671 20 Charts and nomograms 677 21 Normal ranges 687 Index 693 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 1 Clinical approach 1 History taking in patients with hematological disease 2 Physical examination 4 Splenomegaly 6 Lymphadenopathy 8 Unexplained a nemia 10 Patient with elevated hemoglobin 12 Elevated WBC 14 Reduced WBC 16 Elevated platel et count 20 Reduced platelet count 22 Easy bruising 24 Recurrent thromboembolism 26 Pathologica l fracture 28 Raised ESR 30 Serum or urine paraprotein 32 Anemia in pregnancy 34 Thro mbocytopenia in pregnancy 36 Prolonged bleeding after surgery 38 Positive sickle test (HbS solubility test) 40 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 2 History taking in patients with hematological disease 2 Approach to patient with suspected hematological disease An accurate history combined with a careful physical examination are fun- damental parts of clinical assessment. Although the likely hematological diagnosis may be apparent from tests carried out before the patient h as been referred, it is nevertheless essential to assess the clinical background fully \200 \224this may influence the eventual plan of management, especially in older patients. It is important to find 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 fea r 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: 2 Non-specific symptoms such as fatigue, fevers, weight loss. 2 Symptoms relating to anemia e.g. reduced exercise capacity, recent onset of breathlessness and nature of its onset, or worsening of angina, presence of ankle oedema. 2 Symptoms relating to neutropenia e.g. recurrent oral ulceration, skin infections, oral sepsis. 2 Evidence of compromised immunity e.g. recurrent oropharyngeal infec- tion. 2 Details of potential haemostatic problems e.g. easy bruising, bleeding episodes, rashes. 2 Anatomical symptoms, e.g. abdominal discomfort (splenic enlargement or pressure from enla rged lymph nodes), CNS symptoms (from spinal compression). 2 Past medical history, i.e. detail on past illnesses, information on pre- vious surgical procedures which may suggest previous hematological problems (e.g. may sugge st an underlying bleeding diathesis) or be associated with hematological or other sequelae e.g. splenectomy. 2 Drug history: ask about prescribed and non-prescribed medications. 2 Al lergies: since some hematological disorders may relate to chemicals or other environmental hazards specific questions should be asked about occupational factors and hobbies. 2 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 deficiency anem ia. History of previous transfusion(s) and their timing is also critical in some cases e.g. post-transfusion purpura. 2 Tobacco and alcohol consumption is essential; both may produce sig- nificant hematological morbidity. 2 Travel: clearly important in the case of suspected malaria but also rele- vant in considering other causes of hematological abnormality, including HIV infection. 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 3 Clinical approach 3 2 Family history 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 assess- ment of the patient \200\231s social situation. A well taken history also provides a basis for good communication which will often prove very imp ortant once it comes to discussion of the diagnosis. 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 4 Physical examination This forms part of the clinical assessment of the hematology patient. Pay specific attentio n to: 4 General examination \200\224e.g. evidence of weight loss, pyrexia, pallor (not a reliable clinical measure of anemia), jaundice, cyanosis or abnormal pigmentation or skin rashes. The mouth \200\224ulceration, purpura, gum bleeding or infiltration, and the state of the patient \200\231s teeth. Hands and nails may show features associated with hematological ab normalities e.g. koilonychia in chronic iron deficiency (rarely seen today). Record \200\224weight, height, T , pulse and blood pressure; height and weight give impor tant baseline data against which sequential measurements can subsequently be compared. In m yelofibrosis, for example, evidence of significant weight loss in the absence of symptoms m ay be an indication of clinical progression. Examination \200\224of chest and abdomen should focus on detecting the presence of lymphad enopathy, hepatic and/or splenic enlargement. Node sizes and the extent of organ enlargemen t should be carefully recorded. Lymph node enlargement \200\224often recorded in centimete rs e.g. 3cm 3cm 4cm; sometimes more helpful to compare the degree of enlargement with familiar objects e.g. pea. Record extent of liver or spleen enlargement as maximum distanc e palpable from the lower costal margin. Erythematous margins of infected skin lesions \200\224mark these to monitor treatment effe cts. Bones and joints \200\224recording of joint swelling and ranges of movement are standard a spects of hemophilia care. In myeloma, areas of bony tenderness and deformity are commonly present. Optic in the hematology patient. May yield the only objective evidence of ((cid:9)Emergenci es p510) or hyperviscosity hyperleucocytosis ((cid:9)Emergencies p510) such as in e.g. CML. Regular examination form part of routine observations in the severely myelosuppressed pati ent; rarely changes of opportunistic infection such as candidiasis can be seen in the optic fundi. fundi \200\224examination is a key clinical assessment in paraproteinaemias for hemorrhages should Neurological examination \200\224fluctuations of conscious level and confusion are clinica l presentations of hyperviscosity. 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 deficiency. 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 5 Clinical approach 5 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 6 Splenomegaly Many causes. Clinical approach depends on whether splenic enlargement is present as an isol ated finding or with other clinical abnormalities e.g. jaundice or lymphadenopathy. Mild to moderate splenomegaly have a much greater number of causes than massive splenomegaly. 6 Causes of splenomegaly Infection Viral Bacterial Protozoal EBV, CMV, hepatitis SBE, miliary tuberculosis, Salmonella, Brucella Malaria, toxoplasmosis, leishmaniasis Haemolytic Congenital Hereditary spherocytosis, hereditary elliptocytosis Sickle cell disease (infants), thalassa emia Pyruvate kinase deficiency, G6PD deficiency Acquired AIHA (idiopathic or 2 ) Myeloproliferative & leukaemic Myelofibrosis, CML, polycythaemia rubra vera Essential thrombocythaemia, acute leukaemias Lymphoproliferative CLL, hairy cell leukemia, Waldenstr m \200\231s, SLVL, other NHL, Hodgkin \200\231s diseas e, ALL & lymphoblastic NHL Autoimmune disorders & Storage disorders Rheumatoid arthritis, SLE, hepatic cirrhosis Gaucher \200\231s disease, histiocytosis X Nie mann \200\223Pick disease Miscellaneous Metastatic cancer, cysts, amyloid, portal hypertension, portal vein thrombosis, tropical sp lenomegaly Clinical approach essentially involves a working knowledge of the possible causes of spleni c enlargement and determining the more likely causes in the given clinical circumstances by appropriate further investigation. There are fewer causes of massive splenic enlargement, i.e. the spleen tip pal- pable below the level of the umbilicus. Massive splenomegaly 2 Myelofibrosis. 2 Chronic myeloid leukemia. 2 Lymphoproliferative dis ease \200\224CLL and variants including SLVL, HCL and marginal zone lymphoma. 2 Tropical splenomegaly. 2 Leishmaniasis. 2 Gaucher \200\231s disease. 2 Thalassaemia major . 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 7 Clinical approach 7 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 8 Lymphadenopathy Occurs in a range of infective or neoplastic conditions; less frequently enlargement occurs in active collagen disorders. May be isolated, affecting a single node, localized, involvi ng several nodes in an anatomical lymph node grouping, or generalized, where nodes are enla rged at different sites. As well as enlargement in the easily palpable areas (cervical, axi llary and iliac) node enlargement may be hilar or retroperitoneal and identifiable only by imaging. Isolated/localized lymphadenopathy usually results from local infection or neoplas m. Generalized lymphadenopathy may result from systemic causes, especially when symmetrical , as well as infection or neoplasm. Rarely drug-associated (e.g. phenytoin). 8 Causes of lymphadenopathy Infective Bacterial Tonsillitis, cellulitis, tuberculous infections & primary syphilis usually produce isolated or localized node enlargement EBV, CMV, rubella, HIV, HBV, HCV Toxoplasma, histoplasmosis, chlamydia, cat-scratch Viral Other Neoplastic Hodgkin \200\231s disease (typically isolated or localized lymphadenopathy), NHL isolated, generalized or localized, CLL, metastatic carcinoma, acute leukemia (ALL especially, but oc casionally AML) Collagen and other systemic disorders E.g. rheumatoid arthritis, SLE, sarcoidosis History and examination \200\224points to elicit 2 Age. 2 Onset of symptoms, whether progr essing or not. 2 Systemic symptoms, weight loss (>10% body weight loss in <6 months). 2 Nig ht sweats. 2 Risk factors for HIV infection. 2 Local or systemic evidence of infection. 2 E vidence of systemic disorder such as rheumatoid arthritis. 2 Evidence of malignancy; if spl enic enlargement present then lym- phoreticular neoplasm is more likely. 2 Specific disease-related features e.g. pruritus and alcohol induced lymph node pain associated with Hodgkin \200\231s disease. 2 Determine the duration of enlargement associated symptoms, whether nodes are continuing to enlarge and whether tender or not. Distribution of node enl argement should be recorded as well as size of node. Investigations 1. FBC and peripheral blood movie examination. 2. ESR or plasma viscosity. 3 . Screening test for infectious mononucleosis and serological testing for other viruses. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 9 Clinical approach 9 4. Imaging \200\224e.g. chest radiography and abdominal pelvic USS to define hilar, retrope ritoneal and para-aortic nodes. CT scanning may also be helpful. 5. Microbiology \200\224e.g. blood cultures, indirect testing for TB and culture of biopsied or aspirated lymph node material. 6. Lymph node biopsy for definitive diagnosis especially if a neoplastic cause suspected. A spiration of enlarged lymph nodes is generally unsatisfactory in providing effective diagno stic material. 7. Bone marrow examination should be reserved for staging in confirmed lymphoma or leukemia cases \200\224it is not commonly a useful primary investigation of lymphadenopathy. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 10 Unexplained anemia Evaluate with the combined information from clinical history, physical examination and resu lts of investigations. 10 History \200\224focus on 2 Duration of symptoms of anemia \200\224short duration of dyspn oea and fatigue etc. suggests recent bleeding or haemolysis. 2 Specific questioning on blood loss \200\224include system-related questions e.g. GIT and gynecological sources, ask about blood donation. 2 Family history \200\224e .g . in relation to hereditary problems such as HS or ethnic Hb disorders such as thalassaemia or HbSS. 2 Past history \200\224e . g. association of gastrectomy with later occurrence of Fe and/or B12 deficiency. 2 Drug history \200\224including prescribed and non-prescribed medication. 2 Dietary facto rs \200\224mainly relates to folate and Fe deficiency, rarely B12 in vegans. Fe deficiency always occurs because Fe losses exceed intake (it is extremely rare in developed countries for diet to be the sole cause of Fe deficiency). Examination 2 May identify indirectly helpful signs e.g. koilonychia in chronic Fe defi- ciency (rare), jaundice in haemolytic disorders. 2 Lymphadenopathy suggesting lymphoreticular disease or viral infection. 2 Hepatosplenomega ly in lymphoproliferative or myeloproliferative disorders. Full blood count Laboratory investigation of anemia is discussed fully in section 2. Anemia in adult 9 if Hb <13.0g/dL and in adult 3 if Hb <11.5g/dL. MCV useful for initial anemia evaluation 5 MCV (<76fL) Fe deficiency a & b thalassaemia, HbE, HbC Anemia of chronic disorders Normal MCV (78 \200\22398fL) Recent bleeding Anemia of chronic disorders Most non-haematinic deficiency causes Combined Fe + B12/folate deficiency 4 MCV (>100fL) Folate or B12 deficiency Haemolytic anemia Liver disease Marrow dysplasia & failure syndrom es including aplastic anemia 2 to antimetabolite drug therapy e.g. hydroxyurea The need for movie examination, reticulocyte counting and additional tests on the FBC sampl e such as checking for Heinz bodies is based on the initial clinical and FBC findings. The findings from the initial FBC examina- 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 11 Clinical approach 11 tion have a major influence in determining the nature and urgency of further clinical inves tigation. Serum ferritin level will identify iron deficiency and focus on the need for detailed inves tigation for blood loss which, for adult males and postmenopausal females, will frequently require large bowel examination with colonoscopy or barium enema, and gastroscopy. BM exami nation may occasionally be required. Anemia is not a diagnosis \200\224it is an abnormal clinical finding 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. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 12 Patient with elevated hemoglobin Finding a raised Hb concentration requires a systematic clinical approach for differential diagnosis and further investigation. Initially it is essential to check whether the result ties in with the known clinical findings \200\224if unex- pected the FBC should be re-chec ked to exclude a mix-up over samples or a sampling artifact. Dehydration and diuretic thera py may 4 the Hct and these should be excluded in the initial phase of assessment. 12 Having determined that the 4 Hb concentration is genuine the issue is whether there is a ge nuine increase in red cell mass or not, and the expla- nation 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 2 Recent travel and residence at high altitude (>3000 m). 2 COAD, other hypoxic respiratory conditions, cyanotic congenital heart disease, other cardiac problems causing hypoxia. 2 Smoking \200\224heavy cigarette smoking causes 4 carboxyHb levels leading to 4 RBC mass to compensate for loss of O2 carrying capacity. 2 Ventilatory impairment 2 to gross obesity, alveolar hypoventilation (Pickwickian syndrome). 2 Possibility of high-affinity Hb abnormalities arises if there is a FH of polycythaemia, o therwise requires assessment through Hb analysis. 2 If obvious secondary causes excluded possibilities include: Spurious polycythaemia \200\224pseudopolycythaemia or Gaisbock \200\231s syndrome, associa ted 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 temperature and presence of splenomegaly are helpful clinical findings to suggest this diagnosis. Inappropriate erythropoietin excess \200\224occurs in a variety of benign and malignant re nal disorders. Rare complication of some tumors including hepatoma, uterine fibroids and ce rebellar haemangioblastoma. Part of clinical assessment must also include an evaluation of thrombotic risk; previous th rombosis or a family history of such problems increase the urgency of investigation and app ropriate treatment (cid:9) p240 \200\223249. 0 1 C l i n i Erythropoietin c a l a Anemia p p Hypoxia r o a c h . q x d 1 tissue anoxia Kidney Erythropoietin 0 . 1 2 . Bone marrow 2 0 Androgens 0 BFU-E & CFU-E 3 C 0 Thyroxine l i n i c a l 3 Growth hormone . 5 3 Corticosteroids P Erythropoiesis M P a p p r o a c h a g e 1 3 Increased RBC mass 1 3 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 14 Elevated WBC Leucocytosis is defined as elevation of the white cell count >2 SD above the mean. The dete ction of leucocytosis should prompt immediate scrutiny of the automated WBC differential (g enerally accurate except in leukemia) and the other FBC parameters. Blood movie should be e xamined and a manual differential count performed. Important to evaluate leucocy- tosis in terms of the age-related absolute normal ranges for neutrophils, lymphocytes, monocytes, eo sinophils and basophils ((cid:9) p688, 690) and the presence of abnormal cells: immature gr anulocytes, blasts, nucleated red cells and \200\230atypical cells \200\231. Leukaemoid re action \200\224leucocytosis >50 109/L defines a neutrophilia with marked \200\230left s hift \200\231 (band forms, metamyelocytes, myelocytes and occasionally promyelocytes and my eloblasts in the blood movie). Differential diagnosis is chronic granulocytic leukemia (CGL ) and in children, juvenile CML. Primitive granulocyte precursors are also frequently seen in the blood movie of the infected or stressed neonate, and any seriously ill patient e.g. on ITU. 14 Leucoerythroblastic blood movie \200\224contains myelocytes, other primitive granulocytes, nucleated red cells and often tear drop red cells, is due to bone marrow invasion by tumor , fibrosis or granuloma formation and is an indication for a bone marrow biopsy. Other caus es include anorexia and haemolysis. Leucocytosis due to blasts \200\224suggests diagnosis of acute leukemia and is an indicati on for cell typing studies and bone marrow examination. FBC, blood movie, white cell differential count and the clinical context in which the leuco cytosis is detected will usually indicate whether this is due to a 1 hematological abnorm ality or reflects a 2 response. (cid:2) It is clearly important to seek a history of symptoms of infection and examine the patient for signs of infection or an underlying hematological disorder. Neutrophilia 2 2 to acute infection is most common cause of leucocytosis. 2 Usually modes t (uncommonly >30 109/L), associated with a left shift and occasionally toxic granulation or vacuolation of neutrophils. 2 Chronic inflammation causes less marked neutrophilia often associated with monocytosis. 2 Moderate neutrophilia may occur following steroid therapy, heatstroke and in patients with solid tumors. 2 Mild neutrophilia may be induced by stress (e.g. immediate postopera- tive period) and exercise. 2 May be seen in the immediate aftermath of a myocardial infarction or major seizure. 2 Frequently found in states of chronic bone marrow stimulation (e.g. chronic haemolysis, ITP) and asplenia. 2 Primary hematological causes of neutrophilia are less common. CML is often the cause of e xtremely high leucocyte counts (>200 109/L), predominantly neutrophils with marked left shift, basophilia and occa- 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 15 Clinical approach 15 sional myeloblasts. A low LAP score and the presence of the Ph chro- mosome on karyotype an alysis are usually helpful to differentiate CGL from a leukaemoid reaction. 2 Less common are juvenile CML, transient leukaemoid reaction in Down syndrome, hereditary neutrophilia and chronic idiopathic neu- trophilia. Bone marrow examination is rarely necessary in the investigation of a patient with isolated neutrophilia. Investigation of a leukaemoid reaction, leucoerythroblastic blood movie and possible CGL or juvenile CML are firm indications for a bone marrow aspirate and trephine b iopsy. Bone marrow culture, including culture for atypical mycobacteria and fungi, may be u seful in patients with persistent pyrexia or leucocytosis. Lymphocytosis 2 Lymphocytosis >4.0 109/L. 2 Normal infants and young children <5 have a higher proportion and concentration of lymphocytes than adults. 2 Rare in acute bacterial infection except in pertussis (may be >50 109/L). 2 Acute infectious lymphocytosis also seen in children, usually associated with transient lymphocytosis and a mild constitutional reaction. 2 Characteristic of infectious mononucleosis but these lymphocytes are often large and atypical and the diagnosis may be confirmed with a het- erophil agglutinati on test. 2 Similar atypical cells may be seen in patients with CMV and hepatitis A infection. 2 Chronic infection with brucellosis, tuberculosis, secondary syphilis and congenital syphilis may cause lymphocytosis. 2 Lymphocytosis is characteristic of CLL, ALL and occasionally NHL. Where primary hematological cause suspected, immunophenotypic analysis of the peripheral bl ood lymphocytes will often confirm or exclude a neoplastic diagnosis. BM examination is ind icated if neoplasia is strongly suspected and in any patient with concomitant neutropenia, anemia or thrombocytopenia. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 16 Reduced WBC Although not entirely synonymous, it is uncommon for absolute leu- copenia (WBC <4.0 109 /L) to be due to isolated deficiency of any cell other than the neutrophil though in marked leucopenia several cell lines are often affected. 16 (cid:2) Neutropenia Defined as a neutrophil count <2.0 109/L. The risk of infective comp lica- tions is closely related to the absolute neutrophil count. More severe when neutropen ia is due to impaired production from chemotherapy or marrow failure rather than to periphe ral destruction or maturation arrest where there is often a cellular marrow with early neut rophil precursors and normal monocyte counts. Type of infection determined by the degree an d duration of neutropenia. Ongoing chemotherapy further increases the risk of serious bacte rial and fungal opportunistic infection and the pres- ence of an indwelling intravenous cat heter increases the incidence of infection with coagulase-negative staphylococci and other skin commen- sals. Patients with chronic immune neutropenia may develop recurrent stomatiti s, gingivitis, oral ulceration, sinusitis and peri-anal infection. Neutrophil count Risk of infection 1.0 \200\2231.5 109/L 0.5 \200\2231.0 109/L No significant increased risk of infection. Some increase in risk; some fevers can be treated as an outpatient. <0.5 109/L Major increase in risk; treat all fevers with broad spectrum IV antibiotics as an inpatient . The history and physical examination provide a guide to the subsequent management of a pati ent with neutropenia. Simple observation is appro- priate initially for an asymptomatic pat ient with isolated mild neutropenia who has an unremarkable history and examination. If the re has been a recent viral illness or the patient can discontinue a drug which may be the c ause, follow-up over a few weeks may see resolution of the abnormality. Investigations BM examination \200\224if there is concomitant anemia or thrombocytopenia, if there is a history of significant infection or if lymphadenopathy or organomegaly are de tected on examination. Usually unhelpful in patients with an isolated neutropenia >0.5 1 09/L. However, if neutropenia per- sists, bone marrow aspiration, biopsy, cytogenetics and serology for col- lagen diseases, anti-neutrophil antibodies, HIV and immunoglobulins shoul d be performed. Differential diagnoses Isolated neutropenia may be the presenting feature of myelodysplasia, aplastic anemia, Fanc oni \200\231s anemia or acute leukemia but these 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 17 Clinical approach 17 conditions will usually be associated with other hematological abnormalities. Post-infectious (most usually post-viral) neutropenia may last several weeks and may be fol lowed by prolonged immune neutropenia. Severe sepsis particularly at the extremes of life. Drugs \200\224cytotoxic agents, and many others, notably phenothiazines, many antibiotics, NSAIDs, anti-thyroid agents and psychotropic agents. Recovery of neutrophils usually start s within a few days of stopping the offending drug. Autoimmune neutropenia due to anti-neutrophil antibodies may occur in isolation or in assoc iation with haemolytic anemia, immune thrombocytopenia or SLE. Felty s syndrome neutropenia rheumatoid arthritis, and splenomegaly. is accompanied by seropositive Chronic benign neutropenia of infancy and childhood is associated with fever and infection but resolves by age 4, probably also has an immune basis. Benign familial neutropenia is a feature of rare families and of certain racial groups, not ably negroes, is associated with mild neutropenia but no propensity to infection. Chronic idiopathic neutropenia is a diagnosis of exclusion, associated with severe neutrope nia but often a benign course. Cyclical neutropenia is a condition of childhood onset and dominant inheritance characteriz ed by severe neutropenia, fever, stomatitis and other infections occurring with a periodici ty of 4 weeks. Hereditary causes (less common) include Kostmann syndrome ((cid:9) p459), Shwachman \200 \223Diamond \200\223Oski syndrome ((cid:9) p459), Chediak \200\223 Higashi syndrome ((cid:9 ) p465), reticular dysgenesis and dyskeratosis congenita. Management Febrile episodes should be managed according to the severity of the neu- tropeni a (see table) and the underlying cause (bone marrow failure is associated with more life-th reatening infections). Broad spectrum IV antibiotics may be required and empirical systemic antifungal therapy may be required in those who fail to respond to antibiotics. Prophylact ic antibi- otic and antifungal therapy may be helpful in some patients with chronic neutrop enia as may G-CSF. Antiseptic mouthwash is of value and regular dental care is important. (cid:2) Lymphopenia Lymphopenia (<1.5 109/L) may be seen in acute infections, cardiac fa ilure, pancreatitis, tuberculosis, uraemia, lymphoma, carcinoma, SLE and 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 18 other collagen disease, corticosteroid therapy, radiation, chemotherapy and anti-lymphocyte globulin. Most common cause of chronic severe lym- phopenia in recent years has been HIV i nfection ((cid:9) p414). Chronic severe lymphopenia (<0.5 109/L) is associated both with opportunistic infections notably Candida species, Pneumocystis carinii, CMV, Herpes zoster, Mycoplasma spp., Crypto sporidium and toxoplasmosis and with an increased incidence of neoplasia particularly NHL, Kaposi \200\231s sarcoma and skin and gastric carcinoma. 18 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 19 Clinical approach 19 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 20 Elevated platelet count Thrombocytosis is defined as a platelet count >450 109/L. May be due to a primary myelop roliferative disorder (MPD) or a secondary reactive feature. If the platelet count is marke dly elevated a patient with a myelo- proliferative disorder has a risk of hemorrhage (due t o the production of dysfunctional platelets), or thrombosis, or both. The patient \200\231s history may reveal features of the condition to which the elevated platelet count is secon dary. Clinical examination may provide similar clues or reveal the presence of palpable spl enomegaly which suggests a myeloproliferative disorder. FBC may provide useful information: marked leucocytosis 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 myeloprolifera- t ive disorder when associated with thrombocytosis. Unusual for reactive thrombocytosis to ca use a platelet count >1000 109/L. Note: platelet counts below this may occur in myelopro liferative disorders. 20 Differential diagnosis Disorders associated with 4 platelets Myeloproliferative disorders Primary thrombocythaemia Polycythaemia rubra vera Chronic granulocytic leukemia Idiopathic myelofibrosis Hemorrhage Trauma Surgery Iron deficiency anemia Malignancy (ca lung, ca breast, Hodgkin \200\231s disease) Acute & chronic infection Inflammatory disease e.g. rheumatoid arthritis , UC Post-splenectomy Investigation 2 BM aspirate may show megakaryocyte abnormalities in MPD. 2 BM trephine biop sy may show clusters of abnormal megakaryocytes and increased reticulin or fibrosis in MPD. Management 2 In reactive thrombocytosis treat the underlying condition. 2 Unusual for treat ment to 5 the platelet count to be necessary in a patient with reactive thrombocytosis. 2 Consider low dose aspirin (or if contraindicated, dipyridamole). 2 Reactive thrombocytosi s is generally transient. 2 If secondary to iron deficiency \200\224review FBC after iron therapy: the platelet count normalizes if thrombocytosis was due to iron deficiency. 2 Iron deficiency may have masked PRV \200\224this will be revealed by iron therapy. 2 If impossible to define the cause of thrombocytosis then a watch-and- wait policy should be followed in an asymptomatic patient. 2 If MPD is suspected \200\224( cid:9) Essential thrombocythaemia, p250. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 21 Clinical approach 21 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 22 Reduced platelet count Thrombocytopenia is defined as platelet count <150 109/L. Although there is no precise p latelet count at which a patient will or will not bleed, most patients with a count >50 109/L are asymptomatic. The risk of spontaneous hemorrhage increases significantly <20 1 09/L. Purpura is the most common presenting symptom and is usually found on the lower limbs and areas subject to pressure. May be followed by bleeding gums, epistaxis or more serious life-threatening hemorrhage. A patient with newly diagnosed severe thrombocytopenia with o r without purpura is a medical emergency and should be admitted for further investigation a nd treatment. 22 Confirm low platelet count by examination of the blood sample for clots and the blood movie for platelet aggregates (causing pseudothrombocy- topenia). History and examination will d etermine 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 increased con sumption. FBC may be helpful as the mean platelet volume (MPV) is often elevated in the lat ter group (large platelets may also be seen on the blood movie). May also reveal additional hematological abnormalities (normocytic anemia or neutropenia) suggestive of a bone marrow disorder. A coagulation screen should also be performed. Examination of the bone marrow is the definitive investigation in all patients with moderate or severe thrombocytopenia \200 \224may reveal normal megakaryocytes or compensatory hyperplasia in peripheral destruction syndromes or marrow hypoplasia or infiltration. Tests for platelet anti- bodies are unrelia ble but an autoimmune screen may be helpful to exclude lupus. Management Treat underlying condition. Most patients with a platelet count >30 109/L req uire no specific therapy. Avoid aspirin. In the event of life-threat- ening hemorrhage plat elet transfusion should be administered to throm- bocytopenic patients with the exception o f those with heparin-induced thrombocytopenia and TTP. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 23 Clinical approach 23 Failure of production Increased consumption Drugs & chemicals (p392) ITP (p388) Viral infection Drugs (p392) Radiation DIC (p512) Aplastic anemia (p122) Infection Leukemia Massive hemorrhage & transfusion (p524) Marrow infiltration (p120, 634) SLE Megaloblastic anemia (p60 \200\22364) CLL & lymphoma (p168, 194) HIV (p414) Heparin (p588) TTP (p530) Hypersplenism (p392) Post-transfusion purpura (p392) HIV (p414) 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 24 Easy bruising Evaluation of a patient who complains of easy bruising involves a detailed history, physica l examination with particular attention to any current haemorrhagic lesions and the perform ance of basic haemostatic investiga- tions. More common in 3 and often difficult to evaluat e. Also a frequent complaint in the elderly. 24 History Careful attention to the history is essential to the diagnosis of all the haemorrha gic disorders and one must attempt to define the nature of the bruising in a patient with t his complaint. Note: many normal healthy people believe that they have excessive bleeding o r bruising. Conversely some people with haemorrhagic disorders and abnormal bleeding histor ies will not volunteer the information unless asked directly or indeed may con- sider their bleeding to be normal. Remember that excessive bruising may be a manifestation of a blood vessel disorder rather than a coagulopathy or platelet disorder. Ask about Presenting complaint \200\224How long and how frequently has easy bruising occurr ed? Is it ecchymoses or purpura? How extensive are bruises? Are they located in areas subje ct to trauma (e.g. limbs) or pressure (e.g. waist band)? Do petechiae occur? Are bruises pa inful? Is there a palpable knot or cord? How long to resolution? How many currently? Associated symptoms Has there been gum bleeding? Has the patient experienced prolonged blee ding after skin trauma, dental extraction, childbirth or surgery? Has there been any other form of hemorrhage e.g. epistaxis, menorrhagia, joint or soft tissue haematoma, haematemesi s, melaena, haemoptysis or haematuria? Is there a history of poor wound healing? Family history Has any other family member a history of excessive bleeding or bruising? Drug history Is the patient on any medication (remember self-medication of vitamins and foo d supplements), most notably aspirin, anticoagulant therapy? Systematic enquiry Is there evidence of a disorder associated with a haemorrhagic tendency e.g. hepatic or renal failure, malabsorption, leukemia, connective tissue disorder or amylo id? Physical examination Haemorrhagic skin lesions are likely to be present in a patient with a serious problem and their distribution will often indicate the extent to which they are li kely to be related to trauma. Senile purpura is almost invariably on the hands and forearms . True purpura is easily differentiated from erythema and telangiectasis by pressure. Petec hiae are highly sugges- tive of a platelet or vascular disorder whilst palpable purpura is associated with anaphylactoid purpura. In addition there may be other physical find- ings w hich may indicate an underlying disorder e.g. splenomegaly or lym- 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 25 Clinical approach 25 phadenopathy in leukemia, signs of hepatic failure, telangiectasia in Osler \200\223Rendu \200\223Weber syndrome or hyperextensible joints and paper-thin scars in Ehlers \200\223Dan los syndrome. Basic haemostatic investigations All patients should be investigated except those in whom h istory and examination has given strong grounds for believing that they are normal and in w hom there is a history of a normal response to a haemostatic challenge e.g. surgery or dent al extraction. Screening tests 2 FBC and blood movie. 2 APTT. 2 PT. 2 Thrombin clotting time and/or fibrin ogen. 2 Bleeding time (a largely obsolete investigation, of dubious utility). If these investigations are normal there is no indication for further haemo- static investi gations unless the history provides strong grounds for believing that there is indeed a hae mostatic disorder. The appropriate further investigation of the haemostatic mechanism is di scussed in Section 10. Differential diagnoses 2 Common diagnoses \200\223 Simple easy bruising (purpura simplex). \200\223 Trauma (including non-accidenta l injury in children). \200\223 Senile purpura. 2 Haemostatic defects \200\223 Thrombocytopenia. \200\223 Platelet function defects. \200\223 Coagulation abno rmalities (rarely). 2 Vascular defects \200\223 Corticosteroid excess. \200\223 Collagen diseases. \200\223 Uraemia. \200\223 Dysproteinaemias. \200\223 Anaphylactoid purpura. \200\223 Ehlers \200\223Danlos syndrome . \200\223 Scurvy. \200\223 Vasculitis. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 26 Recurrent thromboembolism