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 A hypercoagulable state should be suspected in all patients with recurrent thromboembolic d isease, family history of thrombosis, thrombosis at a young age or at an unusual site (in a ddition to recurrent thromboem- bolism) associated with inherited thrombophilia. Further im portant aspects of the history are precipitating factors at the time of thrombosis and life style considerations e.g. smoking, exercise and obesity. Clin- ical examination may reveal signs suggestive of an associated underlying condition. 26 Hypercoagulable states Inherited Activated protein C resistance (factor V Leiden) Protein C deficiency Protein S deficiency Prothrombin gene mutation Hyperhomocysteinaemia Sickle cell disease Antithrombin deficiency and some very rare abnormalities of fibrinogen, plasminogen and plasminogen activator Acquired Immobilization Oral contraceptive or estrogen therapy Postpartum Old age Postoperative Mali gnancy (notably Ca pancreas) Nephrotic syndrome Myeloproliferative disorders Hyperhomocyste inaemia Antiphospholipid syndrome (lupus anticoagulant) Hyperviscosity Paroxysmal nocturnal haemoglobinuria Thrombotic thrombocytopenic purpura Heparin-induced thrombocytopenia Laboratory Investigation (cid:9) Thrombophilia p394. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 27 Clinical approach 27 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 28 Pathological fracture Fracture in a bone compromised by the presence of a pathological process resulting in fract ure occurring following relatively minor trauma. Most commonly due to local neoplastic invo lvement or osteoporosis. 28 Hematological causes 2 Local bony damage. 2 Myelomatous deposits. 2 Lymphoma. 2 Metastatic carcinoma ( marrow infiltration); breast, prostate and lung are commoner primary sites. 2 Gaucher \200\231s disease. 2 Sickle cell anemia. 2 Homozygous thalassaemia. 2 Osteoporosi s from prolonged corticosteroid therapy e.g. for autoim- mune disease. Clinically Presentation as local pain, discomfort and restriction of mobility. Diagnosis Confirmed by x-ray or other imaging. Management 2 Awareness of risk/possibility and early diagnosis. 2 Analgesia. 2 Orthopedic \200\224immobilization and support as appropriate for nature and site of injury, surgical i ntervention including pinning or other fixation. 2 Radiotherapy \200\224local management of fracture 2 to local malignancy. 2 Mobilization \200\224physiotherapy. 2 Treatment of underlying condition predisposing to fracture. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 29 Clinical approach 29 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 30 Raised ESR The ESR remains an established, empirical test clinically useful as a method for identifyin g and monitoring the acute phase response. It is influenced by changes in fibrinogen, a-mac roglobulins and immunoglobulins which enhance red cell aggregation in vitro. 30 Plasma viscosity is also an effective measure of acute phase reactants and can be used as a n alternative to the ESR in clinical practice; increases in ESR and plasma viscosity genera lly parallel each other. Normal ranges 2 0 \200\22310mm/h for 9 18 \200\22365 years. 2 1 \200\22320mm/h for 3 18 \200\22365 years. 2 Upper limits of normal increase by 5 \200\22310mm/h for patients >65 ye ars. 2 Other factors e.g. Hct influence the ESR. 2 Should be regarded as semiquantitative. 2 Marked elevations are clinically significant. 2 Modest elevations can be more problematic to interpret. The main advantages to the ESR are its low cost and technical simplicity allied to the abse nce of a more accurate, inexpensive and technically simple alternative. Causes of raised ESR Pregnancy Increases in pregnancy; maximal in 3rd trimester Infections Acute and chronic infections, including TB Note: 4 ESR also occurs in HIV infection Collagen disorders Rheumatoid, SLE, polymyalgia rheumatica, vasculitides etc. (including temporal arteritis); ESR useful as non-specific monitor of disease activity Other inflammatory processes Inflammatory bowel disease, sarcoidosis, post-MI Neoplastic conditions Carcinomatosis, NHL, Hodgkin \200\231s disease and paraproteinaemias (benign & malignant) Investigations Given the wide range of situations in which a raised ESR can arise, further investigation depends on a carefully conducted history and examination. In the absence of l ikely causes from these, simple initial laboratory and radi- ology assessments to include u rinalysis, full blood count and movie examina- tion, urea, electrolytes, plasma protein ele ctrophoresis, an autoimmune profile and CXR should represent a practical and pragmatic prim ary diag- nostic screen. (cid:9) p632. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 31 Clinical approach 31 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 32 Serum or urine paraprotein Differential diagnosis 32 Common 2 Monoclonal gammopathy of undetermined significance (MGUS). 2 Myeloma. 2 Solitary p lasmacytoma. 2 Lymphoproliferative disorders e.g. CLL, NHL, Waldenstr m \200\231s. Less common 2 Autoimmune disorders e.g. rheumatoid arthritis, SLE. 2 Polymyalgia rheumatica . Rare 2 AL amyloid (primary amyloid). 2 Plasma cell leukemia. 2 Heavy chain disease. Discriminating clinical features MGUS \200\224no symptoms or signs, normal FBC and biochemical profile, paraprotein level < 30g/L and stable, no immuneparesis (rarely present), BM plasma cells <10%, no lytic lesions . Plasmacytoma \200\224localized bone pain, low paraprotein level, isolated bony lesion. Myeloma \200\224symptoms and signs of anemia or hyperviscosity ((cid:9) p510); bone pain o r tenderness, raised Ca2+, creatinine, urate; high b-2 microglobulin and low albumin; immun eparesis; paraprotein >30g/L of IgG or >20g/L of IgA or heavy BenceJones proteinuria; BM >1 0% plasma cells; lytic bone lesions on x-ray. Minimum diagnostic criteria are at least 2 of emboldened items. Plasma cell leukemia \200\224as myeloma but fulminant history. Plasma cells seen on blood movie. Heavy chain disease \200\224rare, characterized by a single heavy chain only in serum or u rine electrophoresis. Presence of any light chain excludes. Amyloid \200\224myriad clinical features. Diagnosis on biopsy of affected site or, if inac cessible, by BM or rectal biopsy \200\224characteristic fibrils stain with Congo Red and s how green birefringence in polarized light. CLL and NHL \200\224systemic symptoms e.g. fever, night sweats, weight loss. Lymphadenopat hy or hepatosplenomegaly likely. Confirm on BM or node biopsy. Waldenstr m \200\231s \200\224as hyperviscosity ((cid:9) p284). for CLL but with symptoms or signs of Autoimmune disorders \200\224suggested by multisystem disease. Confirm on autoimmune profi le rheumatoid factor, ANA, ANCA. joint pain, skin rashes, including (cid:9) p272. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 33 Clinical approach 33 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 34 Anemia in pregnancy Physiological changes in red cell and plasma volume occur during pregnancy. 34 2 Red cell mass 4 by \211 30%. 2 Plasma volume 4 \211 60%. 2 Net effect to 4 blood volume by \211 50% with lowering of the normal Hb concentration to 10.0 \200\22311.0g/dL during pregnancy. MCV increases during pregnancy. 2 Iron deficiency is a common problem and cause of anemia in pregnancy. Cause of 4 requirements 4 Red cell mass Fetal requirements Placental requirements Basal los ses over pregnancy (1.0 \200\2231.5mg/d) Amount of additional Fe 500mg 300mg 5mg 250mg These result in a total requirement of \211 1000mg Fe requiring an average daily intake of 3.5 \200\2234.0mg/d. Average Western diet provides <4.0mg Fe/d so that balance is marginal during pregnancy. Diets with Fe mainly in non- haem form (e.g. vegetables) provide less Fe available for absorption. Thus a high risk of developing Fe deficiency anemia which is exa cerbated if pre- conception Fe stores are reduced. Folate requirements are increased during pregnancy because of increased cellular demands; f olate levels tend to drop during pregnancy. Prophylaxis recommendation to give 40 \200\22360mg elemental Fe/d which will increase avail ability of dietary absorbable Fe and protect against chronic Fe deficiency; debated whether supplements required by all pregnant women or only for those in at-risk socio-economic and nutritionally deficient groups. Folate supplementation is recommended for all and also app ears to reduce incidence of neural tube defects. 2 Dilutional anemia \200\224Hb seldom <10.0g/dL (requires no therapy). 2 Fe deficiency \200\224may occur with normal MCV because of 4 MCV associ- ated with pregnancy; check serum ferritin and give Fe replacement; assess and treat the underlying cause. 2 Blood loss \200\224sudden 5 in Hb may signify fetomaternal bleeding or other forms of concealed obstetric bleeding. 2 Folate deficiency \200\224macrocytic anemia in pregnancy almost invariably will be due t o folate deficiency (B12 deficiency is extremely rare during pregnancy). 2 Microangiopathic haemolysis/DIC may be seen in eclampsia or fol- lowing placental abrupti on or intrauterine death. HELLP syndrome (p34) is rare but serious cause of anemia. 2 Anemia may also arise during pregnancy from other unrelated causes and should be investigated. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 35 Clinical approach 35 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 36 Thrombocytopenia in pregnancy A normal uncomplicated pregnancy is associated with a platelet count in the normal range th ough up to 10% of normal deliveries may be associ- ated with mild thrombocytopenia (>100 109/L). Detection of thrombo- cytopenia in a pregnant patient requires consideration not o nly of the diagnoses listed in the previous section but also the conditions associated with pregnancy which cause thrombocytopenia. An additional important consideration is the possi ble effect on the fetus and its delivery. 36 If thrombocytopenia is detected late in pregnancy, most women will have a platelet count re sult from the booking visit (at 10 \200\22312 weeks) for com- parison. Mild thrombocytopeni a (100 \200\223150 109/L) detected for the first time during an uncomplicated pregnancy is not associated with any risk to the fetus nor does it require special obstetric interven tion other than hos- pital delivery. Non-immune thrombocytopenia 2 Thrombocytopenia may develop in association with pregnancy-in duced hypertension, pre-eclampsia or eclampsia. Successful treatment of hypertension may be assoc iated with improvement in thrombocy- topenia which is believed to be due to consumption. Tr eatment of hypertension, pre-eclampsia or eclampsia may necessitate delivery of the fetus w ho is not at risk of thrombocytopenia. l HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) may occur in pregnancy. 2 A number of obstetric complications, notably retention of a dead fetus, abruptio placenta e and amniotic fluid embolism, are associated with DIC ((cid:9) p512). Immune thrombocytopenia may occur in pregnancy and women with chronic ITP may become pregna nt. Therapeutic considerations must include an assessment of the risk to the fetus of trans placental passage of antiplatelet antibody causing fetal thrombocytopenia and a risk of hem orrhage before or during delivery. There is no reliable parameter for the assessment of fet al risk which, although relatively low, is most significant in women with pre-existing chro nic ITP. Note: the severity of the mother \200\231s ITP has no bearing on the fetal platele t count. Women with a platelet count <20 109/L due to ITP should receive standard predni solone therapy or IVIg ((cid:9) p388). If prednisolone fails or is contraindicated, IVIg sh ould be administered and may need to be repeated at 3 week intervals. Splenectomy should be avoided (high rate of fetal loss). Enthusiasm has waned for assessing the fetal platelet c ount during pregnancy by cordocentesis followed by platelet transfusion. Fetal scalp sampli ng in early labor is unreliable and hazardous. Delivery should occur in an obstetric unit w ith pediatric support and the neonate \200\231s platelet count should be monitored for seve ral days as delayed falls in the platelet count occur. BCSH Guidelines (2003) Guidelines for the investigation and management of idiopathic thromb o- cytopenic purpura in adults, children and in pregnancy. Br J Haematol, 120, 574 \200\223 596. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 37 Clinical approach 37 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 38 Prolonged bleeding after surgery Prolonged bleeding following surgery often requires urgent haematolog- ical opinion and inv estigation. Usually the cause of the bleeding is surgical, i.e. due to local factors, and n ot a reflection of any underlying systemic bleeding disorder. 38 History and clinical assessment 2 Past history in relation to previous haemostatic challeng es e.g. previous surgery, dental extractions. Ask specific questions about whether blood transfusion was req uired. 2 Presence of specific clinical problems e.g. impaired liver or renal function. 2 Recent dr ug history \200\224especially aspirin or NSAIDs which can affect platelet function. Also enquire about cytotoxic drugs and anticoagulants. 2 Family history of bleeding problems especially after surgery. 2 Nature of the surgery and intrinsic haemorrhagic risks of procedure. 2 Whether surgery was elective or emergency (in emergency surgery known risk factors are less likely to have been corrected). 2 Check case record or ask surgeon/anesthetist for information on intraoperative bleeding, technical problems etc. 2 Whether surgery involves a high risk of triggering DIC e.g. pancreatic or major hepatobiliary surgery. 2 Detailed physical examination is not usually practical but bruising, ecchymoses or purpura should be assessed especially if remote from the site of surgery. 2 What blood products have been used and over how long? Transfusion of several units of RBC s over a short period of time will dilute avail- able clotting factors. 2 Review preoperative investigation results and other information avail- able in the record on past procedures and/or investigations. Investigation 2 Ensure samples not taken from heparinised line. 2 FBC with platelet count a nd blood movie examination. 2 PT, APTT and fibrinogen. With normal platelets and coagulation screen bleeding is usually sur- gical and the patient should be supported with blood and urgent sur- gical re-exploration undertaken. Platelet f unction abnormalities may occur with aspirin/NSAIDs, uraemia or extracorporeal circuits. Pr olongation of both PT and APTT suggests massive bleeding and inad- equate replacement, DIC, underlying liver disease or oral anticoagu- lants. Disproportionate, isolated increases in either PT or APTR are more likely to indicate previously undiagnosed clotting factor defic ien- cies. A low platelet count may reflect dilution and consumption from bleeding or DIC i f platelets were known to be normal preoperatively. Treatment 2 Low platelets or platelet function abnormalities: Give 1 \200\2232 adult doses of platelets stat. 2 DIC \200\224give 2 adult doses of platelets are 4 units FFP (10 \200\22320 units of cryop recipitate if fibrinogen low) and recheck PT, APTT and FBC. 2 Anticoagulant effect: heparin \200\224reverse with protamine sulfate. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 39 Clinical approach 39 warfarin \200\224reverse with FFP or PCC. 2 Empirical tranexamic acid or aprotinin may be tried if bleeding con- tinues despite the above. 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 40 Positive sickle test (HbS solubility test) The decreased solubility of deoxyHbS forms the basis of this test. Blood is added to a buff ered solution of a reducing agent e.g. sodium dithionate. HbS is precipitated by the soluti on and produces a turbid appearance. Note: does not discriminate between sickle cell trait and homozygous disease. 40 Use This is a quick screening test (takes 20 mins), often used preoperatively to detect Hb S. Action if sickle test +ve 2 Delay elective operation until established whether disease or t rait. 2 Ask about family history of sickle cell anemia or symptoms of SCA. 2 FBC and movie. FBC and movie features of sickle trait vs. disease FBC \200\224 normal or 5 MCV & MCH, no anemia Movie normal (may be microcytosis or target c ells) Sickle cell trait Sickle cell disease FBC \200\224Hb 7 \200\2238g/dL (range 4 \200\22311g/dL) Movie \200\224sickled RBCs, target cells, polychromasia, basophilic stippling, NRBC (hyposplenic features in adults) 2 Hb electrophoresis. 2 Group and antibody screen serum. False +ve results 2 Low Hb. 2 Severe leucocytosis. 2 Hyperproteinaemia. 2 Unstable Hb. False \200\223ve results 2 Infants <6 months. 2 HbS <20% (e.g. following exchange blood tr ansfusion). Sickle test not recommended as a screening test in pregnancy as it will not detect other Hb variants that interact with HbS e.g. b thalassaemia trait. Standard Hb electrophoresis of at-risk groups should be performed (and of all pregnant women if a high local ethnic popula tion). 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 41 Clinical approach 41 01-Clinical approach.qxd 10.12.2003 03.53 PM Page 42 42 This page intentionally left blank 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 43 Red cell disorders 2 The peripheral blood movie in anaemias 44 Anemia in renal disease 46 Anemia in endocrine disease 48 Anemia in joint disease 50 Anemia in gastr ointestinal disease 52 Anemia in liver disease 54 Iron deficiency anemia 56 Vitamin B12 deficiency 60 Folate deficiency 62 Other causes of megaloblastic anemia 64 Anemia in other deficiency states 66 Haemolytic syndromes 68 Genetic control of hemoglobin prod uction 70 Sickling disorders 7 2 HbS \200\223 new therapies 76 Sickle cell trait (HbAS) 78 Other sickling disorders 80 Other ha emoglobinopathies 82 Unstable haemoglobins 84 Thalassaemias 86 a thalassaemia 86 b thalassaemia 88 Other thalassaemias 92 Hereditary persistence of fetal hemog lobin 93 Hb patterns in hemoglobin di sorders 94 Non-immune haemo lysis 96 Hereditary spherocytosis 98 Hereditary elliptocytosis 100 Glucose-6-phosphate dehydrogenase deficie ncy 102 Pyruvate kinase deficiency 104 Other red ce ll enzymopathies 106 Drug-induced haemolytic anemia 108 Methaemoglobinaemia 110 Microangiopathic haemolytic anemia (MAHA) 112 Acanthocytosis 114 Autoimmune haem olytic anemia 116 Co ld haemagglutinin disease (CHAD) 118 Leucoerythroblastic anemia 120 Aplastic anemia 122 Paroxysmal nocturnal haemoglobinur ia 124 Pure red cell aplasia 126 Iron overload 128 Transfusion haemosiderosis 130 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 44 The peripheral blood \201lm in anaemias Morphological abnormalities and variants Microcytic RBCs Fe deficiency, thalassaemia trait & syndromes, congenital sideroblastic anemia, anemia of c hronic disorders 44 Macrocytic RBCs Alcohol/liver disease (round macrocytes), MDS, pregnancy and newborn, haemolysis, B12 or fo late deficiency, hydroxyurea and antimetabolites (oval macrocytes), acquired sideroblastic anemia, hypothyroidism, chronic respiratory failure, aplastic anemia Dimorphic RBCs Fe deficiency responding to iron, mixed Fe and B12/folate deficiency, sideroblastic anemia, post-transfusion Polychromatic RBCs Response to bleeding or haematinic Rx, haemolysis, BM infiltration Spherocytes HS, haemolysis e.g. warm AIHA, delayed transfusion reaction, ABO HDN, DIC and MAHA, post-sp lenectomy Pencil/rod cells Fe deficiency anemia, thalassaemia trait & syndromes, PK deficiency Elliptocytes Hereditary elliptocytosis, MPD and MDS Fragmented red cells MAHA, DIC, renal failure, HUS, TTP Teardrop RBCs Myelofibrosis, metastatic marrow infiltration, MDS Sickle cells Sickle cell anemia, other sickle syndromes (not sickle trait) Target cells Liver disease, Fe deficiency, thalassaemia, HbC syndromes. Crenated red cells Usually storage or EDTA artifact. Genuine RBC crenation may be seen post-splenectomy and in renal failure Burr cells Renal failure Acanthocytes Hereditary acanthocytosis, a-b-lipoproteinaemia, McLeod red cell phenotype, PK deficiency, chronic liver disease (esp. Zieve \200\231s) Bite cells G6PD deficiency, oxidative haemolysis Basophilic stippling Megaloblastic anemia, lead poisoning, MDS, haemoglobinopathies Rouleaux Chronic inflammation, paraproteinaemia, myeloma 44 Reticulocytes Bleeding, haemolysis, marrow infiltration, severe hypoxia, response to haematinic therapy Heinz bodies Not seen in normals (removed by spleen), small numbers seen post-splenectomy, oxidant drugs , G6PD deficiency, sulphonamides, unstable Hb (Hb Zurich, K ln) Howell-Jolly bodies Made of DNA, generally removed by the spleen, dyserythropoietic states e.g. B12 deficiency, MDS, post-splenectomy, hyposplenism H bodies HbH inclusions, denatured HbH (b4 tetramer), stain with methylene blue, seen in HbH disease ( \200\223 \200\223/ \200\223 a), less prominent in a thalassaemia trait, not present in normals Hyposplenic blood movie Howell \200\223Jolly bodies, target cells, occasional nucleated RBC s, lymphocytosis, macrocytosis, acanthocytes 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 45 Red cell disorders 45 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 46 Anemia in renal disease Anemia is consistently found in the presence of chronic renal failure. Severity generally r elates to the degree of renal impairment. The domi- nant mechanism is inadequate production of erythropoietin. Other con- tributory factors include (i) suppressive effects of uraemia and (ii) 5 in RBC survival. Uraemia impairs platelet function leading to blood loss and Fe deficiency. Small amounts of blood are inevitably left in the tubing fol- lowing dialysis so that blood loss and Fe deficiency are further contribu- in dialysis and tory supplementa tion is required to avoid deficiency. Aluminum toxicity (from trace amounts in dialysis flu ids) and osteitis fibrosa from hyperparathy- roidism are rare contributory factors. 46 factors in dialysis patients. Folate is lost Laboratory features 2 Hb typically 5.0 \200\22310.0g/dL. 2 MCV 6. 2 Blood movie \200\224 m ostly normochromic RBCs; schistocytes and acantho- cytes present. No specific abnormalities in WBC or platelets. 2 Microangiopathic haemolytic changes present in vasculitic collagen dis- orders with renal failure and classically in HUS and TTP. Management 2 Short term treatment with RBC transfusion, based on symptoms (not Hb). 2 Corre ction of Fe and folic acid deficiencies. 2 Erythropoietin (Epo) will correct anemia in most patients. Start at 50 \200\223100units/kg SC 3/week. Give IV iron at same time. Response apparent <10 weeks; reduced doses required as mainte- nance. Renal Association guidelines have been produced for applica- tion and monitoring of Epo therapy. Although expensive it improves qu ality of life and avoids transfusion dependency and iron overload. Side effects of Epo 2 4 BP. 2 Pure red cell aplasia. 2 Thrombotic tendency. Blood movie: chronic renal failure with burr (irregular shaped) cells. (cid:27) www.nephronline.org/standards3/ 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 47 Red cell disorders 47 Eschbach, J.W. et al. (1987) Correction of the anemia of end-stage renal disease with recom binant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med, 316, 73 \200\22378; Levin, N., et al. (1997) National Kidney Foundation: Dialysis Outc ome Quality Initiative develop- ment of methodology for clinical practice guidelines. Neph rol Dial Transplant, 12, 2060 \200\2232063. 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 48 Anemia in endocrine disease Anemia and other hematological effects occur in various endocrine dis- orders. The abnormal ities will usually correct as the endocrine abnor- mality is corrected. Pituitary disorders 48 Deficiency/hypopituitarism is associated with normochromic, normo- cytic anemia; associated leucopenia may also occur. Abnormalities correct as normal function is restored, by replac ement therapy. Thyroid disorders Hypothyroidism may produce a mild degree of anemia; MCV usually 4 but may be normal. Corrects on restoration of normal thyroid function. Menorrhagia occurs in hypot hyroidism and can result in associated Fe deficiency. B12 levels should be checked because of the association with other autoimmune disorders (e.g. pernicious anemia). Thyrotoxicosis may be associated with mild degrees of normochromic anemia in 20% of cases w hich corrects as function is normalized. Erythroid activity is increased but a disproportio nate increase in plasma volume means either no change in Hb concentration or mild anemia. H aematinic deficiencies occur and should be excluded. Adrenal disorders Hypoadrenalism results in normochromic, normocytic anemia; the plasma volume is 5 which mas ks the true degree of associated anemia. The abnormalities are corrected by replacement min eralocorticoids. Hyperadrenalism (Cushing \200\231s) results in erythrocytosis with a typical net increase i n Hb (by 1 \200\2232g/dL). Occurs whether Cushing \200\231s is primary or iatrogenic. Mecha nism is unclear. Parathyroid disorders \200\224hyperparathyroidism may be associated with anemia from impai rment of erythropoietin production, or in some cases from secondary marrow sclerosis. Sex hormones \200\224androgens are occasionally used to stimulate red cell production in a plastic anemia. The influence of androgens explains the higher Hb in adult 9 cf. 3. Diabete s mellitus when poorly controlled may be associated with anemia; however, the majority of h ematological abnormalities in diabetes mellitus result from secondary disease related compl ications e.g. renal failure. stimulate erythropoiesis and 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 49 Red cell disorders 49 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 50 Anemia in joint disease Rheumatoid arthritis, psoriatic arthropathy and osteoarthritis may be complicated by anemia . Various factors contribute to anemia, com- monly more than one is present, especially in rheumatoid arthritis. Some of the mechanisms that give rise to anemia in rheumatoid also ap ply in other connective tissue disease, e.g. SLE, polyarteritis nodosa, etc. 50 Anemia of chronic disorders (ACD) ACD is a cytokine-driven suppression of red cell producti on. The clinical problem is to being able to recognize the presence of other contributory f actors in pathogenesis of the anemia. Bone marrow macrophages fail to pass their stored iro n to developing RBCs and a lower than expected rise in erythropoietin suggesting some inhib ition in its pathway. Marrow also appears less responsive to Epo. 4 IL-1 has been identifie d. Detailed studies suggest a synergistic effect of IL-1 with T-cells to produce IFN-g whic h can suppress erythroid activity. May also be 4 levels of TNF-a which inhibits erythropoie sis through release of IFN-b from marrow stromal cells. Typical features of ACD 2 Hb range 7.0 \200\22311.0g/dL. 2 MCV is usually 6 but when longst anding the MCV is moderately 5 (may look like iron deficiency). 2 Ferritin usually 6 but may be 4. 2 Serum iron 6 or 5, TIBC 6 or 5. 2 Serum transferrin re ceptor levels normal. 2 Bone marrow Fe stores plentiful. Additional mechanisms of anemia in rheumatoid disease Autoimmune phenomena Warm antibody AIHA in association with rheumatoid and other collagen disorders; movie will show reticulocytosis and +ve DAT Red ce ll aplasia Drug related problems Chronic blood loss (caused by medication) Drug side effects e.g. macrocytosis from antimeta bolite immunosuppressives, e.g. azathioprine and methotrexate, oxidative haemolysis seconda ry to dapsone or sulfasalazine (occurs in normal individuals as well as those with G6PD def iciency) Anemia secondary to gold therapy for rheumatoid arthritis Idiosyncratic reactions, unexplained or unforeseeable reactions such as marrow aplasia Rare autoimmune haemolysis d ue to mefenamic acid, diclofenac or ibuprofen 2 to other organ problems Hypersplenism, Felty \200\231s syndrome in rheumatoid, renal failure in SLE or polyarteritis 02-red cell disorders.qxd 10.12.2003 04.10 PM Page 51