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 Easy bruising Evaluation of a patient who complains of easy bruising involves a detailed hi story, physical examination with particular attention to any current haemorrhagic lesions, and the performance of basic haemostatic investigations. More common in \231\200 and often diffi cult to evaluate. Also a frequent complaint in the elderly. History Careful attentio n to the history is essential to the diagnosis of all the haemorrhagic disorders and one mu st attempt to defi ne the nature of the bruising in a patient with this complaint. Note: ma ny normal healthy people believe that they have excessive bleeding or bruising. Conversely some people with haemorrhagic disorders and abnormal bleeding his- tories will not voluntee r the information unless asked directly or indeed may consider 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 a nd how frequently has easy bruising occurred? Is it ecchymoses or purpura? How extensive ar e bruises? Are they located in areas subject to trauma (e.g. limbs) or pressure (e.g. waist band)? Do petechiae occur? Are bruises painful? How long to reso- lution? How many current ly? Associated symptoms Has there been gum bleeding? Has the patient experienced prolonged bleeding after skin trauma, dental extraction, childbirth, or surgery? Has there been any o ther form of hemorrhage, e.g. epistaxis, menorrhagia, joint or soft tissue haematoma, haema temesis, melaena, haemoptysis, or haematuria? Is there a history of poor wound healing? Fam ily history Has any other family member a history of excessive bleeding or bruising? Drug h istory Is the patient on any medication (remember self-medication of vitamins and food supp lements), most notably aspirin, anticoagulant therapy? Systematic enquiry Is there evidence of a disorder associated with a haemorrhagic tendency, e.g. hepatic or renal failure, mala bsorption, leukemia, lymphoma, con- nective tissue disorder, or amyloidosis? Physical exami nation Haemorrhagic skin lesions are likely to be present in a patient with a serious probl em and their distribution will often indicate the extent to which they are likely to be rel ated to trauma. Senile purpura is almost invariably on the hands and forearms. True purpura is easily diff erenti- ated from erythema and telangiectasis by pressure. Petechiae are hi ghly suggestive of a platelet or vascular disorder whilst palpable purpura are associated w ith anaphylactoid purpura. In addition there may be other physical fi ndings which may indi cate an underlying disorder, e.g. spleno- 21 EASY BRUISING megaly or lymphadenopathy in leukemia or lymphoma, signs of hepatic failure, telangiectasia in hereditary haemorrhagic telangiectasia (HHT or Osler \200\223Rendu \200\223Weber syndro me) or hyperextensible joints and paper- thin scars in Ehlers \200\223Danlos 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 den tal extraction. Screening tests \200 FBC and blood fi lm. \200 Activated partial thromboplastin time (A PTT). \200 Prothrombin time (PT). \200 Thrombin clotting time and/or fi brinogen. \200 Bleeding time is now an obsolete investigation of dubious value and no longer performed. If these investigations are normal there is no indication for further haemo static investig ations unless the history provides strong grounds for believing that there is indeed a haem ostatic disorder. The appro- priate further investigation of the haemostatic mechanism is d iscussed in Chapter 10 (E Haemostasis and thrombosis, p.453). Diff erential diagnoses \200 Common diagnoses: Simple easy bruising (purpura simplex). \200 Trauma (including non-accidental injury in c hildren). \200 Senile purpura. \200 Haemostatic defects: Thrombocytopenia. \200 Platelet function defects. \200 Coagulation abnormalities (rarel y). \200 Patient on anticoagulant drugs or anti-platelet agents. Vascular defects: Corticosteroid use/excess. \200 Collagen diseases. \200 Uraemia. \200 Dysproteinaemia s. \200 Anaphylactoid purpura. \200 Ehlers \200\223Danlos syndrome. \200 Scurvy. \200 Vasculitis. 22 CHAPTER 1 Clinical approach Recurrent thromboembolism A hypercoagulable state should be suspected in all patients with recur- rent thromboembolic disease, family history of thrombosis, thrombosis at a young age or at an unusual site (in addition to recurrent thrombo- embolism) associated with inherit ed thrombophilia (see Table 1.7). Further important aspects of the history are precipitatin g factors at the time of thrombosis and lifestyle considerations, e.g. smoking, exercise, a nd obesity. Clinical examination may reveal signs suggestive of an asso- ciated underlying condition. Table 1.7 Hypercoagulable states Activated protein C resistance (factor V Leiden) Inherited Protein C defi ciency Protein S defi ciency Prothrombin gene mutation Hyperhomocysteinaemia Sickle cell disease Antithrombin defi ciency and some very rare abnormalities of fi brinogen, plasminogen, and plasminogen activator Immobilization Acquired Oral contraceptive or estrogen therapy Postpartum Old age Postoperative Malignancy (notably Ca pancreas) Nephrotic syndrome Myeloproliferative disorders Hyperhomocysteinaemia Antiphospholipid syndrome (lupus anticoagulant) Hyperviscosity Paroxysmal nocturnal haemoglobinuria Thrombotic thrombocytopenic purpura Heparin-induced thrombocytopenia Laboratory investigation E See Thrombophilia, p.530. Further reading Kyrle, P.A., et al. (2004.) The risk of recurrent venous thromboembolism in men and women. N Engl J Med, 350, 2558 \200\22363. 23 PATHOLOGICAL FRACTURE Pathological fracture Fracture in a bone compromised by the presence of a pathological proc ess resulting in fracture following relatively minor trauma. Most commonly due to local neo plastic involvement or osteoporosis. Hematological causes \200 Local bony damage. \200 Myelomatous deposits, solitary bone p lasmacytoma (SBP). \200 Lymphomatous infi ltration. \200 Metastatic carcinoma ( marro w infi ltration); breast, prostate, and lung are most common 1 sites. Gaucher disease. \200 Sickle cell anemia. \200 Homozygous thalassaemia. \200 Osteopor osis from prolonged corticosteroid therapy, e.g. for autoimmune or respiratory disease. Clinically Presentation as local pain, discomfort, and restriction of mobility. Diagnosis Confi rmed by x-ray or other imaging. Management \200 Awareness of risk/possibility and early diagnosis. \200 Analgesia. \200 Orthopedic \200\224immobilization and support as appropriate for nature and site of i njury, surgical intervention including pinning or other fi xation. Radiotherapy \200\224local management of fracture 2 to local malignancy. If patient eligi ble for orthopedic/spinal surgery then radiotherapy post-surgery. Mobilization \200\224physiotherapy. \200 Treatment of underlying condition predisposing t o fracture. \200 Prophylactic surgery/pinning of critical lesions. 24 CHAPTER 1 Clinical approach Raised ESR The ESR remains an established, empirical test clinically useful as a method for identifying and monitoring the acute phase response. It is infl uenced by changes in fi br inogen, -macroglobulins, and immunoglob- ulins which enhance red cell aggregation in vitr o. (see Table 1.8). Plasma viscosity (PV) is also an eff ective measure of acute phase reac- tants and can be u sed as an alternative to the ESR in clinical practice; i in ESR and plasma viscosity genera lly parallel each other. PV is not readily available in all laboratories. Normal ranges \200 0 \200\22310mm/h for \231\202 18 \200\22365 years. \200 1 \200\2232 0mm/h for \231\200 18 \200\22365 years. \200 Upper limits of normal i by 5 \200\22310mm/ h for patients >65 years. \200 Other factors, e.g. haematocrit (Hct) infl uences the ESR. \200 Should be regarded as semiquantitative. \200 Marked elevations are clinically sig nifi cant. \200 Modest elevations can be more problematic to interpret and are non-specifi c. 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. Table 1.8 Causes of raised ESR i in pregnancy; maximal in 3rd trimester Pregnancy Acute and chronic infections, including TB Note:i ESR also occurs in HIV infection Infections Rheumatoid, SLE, polymyalgia rheumatica, vasculitides, etc. (including temporal arteritis); ESR useful as non-specifi c monitor of disease activity Collagen disorders Infl ammatory bowel disease, sarcoidosis, post-MI Other in \202 ammatory processes Carcinomatosis, NHL, Hodgkin lymphoma and paraproteinaemias (benign and malignant) Neoplastic conditions 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, FBC and blood fi lm examination, urea, electrolytes, serum protein electrophores is, an autoimmune profi le, and CXR should represent a practical and pragmatic 1 diagnost ic screen. E See Hematological investigations, p.745. Further reading Gabay, C., et al. (1999). Acute-phase proteins and other systemic responses to infl ammation. N Engl J Med, 340, 448 \200\22354. 25 SERUM OR URINE PARAPROTEIN Serum or urine paraprotein Diff erential diagnosis Common \200 Monoclonal gammopathy of undetermined signifi cance ( MGUS). \200 Smoldering myeloma. \200 Multiple myeloma. \200 Solitary bone or extra-os seus plasmacytoma. \200 Lymphoproliferative disorders, e.g. CLL, NHL, Waldenstr m. Less common \200 Autoimmune disorders, e.g. rheumatoid arthritis, SLE. \200 Polymyalgia rheu matica. Rare \200 AL amyloid (1 amyloid). \200 Plasma cell leukemia. \200 Heavy chain disea se. Discriminating clinical features MGUS \200\224no symptoms or signs of end-organ damage, nor mal FBC and biochemical profi le, paraprotein level <30g/L and stable, immuneparesis (rarel y present), BM plasma cells <10%, no lytic lesions. Smoldering myeloma \200\224as for MGUS but higher stable paraprotein level >30g/L or BM plasma cells >10% without end-organ damage . Plasmacytoma \200\224localized bone pain, low paraprotein level, isolated bony lesion. My eloma \200\224symptoms and signs of anemia or hyperviscosity (E see Hyperviscosity, p.646); bone pain or tenderness, lytic bone lesions, raised Ca2+, creatinine, urate; high 2 micr oglobulin and low albumin; immunepa- resis; In the presence of myeloma related organ or tis sue impairment, no minimum level for serum paraprotein or BM plasma-cell percentage. Plasma cell leukemia \200\224as myeloma but fulminant history. Plasma cells seen on blood fi lm. Heavy chain disease \200\224rare, characterized by a single heavy chain only in serum or ur ine electrophoresis. Presence of any light chain excludes. Amyloid \200\224myriad clinical features. Diagnosis on biopsy of aff ected site or, if inaccessible, by BM or rectal biopsy \200\224characteristic fi brils stain with Congo Red and show green birefringence in polar ized light. CLL and NHL \200\224systemic symptoms, e.g. fever, night sweats, weight loss. L ymphadenopathy or hepatosplenomegaly likely. Confi rm on BM or node biopsy. Waldenstr m \200\224as for CLL but with symptoms or signs of hyperviscosity (E Waldenstr m macroglobul inaemia, p.368). Autoimmune disorders \200\224suggested by joint pain, skin rashes, multisy stem disease. Confi rm on autoimmune profi le including rheumatoid factor, ANA, ANCA. E See Multiple myeloma, p.336. 26 CHAPTER 1 Clinical approach Anemia in pregnancy Physiological changes in red cell and plasma volume occur during pregna ncy. \200 Red cell mass i by \211 30%. \200 Plasma volume i \211 60%. \200 Net eff ect to i blood volume by \211 50% with lowering of the normal. \200 Hb concentration to 10.0 \200\22311.0g/dL during pregnancy. MCV i during pregnancy. Fe defi ciency is a common problem and cause of anemia in pregnancy (see Table 1.9). Table 1.9 Iron utilization in pregnancy Cause of i requirements Amount of additional Fe i Red cell mass 7500mg Fetal requirements 7300mg Placental requirements 75mg Basal losses over pregnancy (1.0 \200\2231.5mg/d) 7250mg 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 absorp- tion. Thus a high risk of developing Fe defi ciency anemia which is e xac- erbated if preconception Fe stores are reduced. Folate requirements are i during pregn ancy because of i cellular demands; folate levels tend to drop during pregnancy. Prophylaxi s recommendation to give 40 \200\22360mg elemental Fe/d which will i availability of dietar y absorbable Fe and protect against chronic Fe defi ciency; debated whether supplements req uired by all pregnant women or only for those in at-risk socio economic and nutritionally d efi - cient groups. Folate supplementation is recommended for all and also appears to reduc e incidence of neural tube defects. \200 Dilutional anemia \200\224Hb seldom <10.0g/dL (r equires no therapy). \200 Fe defi ciency \200\224may occur with normal MCV because of i M CV associated with pregnancy; check serum ferritin and give Fe replacement; assess and trea t the underlying cause. Blood loss \200\224sudden d in Hb may signify fetomaternal bleeding or other forms of concealed obstetric bleeding. Folate defi ciency \200\224macrocytic anemia in pregnancy almost invariably will be due to folate defi ciency (B12 defi ciency is extremely rare during pregnancy). Microangiopathic haemolysis/disseminated intravascular coagulation (DIC) may be seen in ecl ampsia or following placental abruption or intrauterine death. HELLP syndrome (E p.96) is a rare but serious cause of anemia. Anemia may also arise during pregnancy from other unrelated causes and should be investigated. 27 THROMBOCYTOPENIA IN PREGNANCY Thrombocytopenia in pregnancy A normal uncomplicated pregnancy is associated with a platele t count in the normal range though up to 10% of normal deliveries may be associated with mi ld thrombocytopenia (>100 \227 109/L). Detection of thrombocytopenia in a pregnant patient requires consideration not only of the diagnoses listed in the previous topic (E Anemia in pregnancy, p.26) but also the conditions associated with pregnancy which cause thrombocyto penia. An additional important consideration is the possible eff ect on the fetus and its d elivery. 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 comparison. Mild thrombocytopenia (100 \200\223150 \227 109/L) detected for the fi rst time during an uncomplicated pregnanc y is not associated with any risk to the fetus nor does it require special obstetric interv ention other than hospital delivery. Non-immune thrombocytopenia \200 Thrombocytopenia may develop in association with pregnan cy- induced hypertension, pre-eclampsia, or eclampsia. Successful treatment of hypertension may be associated with improvement in thrombocytopenia which is believed to be due to cons umption. Treatment of hypertension, pre-eclampsia, or eclampsia may necessitate delivery of the fetus who is not at risk of thrombocytopenia. HELLP syndrome (haemolysis, elevated liv er enzymes, and low platelets) may occur in pregnancy. A number of obstetric complications, notably retention of a dead fetus, abruptio placentae, and amniotic fl uid embolism, are associated with DIC (E Dissemi nated intravascular coagulation, p.494). 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 signifi cant in women with pre-existing chr onic ITP. Note: the severity of the mother \200\231s ITP has no bearing on the fetal platel et count. Women with a platelet count <20 \227 109/L due to ITP should receive standard pr ednisolone therapy or IVIg (E Immune thrombocy- topenia, p.492). If prednisolone fails or i s contraindicated, IVIg should be administered and may need to be repeated at 3-week interv als. Splenectomy should be avoided (high rate of fetal loss). Enthusiasm has waned for asse ssing the fetal platelet count during pregnancy by cordo- centesis followed by platelet tra nsfusion. Fetal scalp sampling in early labor is unreliable and hazardous. Delivery should occur in an obstetric unit with pediatric support and the neonate \200\231s platelet count should be monitored for several days as delayed falls in the platelet count occur. Further reading BCSH Guidelines (2003). Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol, 12 0, 574 \200\22396. 28 CHAPTER 1 Clinical approach Prolonged bleeding after surgery Prolonged bleeding following surgery often requires urgent haemato- logical opinion and investigation. The cause of the bleeding is usually surgical, rather than due to any underlying systemic bleeding disorder. History and clinical assessment \200 Past history in relation to previous haemostatic cha llenges, e.g. previous surgery, dental extractions. Ask specifi c questions about whether blood transfusi on was required. Presence of specifi c clinical problems, e.g. impaired liver or renal function. \200 Rece nt drug history \200\224especially aspirin or NSAIDs which can aff ect platelet function. Also enquire about cytotoxic drugs and anticoagulants. Family history of bleeding problems especially after surgery. \200 Nature of the surgery and intrinsic haemorrhagic risks of procedure. \200 Whether surgery was elective or emerg ency (in emergency surgery known risk factors are less likely to have been corrected). Check case record or ask surgeon/anesthetist for information on intraoperative bleeding, technical problems, etc. Whether surgery involves a high risk of triggering DIC, e.g. pancreatic or major hepatobiliary surgery. Detailed physical examination is not usually practical but bruising, ecchymoses, or purpura should be assessed especially if remote from the site of surgery. What blood products have been used and over how long? Transfusion of several units of RBCs over a short period of time will dilute available clot ting factors. Review preoperative investigation results and other information available in the record on past procedures and/or investigations. Investigations \200 Ensure samples not taken from heparinized line. \200 FBC with plate let count and blood fi lm examination. \200 PT, APTT, and fi brinogen. With normal platelets and coagulation screen bleeding is usually surgical and the patient s hould be supported with blood and urgent surgical re-exploration undertaken. Platelet funct ion abnormalities may occur with aspirin/NSAIDs, uraemia, or extracorporeal circuits. Prolo ngation of both PT and APTT suggests massive bleeding and inadequate replacement, DIC, unde rlying liver disease, or oral antico- agulants. Disproportionate, isolated i in either PT o r APTR are more likely to indicate previously undiagnosed clotting factor defi ciencies. A low platelet count may refl ect dilution and consumption from bleeding or DIC if platelets were known to be normal preoperatively. Treatment \200 Low platelets or platelet function abnormalities: give 1 \200\2232 adult d oses of platelets stat. DIC \200\224give 2 adult doses of platelets and 4 units fresh frozen plasma (FFP) (10 \200 \22320 units of cryoprecipitate if fi brinogen low) and recheck PT, APTT, and FBC. 29 PROLONGED BLEEDING AFTER SURGERY Anticoagulant eff ect: Heparin \200\224reverse with protamine sulfate. \200 Warfarin \200\224reverse with FFP or PCC. Empirical tranexamic acid or aprotinin may be tried if bleeding continues despite the above. Further reading Michel, M., et al. (2003). Intravenous anti-D as a treatment for immune thr ombocytopenic purpura (ITP) during pregnancy. Br J Haematol, 123, 142 \200\2236. 30 CHAPTER 1 Clinical approach Positive sickle test (HbS solubility test) The d solubility of deoxyHbS forms the basis of this test. Blood is added to a buff ered solution of a reducing agent e.g. sodium dithionat e. HbS is precipitated by the solution and produces a turbid appearance. Note: does not dis criminate between sickle cell trait and homozygous disease. Use This is a quick screening test (takes 720min), often used preoperatively to detect HbS. Action if sickle test +ve \200 Delay elective operation until established whether disease or trait. \200 Ask about family history of sickle cell anemia or symptoms of SCA. \200 FBC and fi lm (Table 1.10). \200 Hb electrophoresis, or more commonly HPLC. \200 Group and antibody screen serum. False +ve results \200 Low Hb. \200 Severe leucocytosis. \200 Hyperproteinaemia. \200 Unstable Hb. False \210\222ve results \200 Infants <6 months. \200 HbS <20% (e.g. following exchang e blood transfusion). Sickle test not recommended as a screening test in pregnancy as it will not detect other Hb variants that interact with HbS e.g. thalassaemia trait. Standard Hb electrophoresis of at-risk groups should be per- formed (and of all pregnant women if a high local ethnic pop ulation). Table 1.10 FBC and fi lm features of sickle trait vs. disease FBC \200\224normal or d MCV and MCH, no anemia Movie normal (may be microcytosis or target cells) Sickle cell trait FBC \200\224Hb 77 \200\2238g/dL (range 74 \200\22311g/dL) Sickle cell disease Movie \200\224sickled RBCs, target cells, polychromasia, basophilic stippling, NRBC (hyposp lenic features in adults) Further reading Balasubramaniam, J., et al. (2001) Evaluation of a new screening test for s ickle cell hemoglobin. Clin Lab Haematol, 23, 379 \200\22383. 31 Chapter 2 Red cell disorders The peripheral blood fi lm in anaemias 32 Anemia in renal disease 34 Anemia in endocrine di sease 36 Anemia in joint disease 38 Anemia in gastrointestinal disease 40 Anemia in liver d isease 41 Iron (Fe) defi ciency anemia 42 Vitamin B12 defi ciency 46 Folate defi ciency 48 Other causes of megaloblastic anemia 50 Anemia in other defi ciency states 51 Haemolytic sy ndromes 52 Genetic control of hemoglobin production 54 Sickling disorders 56 HbS \200\224si ckle-modifying therapies 62 Sickle cell trait (HbAS) 64 Other sickling disorders 65 Other h aemoglobinopathies 66 Unstable haemoglobins 68 Thalassaemias 70 thalassaemia 72 thala ssaemia 74 Other thalassaemias 79 Hereditary persistence of fetal hemoglobin 80 Hb patterns in hemoglobin disorders 81 Non-immune haemolysis 82 Hereditary spherocytosis 84 Hereditary elliptocytosis 87 Glucose-6-phosphate dehydrogenase (G6PD) defi ciency 88 Pyruvate kinase defi ciency 91 Other red cell enzymopathies 92 Drug-induced haemolytic anemia 94 Methaemogl obinaemia 95 Microangiopathic haemolytic anemia 96 Acanthocytosis 97 Autoimmune haemolytic anemia 98 Cold haemagglutinin disease 100 Leucoerythroblastic anemia 101 Aplastic anemia 10 2 Paroxysmal nocturnal haemoglobinuria 104 Pure red cell aplasia 106 Fe overload 107 Transf usion haemosiderosis 110 32 CHAPTER 2 Red cell disorders The peripheral blood \201 lm in anaemias Basic evaluation in anemia includes the microsco pic examination of the red blood cells. These may show features suggestive of the underlyin g cause of the anemia as shown in Table 2.1. 33 THE PERIPHERAL BLOOD movie IN ANAEMIAS Table 2.1 Morphological abnormalities and variants Microcytic RBCs Fe defi ciency, thalassaemia trait and syndromes, congenital sideroblastic anemia, anemia of chronic disorders Macrocytic RBCs Alcohol/liver disease (round macrocytes), MDS, pregnancy and newborn, haemolysis, B12 or folate defi ciency, hydroxyurea and antimetabolites (oval m acrocytes), acquired sideroblastic anemia, hypothyroidism, chronic respiratory failure, apl astic anemia Dimorphic RBCs Fe defi ciency responding to Fe, mixed Fe and B12/folate defi ciency, sideroblastic anemia, post-transfusion Response to bleeding or haematinic Rx, haemolysis, BM infi ltration Polychromatic RBCs HS, haemolysis, e.g. warm AIHA, delayed transfusion reaction, ABO HDN, DIC, and MAHA, post- splenectomy Spherocytes Fe defi ciency anemia, thalassaemia trait and syndromes, PK defi ciency Pencil/rod cells Hereditary elliptocytosis, MPD, and MDS Elliptocytes MAHA, DIC, renal failure, HUS, TTP Fragmented RBCs Teardrop RBCs Myelofi brosis, metastatic marrow infi ltration, MDS Sickle cell anemia, other sickle syndromes (not sickle trait) Sickle cells Liver disease, Fe defi ciency, thalassaemia, HbC syndromes Target cells Usually storage or EDTA artifact. Genuine RBC crenation may be seen post-splenectomy and in renal failure Crenated red cells Renal failure Hereditary acanthocytosis, a- -lipoproteinaemia, McLeod red cell phenotype, PK defi ciency, chronic liver disease (esp. Zieve \200\231s) Burr cells Acanthocytes G6PD defi ciency, oxidative haemolysis Bite cells Megaloblastic anemia, lead poisoning, MDS, haemoglobinopathies Basophilic stippling Chronic infl ammation, paraproteinaemia, myeloma Rouleaux Bleeding, haemolysis, marrow infi ltration, severe hypoxia, response to haematinic therapy i reticulocytes Not seen in normals (removed by spleen), small numbers seen post-splenectomy, oxidant drugs , G6PD defi ciency, sulfonamides, unstable Hb (Hb Zurich, K ln) Heinz bodies Made of DNA, generally removed by the spleen, dyserythropoietic states, e.g. B12 defi cienc y, MDS, post- splenectomy, hyposplenism HbH inclusions, denatured HbH ( 4 tetramer), stain with methylene blue, seen in HbH disease ( \210\222 \210\222/ \210\222 ), less prominen t in thalassaemia trait, not present in normals Howell \200\223Jolly bodies, target cell s, occasional nucleated RBCs, lymphocytosis, macrocytosis, acanthocytes Howell \200\223Jolly bodies H bodies Hyposplenic blood \201 lm 34 CHAPTER 2 Red cell disorders Anemia in renal disease Anemia is consistently found in the presence of chronic renal failu re since the kidneys are the main source of erythropoietin. Severity gen- erally relates to the degree of renal impairment although anemia may occur even if modest renal impairment. The dominant mechanism is inadequate production of erythropoietin (EPO). Other contributory factors include (i) suppressive eff ects of uraemia and (ii) d in RBC sur- vival. Uraemia impairs platelet function l blood loss and Fe defi ciency. Small amounts of blood are inevi tably left in the tubing following dialysis so that blood loss and Fe defi ciency are furth er contributory factors in dialysis patients. Folate is lost in dialysis and supplementatio n is required to avoid defi ciency. Aluminum toxicity (from trace amounts in dialysis fl ui ds) and osteitis fi brosa from hyperparathyroidism are rare contribu- tory factors. Laboratory features \200 Hb typically 5.0 \200\22310.0g/dL. \200 MCV n. \200 Blood fi lm \200\224mostly normochromic RBCs; schistocytes and acanthocytes present. No specifi c abnormalities in WBC or platelets (see Fig 2.1). Microangiopathic haemolytic changes present in vasculitic collagen disorders with renal failure and classically in HUS and TTP. Management \200 Short-term treatment with RBC transfusion, based on symptoms (not Hb concentration). Correction of Fe and folic acid defi ciencies. \200 EPO will correct anemia in most patie nts. \200 Start at 50 \200\223100 units/kg SC \227 3/week. Give IV Fe at same time. Response apparent <10 weeks; reduced doses required as maintenance. Renal Association guide lines have been produced for application and monitoring of EPO therapy. Although expensive it improves quality of life and avoids transfusion dependency and Fe overload. Side eff ects of EPO \200 i BP. \200 Pure red cell aplasia. \200 Thrombotic tendency. 35 anemia IN RENAL DISEASE Fig. 2.1 Blood fi lm: chronic renal failure with burr (irregular shaped) cells (E see color plate section). Further reading Eschbach, J.W. et al. (1987). Correction of the anemia of end-stage renal d isease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med, 316, 73 \200\2238. Levin, N. et al. (1997). National Kidney Foundatio n: Dialysis Outcome Quality Initiative \200\223 development of methodology for clinical pra ctice guidelines. Nephrol Dial Transplant, 12, 2060 \200\2233. 36 CHAPTER 2 Red cell disorders Anemia in endocrine disease Anemia and other hematological eff ects occur in various endocr ine disorders. The abnormalities will usually correct as the endocrine abnor- mality is cor rected. Pituitary disorders De \201 ciency/hypopituitarism is associated with normochromic, normoc ytic anemia; associated leucopenia may also occur. Abnormalities correct as normal function is restored, by replacement therapy. Thyroid disorders Hypothyroidism may produce a mild degree of anemia; MCV usually i but may be normal. Corrects on restoration of normal thyroid function. Menorrhagia occurs in hypot hyroidism and can result in associated Fe defi ciency. 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 i but a disproportionate inc rease in plasma volume means either no change in Hb concentration or mild anemia. Haematini c defi ciencies occur and should be excluded. Adrenal disorders Hypoadrenalism results in normochromic, normocytic anemia; the plasma vol ume is d which masks the true degree of associated anemia. The abnormalities are corrected by replacement mineralocorticoids. 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 1 or iatro- genic. Mechani sm is unclear. Parathyroid disorders \200\224hyperparathyroidism may be associated with anemia from impair ment of EPO production, or in some cases from 2 marrow sclerosis. Sex hormones \200\224androgens stimulate erythropoiesis and are occasionally used to stimul ate red cell production in aplastic anemia. The infl uence of androgens explains the higher Hb in adult \231\202 compared with \231\200. Diabetes mellitus when poorly controlled ma y be associated with anemia; however, the majority of hematological abnormalities in dia- b etes mellitus result from 2 disease-related complications, e.g. renal failure. Further reading Spivak, J.L. (2000). The blood in systemic disorders. Lancet, 355, 1707 \200\22312. 37 anemia IN ENDOCRINE DISEASE 38 CHAPTER 2 Red cell disorders Anemia in joint disease Rheumatoid arthritis, psoriatic arthropathy, and osteoarthritis may be com- plicated by anemia. Various factors contribute to anemia; commonly more than one i s present, especially in rheumatoid arthritis. Some of the mechanisms that give rise to ane mia in rheumatoid also apply in other con- nective tissue disease, e.g. SLE, polyarteritis nodosa, etc. (see Table 2.2) Anemia of chronic disorders (ACD) ACD is a cytokine-driven suppression of red cell producti on. The clinical problem is being able to recognize the presence of other contributory fact ors in the pathogenesis of the anemia. BM macrophages fail to pass their stored Fe to devel oping RBCs and a lower than expected rise in EPO suggests some inhibition in its pathway. M arrow also appears less responsive to EPO. i IL-1 has been identifi ed. Detailed studies su ggest a synergistic eff ect of IL-1 with T-cells to produce IFN- which can sup- press ery throid activity. May also be an i level of TNF- which inhibits erythropoiesis through rel ease of IFN- from marrow stromal cells. Typical features of ACD \200 Hb range 7.0 \200\22311.0g/dL. \200 MCV is usually n but w hen longstanding the MCV is moderately d (may look like Fe defi ciency). \200 Ferritin usually n but may be i. \200 Serum Fe n o r d, TIBC n or d. (Note: Fe and TIBC tests now obsolete). Serum transferrin receptor levels normal. \200 i zinc protoporphyrin level. \200 BM Fe stores plentiful. Table 2.2 Additional mechanisms of anemia in rheumatoid disease Warm antibody AIHA in association with rheumatoid and other collagen disorders; fi lm will show reticulocytosis and +ve DAT Autoimmune phenomena Red cell aplasia Chronic blood loss (caused by medication) Drug-related problems Drug side eff ects e.g. macrocytosis from antimetabolite immunosuppressives, e.g. azathiopr ine and methotrexate, oxidative haemolysis 2 to dapsone or sulfasalazine (occurs in norma l individuals as well as those with G6PD defi ciency) Anemia 2 to gold therapy for rheumatoid arthritis Idiosyncratic reactions, unexplained or unforeseeable reactions such as marrow aplasia Rare autoimmune haemolysis due to mefenamic acid, diclofenac, or ibuprofen Hypersplenism, Felty \200\231s syndrome in rheumatoid, renal failure in SLE or polyarteriti s 2 to other organ problems 39 anemia IN JOINT DISEASE