xxv SYMBOLS AND ABBREVIATIONS REAL RES RFLP Rh rhAPC rhG-CSF rHuEPO RI RIA RIC RiCoF RIPA RS RT RT-PCR s SAA SAGM SaO2 SA P SB SBP SC SCA SCBU SCD SCID SCT SD SE SEP SLE SLL SLVL SM SM-AHNMD systemic mastocytosis with an associated clonal Revised European American Lymphoma reticuloendothelial system restriction fragment length p olymorphism Rhesus recombinant human activated protein C recombinant human granulocyte colo ny stimulating factor recombinant human erythropoietin remission induction radioimmunoassay reduced-intensity conditioning ristocetin cofactor ristocetin-induced platelet agglutinati on Reed \200\223Sternberg or ringed sideroblasts reptilase time reverse transcriptase polym erase chain reaction second serum amyloid A protein saline adenine glucose mannitol arteria l oxygen saturation serum amyloid P protein Sudan solitary plasmacytoma of bone subcutaneou s sickle cell anemia special care baby unit sickle cell disease severe combined immunodefi ciency stem cell transplantation or silica clot time standard deviation secondary erythrocy tosis extramedullary plasmacytoma systemic lupus erythematosus small lymphocytic lymphoma s plenic lymphoma with villous lymphocytes systemic mastocytosis hematological non-mast cell lineage disease surface membrane immunoglobulin splenic margina l zone lymphoma short of breath SmIg SMZL SOB xxvi SYMBOLS AND ABBREVIATIONS SPB SPD stat sTfR SVC SVCO T t1 \201\2042 T4 TA-GVHD TAM TAR TB TBI TCR tds TdT TEC TEG T ENS TF TFT TGF-B TI TIA TIBC tiw TKI TLS TNF topo II TORCH TPA TPI TPN TPO TPR TRAP TRM TSE solitary plasmacytoma of bone storage pool disorders/defi ciency statim (immediate; as init ial dose) soluble transferrin receptor superior vena cava superior vena caval obstruction t emperature half-life thyroxine transfusion-associated graft-versus-host disease transient a bnormal myelopoiesis thrombocytopenia with absent radius tuberculosis total body irradiatio n T-cell receptor ter die sumendum (to be taken 3 times a day) terminal deoxynucleotidyl tr ansferase transient erythroblastopenia of childhood thromboelastography transcutaneous nerv e stimulation tissue factor thyroid function test(s) transforming growth factor-B transfusi on-independence transient ischaemic attack total iron binding capacity three times in a wee k tyrosine kinase inhibitor tumor lysis syndrome tumor necrosis factor topoisomerase II tox oplasmosis, rubella, cytomegalovirus, herpes simplex tissue plasminogen activator triphosph ate isomerase total parenteral nutrition thrombopoietin temperature, pulse, respiration tar trate-resistant acid phosphatase treatment-related mortality transmissible spongiform encep halopathy xxvii SYMBOLS AND ABBREVIATIONS TSH TT TTP TXA TXA2 U&E U UC UFH ULN URTI US USS UTI VAD thyroid-stimulating hormone thrombin time thrombotic thrombocytopenic purpura tranexamic ac id thromboxane A2 urea and electrolytes unit ulcerative colitis unfractionated heparin uppe r limit of normal upper respiratory tract infection ultrasound ultrasound scan urinary trac t infection vincristine doxorubicin (adriamycin) dexamethasone regimen vincristine, carmust ine (BCNU), doxorubicin, prednisolone vincristine, carmustine, melphalan, cyclophosphamide, prednisolone vena cava Venereal Disease Research Laboratory vascular endothelial growth fa ctor ventricular fi brillation factor VIII clotting activity vitamin K vincristine, melphal an, cyclophosphamide, prednisolone melphalan, prednisolone, bortezomib veno-occlusive disea se venous thromboembolism volunteer unrelated donor von Willebrand disease von Willebrand f actor von Willebrand factor antigen Wiskott \200\223Aldrich syndrome white blood cell whole -brain radiotherapy white cell count Waldenstr m macroglobulinaemia cross-match cross-link ed fi brin degradation products zinc protoporphyrin VBAP VBMCP VC VDRL VEGF VF VIII:C Vit K VMCP VMP VOD VTE VUD vWD vWF vWFAg WAS WBC WBRT WCC WM X-match XDPs ZPP This page intentionally left blank 1 Chapter 1 Clinical approach History taking in patients with hematological disease 2 Physical examination 4 Splenomegaly 5 Lymphadenopathy 6 Unexplained anemia 8 Patient with elevated hemoglobin 10 Elevated whit e blood cell (WBC) count 12 Reduced WBC count 14 Elevated platelet count 16 Reduced platele t count 18 Easy bruising 20 Recurrent thromboembolism 22 Pathological fracture 23 Raised ES R 24 Serum or urine paraprotein 25 Anemia in pregnancy 26 Thrombocytopenia in pregnancy 27 Prolonged bleeding after surgery 28 Positive sickle test (HbS solubility test) 30 2 CHAPTER 1 Clinical approach History taking in patients with hematological disease Approach to patient with suspected hematological disease An accurate history combined with a careful physical examination are fundamental parts of clinical assessment. Although the l ikely haema- tological diagnosis may be apparent from tests carried out before the patient has been referred, it is nevertheless essential to assess the clinical background fully \200\224this may infl uence the eventual plan of management, especially in older patients. It is important to fi nd out early on in the consultation what the patient may already have been told prior to referral, or what he/she thinks the diagnosis may be. There is often fe ar and anxiety about diagnoses such as leukemia, hemophilia, or HIV infection. Presenting symptoms and their duration A full medical history needs to be taken to which is added direct ques- tioning on relevant features associated with presenting symptoms: \200 Non-specifi c symptoms such as fatigue, fevers, weight loss. \200 Symptoms relating to anemia, e.g. reduced exercise capacity, recent onset of breathlessness and nature of its on set, or worsening of angina, presence of ankle oedema. Symptoms relating to neutropenia, e.g. recurrent oral ulceration, skin infections, oral sepsis. Evidence of compromised immunity, e.g. recurrent oropharyngeal infection. \200 Details of potential haemostatic problems, e.g. easy bruising, bleeding episodes, rashes. Anatomical symptoms, e.g. abdominal discomfort (splenic enlargement or pressure from enlarged lymph nodes), CNS symptoms (from spinal compression). Past medical history, i.e. detail on past illnesses, information on previous surgical procedures which may suggest previous hematological problems (e.g. may suggest an underlying bleeding diathesis) or be associated with hematological or other seq uelae, e.g. splenectomy. Drug history: ask about prescribed and non-prescribed medications. \200 Allergies: since some hematological disorders may relate to chemicals or other environmental hazards specifi c questions should be asked about occupational factors and hobbies. Transfusion history: ask about whether the patient has been a blood donor and how much he/she has donated. May occasionally be a factor in iron (Fe) defi cienc y anemia. History of previous transfusion(s) and their timing is also critical in some case s, e.g. post- transfusion purpura. Tobacco and alcohol consumption is essential; both may produce signifi cant hematological morbidity. Travel: clearly important in the case of suspected malaria but also relevant in considering other causes of hematological abnormality, including HIV infection. 3 HISTORY TAKING IN PATIENTS WITH hematological DISEASE Family history is also important, especially in the context of inherited hematological disorders. A complete history for a patient with a hematological disorder should provide all the relev ant medical information to aid diagnosis and clinical assessment, as well as helping the he matologist to have a working assessment of the patient \200\231s social situation. A well-t aken history also provides a basis for good communication which will often prove very impor tant once it comes to discussion of the diagnosis. 4 CHAPTER 1 Clinical approach Physical examination This forms part of the clinical assessment of the hematology patient. Pay specifi c attention to: General examination \200\224e.g. evidence of weight loss, pyrex ia, pallor (the latter is not a reliable clinical measure of anemia), jaundice, cyanosis, o r abnormal pigmentation or skin rashes. The mouth \200\224ulceration, purpura, gum bleeding , or infi ltration, and the state of the patient \200\231s teeth. Hands and nails may show features asso- ciated with hematological abnormalities, e.g. koilonychia in chronic Fe defi ciency (rarely seen today). Record \200\224weight, height, T , pulse, and blood pressure; height and weight give important baseline data against which sequential measure- ments can subsequently be compared. In myelofi brosis, for example, evidence of signifi cant weight loss in the absence of symptoms may be an indication of clinical progression. Examination \200\224of chest and abdomen should focus on detecting the presence of lymphadenopathy, hep atic and/or splenic enlargement. Node sizes and the extent of organ enlargement should be c arefully recorded. Lymph node enlargement \200\224often recorded in centimeters e.g. 3cm \227 3cm \227 4cm; sometimes more helpful to compare the degree of enlarge- ment with fami liar objects, e.g. pea. Record extent of liver or spleen enlargement as maximum distance pa lpable from the lower costal margin. Erythematous margins of infected skin lesions \200\224 mark these to monitor treatment eff ects. Bones and joints \200\224recording of joint swell ing and ranges of move- ment are standard aspects of hemophilia care. In myeloma, areas of bony tenderness and deformity are commonly present. Optic fundi \200\224examination is a ke y clinical assessment in the haema- tology patient. May yield the only objective evidence o f hyperviscosity in paraproteinaemias (E Hyperviscosity, p.646) or hyperleucocytosis (E Leu costasis, p.663) such as in, e.g. CML. Regular examination for hemorrhages should form part of routine observations in the severely myelosuppressed patient; rarely changes of opportu nistic infection such as candidiasis can be seen in the optic fundi. Neurological examinati on \200\224fl uctuations of conscious level and confusion are clinical presentations of hyp erviscosity. Isolated nerve palsies in a patient with acute leukemia are highly suspicious of neurological involvement or disease relapse. Peripheral neuropathy and long tract signs are well-recognized complications of B12 defi ciency. 5 SPLENOMEGALY Splenomegaly Many causes. Clinical approach depends on whether splenic enlargement is prese nt as an isolated fi nding or with other clinical abnormalities, e.g. jaundice or lymphaden opathy. Mild-to-moderate splenomegaly has a much greater number of causes than massive sple nomegaly (see Table 1.1). Table 1.1 Causes of splenomegaly Viral EBV, CMV, hepatitis Infection Bacterial SBE, miliary tuberculosis, Salmonella, Brucella Protozoal Malaria, toxoplasmosis, leishmaniasis Congenital Hereditary spherocytosis, hereditary elliptocytosis, sickle cell disease (infants), thalass aemia, pyruvate kinase defi ciency, G6PD defi ciency Haemolytic Acquired AIHA (idiopathic or 2 ) Myelofi brosis, CML, polycythaemia rubra vera, essential thrombocythaemia, acute leukaemias Myeloproliferative and leukaemic CLL, hairy cell leukemia, Waldenstr m, SLVL, other NHL, Hodgkin lymphoma, ALL and lymphobl astic NHL Lymphoproliferative Rheumatoid arthritis, SLE, hepatic cirrhosis, Gaucher \200\231s disease, histiocytosis X, N iemann \200\223Pick disease Autoimmune disorders and storage disorders Metastatic cancer, cysts, amyloid, portal hypertension, portal vein thrombosis, tropical sp lenomegaly Miscellaneous Clinical approach essentially involves a working knowledge of the pos- sible causes of sple nic enlargement and determining the more likely causes in the given clinical circumstances by appropriate further investi- gation. There are fewer causes of massive splenic enlargeme nt, i.e. the spleen tip palpable below the level of the umbilicus. Massive splenomegaly \200 Myelofi brosis. \200 Chronic myeloid leukemia (CML). \200 L ymphoproliferative disease \200\224chronic lymphocytic leukemia (CLL) and variants includin g splenic lymphoma with villous lymphocytes (SLVL), hairy cell leukemia (HCL) and marginal zone lymphoma. Tropical splenomegaly. \200 Leishmaniasis. \200 Gaucher \200\231s disease. \200 Thala ssaemia major. 6 CHAPTER 1 Clinical approach Lymphadenopathy Occurs in a range of infective or neoplastic conditions; less frequently en largement occurs in active collagen disorders. May be isolated, aff ecting a single node, l ocalized, involving several nodes in an anatomical lymph node grouping, or generalized, whe re nodes are enlarged at diff erent sites. As well as enlargement in the easily palpable ar eas (cervical, axillary, and iliac), node enlargement may be hilar or retroperitoneal and i dentifi able only by imaging. Isolated/localized lymphadenopathy usually results from local infection or neoplasm. Generalized lymphadenopathy may result from systemic causes, especi ally when symmetrical, as well as infection or neoplasm (see Table 1.2). Rarely drug-associ ated (e.g. phenytoin). Table 1.2 Causes of lymphadenopathy Bacterial Tonsillitis, cellulitis, tuberculous infections, and Infective 1 syphilis usually produce isolated or localized node enlargement Viral EBV, CMV, rubella, HIV, HBV, HCV Other Toxoplasma, histoplasmosis, chlamydia, cat-scratch Hodgkin lymphoma (typically isolated or localized lymphadenopathy), NHL isolated, generaliz ed or localized, CLL, metastatic carcinoma, acute leukemia (ALL especially, but occasionall y AML) Neoplastic E.g. rheumatoid arthritis, SLE, sarcoidosis Collagen and other systemic disorders History and examination \200\224points to elicit \200 Age. \200 Onset of symptoms, whet her progressing or not. \200 Systemic symptoms, weight loss (>10% body weight loss in <6 months). \200 Night sweats. \200 Risk factors for HIV infection. \200 Local or system ic evidence of infection. \200 Evidence of systemic disorder such as rheumatoid arthritis . \200 Evidence of malignancy; if splenic enlargement present then lymphoreticular neoplasm is more likely. Specifi c disease-related features, e.g. pruritus and alcohol-induced lymph node pain associated with Hodgkin disease. Determine the duration of enlargement associated symptoms, whether nodes are continuing to enlarge, and whether tender or not. Distribution of node enlargement should be recorded as well as size of node. Investigations \200 Full blood count (FBC) and peripheral blood fi lm examination. \200 Erythrocyte sedimentation rate (ESR) or plasma viscosity. \200 Screening test for infect ious mononucleosis and serological testing for other viruses. 7 LYMPHADENOPATHY Imaging \200\224e.g. chest radiography; chest abdominal pelvic computed tomography (CT) scanning may also be helpful to defi ne hilar, retroperitoneal, and para-ao rtic nodes. Microbiology \200\224e.g. blood cultures, indirect testing for tuberculosis (TB), and cultu re of biopsied or aspirated lymph node material. \200 Lymph node biopsy for defi nitive d iagnosis especially if a neoplastic cause suspected. Aspiration of enlarged lymph nodes is generally unsatisfactory in providing eff ective diagnostic material. Avoid biopsy of groin nodes since these often show only non-specifi c features. \200 Bone marrow (BM) examinat ion should be reserved for staging in confi rmed lymphoma or leukemia cases \200\224it is n ot commonly a useful 1 investigation of lymphadenopathy. 8 CHAPTER 1 Clinical approach Unexplained anemia Evaluate with the combined information from clinical history, physical e xamination, and results of investigations (see Table 1.3). History \200\224focus on: \200 Duration of symptoms of anemia \200\224short duration of d yspnoea and fatigue etc. suggests recent bleeding or haemolysis. Gradual anemia of longer duration ofte n associated with adaptation and fewer symptoms. \200 Specifi c questioning on blood loss \200\224include system-related questions, e.g. gastrointestinal tract (GIT) and gynecologi cal sources, ask about blood donation. Family history \200\224e.g. in relation to hereditary problems such as hereditary spherocytosis (HS) or ethnic hemoglobin (Hb) disorders such as thalassaemia or H bSS. Past history \200\224e.g. association of gastrectomy with later occurrence of Fe and/or B12 defi ciency. Drug history \200\224including prescribed and non-prescribed medication. \200 Dietary fac tors \200\224mainly relates to folate and Fe defi ciency, rarely B12 in vegans. Fe defi cie ncy always occurs because Fe losses exceed intake (it is extremely rare in developed countr ies for diet to be the sole cause of Fe defi ciency). Examination \200 May identify indirectly helpful signs, e.g. koilonychia in chronic Fe defi ciency (rare), jaundice in haemolytic disorders. Lymphadenopathy suggesting lymphoreticular disease or viral infection. \200 Hepatosplenom egaly in lymphoproliferative or myeloproliferative disorders. Full blood count Laboratory investigation of anemia is discussed fully in E Chapter 2. Anem ia in adult \231\202 if Hb <13.0g/dL and in adult \231\200 if Hb <11.5g/dL. 9 UNEXPLAINED anemia Table 1.3 MCV useful for initial anemia evaluation Fe defi ciency & thalassaemia, HbE, HbC Anemia of chronic disorders d MCV (<76fL) Recent bleeding Normal MCV (78 \200\22398fL) Anemia of chronic disorders Most non-haematinic defi ciency causes Combined Fe + B12/folate defi ciency Folate or B12 defi ciency i MCV (>100fL) Haemolytic anemia Liver disease Marrow dysplasia and failure syndromes including aplastic anemia 2 to antimetabolite drug therapy, e.g. hydroxyurea (now called hydroxcarbamide) The need for fi lm examination, reticulocyte counting, and additional tests on the FBC samp le such as checking for Heinz bodies is based on the initial clinical and FBC fi ndings. Th e fi ndings from the initial FBC examination have a major infl uence in determining the nat ure and urgency of further clinical investigation. Serum ferritin level will identify Fe defi ciency and focus on the need for detailed invest igation for blood loss which, for adult males and postmen- opausal females, will frequently require large bowel examination with colonoscopy or barium enema, and gastroscopy. BM exam ination may occasionally be required. Anemia is not a diagnosis \200\224it is an abnormal clinical fi nding requiring an explanat ion for its cause. There is no place for empirical use of Fe therapy for management and tre atment of \200\230anemia \200\231 in modern medical practice. 10 CHAPTER 1 Clinical approach Patient with elevated hemoglobin Finding a raised Hb concentration requires a systematic cl inical approach for diff erential diagnosis and further investigation. Initially it is esse ntial to check whether the result ties in with the known clinical fi ndings \200\224if unex pected the FBC should be re-checked to exclude a mix-up over samples or a sampling artifact . Dehydration and diuretic therapy may i the Hct and these should be excluded in the initia l phase of assessment. Having determined that the i Hb concentration is genuine the issue is whether there is a ge nuine i in red cell mass or not, and the explanation for the elevated Hb. Anoxia is a major stimulus to RBC production and will result in an increase in erythropoiet in with consequent erythrocytosis. History and examination should assess: \200 Recent travel and residence at high altitude (>3000m). \200 Chronic obstructive airways disease (COAD), other hypoxic respiratory conditions, cyanotic congenital heart disease, other cardiac problems causing h ypoxia. Smoking \200\224heavy cigarette smoking causes i carboxyHb levels leading to i red blood ce ll (RBC) mass to compensate for loss of O2 carrying capacity. Ventilatory impairment 2 to gross obesity, alveolar hypoventilation (Pickwickian syndrome). Possibility of high-affi nity Hb abnormalities arises if there is a family history (FH) of polycythaemia, otherwise requires assessment through Hb analysis. If obvious 2 causes excluded possibilities include: Spurious polycythaemia \200\224pseudopolycythaemia or Gaisbock \200\231s syndrome, associat ed features can include cigarette smoking, obesity, hypertension, and excess alcohol consum ption; sometimes described as \200\230stress polycythaemia \200\231. Primary proliferative polycythaemia (polycythaemia rubra vera) \200\224 plethoric facies, history of pruritus after bathing or on change of environmental temperatu re, and presence of splenomegaly are helpful clinical fi ndings to suggest this diagnosis. Inappropriate erythropoietin excess \200\224occurs in a variety of benign and malignant renal disorders. Rare complication of some tumors including hepatoma, uterine fi broids, and cerebellar haemangioblastoma. Part of clinical assessment must also include an evaluation of throm- botic risk; previous thrombosis or a family history of such problems i the urgency of investigation and appropri ate treatment (E see also Chapter 7, pp.264 \200\223276). Anemia and hypoxia are detected by the renal sensors. This leads to i production of erythro poietin (EPO) which drives the marrow (through BFU-E and CFU-E) to produce RBCs. Other fact ors may also drive red cell production, including androgens and growth hormone as shown in Fig. 1.1. 11 PATIENT WITH ELEVATED hemoglobin Anemia Hypoxia Tissue anoxia Kidney Erythropoietin Bone marrow BFU-E & CFU-E Androgens Thyroxine Growth hormone Corticosteroids Erythropoiesis Increased RBC mass Fig. 1.1 Erythopoietin Further reading McMullin, M.F., et al. (2005) Guidelines for the diagnosis, investigation a nd management of polycythaemia/erythrocytosis. Br J Haematol, 130, 174 \200\22395. 12 CHAPTER 1 Clinical approach Elevated white blood cell (WBC) count Leucocytosis is defi ned as elevation of the white ce ll count (WCC) >2 SD above the mean. The detection of leucocytosis should prompt immediate scrutiny of the automated WBC diff erential (generally accu- rate except in leukemia) and t he other FBC parameters. A blood fi lm should be examined and if in doubt a manual diff ere ntial count should be performed. It is important to evaluate leucocytosis in terms of the a ge-related absolute normal ranges for neutrophils, lymphocytes, mono- cytes, eosinophils, a nd basophils (E Normal ranges (adult), p.810; Pediatric normal ranges, p.812) and the prese nce of abnormal cells: immature granulocytes, blasts, nucleated red cells, and \200\230aty pical cells \200\231. Leukaemoid reaction \200\224leucocytosis >50 \227 109/L defi nes a n eutrophilia with marked \200\230left shift \200\231 (band forms, metamyelocytes, myelocyte s, and occasionally promyelocytes and myeloblasts in the blood fi lm). Diff erential diagno sis is CML and in children, juvenile CML. Primitive granulocyte precursors are also frequen tly seen in the blood fi lm of the infected or stressed neonate, and any seriously ill pati ent, e.g. on the intensive therapy unit (ITU). Leucoerythroblastic blood fi lm \200\224cont ains myelocytes, other primitive granulocytes, nucleated red cells, and often tear drop red cells; is due to BM invasion by tumor, fi brosis, or granuloma formation and is often an i ndication for a BM biopsy. Other causes include anorexia, haemolysis, and severe illness. L eucocytosis due to blasts \200\224suggests diagnosis of acute leukemia and is an indication for cell typing studies and BM examination. FBC, blood fi lm, white cell diff erential cou nt, and the clinical context in which the leucocytosis is detected will usually indicate wh ether this is due to a 1 hematological abnormality or refl ects a 2 response. 2 It is clearly important to seek a history of symptoms of infection and examine the patien t for signs of infection or an underlying haematolog- ical disorder. Neutrophilia \200 2 to acute infection is most common cause of leucocytosis. \200 Usually modest (uncommonl y >30 \227 109/L), associated with a left shift and occasionally toxic granulation or vacu olation of neutrophils. Chronic infl ammation causes less marked neutrophilia often associated with monocytosis. Moderate neutrophilia may occur following steroid therapy, heatstroke, and in patients with solid tumors. Mild neutrophilia may be induced by stress (e.g. immediate postoperative period) and exercise. May be seen following a myocardial infarction or major seizure. \200 Frequently found in states of chronic BM stimulation (e.g. chronic haemolysis, idiopathic thrombocytopenic purpura (ITP) and asplenia. 1 hematological causes of neutrophilia are less common. CML is often the cause of extremely high leucocyte counts (>200 \227 109/L), predominantly neutro phils with marked left shift, basophilia, and occasional myeloblasts. The presence of the P h chromosome on 13 ELEVATED WHITE BLOOD CELL (WBC) COUNT karyotype analysis are usually helpful to diff erentiate CML from a leukaemoid reaction. Less common are juvenile CML, transient leukaemoid reaction in Down syndrome, hereditary ne utrophilia, and chronic idiopathic neutrophilia. Neutrophilia is often seen after treatment with granulocyte colony stimulating factor (G-CSF). BM examination is rarely necessary in the investigation of a patient with isolated neutroph ilia. Investigation of a leukaemoid reaction, leucoeryth- roblastic blood fi lm, and possib le chronic granulocytic leukemia (CGL) or juvenile CML are fi rm indications for a BM aspir ate and trephine biopsy. BM culture, including culture for atypical mycobacteria and fungi, may be useful in patients with persistent pyrexia or leucocytosis. Lymphocytosis \200 Lymphocytosis >4.0 \227 109/L. \200 Normal infants and young childr en <5 years have a higher proportion and concentration of lymphocytes than adults. Rare in acute bacterial infection except in pertussis (may be >50 \227 109/L). Acute infectious lymphocytosis also seen in children, usually associated with transient lymphocytosis and a mild constitutional reaction. Characteristic of infectious mononucleosis but these lymphocytes are often large and atypic al and the diagnosis may be confi rmed with a heterophile antibody agglutination test (Mono spot; Paul \200\223Bunnell). \200 Similar atypical cells may be seen in patients with CMV and hepatitis A infection. Chronic infection with brucellosis, TB, 2 syphilis, and congenital syphilis may cause lymphocytosis. Lymphocytosis is characteristic of CLL, acute lymphoblastic leukemia (ALL), and occasionally non-Hodgkin lymphoma (NHL). Where a 1 hematological cause is suspected, immunophenotypic anal- ysis of the peripheral blood lymphocytes will often confi rm or exclude a neoplastic diagnosis. BM examination is indicated if neoplasia is strongly suspected and in any patient with concomitant neutropen ia, anemia, or thrombocytopenia, or if there are constitutional symptoms, e.g. night sweats , weight loss. 14 CHAPTER 1 Clinical approach Reduced WBC count It is uncommon for absolute leucopenia (WBC <4.0 \227 109/L) to be due t o isolated defi ciency of any cell other than the neutrophil though in marked leucopenia se veral cell lines are often aff ected. 2 Neutropenia Defi ned as a neutrophil count <2.0 \227 109/L. The risk of infective com- p lications is closely related to the absolute neutrophil count. More severe when neutropenia is due to impaired production from chemotherapy or marrow failure rather than to periphera l destruction or maturation arrest where there is often a cellular marrow with early neutro phil pre- cursors and normal monocyte counts. Type of infection determined by the degree an d duration of neutropenia (see Table 1.4). Ongoing chemo- therapy further i the risk of ser ious bacterial and fungal opportunistic infection and the presence of an indwelling IV cath eter i the incidence of infection with coagulase-negative staphylococci and other skin comm en- sals. Patients with chronic immune neutropenia may develop recurrent stomatitis, gingiv itis, oral ulceration, sinusitis, and peri-anal infection. Table 1.4 Clinical signifi cance of neutropenia Neutrophil count 1.0 \200\2231.5 x 109/L 0.5 \200\2231.0 x 109/L Risk of infection No signifi cant i risk of infection Some i in risk; some fevers can be treated as an outpatient <0.5 x 109/L Major i in risk; treat all fevers with broad spectrum IV antibiotics as an inpatient History and physical examination provide a guide to the subsequent man- agement of a patien t with neutropenia. Simple observation is appropriate initially for an asymptomatic patient with isolated mild neutropenia who has an unremarkable history and examination. If there h as been a recent viral illness or the patient can discontinue a drug which may be the cause , follow-up over a few weeks may see resolution of the abnormality. Investigations BM examination if there is concomitant anemia or thrombocytopenia, history o f signifi cant infection, or if lymphadenopathy or organomegaly on examination. Usually unh elpful in patients with an isolated neutropenia >0.5 \227 109/L. However, if neutropenia p ersists, perform BM aspiration, biopsy and cytogenetics, and check serology for collagen di seases, anti- neutrophil antibodies, autoantibodies, HIV, and immunoglobulins. Diff erential diagnoses Isolated neutropenia may be the presenting feature of myelodysplasi a, aplastic anemia, Fanconi anemia, or acute leukemia but these condi- tions will usually b e associated with other hematological abnormalities. Post-infectious (most usually post-vir al) neutropenia may last several weeks and may be followed by prolonged immune neutropenia. 15 REDUCED WBC COUNT Severe sepsis \200\224particularly at the extremes of life. Drugs \200\224cytotoxic agents and many others, e.g. phenothiazines, many antibiotics, non-steroidal anti-infl ammatory dr ugs (NSAIDs), antithyroid agents, and psychotropic drugs. Neutrophil recovery starts within a few days of stopping off ending drug. Autoimmune neutropenia due to antineutrophil antib odies may occur in isolation or in association with haemolytic anemia, ITP, or systemic lup us erythematosus (SLE). Felty \200\231s syndrome neutropenia is accompanied by seropositive rheumatoid arthritis and splenomegaly. Chronic benign neutropenia of infancy and childhood is associated with fever and infection; resolves by age 4 years, probably has immune basis . Benign familial or racial neutropenia is a feature of rare families and of certain racial groups, notably of patients of black African descent, is associated with mild neutropenia but no propensity to infection. Chronic idiopathic neutropenia is a diagnosis of exclusion, associated with severe neutropenia but often a benign course. Cyclical neutropenia is a co ndition usually of childhood onset and domi- nant inheritance characterized by severe neutr openia, fever, stomatitis, and other infections occurring at 4-week intervals. Hereditary c auses (less common) include Kostmann syndrome (E p.597), Shwachman \200\223Diamond \200\223 Oski syndrome (E p.597), Chediak \200\223Higashi syn- drome (E p.603), reticular dysgenesis , and dyskeratosis congenita. Management Febrile episodes should be managed according to th e severity of the neutro- penia (Table 1.4) and the underlying cause (BM failure is associa ted with more life-threatening infections). Broad-spectrum IV antibiotics may be required a nd empirical systemic antifungal therapy may be required in those who fail to respond to an tibiotics. Prophylactic antibiotic and antifungal therapy may be helpful in some patients w ith chronic neutropenia as may G-CSF. Antiseptic mouthwash is of value and regular dental c are is important. 2 Lymphopenia Lymphopenia (<1.5 \227 109/L) may be seen in acute infecti ons, cardiac failure, pancreatitis, tuberculosis, uraemia, lymphoma, carcinoma, SLE and oth er collagen diseases and after corticosteroid therapy, radiation, chemotherapy, and antilym phocyte globulin therapy. Most common cause of chronic severe lymphopenia in recent years i s HIV infection (E HIV infection and AIDS, p.552). Chronic severe lymphopenia (<0.5 \227 1 09/L) is associated both with opportunistic infections notably Candida spp., Pneumocystis j iroveci, CMV, herpes zoster, Mycoplasma spp., Cryptosporidium, and toxoplasmosis and with a n i incidence of neoplasia particularly NHL, Kaposi \200\231s sarcoma and skin and gastric carcinoma. Further reading Palmblad, J.E., et al. (2002) Idiopathic, immune, infectious, and idiosyncr atic neutropenias. Semin Hematol, 39, 113 \200\22320. 16 CHAPTER 1 Clinical approach Elevated platelet count Thrombocytosis is defi ned as a platelet count >450 \227 109/L. Ma y be due to a primary myeloproliferative neoplasm (MPN) or a secondary reactive feature. If the platelet count is markedly elevated a patient with a MPN has a risk of hemorrhage (due to the production of dysfunctional plate- lets), or thrombosis, or both. The patient \200 \231s history may reveal features of the condition to which the elevated platelet count is 2 . Clinical exami- nation may provide similar clues or reveal splenomegaly which suggests a myeloproliferative neoplasm (MPN). FBC may provide useful informa- tion: marked leucocyt osis with left shift (in the absence of a history of infection), basophilia, or an elevated haematocrit and red cell count are highly suggestive of a MPN when associated with thrombo cytosis. Unusual for reactive thrombocytosis to cause a platelet count >1000 \227 109/L. ( see Table 1.5) Note: platelet counts below this may occur in MPNs. Diff erential diagnosis Table 1.5 Diff erential diagnosis of thrombocytosis Myeloproliferative neoplasms Disorders associated with i platelets 1 thrombocythaemia Hemorrhage Polycythaemia vera Trauma Chronic myeloid leukemia Surgery Idiopathic myelofi brosis Fe defi ciency anemia Malignancy (Ca lung, Ca breast, Hodgkin disease) Acute and chronic infection Infl ammatory disease, e.g. rheumatoid arthritis, UC Post-splenectomy Investigation \200 BM aspirate may show megakaryocyte abnormalities in MPN. \200 BM tre phine biopsy may show marked myeloid hyperplasia, clusters of abnormal megakaryocytes, and i reticulin or fi brosis in MPN. Management \200 In reactive thrombocytosis treat the underlying condition. \200 Unusual to require treatment to d the platelet count in a patient with reactive thrombocytosis. \200 Consider low-dose aspirin. \200 Reactive thrombocytosis i s generally transient. \200 If 2 to Fe defi ciency \200\224review FBC after Fe therapy: the platelet count normalizes if thrombocytosis was due to Fe defi ciency. Fe defi ciency may have masked PRV \200\224this will be revealed by Fe therapy. 17 ELEVATED PLATELET COUNT If impossible to defi ne the cause of thrombocytosis then a watch- and-wait policy should b e followed in an asymptomatic patient. \200 If MPN is suspected \200\224E see Essential t hrombocythaemia, p.281. 18 CHAPTER 1 Clinical approach Reduced platelet count Thrombocytopenia is defi ned as a platelet count <150 \227 109/L. A lthough there is no precise platelet count at which a patient will or will not bleed, most patients with a count >20 \227 109/L are asymptomatic. The risk of spontaneous hemorrhage i signifi cantly <10 \227 109/L. Purpura is the most common presenting symptom usually fou nd on the lower limbs and areas subject to pressure. May be followed by bleeding gums, epis taxis, or more serious life-threatening hemorrhage. A patient with newly diagnosed severe t hrombocytopenia with or without purpura is a medical emergency and may require admission fo r further investigation and treatment. Confi rm low platelet count by examination of the blood sample for clots (artefactual low p latelets) and the blood fi lm for platelet aggre- gates (causing pseudo-thrombocytopenia, o r \200\230false \200\231 thrombocytopenia). If aggregates are seen a FBC should be repeate d in a citrate sample. History and examination will determine the clinical severity of the thrombocytopenia and should also reveal the duration of symptoms, presence of any prodromal illness, causative medication, or underlying disease. Determine whether the cause of thrombocytopenia is failure of produc- tion or i consumption (see Table 1.6). FBC may be helpful as the MPV is often elevated in the latter group (larg e platelets may also be seen on the blood fi lm). May also reveal additional hematological abnormali- ties (normocytic anemia or neutropenia) suggestive of a BM disorder. A coagulati on screen should also be performed. Examination of the BM is the defi nitive investigation in all patients with moderate or severe thrombocytopenia \200\224may reveal normal megakary ocytes or compensa- tory hyperplasia in peripheral destruction syndromes or marrow hypo- pl asia or infi ltration. Tests for platelet antibodies are unreliable but an autoimmune scree n may be helpful to exclude lupus. Management Treat underlying condition. Most patients with a platelet count >30 \227 109/L require no specifi c therapy but should be investigated. Avoid antiplatelet agents and anti coagulants. In the event of life-threatening hemorrhage platelet transfusion should be admi nistered to thrombocytopenic patients with the exception of those with HITT and TTP. 19 REDUCED PLATELET COUNT Table 1.6 Diff erential diagnosis of thrombocytopenia Failure of production Increased consumption Drugs and chemicals (E p.490) ITP (E p.492) Viral infection Drugs (E p.490) Radiation DIC (E p.494) Infection Aplastic anemia (E p.102) Leukemia Massive hemorrhage and transfusion (E p.508) Marrow infi ltration SLE Megaloblastic anemia (E p.46) CLL and lymphoma (E p.490) HIV (E p.553) Heparin (E p.510) TTP (E p.538) Hypersplenism (E p.492) Post-transfusion purpura (E p.492) HIV (E p.553) Further reading Spencer, F.A. (2000). Heparin-induced thrombocytopenia: patient profi les a nd clinical manifestations. J Thromb Thrombolysis, 10, (Suppl. 1), 21 \200\2235. 20 CHAPTER 1 Clinical approach