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Haematology in Critical Care E-Book

Jecko Thachil

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Issues of thrombosis, bleeding, and transfusion are extremely common, and often complex, in critically ill patients. Haematology in Critical Care: A Practical Handbookprovidesa dependable source of expert guidance on how to handle common haematological problems seen in the critical care setting, as well as the acute care of patients with a primary haematological disorder. Full-time clinical haematologists, regularly attending on intensive care, the Editors begin with an approach to abnormal laboratory tests, following with a disease-orientated approach to topics such as coagulation and haematological malignancy. Other key topics include paediatric and neonatal care, transfusion, point of care testing and the emergency presentation of haematological disease. This title brings together two of the most highly scientific specialties in clinical practice, delivering a practical approach to these problems, and guiding the clinician through the diagnosis and management of common scenarios encountered in the ICU.

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Haematology in Critical Care

A Practical Handbook

EDITED BY

Jecko Thachil, MRCP, FRCPath

Consultant Haematologist

Department of Haematology

Central Manchester University Hospitals NHS Foundation Trust

Manchester, UK

Quentin A. Hill, MRCP, FRCPath

Consultant Haematologist

Department of Haematology

Leeds Teaching Hospitals NHS Trust

Leeds, UK

This edition first published 2014© 2014 by John Wiley & Sons, Ltd.

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Library of Congress Cataloging-in-Publication Data

Haematology in critical care : a practical handbook / edited by Jecko Thachil, Quentin A. Hill.p. ; cm.Includes bibliographical references and index.

ISBN 978-1-118-27424-8 (cloth)I. Thachil, Jecko, editor. II. Hill, Quentin A., editor[DNLM: 1. Hematologic Diseases–diagnosis–Handbooks. 2. Hematologic Diseases–therapy–
Handbooks. 3. Critical Care–methods–Handbooks. 4. Hematology–methods–Handbooks. WH 39]RC633616.1′5–dc23

2014005978

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover images: blood film images – courtesy of Quentin A. Hill; ICU monitor – iStockphoto/© flubydust; blood bag – iStockphoto/© pictorico; respiratory mask – iStockphoto/© JuanmoninoCover design by Andy Meaden

List of Contributors

Shubha Allard, MD, FRCP, FRCPathConsultant Haematologist and Honorary Clinical Senior LecturerClinical HaematologyBarts and the London NHS TrustNHS Blood and TransplantLondon, UK

Arvind Arumainathan, MBChB (Hons), MRCP, FRCPathConsultant HaematologistDepartment of HaematologyRoyal Liverpool University HospitalLiverpool, UK

Roopen Arya, MA, PhD, FRCP, FRCPathProfessor of Thrombosis and HaemostasisKing’s Thrombosis CentreDepartment of Haematological MedicineKing’s College Hospital NHS Foundation TrustLondon, UK

Jon BaileyAcademic Clinical Fellow in Emergency MedicineOxford University HospitalsJohn Radcliffe HospitalOxford, UK

Sarah A. Bennett, MRCPClinical Research Fellow in CoagulationKing’s Thrombosis CentreDepartment of Haematological MedicineKing’s College Hospital NHS Foundation TrustLondon, UK

Andrew Breen, MBChB, FRCA, FFICMConsultant in Critical Care MedicineAdult Critical CareSt James’s University HospitalLeeds, UK

Therese A. Callaghan, BSc (Hons), MB ChB, FRCP, FRCPathConsultant HaematologistNHS Blood and TransplantLiverpool, UK

Medical DepartmentRoyal Liverpool University HospitalLiverpool, UK

Joydeep Chakrabartty, MBBS, MRCP, FRCPathConsultant HaematologistMIOT HospitalChennai, India

Leon Cloherty, MB ChB, FRCA, FFICMConsultant in Anaesthesia and Intensive Care MedicineDepartment of Critical CareRoyal Liverpool University HospitalLiverpool, UK

Daniel Collins, BPharm (Hons), PGDipClinPharm, MRPharmS, IPHaematology PharmacistDepartment of PharmacyRoyal Liverpool University HospitalLiverpool, UK

Tim Collyns, MA, MB, BChir, FRCPathConsultant MicrobiologistLeeds Teaching Hospitals TrustSt James’s University HospitalLeeds, UK

Nicola S. Curry, MA, MRCP, FRCPathConsultant HaematologistOxford Haemophilia and Thrombosis CentreOxford University HospitalsOxford, UK

Department of HaematologyOxford University HospitalsOxford UniversityOxford, UK

Khaled El-Ghariani, MA, FRCP, FRCPathConsultant in Haematology and Transfusion Medicine & Clinical DirectorDepartment of Stem Cells and Therapeutic Apheresis ServicesNHS Blood and Transplant and Sheffield Teaching Hospitals NHS TrustSheffield, UK

Honorary Senior LecturerUniversity of SheffieldSheffield, UK

Peter A. Hampshire, FRCA, FFICMConsultant in Intensive Care and AnaesthesiaDepartment of Critical CareRoyal Liverpool and Broadgreen University Hospitals NHS TrustLiverpool, UK

Fran Hartley, RGN, BSc, PG Cert (Clinical Education)Transfusion PractitionerHospital Transfusion TeamLeeds Teaching Hospitals NHS TrustLeeds, UK

Catharina Hartman, MB ChB, MCEMSpecialty RegistrarIntensive Care UnitAberdeen Royal InfirmaryAberdeen, UK

Stephen F. Hawkins, MB ChB (Hons), MRCP, FRCPath, PhDConsultant HaematologistDepartment of HaematologyRoyal Liverpool University HospitalLiverpool, UK

Quentin A. Hill, MRCP, FRCPathConsultant HaematologistDepartment of HaematologyLeeds Teaching Hospitals NHS TrustLeeds, UK

Jo Howard, MB BChir, MRCP, FRCPathConsultant HaematologistDepartment of HaematologyGuy’s and St Thomas’ NHS Foundation TrustLondon, UK

Charlotte Kallmeyer, MD, MRCP, FRCPathConsultant HaemotologistDepartment of HaematologySt James’s University HospitalLeeds Teaching Hospitals NHS TrustLeeds, UK

Anne Kelly, MA, MB, Bchir, MRCPCHClinical Research FellowDepartment of HaematologyDivision of Transfusion MedicineUniversity of Cambridge/NHS Blood and Transplant CambridgeCambridge, UK

Suzanne Kite, MA, FRCPConsultant in Palliative MedicinePalliative Care TeamSt James’s University HospitalLeeds, UK

Jerrold H. Levy, MD, FAHA, FCCMProfessor of AnesthesiologyDepartment of Anesthesiology and Critical CareDuke University School of MedicineDurham, NC, USA

Vanessa Martlew, MA, MB ChB, FRCP, FRCPath, FRCPEdinConsultant HaematologistDepartment of HaematologyRoyal Liverpool HospitalLiverpool, UK

Helen V. New, PhD, FRCP, FRCPathHonorary Senior LecturerConsultant in Paediatric Haematology and Transfusion MedicineDepartment of PaediatricsImperial College Healthcare NHS Trust/NHS Blood and TransplantLondon, UK

Derek R. Norfolk, MB, BS, FRCP, FRCPathConsultant in Haematology and Transfusion MedicineNHS Blood and TransplantLeeds Teaching Hospitals NHS TrustLeeds, UK

Elankumaran Paramasivam, MBBS, MD, MRCP, EDICM, FICMConsultant in Respiratory and Intensive Care MedicineSt James’s University HospitalLeeds, UK

Amrana Qureshi, MB BChir, MRCPCH, FRCPathConsultant Paediatric HaematologistPaediatric Haematology and Oncology Children’s HospitalJohn Radcliffe HospitalOxford, UK

Amin Rahemtulla, PhD, FRCPConsultant HaematologistDepartment of HaematologyImperial College Healthcare NHS TrustHammersmith HospitalLondon, UK

Andrew Retter, MBBS, BSc, MRCP, DICMHaematology RegistrarDepartment of HaematologyGuy’s and St Thomas’ NHS Foundation TrustLondon, UK

Intensive Care DepartmentGuy’s and St Thomas’ NHS Foundation TrustLondon, UK

Michael Richards, MA, BM, BCh, DM, MRCP, FRCPathDepartment of Paediatric HaematologyConsultant Paediatric HaematologistLeeds Children’s HospitalLeeds, UK

Marie Scully, BSc (Hons), MD, MRCP, FRCPathConsultant HaematologistDepartment of HaematologyUniversity College Hospital LondonLondon, UK

John Snowden, BSc (Hons), MB ChB, MD, FRCP, FRCPathConsultant Haematologist and Director of BMTDepartment of HaematologySheffield Teaching Hospitals NHS Foundation TrustSouth Yorkshire, UK

Honorary ProfessorDepartment of OncologyUniversity of SheffieldSheffield, UK

Simon J. Stanworth, FRCP, FRCPath, DPhilConsultant HaematologistNHS Blood and Transplant/Oxford University Hospitals NHS TrustJohn Radcliffe HospitalOxford, UK

Honorary Senior Clinical LecturerDepartment of HaematologyUniversity of OxfordOxford, UK

Jecko Thachil, MRCP, FRCPathConsultant HaematologistDepartment of HaematologyCentral Manchester University Hospitals NHS Foundation TrustManchester, UK

Mari Thomas, MA (Cantab), MRCP, FRCPathClinical Research FellowHaemostasis Research UnitUniversity College LondonLondon, UK

Joost J. van Veen, FRCP, FRCPath, MDConsultant HaematologistDepartment of HaematologySheffield Haemophilia and Thrombosis CentreSheffield Teaching Hospitals NHS Foundation TrustSheffield, UK

Jonathan Wallis, BA, MB BS, FRCP, FRCPathConsultant HaematologistDepartment of HaematologyNewcastle upon Tyne NHS Acute Hospitals TrustNewcastle upon Tyne, UK

Stephen Webber, MBChB, FRCA, FFICMCritical Care ConsultantDepartment of Anaesthesia and Critical CareSheffield Teaching Hospitals NHS Foundation TrustSouth Yorkshire, UK

Nigel Webster, MBChB, PhD, FRCA, FRCP, FRCS, FFICMProfessor of Anaesthesia and Intensive CareAnaesthesia and Intensive CareInstitute of Medical SciencesUniversity of AberdeenAberdeen, UK

Richard Wenstone, MBChB, FRCA, FFICMConsultant IntensivistDepartment of Critical CareRoyal Liverpool University HospitalLiverpool, UK

Anne M. Winkler, MDAssistant ProfessorDepartment of Pathology and Laboratory MedicineEmory University School of MedicineAtlanta, GA, USA

Medical DirectorGrady Health System Transfusion ServiceAtlanta, GA, USA

Assistant Medical DirectoryEmory Special Coagulation LaboratoryAtlanta, GA, USA

Stephen Wright, MRCP, FRCA, FFICMConsultant in Intensive Care and AnaesthesiaDepartment of Perioperative and Critical CareFreeman HospitalNewcastle upon Tyne, UK

Preface

Patients with a primary haematological disorder account for 1–2% of admissions to intensive care units. In the UK, patients are usually managed on a mixed medical and surgical unit where low patient numbers may limit the degree of expertise that can be developed. In contrast, almost all critically ill patients require a full blood count and coagulation screen. These tests are frequently abnormal and require interpretation. Issues of thrombosis, bleeding, and transfusion are also extremely common in critically ill patients.

This book is a practical guide to the investigation and management of these common problems as well as the acute aspects of care in patients with a primary haematological disorder. We are full-time clinical haematologists, and both regularly attend on intensive care. We have started with an approach to abnormal laboratory tests and then taken a disease-orientated approach to topics such as coagulation and haematological malignancy. Other key topics include paediatric and neonatal care, transfusion, point-of-care testing and the emergency presentation of haematological disease.

Quentin A. Hill

Jecko Thachil

Acknowledgements

I would like to thank a number of individuals for kindly reviewing and commenting on specific areas of the text, including Dr Andy Breen, Dr Sharon English, Dr Mike Bosomworth, Dr Mervyn Davies and Professor David Bowen.

I would also like to thank my family for their support: my parents who have led by example, to Anita for her patience and to Lila and Reuben, stars twinkling at ground level.

QAH

I would like to thank my parents for their continued blessings, my wife Gail for her patience and support and my children Nimue, Neah and Izahak for the tremendous bliss.

JT

Section 1Approach to Abnormal Blood Tests

Chapter 1Diagnostic Approach to Anaemia in Critical Care

Stephen F. Hawkins1 and Quentin A. Hill2

1 Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

2 Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

Anaemia was defined by the World Health Organization as a haemoglobin (Hb) concentration less than 120 g/L (Hb < 36%) in females and less than 130 g/L (Hb < 39%) in males, but the lower level of the reference range for Hb may vary between laboratories. It is common in critically ill patients, occurring in up to 80% of those in intensive care units (ICUs) [1] with 50–70% having a Hb less than 90 g/L during their admission. By reducing oxygen delivery to the tissues, this may be tolerated poorly in those with cardiorespiratory compromise. In critical care, anaemia is commonly due to multiple factors such as inflammation, blood loss, renal impairment and nutritional deficiencies [2, 3] (see Table 17.1), but it is important to consider treatable causes and identify when more detailed investigation is needed. The role of transfusional support is considered in Chapter 17.

Tissue hypoxia exerts physiological control of Hb by triggering the release of erythropoietin (EPO) by the kidneys, which stimulates bone marrow (BM) erythropoiesis. Hb will increase so long as there are no underlying BM disorders (e.g. myelodysplasia) and there are adequate supplies of iron, vitamin B12 and folic acid. When a rapid marrow response occurs (e.g. following haemorrhage or replacement of a deficient vitamin), reticulocytes (young erythrocytes) enter the blood in large numbers and can be identified on the blood film (polychromasia) or by an elevated reticulocyte count. The normal lifespan for erythrocytes is 120 days, before being removed by the reticuloendothelial system (predominantly in the spleen and liver), but their lifespan may be shortened by inflammation, haemorrhage or haemolysis.

Diagnostic approach to anaemia in critical care

In the history, note pre-existing co-morbidities including renal and cardiac impairment. Also note medications, diet and symptoms suggestive of blood loss. Examine for jaundice, lymphadenopathy or organomegaly.

If there is a sudden unexpected drop in Hb, this may be a sampling error; consider repeating the full blood count (FBC).

Is the anaemia acute or chronic? This may inform the diagnosis, likely tolerance of anaemia and treatment strategy. Only 10–15% of ICU patients have chronic anaemia prior to admission [4].

Is the anaemia isolated or are there other cytopenias? Thrombocytopenia (

Chapter 3

) is also a common finding (~40% of ICU patients) and will therefore often coexist with anaemia in critically ill patients. Common causes of both include sepsis, organ failure and acute blood loss, but important differentials include disseminated intravascular coagulation (DIC) (

Chapter 9

) and thrombotic microangiopathies (TMAs) (

Chapter 11

). Review the clotting and blood film. Haemophagocytic lymphohistiocytosis (HLH) is an important cause of fever and cytopenias that can present with single or multiple organ failure (see succeeding text under extrinsic causes of extravascular haemolysis).

Pancytopenia may be an artefact (i.e. dilution during sampling) or result from BM failure or infiltration, infection, HLH, hypersplenism, drugs, autoimmune disease or megaloblastic anaemia. If pancytopenia is present, examine for splenomegaly and request a blood film and haematinics. If the cause remains unclear, the advice of a haematologist should be sought as a BM examination may be required.

If the cause of an isolated anaemia remains unclear, it is worth classifying on the basis of the mean cell volume (MCV) as this helps to direct further investigation (Figure 1.1).

Figure 1.1 Investigation of anaemia in critical care. MCV, mean cell volume; DIC, disseminated intravascular coagulation; TMAs, thrombotic microangiopathies; HLH, haemophagocytic lymphohistiocytosis; BM, bone marrow; AoCD, anaemia of chronic disease; PNH, paroxysmal nocturnal haemoglobinuria.

Normocytic anaemia (MCV within the normal range)

Anaemia is most commonly normocytic in critically ill patients and usually multifactorial [4]. Iatrogenic reasons include frequent blood sampling and haemodilution (intravenous fluid administration). Occult blood loss can occur as a result of gastrointestinal mucosal inflammation and contributed to by coagulation defects, thrombocytopenia and uraemia. Another important reason is secondary anaemia, also termed anaemia of chronic disease (AoCD) or anaemia of inflammation. This is the most common cause of anaemia in hospitalized patients and can be caused by infection, cancer, autoimmune disease or chronic kidney disease [5]. This results in a functional iron deficiency, whereby adequate iron stores are present but the availability of iron for erythropoiesis is reduced. Hepcidin, a peptide produced by the liver in response to inflammatory cytokines, may be at least in part responsible for this phenomenon. Typically, ferritin is elevated and serum iron and transferrin saturation are low. Iron supplementation usually produces no improvement (in contrast to true iron deficiency). In addition to functional iron deficiency, inflammation results in reduced EPO production, reduced marrow sensitivity to EPO and shortened red cell survival.

Check haematinics as combined deficiencies can result in a normal MCV. Additionally, due to the acute phase response, a normal ferritin does not exclude iron deficiency. Consideration should be given to the possibility of occult or recent bleeding. The anaemia is likely to resolve with improvement of the underlying conditions. Meanwhile, supportive management (including transfusion when required; see Chapter 17) is the mainstay of therapy, and blood sampling should be kept to a minimum.

Microcytic anaemia (MCV below the normal range)

This is often a result of iron deficiency (blood loss, malabsorption or dietary deficiency). It can also occur during prolonged and severe illness as an extreme form of AoCD. Less commonly, microcytosis can be due to a haemoglobinopathy (e.g. thalassaemia trait), acaeruloplasminaemia, myelodysplasia, hyperthyroidism, lead poisoning and some rare congenital conditions (e.g. congenital sideroblastic anaemia).

Iron deficiency can be associated with a thrombocytosis, especially with bleeding. Less frequently, severe iron deficiency may also result in a leukopenia and thrombocytopenia. The blood film may show hypochromic, microcytic red cells, polychromasia and pencil cell poikilocytes. The usual tests of iron status (ferritin and iron studies) are less likely to be informative in the critically ill patient. A reliable measure of iron storage is specially stained BM aspirate slides, but this may not identify acute blood loss and is not usually justifiable solely for this purpose. Instead, if the clinical picture and blood film are compatible, consider a trial of iron replacement and appropriate investigations to identify a cause.

Consider additional testing:

Lead level if prominent basophilic stippling on film or clinical suspicion

Thyroid function if relevant clinical symptoms/signs

BM if dysplastic blood film (haematology referral)

Hb electrophoresis if target cells, long-standing microcytosis, iron replete or not of northern European ethnicity

Macrocytic anaemia (MCV above the normal range)

The leading causes of macrocytic anaemia are alcohol abuse, megaloblastic anaemia (deficiency of vitamin B12 and/or folic acid) and accelerated erythropoiesis (e.g. in response to bleeding or haemolysis).

Other causes include medications (e.g. some chemotherapy agents, hydroxycarbamide, methotrexate, azathioprine, zidovudine, phenytoin), liver dysfunction, hypothyroidism, aplastic anaemia and myelodysplasia. Macrocytosis can occur in pregnancy, in Down syndrome and in smokers.

Spurious causes of macrocytosis include cold agglutinins (red cells agglutinate due to an autoantibody; this will correct by warming a repeat FBC sample), high white cell counts (e.g. acute leukaemia), severe hyperglycaemia (in patient or by sampling close to an intravenous dextrose infusion causing osmotic swelling) or an under-filled tube at venepuncture (increased concentration of EDTA anticoagulant).

Initial Investigations would include liver and thyroid function, B12/folate levels and screening tests for haemolysis (lactate dehydrogenase [LDH], reticulocyte count, haptoglobin, direct Coombs’ test [DCT], bilirubin and blood film examination).

Alcohol excess may be suggested by the history, examination or other blood results (e.g. raised gamma glutamyl transferase). The resulting anaemia and macrocytosis are usually mild, in contrast to megaloblastic anaemia where the MCV may be as high as 120 fl. The blood film may show typical megaloblastic features such as oval macrocytosis and neutrophil hypersegmentation. Folic acid replacement should not be given unless the vitamin B12 level is known as by stimulating erythropoiesis, folic acid may aggravate B12 deficiency thereby precipitating subacute combined degeneration of the cord. In B12 deficiency, heart failure may arise through overenthusiastic blood transfusion, and B12 replacement is usually sufficient. If transfusion is judged essential, transfuse one unit slowly, consider diuretic cover, and then reassess.

Myelodysplasia is a clonal BM disorder characterized by ineffective erythropoiesis. There may be dysplastic changes on blood film or additional cytopenias. Although onset is usually insidious, patients may present acutely with infection or transformation to acute myeloid leukaemia and, if suspected, require a haematology referral.

Haemolysis causes anaemia when increased red cell destruction exceeds the marrow’s capacity to compensate. Typical findings include a reduced haptoglobin, raised LDH and raised unconjugated bilirubin, but these are not fully sensitive or specific. For example, haptoglobin rises as an acute phase response and may fall in liver disease and megaloblastic anaemia and can be congenitally low. The reticulocyte count will only rise if the marrow is healthy. A positive DCT suggests autoimmune haemolysis but can also be positive in other circumstances such as following therapeutic immunoglobulin infusion, recent stem cell or organ transplantation or alloimmunization following recent blood transfusion. Results must therefore be taken in clinical context before diagnosing haemolysis.

Haemolysis can be intravascular or extravascular. Acute intravascular haemolysis can be life-threatening and may require renal or cardiovascular support. Patients may develop chills, fevers, rigors, flank or back pain, dyspnoea, dizziness, tachycardia, hypotension, dark urine, oliguria and shock. Red cell fragments may be present on the blood film; LDH is more markedly elevated compared with extravascular haemolysis. Urine and plasma may become red or brown due to the presence of free Hb. Some Hb is taken up by renal cells and iron stored as haemosiderin is subsequently shed into the urine where it can be detected 1–2 weeks after the onset of haemolysis.

In patients where severe intravascular haemolysis is a major presenting feature, consider:

Was there recent blood transfusion? Most immediate haemolytic transfusion reactions are due to ABO mismatch. Bacterial contamination can present with a similar picture. Investigation and management of transfusion reactions are discussed in

Chapter 14

.

Is there a history of fever and foreign travel or splenectomy? Investigate for falciparum malaria with thin and thick films (also antigen testing if available). Bartonellosis and babesiosis can also invade the red cell, cause haemolysis and be visible on the blood film (see

Chapter 6

). Severe babesiosis often occurs in patients with a history of prior splenectomy.

Always consider

Clostridium perfringens

sepsis. Massive intravascular haemolysis due to alpha-toxin occurs in approximately 10% of cases and is associated with shock and mortality of up to 80%, usually within hours of presentation. Risk factors include diabetes, malignancy or following abdominal surgery. The primary focus is usually hepatobiliary, intestinal or uterine. Infection of a traumatic injury (gas gangrene) can also lead to sepsis. Spherocytes and ghost cells (depigmented red cells) feature on the blood film. Tissue or blood cultures confirm diagnosis. Treatment involves early high-dose antibiotics (e.g. penicillin and clindamycin) and surgical debridement of devitalized tissue.

Review medications (including peri-operative antibiotics and over-the-counter medication). An important differential is drug (or drug metabolite)-induced immune haemolytic anaemia (e.g. second- or third-generation cephalosporins or diclofenac). The DCT may be negative if haemolysis is massive. Further exposure to the causative drug can be fatal.

Has there been accidental (or intentional) ingestion/inhalation of toxic substances? Haemolysis is caused by oxidative damage with the formation of physiologically useless methaemoglobin and denatured Hb, which precipitates (Heinz bodies), damaging the red cell membrane and leading to extravascular and, if severe, intravascular haemolysis. Symptoms of methaemoglobinaemia may also be prominent including cyanosis, headache and fatigue, leading to arrhythmias, seizures and coma in severe cases. Blood is characteristically a chocolate brown colour.

Nitrates. Present in fertilizer and can result in methaemoglobinaemia in infants exposed to well water or vegetable juice. Inhaled amyl nitrite (poppers, liquid gold) used

recreationally

can cause fatal oxidant injury.

Copper sulphate poisoning. Rare in the UK but in some countries is sold over the counter for pesticide and home-made glue and is burnt in houses for religious purposes by Buddhists and Hindus. Hydrated crystals are marine blue and attractive to children. Ingestion is also associated with erosive gastropathy, hepatitis, acute renal failure and rhabdomyolysis.

Sodium chlorate (a weed killer). Not authorized in the European Union member states after May 2010 (decision 2008/865/EC).

Arsine gas. Produced in industrial processes.

Are symptoms associated with cold exposure? In paroxysmal cold haemoglobinuria (PCH), haemolysis is provoked by the cold, resulting in haematuria, back or abdominal pain and fever. It usually follows a viral infection in children and, although often transient, can be severe. The DCT is positive and PCH is confirmed by the Donath–Landsteiner test.

Also consider glucose-6-phosphate dehydrogenase (G6PD) deficiency. There may be a personal or family history and a recent trigger for haemolysis. It is an inherited, X-linked red cell enzyme defect resulting in susceptibility to oxidative damage. It affects an estimated 400 million people worldwide and is most prevalent in sub-Saharan African countries. As well as a variably severe chronic extravascular haemolysis, oxidative stress such as infection, ingestion of fava (broad) beans and various medications (e.g. dapsone, primaquine, nitrofurantoin) leads to acute intravascular haemolysis and bite cells on the blood film. Blood tests are readily available but false-negative results can occur in the presence of a reticulocytosis (higher G6PD levels).

Are there additional cytopenias or a history of venous thrombosis? Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired stem cell disorder that renders blood cells susceptible to complement-mediated injury. It is readily diagnosed with peripheral blood flow cytometry. See

Chapter 32

for further details.

Intravascular haemolysis may not be the major clinical feature of a disorder and is not always fulminant. Examples are listed:

Renal failure – red cell fragments may be present due to uraemia, complications of haemodialysis or the underlying cause of renal failure (e.g. lupus nephritis).

Other extracorporeal circuits (e.g. ventricular assist devices, cardiopulmonary bypass circuits) or following placement of an indwelling transjugular intrahepatic portosystemic shunt (TIPS).

Severe burns.

Drowning.

TMAs. Associations include HIV, autoimmune disease, malignancy, pregnancy, diarrhoeal illness, hypertension and certain drugs (e.g. ciclosporin).

DIC.

Cardiac periprosthetic or perivalvular leaks.

Cold agglutinin disease (CAD). Autoimmune haemolytic anaemia (AIHA) is caused by a cold reactive IgM antibody. The DCT is usually positive to complement only and agglutination is seen on the blood film. The patient and blood products for transfusion should be kept warm

March haemoglobinuria. Caused by intensive exercise, e.g. long-distance running.

Oxidant drugs (e.g. dapsone, salazopyrin) and inherited unstable haemoglobins can give rise to chronic intravascular haemolysis.

Zieve’s syndrome. Rarely, intravascular haemolysis has been described associated with cirrhosis and alcohol excess.

Wilson’s disease. Usually presents with liver or neurological disease, or through family screening, but can occasionally present with acute intravascular haemolysis.

Haemolysis that is mainly extravascular can be caused by intrinsic red cell defects or extrinsic factors.

Intrinsic defects: inherited conditions give rise to a long-term haemolytic state, but decompensated anaemia can occur with additional stress such as haematinic deficiency, pregnancy or infection. Aplastic crisis, classically by parvovirus B19, results in transient interruption of red cell production and reticulocytopenia, which can cause a life-threatening anaemia. Intrinsic defects are reviewed in more depth in Chapter 32.

Disorders of Hb. In thalassaemia, an imbalance of globin chains leads to their precipitation and reduced red cell survival. Structural Hb variants can give rise to sickle cell disease (see

Chapter 18

).

Red cell membrane defects (e.g. hereditary spherocytosis). May be suspected from blood film appearance. variable severity and age of presentation. Sometimes require splenectomy.

Red cell enzyme deficiencies (e.g. pyruvate kinase or pyrimidine 5′ nucleotidase deficiency). These rare inherited conditions usually give rise to a chronic non-spherocytic haemolytic anaemia.

Extrinsic factors:

Liver disease. Mild effect due to alteration of the red cell membrane (e.g. acanthocytes, stomatocytes).

Splenomegaly. Results in increased red cell sequestration and destruction.

Delayed haemolytic transfusion reaction – typically seen 1–2 weeks after transfusion, caused by an anamnestic immune response due to an antibody undetectable during routine pre-transfusion testing.

Warm AIHA. Spherocytes are seen on the blood film. DCT is positive.

Immune haemolysis can also be drug induced or follow solid organ and BM transplantation.

HLH. May be primary or secondary to infection or malignancy. Phagocytosis in the marrow, liver, spleen or lymph nodes leads to cytopenias, organomegaly, fever, deranged liver function and coagulopathy. There may also be neurological symptoms and lymphadenopathy. Fibrinogen may be low and fasting triglycerides and ferritin high.

In conclusion, anaemia is common and usually multifactorial. The cause may be clear from the clinical context, but, if not, classification according to the MCV is helpful in directing investigations. Anaemia is most often normocytic and contributed to by blood loss, haemodilution, impaired EPO release and functional iron deficiency. Consider a haematology referral: where anaemia is prominent and the cause unclear despite investigation and where haemolysis, haemoglobinopathy, TMA or myelodysplasia are suspected or in cases of an unexplained pancytopenia.

References

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2 Fink MP. Pathophysiology of intensive care unit-acquired anemia. Crit Care 2004;8(Suppl. 2):S9–10.

3 Hayden SJ, Albert TJ, Watkins TR et al. Anemia in critical illness: Insights into etiology, consequences and management. Am J Respir Crit Care Med 2012;185(10):1049–57.

4 Walsh TS, Wyncoll DLA, Stanworth SJ. Managing anaemia in critically ill adults. BMJ 2010;341:547–51.

5 Davis SL, Littlewood TJ. The investigation and treatment of secondary anaemia. Blood Rev 2012;26(2):65–71.

Chapter 2Leukopenia

Stephen F. Hawkins1, Jecko Thachil2 and Quentin A. Hill3

1 Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

2 Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

3 Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

Leukopenia is defined as a total white blood count (WBC) or leukocyte count below the lower limit of the reference range for the laboratory in question (e.g. <3.5 × 109/L). Leukopenia on admission to intensive care occurs in approximately 7% of admissions and is associated with increased mortality [1]. It can be a result of a reduction in any of the major subtypes of WBC (neutrophils, lymphocytes, monocytes, eosinophils or basophils), but most frequently neutrophils and/or lymphocytes, which contribute most to the total WBC count. The differential diagnosis of neutropenia and lymphopenia can be seen in Table 2.1.

Table 2.1 Differential diagnosis of leukopenia.

Sepsis

Infection

 Viral (e.g. HIV)

 Bacterial (e.g. TB)

Post-infective

Drug-induced (e.g. phenytoin, cotrimoxazole)

B12 and/or folate deficiency

Immunological (e.g. SLE)

Bone marrow failure (e.g. haematological malignancies)

Neutropenia

The severity of neutropenia may be divided into mild (1.5 − 2 × 109/L), moderate (0.6 − 1.4 × 109/L) or severe (≤0.5 × 109/L). Persistent and severe neutropenia is more likely to be clinically significant and lead to complications. The pathogenesis of neutropenia can include decreased production from the bone marrow, increased destruction in the blood circulation, increased margination to the vascular endothelium, neutrophil aggregation and splenic pooling.

In the ICU setting, neutropenia is usually secondary, most commonly to drugs or infection. A primary haematological cause such as leukaemia or another malignancy will rarely develop in a patient who arrived in the ICU with a normal neutrophil count. A drug-induced cause for neutropenia can easily be overlooked due to the multiple agents the patients may receive. A temporal relationship between the commencement of any drug and the development of neutropenia is usually the only clue and may not be considered. A sudden drop in the count can also suggest drug-induced neutropenia, and often, the neutropenia resolves soon after the discontinuation of the drug.

Any infection can lead to neutropenia, most often viral infections such as influenza, cytomegalovirus (CMV) and respiratory syncytial virus. The most likely bacterial cause for neutropenia is a chronic infection like tuberculosis, brucellosis or typhoid rather than streptococcal or staphylococcal infections. The pathogenesis for this neutropenia includes margination and sequestration in the spleen and in the lungs. HIV infection can frequently cause neutropenia, with over two-thirds of patients being neutropenic sometime during their illness. The mechanisms for this include antibody formation, bone marrow suppression and cytokine-mediated neutrophil destruction, while certain antiretroviral agents may decrease neutrophil counts.

Immunological causes like vasculitis and systemic lupus erythematosus can lead to neutropenia through antibody-mediated destruction. Disease control often leads to resolution of the neutropenia. Haemophagocytic syndrome can cause cytopenias due to macrophage overactivity, consuming blood cells and their precursors. This is can be primary or associated with rheumatological diseases, malignancy and viral infections. Presenting features are discussed in Chapter 1.

Vitamin B12 or folate deficiency can present with neutropenia, with folic acid deficiency developing relatively quickly in patients not supplemented. Associated macrocytic anaemia may provide a clue to this diagnosis and can easily be treated with replacement. Copper deficiency may also be associated with neutropenia due to maturation arrest in the bone marrow or antibody formation. This can occur in patients receiving total parenteral nutrition without adequate copper supplementation, typically with a normocytic anaemia and a normal platelet count. Bone marrow examination can support the diagnosis. Some rarer causes of neutropenia include patients with ketoacidosis and hyperglycaemia, haemodialysis (activation of complement by dialyser membranes, which causes neutrophil aggregation) and cardiopulmonary bypass surgery.

When neutropenia is identified, determine whether it is isolated or associated with other cytopenias. Pancytopenia usually suggests the presence of bone marrow failure (from any cause including drugs) or hypersplenism, usually merits a haematology referral and is discussed in more detail in Chapter 1. The risk of severe, potentially life-threatening infection increases as the neutrophil count drops and is highest for those with severe neutropenia (<0.5 × 109/L) [2], especially when the mechanism is marrow failure since there is no reserve capacity to produce neutrophils. Also review the trend in the WBC count to ascertain whether the problem is new or potentially long standing and to correlate its development with any changes in medication. Neutropenia developing in a septic patient is most likely to be a result of the sepsis, and little specific testing is required other than examination of the blood film which may show characteristic features in the remaining neutrophils (e.g. toxic granulation and left shift). The count should improve as the sepsis resolves, but if not, alternative diagnoses should be considered. If the cause remains unclear, or if the neutropenia is severe, a haematology opinion should be requested as a bone marrow aspirate and trephine biopsy may be required.

Lymphopenia

Lymphopenia can be a pre-existing problem or can develop during the course of an illness. The approach is similar to neutropenia in terms of reviewing the history and previous results. Long-standing lymphopenia is most likely a result of chronic viral infection (such as HIV) but can occur due to generalized marrow failure diseases or (rarely) congenital immunodeficiency syndromes. A sudden-onset lymphopenia may be a result of an acute viral infection (including HIV, EBV and CMV) or due to marrow suppression by drugs (again numerous causes).

Management

In addition to identifying and treating the root cause of leukopenia where possible, it is important to recognize that patients are susceptible to infection and that infections can progress more rapidly than in those with normal WBC counts. Consequently, patients with leukopenia should ideally be managed in a side room (i.e. protective isolation), and if infection is suspected (due to fever or other clinical features such as hypotension), urgent treatment is required. Cultures should be taken and antibiotics started without delay (approach to neutropenic fever in haematology patients is discussed in Chapter 20). The choice of antibiotics should take into account local policy. In some centres, initial empirical therapy for neutropenic sepsis is with intravenous piperacillin–tazobactam, but in others, this is combined with an aminoglycoside (most commonly gentamicin) if renal function has previously been satisfactory. In patients who are allergic to penicillin, options may include meropenem or aztreonam with gentamicin. This will depend on the severity of the penicillin allergy and on local policy, which is influenced by regional variations in microbiological data. Figure 2.1 shows a suggested pathway for neutropenic fever though it is advisable to consult local guidelines.

Figure 2.1 A suggested approach to neutropenic fever. *, Initial dosing is determined by body weight and eGFR and subsequent doses should be guided by plasma gentamicin levels. #, Antibiotic choices will differ according to local resistiance patterns and local policy should be consulted.

In some cases, granulocyte colony-stimulating factor (G-CSF) may be given to facilitate neutrophil recovery, but this can make bone marrow interpretation difficult. Studies looking at G-CSF in the setting of chemotherapy-induced febrile neutropenia have shown that its use reduces the duration of neutropenia and shortens hospital stays but does not improve overall survival [3]. As a result, its use is generally limited to selected groups of patients such as those with severe neutropenia (<0.1 × 109/L) expected to last for more than 10 days and patients with severe hypotensive sepsis. The use of G-CSF remains controversial in the setting of intensive care, and discussion with a haematologist is advisable.

In summary, leukopenia is not uncommon in critical care and is usually due to neutropenia. In the setting of critical illness, infection and sepsis are the predominant causes of leukopenia, though drug-induced reductions are also common. Laboratory investigations should include a blood film and assays of B12 and folate. A haematology referral may be appropriate when the leukopenia is severe or persistent and if advice is needed regarding the management.

References

1 Waheed U, Williams P, Brett S, Baldock G, Soni N. White cell count and intensive care outcome. Anaesthesia 2003;58(2): 180–2.

2 Munshi HG, Montgomery RB. Evidence-based case review: severe neutropenia, a diagnostic approach. West J Med 2000; 172(4):248–52.

3 Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 2005;23:4198–214.

Chapter 3Thrombocytopenia in the Intensive Care Unit

Jecko Thachil

Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

Introduction

Thrombocytopenia is the most common haemostatic abnormality seen in the intensive care unit (ICU). The reported incidence of thrombocytopenia in this setting ranges from 15% to 60% and is more frequently seen in surgical and trauma patients (35–41%) compared to medical patients (20–25%). Approximately half of the patients with thrombocytopenia already have this on arrival at the ICU, while the remainder usually develops it in the first 4 days of being in the ICU.

Prognostic significance

The degree of thrombocytopenia has been regarded as a marker of illness severity in critically ill patients. A lower platelet count on admission to ICU correlates with higher Simplified Acute Physiology Scores (SAPS), Multiple Organ Dysfunction Scores (MODS) and Acute Physiology and Chronic Health Evaluation (APACHE) scores than those with normal platelet counts. It is also an independent predictor of mortality in ICU with the severity of thrombocytopenia being inversely related to survival. A four- to sixfold increase in mortality has been reported if the platelet count is reduced by more than 50% during ICU admission or if the thrombocytopenia is sustained for more than 4 days. Thrombocytopenia has also been associated with longer hospital and ICU stays.

Clinical presentation

Although the well-recognized clinical manifestations of thrombocytopenia are purpura, petechiae and bleeding, it is more common for these symptoms to be absent when the low platelet count is detected. Although the classical definition of thrombocytopenia is a platelet count less than 150 × 109/L, significant or spontaneous bleeding rarely occurs with a platelet count above 50 × 109