemias present more with symptoms of bone marrow failure, those attributable to anaemia, leucopenia and thrombocytopenia, than with symptoms of local infiltration; however, sometimes, particularly in acute lymphoblastic leukaemia, patients experience pain. Neurological symptoms, also more common in the lymphoblastic form, are frequently a sign of central nervous system dissemination.

Systemic symptoms

Lymphomas that are disseminated at presentation are frequently associated with ‘systemic symptoms’ such as weight loss, night sweats and pyrexia. These have prognostic significance and, once properly documented, are included in the staging system as ‘B symptoms’. Their severity is highly variable. Patients with advanced Hodgkin’s lymphoma are prone to night sweats, which may be severe enough to drench the nightclothes and sheets. Fatigue and pruritus may also occur. These malignant disorders are themselves forms of acquired immunodeficiency and recurrent infection is a common finding.

Chemotherapy may limit the disease but will tend to further compromise the immune response. In myeloma and Waldenstrom’s macroglobulinaemia high levels of serum monoclonal proteins secreted by the malignant cells (paraproteins) can potentially lead to ‘hyperviscosity syndrome’, with confusion and neurological symptoms.




Duration of symptoms

In general, those who have symptoms of recent onset are likely to have acquired disorders whereas a lifelong history suggests the possibility of an inherited disorder. This is especially pertinent in patients with a history of easy bruising or bleeding. An inherited disease such as haemophilia is far more likely to cause symptoms from the first year of life than an acquired bleeding tendency such as immune thrombocytopenia (ITP).

History of surgery or trauma

Diagnostic clues may be derived from the patient’s response to surgery or trauma. A past history of surgery with a quick recovery suggests a more recent onset of a significant blood abnormality or haematological disorder. In contrast, repeated excessive bleeding following dental extractions or other surgery is consistent with a lifelong bleeding disorder, possibly an inherited disease.

Drug history

It is difficult to exaggerate the importance of a thorough drug history in patients with suspected haematological disease. Many drugs are implicated in abnormalities of the blood such as:

  • autoimmune haemolytic anaemia – e.g. cephalosporins, penicillins
  • neutropenia – agranulocytosis, e.g. phenothiazines, sulphonamides
  • thrombocytopenia – e.g. quinine, thiazide diuretics.

Bone marrow failure with pancytopenia may occur idiosyncratically (e.g. chloramphenicol) or predictably following cytotoxic chemotherapy. Often the situation is complicated as the patient is on multiple agents, several of which may be causative. Here it is helpful to take an exhaustive history of the temporal relationship of the medication to the blood abnormality − if a low platelet count preceded the commencement of a thiazide diuretic then the drug is unlikely to be the culprit.

It is also obligatory to take a history of drug allergies. Patients with a complex haematological disorder such as leukaemia or lymphoma will inevitably become exposed to many drugs. Whenever there is doubt as to a patient’s medication, it is well worth retaking the history with the tablets to hand. Confused, elderly patients are unlikely to be able to spontaneously recall an elaborate list of 10–20 different drugs.



It is vital to spot a drug-related blood abnormality as prompt cessation of the offending agent usually leads to complete resolution of the symptoms, whereas a failure to make the connection and continuation of the drug may have serious consequences (e.g. septicaemia arising from agranulocytosis).


Family history

Many types of blood disorders are inherited and a family history is a key part of the diagnostic process. The presence of the disease in other family members may be elicited by a simple question but to gain a clear understanding the family tree must be documented to gain an appreciation of the likely mode of inheritance of the disorder. A few of the commoner inherited disorders in haematological practice are listed in Box 17.1.


Red cell disorders:

  • disorders of the membrane – hereditary spherocytosis and elliptocytosis
  • disorders of haemoglobin – sickle cell anaemia and thalassaemia
  • disorders of metabolism – pyruvate kinase and glucose 6-phosphate deficiencies.

Coagulation disorders:

  • factor deficiency – haemophilia A and B
  • combined factor and platelet deficiency – von Willebrand’s disease
  • platelet dysfunction – Bernard-Soulier syndrome (rare)

White cell disorders: rare functional disorders such as chronic granulomatous disease.

β-Thalassaemia is an inherited disorder of red cells. It is an autosomal recessive disorder characterized by reduced or absent production of β haemoglobin chains; the heterozygous (trait or minor) form is usually symptomless whilst the homozygous form leads to the clinically significant disease ‘β-thalassaemia major’,in which the patient develops symptoms of anaemia early in life. It is not always so straightforward.

In hereditary spherocytosis an abnormal red cell membrane leads to haemolysis and possible anaemia. There are many possible causative gene mutations and, accordingly, a variable mode of inheritance. It is important to appreciate this heterogeneity when taking the family history in an affected patient.

A number of coagulation disorders are also inherited. In haemophilia A and B (caused by a short age of clotting factors VIII and IX, respectively) the inheritance is X-linked recessive. Briefly:

  • all males with the abnormal gene have haemophilia
  • all sons of haemophiliac fathers are unaffected
  • all daughters are obligatory carriers
  • daughters of female carriers have a 50 per cent

chance of being themselves carriers.

The commonest inherited coagulation disorder, von Willebrand’s disease, is more complicated, with most but not all forms having autosomal dominant inheritance.

The few examples described above emphasize that a well-taken family history requires not only a methodical approach but also a thorough understanding of the genetics of the implicated disease. Note also that ethnic origin and geography are relevant factors. A child from an African Caribbean background is much more likely to present with sickle cell anaemia than a Caucasian child, whereas the converse is true of iron deficiency caused by coeliac disease. Disorders such as thalassaemia are much more common in particular parts of the world.

Lifestyle and social history

A social history is important to understand the causation of blood abnormalities or disease and to allow the optimal management of the patient. Some blood changes are directly related to the patient’s lifestyle. Heavy smoking may contribute to polycythaemia, poor diet can cause anaemia because of deficiency of iron or folate, and excess alcohol consumption leads to myriad blood abnormalities including macrocytosis, thrombocytopenia and disordered coagulation.

People with chronic and serious blood diseases want to lead as normal a life as possible. A proper history should lead to an understanding of the individual’s support structure and situation outside the hospital clinic and ward. Children with inherited disease such as thalassaemia can easily fall behind at school. The whole family is likely to be under strain; adults may suffer unemployment, financial difficulties and social isolation.



An appreciation of all issues surrounding a patient, including their social history, allows a more holistic view of the person’s medical care and maximizes their chance of a timely return to normality.


Occupational history

Occupational exposure to benzene or other solvents leads to an increased risk of leukaemia. Similarly, studies have suggested links between various occupations such as agricultural work (and presumed exposure to pesticides) or hairdressing (with exposure to chemical dyes) and lymphoma. In practice, connections of this kind are nearly always conjectural and it is difficult to prove a causative effect in individual people.

Travel history

Symptoms caused by an enlarged spleen will carry an entirely different differential diagnosis if the patient has recently returned from an area where malaria and other tropical infectious diseases are commonplace. The incidence of HIV infection, a disease often associated with blood abnormalities, also fluctuates widely around the world. Patients may not think to offer travel information spontaneously so the question must be asked.

Systems review

This is vital as diseases of non-haematopoietic organs may contribute to blood abnormalities and complicate the investigation and treatment of primary blood diseases. Much time can be wasted searching for a haematological cause of anaemia if previously ignored symptoms of chronic gastrointestinal bleeding are not discovered as part of the systems review. In patients with haematological malignancies such as lymphoma, the presence of unexpected symptoms such as headache or loss of peripheral sensation may reflect extranodal infiltration by disease or side effects of chemotherapy drugs (e.g. neuropathy caused by vincristine). A systematic check for cardiorespiratory symptoms is obligatory to detect significant heart or lung disease which might be exacerbated by intensive chemotherapy treatment. In people presenting with a high haematocrit (polycythaemia) or a high platelet count (thrombocytosis) a systemic enquiry is necessary to exclude secondary causes such as hypoxia and infection before a diagnosis of a myeloproliferative disorder is seriously considered. Where the patient is debilitated it is helpful to formally record this using an accepted scoring system such as the Eastern Cooperative Oncology Group (ECOG) system (Table 17.1) or Karnofsky’s (Table 17.2) scales. Document the score, together with other objective measures such as height and weight, and use this to monitor general state or to assess suitability for chemotherapy or other treatments.





Before describing the signs associated with particular haematological syndromes, the importance of initial careful inspection of the patient must be stressed. Many key signs are readily detectable on observation alone and the inexperienced or over-eager examiner can all too easily miss them in his or her enthusiasm to palpate and percuss.



The examination findings can be divided into those potentially found in all patients with significant anaemia (‘general’) and those connected with particular aetiologies (‘specific’).



General findings

The most well known sign of anaemia is pallor of the skin. This is not caused by ‘thinning’ of the blood but by reduced peripheral blood flow. This pallor may be better appreciated by close inspection of the conjunctivae, nail beds, and palmar creases. It is an insensitive sign.

As anaemia becomes more marked, the clinical findings can be explained in terms of a variable degree of cardiopulmonary compensation. Patients are usually comfortable at rest but may become visibly dyspnoeic on minimal exertion. The ‘hyperkinetic’ circulatory response leads to tachycardia, increased arterial pulsation and cardiac flow murmurs.

In severe anaemia there may be frank cardiac failure with the characteristic cardiomegaly, basal inspiratory crepitations in the lungs, and lower limb oedema. Very low haemoglobin levels can be associated with papilloedema and retinal haemorrhages (Fig. 17.2). Anaemia may cause a fever but in practice this is more often a feature of an underlying cause (e.g. malignancy) or a co-existent disorder.



More severe anaemia may cause a systolic flow murmur. This functional murmur must be differentiated from the systolic murmurs of valvular heart disease.


Specific findings

An initial careful inspection of the skin, nails and mouth often reveals diagnostic clues. In severe iron deficiency, the general signs of anaemia may be accompanied by glossitis and angular stomatitis. Because of thinning of the epithelium the tongue can appear dark red in contrast to the facial pallor. If iron deficiency is prolonged it may become smooth and shrunken. The painful red fissures of angular stomatitis appear at the corners of the mouth which may be generally sore. A highly characteristic, but rare, feature of longstanding iron deficiency is koilonychia, in which the nails become concave or ‘spooned’. More commonly, and less dramatically, the nails are brittle and ridged.

As epithelial abnormalities also occur in megaloblastic anaemia, simple inspection also reaps rewards in this disorder. In vitamin B12 deficiency due to pernicious anaemia, the tongue is typically red, smooth and shiny. More profound epithelial dysfunction leads to the neurological signs of subacute combined degeneration of the cord (see also later) whereas the presence of vitiligo is a reminder of the autoimmune nature of the disease.

Haemolytic anaemias may present with jaundice rather than pallor. The accelerated catabolism of haemoglobin releases increased amounts of bilirubin into the plasma. Where the spleen is the site of red cell destruction, it may be palpable. If there is chronic haemolysis in childhood, for instance in the haemoglobinopathies, then expansion of the marrow cavity leads to skeletal abnormalities including frontal bossing of the skull.

Numerous further examples could be quoted − the anaemia of chronic disease may be associated with any of the signs of the innumerable systemic diseases which cause it − but the core message is that careful examination of the anaemic patient can elucidate not only the signs of anaemia itself but also of the underlying cause.


Perhaps the most important sign associated with neutropenia is pyrexia. In the context of severe neutropenia, it usually has to be assumed that the pyrexia is due to infection and not other aetiologies such as malignancy or a drug reaction. A raised temperature is often the only outward sign of a potentially fulminant infection.

Many people with life-threatening neutropenic sepsis have no signs to indicate the primary focus. Because of the lack of normal neutrophils, classical signs of inflammation are frequently absent, making the diagnosis of infection more difficult than usual. Pneumonia may not be accompanied by the classic signs of consolidation and cellulitis may not lead to the usual degree of tenderness and pain. A thorough systemic examination is obligatory as signs are easily overlooked. Extensively search the skin, including the perineal and perianal regions.



Skin infections cause heterogeneous clinical signs; when in doubt seek an expert dermatological opinion.


The mouth is a common focus of infection in neutropenia. Common findings are the mucosal atrophy and plaques of Candida, and ulcers. Neutropenic ulcers are typically yellowish in appearance with regular margins. They may be single or multiple, are not easily removed from the mucosa, and are often painful. Experience is required to reliably differentiate them from other common causes of mouth ulcers in immunosuppressed patients (drug-induced mucositis, aphthous ulcers, herpetic ulcers). Examination of the neutropenic patient is completed with a careful review of all other systems in turn, with particular reference to the possibility of infection. In this situation, regular examination for new signs is vital; the appearance of a previously unheard murmur may be the only clue to the presence of endocarditis.

In lymphopenia, many of the same considerations apply. Undertake examination with knowledge of the likely complicating infections and their characteristic signs. Again, these signs can be surprisingly subtle. In patients presenting with impaired cell-mediated immunity and life-threatening Pneumocystis jirovecii (carinii) pneumonia, up to half will have no abnormal signs on auscultation of the lungs. The development of marked tachypnoea (and hypoxia) on minimal exertion is usually the main diagnostic feature.


Minor reductions in platelet count frequently cause no clinical signs but more significant falls (e.g. to less than 50 × 109/L) usually present as bleeding into the skin (purpura). In general, signs (and symptoms) are more pronounced at any given platelet count where there is reduced platelet production (e.g. in leukaemia) than where there is excessive platelet destruction (e.g. in immune thrombocytopenia).

Thrombocytopenia is a cause of an increase in bruising (ecchymoses). Ecchymoses are easily recognized on routine examination and inspection is usefully accompanied by an enquiry as to the degree of trauma (if any) that produced them. Ecchymoses can be quite persistent and usually undergo a series of colour changes from blue to green and then to yellow and brown as the extravasated blood is degraded. It is sometimes difficult to be certain when bruising is pathological − a scattering of small bruises may be normal in an active child or an athletic adult.

If platelet counts are at very low levels, petechiae appear. These are small reddish blue spots (1−3 mm in diameter) which often occur suddenly in the skin in crops (Fig. 17.3). They may arise anywhere on the body but are often found on dependent areas, particularly the shins. Petechiae are usually less persistent than ecchymoses, tending to disappear within a few days. Because they are composed of extravasated blood they do not fade on pressure. Where these skin signs suggest thrombocytopenia, a careful inspection of the mouth, conjunctivae, and retinas is essential to detect mucosal haemorrhage. In very severe thrombocytopenia, bleeding can be profound leading to haemorrhagic bullae in the skin, blood blisters in the mouth and extensive retinal haemorrhage with reduced visual acuity. The presence of neurological signs is ominous as it suggests a significant intra-cerebral bleed.



Coagulation failure

The signs associated with a pure failure of coagulation (e.g. a deficiency of coagulation factor(s)) are best understood by describing the findings in severe haemophilia. Here, patients have a pattern of bleeding quite different from that described in thrombocytopenia. Bruising may be increased but the chief characteristics of the disease are acute bleeds into joints and muscles with lifelong sequelae. Fortunately, in the modern era, patients receive optimal prophylactic factor replacement regimens and bleeds are much less frequent and severe chronic joint disease is rare. An acute joint bleed (haemarthrosis) presents as a swollen, tender joint with restriction of movement. The skin is warm to the touch. The knees are most often affected, followed by the elbows, ankles, shoulders, wrists and hips. In the absence of optimal treatment, the affected joints of haemophiliac patients become irretrievably damaged with permanent swelling, fixed deformities and associated muscle wasting (Fig. 17.4).



Bleeding into muscles causes both local pain and swelling with eventual discoloration of the skin as the blood drains to the surface. If bleeds into large muscles remain untreated, the compression of adjacent nerves, blood vessels and lymphatics may result. For instance, a bleed into the iliopsoas muscle can compress the femoral nerve, leading to fixed flexion at the hip and sensory loss on the outside of the thigh. In extreme cases, there is wasting of the quadriceps muscle. Chronic muscle bleeding, now rare in developed countries, is a cause of ‘pseudotumours’, which have the potential to track through surrounding tissues including the skin.

Cerebral bleeding is also rare but the finding of papilloedema or other unexplained neurological signs should alert you to this possibility. The related disorder ‘acquired haemophilia’ is caused by an acquired antibody against a coagulation factor (generally factor VIII) and is usually seen in the last decades of life. The diagnosis should especially be considered where very extensive bruising develops for no apparent reason in the presence of a normal platelet count (Fig. 17.5).



The signs relating to thrombocytopenia and coagulation failure have been discussed separately for convenience but patients may have a more general failure of normal haemostasis with features of both platelet lack or loss of function and also coagulation deficiency (e.g. in severe von Willebrand’s disease, following massive transfusion, or in liver failure).


Thrombophilia is a haematological disorder whose physical signs commonly arise from a prothrombotic tendency (i.e. the associated deep vein thrombosis or pulmonary embolism). Patients with thrombophilia may have thrombosis at unusual sites.


Haematological malignancies lead to a protean range of clinical signs and these will be discussed in the disease-orientated section later. At this stage, we will review the examination findings in three specific situations that are ‘haematological emergencies’.

Superior Vena Cava Obstruction

Hodgkin’s and non-Hodgkin’s lymphomas are second only to lung cancer as a cause of superior vena cava obstruction as bulky mediastinal lymphadenopathy is common in these disorders. The mediastinal mass compresses the superior vena cava and the characteristic examination findings, all arising from obstruction of venous return, include plethora and oedema of the face and upper extremities, increased jugular venous pressure and visible dilatation of the collateral veins of the upper thorax and neck. The patient may have a hoarse voice or even stridor.



Spinal cord compression

Myeloma is commonly complicated by spinal cord compression either secondary to vertebral destruction or because of a localized tumour of plasma cells (plasmacytoma). Once suggestive symptoms (e.g. lower limb paraesthesia, urinary difficulty) are reported, an urgent examination will reveal the diagnostic signs. Definitive signs usually appear within a week or so of the symptoms and include loss of sensation below the neurological lesion (sensory level), upper motor neurone weakness in the legs (spastic paraparesis) and loss of sphincter control.

Hyperviscosity syndrome

This may complicate myeloma or, more commonly the IgM-secreting indolent lymphoma termed Waldenström’s macroglobulinaemia. High serum monoclonal protein (paraprotein) levels significantly increase blood viscosity which in turn may lead to visual disturbance, heart failure and neurological symptoms. The classic signs of hyperviscosity are found in the fundus (distended veins, exudates, haemorrhages and blurring of the optic disc) highlighting the need for routine retinal inspection in patients with haematological disease.


Particular examination skills


Examination of the lymph nodes

Enlargement of lymph nodes is referred to as lymphadenopathy or just adenopathy. A wide range of haematological and systemic disorders may lead to lymphadenopathy (Box. 17.2). In clinical practice, examination is usually limited to the peripheral nodes in the cervical, axillary and inguinal regions although, on occasions, bulky intra-abdominal lymphadenopathy may be palpated as an abdominal mass. Optimal examination requires knowledge both of the possible causes of adenopathy and the normal anatomy and drainage of lymph glands.




  • local infection
  • lymphoma
  • metastatic malignancy.


  • systemic infection
  • lymphoma
  • disseminated malignancy
  • other haematological malignancies (e.g. leukaemia)
  • inflammatory disorders (e.g. sarcoidosis, connective tissue disorders).


Examination of the cervical nodes (Fig. 17.6) is most easily performed standing behind the seated patient. After initial examination, nodes may be visible (Fig. 17.7) − each of the anatomical groups is methodically examined on each side. This systematic approach is necessary as it is easy to miss a solitary enlarged node, particularly the supraclavicular nodes lodged behind the clavicle. It is important for the patient to be entirely comfortable to relax the surrounding muscles.




Where an enlarged node is discovered, document its nature in terms of:

  • location
  • size (two dimensions)
  • shape
  • consistency
  • presence/absence of tenderness.

Reactive nodes (e.g. enlarged secondary to infection) are often tender whereas lymphoma infiltrated nodes are classically rubbery and carcinoma infiltrated nodes stony hard but these findings are not consistent.

The detection of cervical lymphadenopathy should lead on to a careful examination of potential drainage sites. A head and neck examination may be usefully supplemented by a specialist ENT referral. A solitary enlarged supraclavicular node can be a sinister sign of metastatic spread from a lung or gastric carcinoma.

The best technique for examining the axillary nodes is illustrated in Figure 17.8. Lie the patient on a couch and support the flexed arm while gently but firmly examining the right axilla with your left hand and the left axilla with your right hand. The nodes are divided into medial, lateral, posterior, central and apical groups. The same methodical approach is adopted as described for the cervical nodes. Inguinal nodes are best examined as part of the abdominal review. The differential diagnosis of a lump in the groin includes hernias and it is helpful to appreciate their features (described elsewhere) as they may be confused with a nodal mass.

The finding of a palpable node or nodes in any of these areas does not necessarily indicate disease. A few small nodes (e.g. up to 0.5 cm) may be felt in a normal neck, particularly in children and younger adults. The tonsillar node at the angle of the mandible may be a little larger. Small incidental nodes in the axillae and inguinal regions are also commonplace. There is no substitute for experience in differentiating small harmless nodes from pathological adenopathy but, in practice, this may be difficult even for the most seasoned examiner. Where there is doubt, a short period of observation may be in order, but if the nodes persist or enlarge then a surgical biopsy is likely to be required.



Examination of the spleen

The spleen is frequently enlarged in blood disorders and in certain systemic diseases (Box 17.3). A normal spleen is not palpable. Examination of the spleen is often performed badly and it is easy to miss both slight splenomegaly and massive enlargement of the organ where it extends across the abdomen into the right iliac fossa. Careful and informed examination will avoid such mistakes.


BOX 17.3 COMMON CAUSES OF SPLENOMEGALY G Acute and chronic infections (e.g. septicaemia, tuberculosis)

  • Haemolytic anaemia
  • Infectious mononucleosis
  • Portal hypertension
  • Myelofibrosis*
  • Chronic myeloid leukaemia*
  • Polycythaemia vera*
  • Lymphoma 
  • Malaria*
  • Leishmaniasis*

*May be massive enlargement.


It is essential for the patient to be warm and comfortable and to have confidence in the examiner. First, inspect the abdomen for masses and then enquire regarding the presence of tenderness. Kneel by the bed and, with your forearm horizontal to the abdomen, palpate each sector prior to examination of the major organs. The abnormal spleen enlarges from behind the tenth rib in a line running diagonally across the abdomen through the umbilicus (Fig. 17.9). Commence palpation in the right iliac fossa to avoid missing massive enlargement and gradually move your hand in stages towards the tenth rib while the patient takes deep breaths.



An enlarged spleen will be felt by the tips of the fingers during deep inspiration. The organ has a notch but, in practice, this is rarely detected. If splenomegaly is suspected but the spleen is not palpable using this technique then it is worth rolling the patient half onto their right side with your left hand supporting the left lower ribs − in this position, a slightly enlarged spleen may be moved forward so the tip becomes just palpable (‘tippable’: Fig. 17.10). Some examiners find it helpful to hold their left hand under the left lower ribs during routine examination.



An enlarged spleen is most likely to be confused with an enlarged left kidney. The spleen has a number of characteristics which should allow it to be definitively identified:

  • the spleen has a distinctive shape
  • it is impossible to get above the spleen
  • the spleen moves with respiration
  • the spleen is dull to percussion
  • the spleen cannot be felt bimanually or ballotted.

The enlarged left kidney, in contrast, is not dull to percussion (it is covered by the colon) and it can be felt bimanually and can be ballotted. It is worth auscultating an enlarged spleen as there may be a ‘splenic rub’ signifying inflammation of the capsule. It is not usually possible to diagnose the cause of splenomegaly by simple examination of the organ, although the degree of enlargement does give a clue, particularly where this is massive.



A thorough history and careful physical examination allied to logical selection and interpretation of laboratory tests are essential for the accurate diagnosis of blood disorders. Radiological procedures also play a vital role but, in the interests of space, only laboratory investigations will be considered.

Basic techniques for examination of the blood and bone marrow

Most blood disorders are characterized by an abnormality in the blood count (or full blood count). This test is performed on a small sample of venous blood anticoagulated in ethylenediaminetetraacetic acid. A typical blood count report contains a large amount of numerical information and it is therefore useful to adopt a systematic approach to interpretation.

The three most important measurements are the:

  • haemoglobin level
  • total white cell count
  • platelet count.

Further numerical data pertain to red cell number, size, and haemoglobinization (all useful in the diagnosis of anaemia) and a differential white cell count (relative numbers of neutrophils, lymphocytes, etc.). The latter information is used in the diagnosis of primary disorders of white cells (e.g. leukaemia) and also insystemicdisorderswherenumericalabnormalitiesof white cells (e.g. neutrophil leucocytosis) are common.

The blood count is generated by an automated analyser; where significant abnormalities are detected, a blood film may be microscopically examined by a trained observer. Blood film morphology has its own complex nomenclature − when a report is obscure, it is worth contacting the laboratory to discuss the findings. Laboratory equipment is not faultless and aberrant results are relatively common. For instance, if a very low platelet count is not associated with typical symptoms and signs then it is worth repeating the sample and asking for a blood film to exclude either a clot in the original sample or ‘clumping’ of platelets in the anticoagulant.

When the cause of a blood abnormality remains unclear then the bone marrow may be examined. A bone marrow aspirate and trephine biopsy are obtained from the posterior iliac crest by a trained operator. The two samples are complementary. The liquid aspirate sample is better for the assessment of individual cell morphology while the solid biopsy allows assessment of marrow architecture and the detection of low level infiltration by malignant disease.

The start point in the investigation of bleeding disorders is the coagulation screen. This usually consists of the prothrombin time (PT), activated partial thromboplastin time (APTT), and quantitation of plasma fibrinogen. Some common causes of an abnormal screen are shown in Table 17.3.



Assessment of the acute phase response is a very useful diagnostic tool in general medicine and in patients with blood disorders. Commonly performed measurements are the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and plasma viscosity − all have their advantages and drawbacks.

Other tests useful in non-malignant disease

  • Haemoglobin electrophoresis: this is useful particularly for the diagnosis of haemoglobinopathies.
  • Reticulocyte count: this is useful in the diagnosis of haemolysis where is it is usually raised.
  • Direct Coombs’ (or antiglobulin) test: this is useful in the diagnosis of autoimmune haemolysis.
  • Estimation of iron (ferritin), vitamin B12 and folate levels: useful in the diagnosis of anaemia.
  • Thrombophilia screen: useful for investigation of a prothrombotic tendency.

Other tests useful in haematological malignancy

  • Immunophenotyping (flow cytometry), cytogenetics, and molecular biology: these are all routinely used in the diagnosis, subclassification and monitoring of haematological malignancy (e.g. leukaemia, lymphoma). Blood and bone marrow samples are routinely examined. Molecular biology techniques (e.g. gene microarrays) are gradually moving from the research laboratory to mainstream clinical practice.
  • Serum and urine electrophoresis: used to detect the monoclonal immunoglobulins and light chains found in myeloma.






Iron deficiency anaemia

In addition to the general symptoms and signs of anaemia there may be more specific symptoms and signs of endothelial cell dysfunction and, more importantly, the underlying cause of deficiency. Iron is required by many different tissues. Chronic deficiency can lead to a sore mouth, glossitis and angular stomatitis. The nails may become brittle, ridged, flattened and even spooned (koilonychia). Dysphagia may result from an oesophageal web (Plummer– Vinson syndrome). Many patients manifest none of these endothelial problems. In children, iron deficiency is a cause of failure to thrive and behavioural problems.



It is crucial to understand the cause of iron deficiency. This may be straightforward (e.g. menorrhagia in an otherwise well young woman) but particularly in men and postmenopausal women there is the possibility of occult gastrointestinal bleeding and a serious pathology such as a colonic tumour. A thorough history of gastrointestinal symptoms and examination of the abdomen, including rectal examination, is necessary.


Megaloblastic anaemia

This is essentially caused by deficiency of vitamin B and/or folate. The most distinctive vitamin B12 deficiency syndrome is pernicious anaemia, a familial autoimmune disorder where the basic abnormalities are gastric parietal cell atrophy, general epithelial cell atrophy and megaloblastic anaemia. Patients typically (but not always) have premature greying and blue eyes. Co-existent autoimmune disorders include the skin disorder vitiligo. Because of the combination of pallor and jaundice (due to low grade haemolysis) the skin may have a lemon yellow tint.

Epithelial changes include glossitis − this is typically painful − and the neurological syndrome ‘subacute combined degeneration of the cord’. The latter arises from demyelination of the dorsal and lateral columns. Common early complaints are of numbness and paraesthesiae in the feet. The clinical signs are of posterior column loss (vibration and position senses with possible Rombergism) and of an upper motor neurone lesion with peripheral neuropathy. Chronic vitamin B12 deficiency is also a cause of dementia and optic atrophy. In modern medical practice, vitamin B12 deficiency is often detected at an early stage and these neurological complications are now rarely seen.



Haemolytic anaemia

Haemolytic anaemia is caused by increased destruction of red cells. There is either a disorder of the red cell itself (usually an inherited disorder, e.g. hereditary spherocytosis) or an abnormality extrinsic to the red cells (usually acquired, e.g. autoimmune haemolytic anaemia). Significant haemolysis is characterized both by the symptoms and signs of anaemia and features attributable to the accelerated catabolism of haemoglobin. The latter leads to the release of increased amounts of bilirubin into the plasma and the clinical sign of jaundice.

Consequences of chronic haemolysis include palpable splenomegaly and bilirubin gallstones with possible clinical features of cholelithiasis. In most haemolytic syndromes the red cell destruction is extravascular (in the spleen and/or liver) but on occasion it is intravascular with the dramatic appearance of haemoglobinuria (Fig. 17.11). Specific inherited and acquired haemolytic disorders have their own particular clinical features (e.g. acrocyanosis in cold autoimmune haemolytic anaemia).


Sickle cell anaemia

Sickle cell syndromes are inherited disorders in which there is an abnormal haemoglobin b-chain: red cells ‘sickle’, becoming misshaped with reduced deformability. Sickle cell trait (Hb AS) causes no clinical problems but sickle cell anaemia (Hb SS) is a serious disorder affecting predominantly the African Caribbean population. Anaemia (due to haemolysis) often causes surprisingly few symptoms as HbS releases oxygen more easily than normal HbA.

In vaso-occlusive crises, patients complain of musculoskeletal pain of variable severity often located around the hips, shoulders and spine. The degree of pain may warrant hospital admission and opiate analgesia. Complications are too numerous to detail here but include cerebral infarction and sequestration syndromes − these should be diagnosed and managed by clinicians with experience of the disease. Other possible signs are lower limb ulceration, proliferative retinopathy and glaucoma. Palpable splenomegaly is not usually a feature as the organ is often infarcted.


The thalassaemias are a highly variable group of inherited disorders of haemoglobin synthesis. As for the sickle cell syndromes, there are minor forms (‘traits’) of little clinical significance but also major clinical syndromes. This section will refer only to β-thalassaemia major. Anaemia is due to a combination of ineffective red cell formation and haemolysis. Symptoms appear at around 3–6 months of life as the production of fetal haemoglobin falls away. Children fail to thrive and develop the characteristic signs of skull bossing and maxillary enlargement due to compensatory expansion of the marrow space. If not properly managed, the disease can also lead to repeated infections, bone fractures, and leg ulcers. Regular transfusion is often necessary; the resultant iron overload can damage the liver, endocrine organs and heart.


Disorders of normal haemostasis


Immune Thrombocytopenia (ITP)

ITP is a disease in which there is immune destruction of platelets. The symptoms and signs are those described for thrombocytopenia. Many patients have only modest reductions in platelet count and are asymptomatic. There are two distinct forms of the disease (although with some overlap). The acute form is most common in childhood. There is acute onset of haemorrhagic symptoms and signs but the syndrome is self-limiting and serious complications (e.g. cerebral haemorrhage) are very rare. The chronic form is more often seen in adult life but again serious complications are infrequent and many patients only develop significant symptoms of excess bruising and bleeding at very low platelet counts (e.g. less than 10 × 109/L).


This is an inherited disorder of coagulation. The most common subtypes are the X-linked disorders haemophilia A (deficiency of coagulation factor VIII) and haemophilia B (deficiency of IX). Both types are divisible into mild, moderate and severe forms dependent on the relevant factor level. The joint and muscle bleeds described in the coagulation failure section only affect men with severe disease (factor level less than 2 per cent of normal). Symptoms often first appear when the affected child begins to crawl; the disorder may be confused with non-accidental injury.

von Willebrand’s disease

von Willebrand’s disease (vWD) is the most common inherited bleeding disorder. The inheritance is more complex than for haemophilia with numerous subtypes. von Willebrand factor (vWF) is an adhesive glycoprotein that both promotes platelet adhesion to damaged endothelium and transports and stabilizes factor VIII. In vWD there is a deficiency of normal vWF and, in more serious cases, there are symptoms and signs of both platelet dysfunction and coagulation deficiency. In practice, the most common complaints are of epistaxes, gum bleeding, menorrhagia, and easy bruising. Milder cases may only experience excess bleeding following surgery or trauma. Haemarthroses and muscle bleeds are rare.


Myeloproliferative disorders


Polycythaemia vera and myelofibrosis

Polycythaemia vera must be distinguished from other causes of a raised haematocrit (e.g. secondary polycythaemia); the recent discovery of the JAK2 mutation, found in almost all cases of polycythaemia vera, has greatly facilitated the diagnosis. Affected patients often present with symptoms secondary to the raised red cell mass and total blood volume and associated hyperviscosity, such as:

  • lethargy
  • excess sweating
  • dizziness
  • pruritus (particularly after a hot bath).

There is an increased incidence of arterial and venous thrombosis and, more rarely, a bleeding tendency due to platelet dysfunction. The classic clinical sign is facial plethora (Fig. 17.12) sometimes accompanied by rosacea. The spleen is palpable in a minority of cases.

The essential features of myelofibrosis are bone marrow fibrosis and splenomegaly. The spleen is palpable in almost all cases and massive in around 10 per cent. Hepatomegaly is seen in two-thirds of cases.




Haematological malignancies


Acute leukaemia

Many of the symptoms of acute leukaemia can be explained in terms of the pancytopenia (i.e. anaemia, leucopenia and thrombocytopenia) caused by the infiltration of the bone marrow by leukaemic cells. Specific subtypes of the disease do have additional particular characteristics which will be noted here.

In acute myeloid leukaemia (AML), the acute promyelocytic subtype (FAB M3, t(15;17)) is associated with a life-threatening coagulopathy. Neurological symptoms or signs often indicate intracerebral bleeding. Tissue infiltration (e.g. splenomegaly, skin and gingival infiltration, Fig. 17.13) tends to be more common where there is monocytic morphology (e.g. FAB M5).



In acute lymphoblastic leukaemia (ALL), there is a higher risk of central nervous system involvement than in AML. There may be symptoms and signs of raised intracranial pressure (e.g. headache, vomiting, and papilloedema) or cranial nerve palsies (particularly VI and VIII). The T-ALL subtype is a cause of mediastinal lymphadenopathy and pleural effusion. In males, routinely examine the testes.

Chronic leukaemia

The two types of chronic leukaemia are conveniently discussed together but their biology and clinical features are very different.

In chronic myeloid leukaemia (CML), patients often present in the chronic phase of the disease with symptoms of anaemia accompanied by anorexia and weight loss. Splenomegaly is the most consistent physical finding; this may be massive causing discomfort, bloating and satiety. Very high white cell counts can lead to the symptoms and signs of hyperviscosity syndrome. The chronic phase may transform to ‘blast crisis’ where the features are those of acute leukaemia.

In chronic lymphocytic leukaemia (CLL), the characteristic symptoms are of anaemia, recurrent infections, and weight loss. Lymphadenopathy and hepatosplenomegaly occur but the spleen is rarely massively enlarged. In advanced disease, other tissues such as the gastrointestinal tract and the lungs may become affected. Fortunately, many patients have early stage disease and diagnosis of CLL is often made from a routine blood count in an asymptomatic patient. The same is increasingly true of CML.


The clinical presentation of lymphoma is heterogeneous as the disease may involve any organ in the body containing lymphoid tissue; however, we can make some generalizations.

In classical Hodgkin’s lymphoma, patients usually present with asymmetrical, painless lymphadenopathy. This is most often cervical and, in the nodular sclerosing histological subtype, is frequently associated with a mediastinal nodal mass (a potential cause of superior vena cava obstruction). Nodes may fluctuate in size. Hepatosplenomegaly is common but rarely massive. Systemic symptoms are important in staging and include fever, night sweats and weight loss. The fever may have a cyclical nature (Pel–Ebstein fever).

Non-Hodgkin’s lymphoma is divisible into many subtypes but, in broadest terms, there are aggressive potentially curable forms (e.g. diffuse large B-cell lymphoma) and more indolent forms which are less curable (e.g. follicular lymphoma). Lymphadenopathy is a prominent finding (see Fig. 17.7) but the presentation is more varied than in Hodgkin’s lymphoma with a greater chance of extra-nodal disease (e.g. central nervous system, gastrointestinal tract, skin). Systemic symptoms are often surprisingly absent until advanced disease.


This is a malignant disorder in which there is an uncontrolled proliferation of plasma cells in the bone marrow. Secretion of proteins by the malignant clone leads to organ dysfunction and destruction. Most patients have bone pain at presentation. This often manifests as back pain and is all too easily dismissed. With time, the pain becomes persistent and severe and may be associated with evidence of bone destruction such as pathological fractures or vertebral collapse leading to scoliosis and loss of height. There is a risk of spinal cord compression.

Infiltration of the bone marrow causes the symptoms and signs of pancytopenia. As normal immunoglobulin levels are low, there is a tendency to recurrent bacterial infection. Renal failure, hypercalcaemia, and amyloidosis will all lead to the recognized symptoms and signs (see other chapters). Hyperviscosity syndrome can arise where there is a very high serum paraprotein level but this is more common in the related disorder, Waldenström’s macroglobulinaemia.



  • Benign and malignant disorders of the blood are associated with diverse symptoms and signs.
  • Abnormalities of normal blood cells and normal coagulation lead to largely predictable symptoms and signs.
  • Anaemia typically causes symptoms and signs arising from the blood’s reduced oxygen carrying capacity leading in turn to tissue hypoxia and the body’s attempts to compensate. These include:
    • fatigue
    • dyspnoea
    • palpitations
    • faintness
    • pallor
    • tachycardia.
  • Leucopenia leads to a predisposition to frequent and/or severe infection. Neutropenia classically leads to fulminant bacterial or fungal infection whereas lymphopenia leads to compromised humoral and/or cell-mediated immunity and a wide range of opportunistic infections including bacteria, viruses, fungi and Pneumocystis.
  • Thrombocytopenia (or abnormal platelet function) causes a haemorrhagic tendency characterized by easy bruising, skin petechiae, and bleeding occurring either spontaneously or excessively after surgery or trauma.
  • Coagulation failure, classically seen in the inherited disorder ‘haemophilia’, commonly presents as bleeding into joints and muscles and excessive bleeding following surgery or trauma.
  • Thrombophilia is a clinical disorder of the blood characterized by a predisposition to venous or (less commonly) arterial thrombosis because of abnormally enhanced coagulation.
  • Successful history taking in patients with blood disorders requires knowledge of their common features including symptoms and signs, modes of inheritance and aetiological factors (e.g. drugs).
  • Clinical examination of the lymph nodes and spleen should be methodical and be performed with an understanding of normal anatomy and the causes of lymphadenopathy and splenomegaly.
  • An understanding of the signs and symptoms of ‘haematological emergencies’ is vital. Examples are: superior vena cava obstruction in lymphoma, spinal cord compression in myeloma and hyperviscosity syndrome in Waldenström’s macroglobulinaemia.
  • Laboratory tests, including morphological examination of the blood and bone marrow, are crucial in the diagnosis and classification of blood diseases and must be carefully selected.


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SA Bos, M.D.

Lead Author