Handbook of Venous Thromboembolism E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 739

Veröffentlichungsjahr: 2017

Beschreibung

A clinically oriented handbook providing up-to-date recommendations for mastering the practical aspects of patient management for venous thromboembolism

Venous thromboembolism (VTE) is associated with high morbidity and mortality both in and out of the hospital setting, and is one of the commonest reasons for hospital attendances and admissions. Designed as a practical resource, the Handbook of Venous Thromboembolism covers the practical aspects of venous thromboembolism management in short and easily followed algorithms and tables. This important text helps physicians keep up-to-date with the latest recommendations for treating venous thromboembolism in clinic-oriented settings. Experts in fields such as the radiological diagnosis of pulmonary embolism and thrombophilia testing, give a succinct summary of the investigation, diagnosis and treatment of venous thromboembolism and include evidence-based guidelines.

With contributions from a team on internationally recognized experts, Handbook of Venous Thromboembolism is a source of information that specialists in the field can recommend to non-specialists and which the latter will be able to review to assist in their education and management of this wide-spread condition. This vital resource:

• Comprises of a clinically focused handbook, useful as a daily resource for the busy physician
• Offers a handbook written by an international team of specialists offering their experience on the practical aspects of venous thromboembolism management
• Addresses venous thrombosis prevention, a major focus for healthcare providers
• Includes coverage on controversies in the management of venous thromboembolism so clinicians can understand how experts are practicing in real scenarios

Written for hematology trainees, emergency and acute medicine physicians, junior doctors, and primary care physicians, Handbook of Venous Thromboembolism covers the basics for treating patients with venous thromboembolism and offers guidelines from noted experts in the field.

Leseprobe

Table of Contents

Cover

Title Page

List of Contributors

Foreword

Section I: Clinical Overview

1 Risk Factors for Venous Thromboembolism

Introduction

Previous VTE

Surgery

Hospitalised Medical Patients

Cancer Associated Thrombosis (CAT)

Pregnancy

Combined Oral Contraceptive Use

Family History of VTE and Thrombophilia

Obesity

Travel

Substance Abuse

Conclusion

Further Reading

2 Management of Venous Thrombosis in the Lower Limbs

Introduction

Diagnosis

Treatment

Further Reading

3 Clinical Presentation of Acute Pulmonary Embolism

Introduction

Symptoms of Acute PE

Clinical Signs of Acute PE

Differential Diagnosis

Clinical Presentation in Specific Patient Subgroups

Clinical Presentation and Associated Prognosis

Summary

Further Reading

Section II: Diagnosis

4 Clinical Prediction Scores

Pulmonary Embolism

Deep Vein Thrombosis

Potential Pitfalls

Key Reading

5 Laboratory Aspects in Diagnosis and Management of Venous Thromboembolism

Introduction

Laboratory Diagnostics of Venous Thromboembolism

Laboratory Prediction of Recurrent Venous Thromboembolism

Laboratory Monitoring of Anticoagulant Therapy

References

6 Thrombophilia Testing

Introduction

Inherited Risk Factors

Acquired Risk Factors

Mixed Risk Factors

Indications for Thrombophilia Testing

Further Reading

7 Radiological Diagnosis of Pulmonary Embolism

Introduction

Ventilation‐perfusion Scanning (V/Q Scintigraphy)

Spiral Computed Tomography Pulmonary Angiography (CTPA)

The Issue of Subsegmental PE

Haemodynamic Assessment of Patients with PE

Latest Trends

Cost‐effectiveness

Summary

References

8 The Antiphospholipid Syndrome

Antiphospholipid Antibodies: Epidemiology and Antigenic Specificities

Thrombosis

Management of APS

Management of Pregnancy

Management of Catastrophic APS

Review Articles

Guidelines

References

Section III: Treatment

9 Inpatient or Outpatient Anticoagulation

Introduction

Deep Vein Thrombosis

Pulmonary Embolism

Sub‐segmental Pulmonary Embolism

The Importance of a VTE Clinic

Cost‐effectiveness

Summary

Further Reading

10 An Anticoagulant Service in Practice

History

Current Organisation

Referral Process

Induction Appointments

Hospital Discharge Patients

Anticoagulant Clinic Structure

Self‐testing Patients

Direct Oral Anticoagulants (DOACs)

The Future of GCAS

Further Reading

11 Point of Care Testing

International Normalised Ratio (INR)

Quality Control

Comparison with Laboratory Results

Limitations of POC devices

POC D‐dimer tests

Key Learning for POC INR Testing

Further Reading

12 Direct Oral Anticoagulants in the Prevention and Management of Venous Thromboembolism

DOACs in treatment and prevention of Venous Thromboembolism: Introduction

Oral Direct Thrombin Inhibitors

Oral Xa Inhibitors

Systematic reviews and meta‐analyses of DOACs

Practical Issues for DOAC Usage

DOAC use in Specific Patient Subgroups

Further Reading

13 The Role of Thrombolysis in the Management of Venous Thromboembolism

Introduction

Rationale Behind CDT for Acute DVT

Pre‐procedural Evaluation and Indications

Contraindications

Technical Aspects of CDT

CDT Pros and Cons

Outcomes for CDT in DVT

Thrombolysis in Pulmonary Embolism

Upper Extremity DVT

Further Reading

References

14 Inferior Vena Cava Filters in the Management of Venous Thromboembolism

Introduction

Evidence for IVCFs

Complications of IVCFs

IVCF Retrieval

IVCFs and Anticoagulation

Specific Indications for IVCF Placement

IVCF for Primary PE Prophylaxis

Conclusion

Further Reading

Disclosures

References

Section IV: Special Situations

15 VTE in Pregnancy

Introduction

Incidence

Normal Physiological Changes of Pregnancy

Risk Factors

Thrombophilias

VTE Prophylaxis in Pregnancy

Diagnosis of VTE in pregnancy

Management

IVC Filters

VTE in Unusual Sites

Thrombophilia Screening

Massive PE/thrombolysis

Thrombolysis for PE in Pregnancy

Post‐thrombotic Syndrome

Follow‐up

Further Reading

16 Paediatric Venous Thromboembolism

Incidence

Paediatric Pathophysiology

Risk Factors

Clinical Manifestations

Diagnosis

Treatment

Treatment Recommendations

Complications

Post‐thrombotic Syndrome (PTS)

Follow‐up

Further Reading

17 Cancer‐associated Thrombosis

Introduction

Pathophysiology of Cancer‐associated Thrombosis

The Psychological Impact of CAT

Diagnosis of CAT

Challenges in the Management of CAT

Initial Treatment

Long‐term Anticoagulation

Challenging Cases

Use of Inferior Vena Cava Filters

Thromboprophylaxis in Hospitalised Cancer Patients

Thromboprophylaxis in Ambulant Cancer Patients Receiving Chemotherapy

Conclusion

Further Reading

18 Venous Thromboembolism Management in Obese Patients

Challenges of VTE Diagnosis

Treatment of VTE

Drugs Where Recognised Therapeutic Drug Monitoring Overcomes the Challenges of any Changes That Obesity May Have on Drug Pharmacokinetic Profiles

Direct Oral Anticoagulants (DOACs)

Further Reading

19 Venous Thromboembolism in Intensive Care

Introduction

Incidence

Diagnosis

Thromboprophylaxis or Not?

Mechanical Thromboprophylaxis

Treatment of Venous Thromboembolism in the Critically Ill

Conclusion

Further Reading

20 Venous Thromboembolism; a Primary Care Perspective

Introduction

Prevention

References

Section V: Unusual Site Thrombosis

21 Cerebral Venous Thrombosis

Aetiology

Pathophysiology

Clinical Presentation

Diagnosis

Treatment

Secondary Prevention in Patients at Risk

Prognosis

Suggested Further Reading

Financial Disclosure

References

22 Upper Extremity Thrombosis

Overview

Background and Classification

Epidemiology and Risk Factors

Prevention

Diagnosis

Approach to the Diagnosis of Suspected UEDVT

Interventional and Endovascular Therapies

Surgical Treatment

Management of CVC/PICC Devices with UEDVT

Prognosis and Complications

References

23 Management of Intra‐abdominal Thrombosis

Splanchnic Vein Thrombosis

Renal Vein Thrombosis

Ovarian Vein Thrombosis

Further Reading

References

24 Thrombosis in the Retinal Circulation

Introduction

Basic Eye Anatomy

Retinal Vein Occlusion

Retinal Artery Occlusion

Conclusions

Further Reading

Conflicts of Interest/disclosures

References

Section VI: Long‐term Sequelae of VTE

25 Post‐thrombotic Syndrome

Introduction

Pathophysiology

Signs and Symptoms

Risk Factors for Developing PTS

Quality of Life

Scoring Systems

Investigations

Treatment

Prevention Strategies

Further Reading

26 Chronic Thromboembolic Pulmonary Hypertension

Introduction

Epidemiology

Pathophysiology

Clinical Presentation and Patient Evaluation

Treatment

Summary

Further Reading

Bibliography

27 Predicting Recurrent VTE

Factors Influencing Risk of Recurrent VTE

Clinical Prediction Rules for Recurrent VTE

Conclusions

Further Reading

Section VII: Controversies

28 Cancer Screening in Unprovoked Venous Thromboembolism

Further Reading

29 Sub‐segmental and Incidental PE – to Treat or Not?

Introduction

Definitions

Who Gets Incidental/Subsegmental PE?

The Issue of Sub‐segmental PE

Management Approach to Incidental/Sub‐segmental PE

Conclusion

Further Reading

30 Management of Distal Vein Thrombosis

Diagnosis of Distal Deep‐vein Thrombosis

Treatment of Isolated Distal Deep‐vein Thrombosis

References

Section VIII: Prevention

31 A Summary of the Evidence for VTE Prevention, with a Focus on the Controversies

Introduction

Hospitalised Patients

Further Reading

32 VTE Prevention: Real World Practice

The Strategy

Risk Assessment

Appropriate Thromboprophylaxis (TP)

Further Reading

33 VTE Root Cause Analysis – How To Do It

Background

RCA Goes Political; the English Experience

Aims

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Risk factors for venous thromboembolic disease.

Table 1.2 Surgical risk factors for VTE.

Table 1.3 Medical conditions with increased risk of VTE.

Table 1.4 Risk factors for cancer‐associated VTE.

Table 1.5 Pregnancy and risk factors for VTE.

Chapter 03

Table 3.1 Prevalence of clinical characteristics in patients with suspected PE.

Table 3.2 Differential diagnosis of PE according to the key presenting symptom.

Chapter 04

Table 4.1 PERC score.

Table 4.2 Wells score for pulmonary embolism.

Table 4.3 Wells score for deep vein thrombosis.

Table 4.4 Oudega rule.

Chapter 05

Table 5.1 Wells’ score for the diagnosis of venous thromboembolism (Wells

et al

., 1997, 2003).

Table 5.2 Characteristics of current anticoagulant drugs and their laboratory monitoring.

Chapter 06

Table 6.1 Inherited, acquired and mixed coagulation‐related risk factors for thrombosis.

Table 6.2 Prevalence of thrombophilia abnormalities and relative risk of thrombosis.

Table 6.3 Current indications for which thrombophilia testing can be considered.

Chapter 07

Table 7.1 Recommendations for the use of CTPA for suspected PE.

Chapter 08

Table 8.1 Criteria for diagnosis of APS (Miyakis

et al

., 2006).

Chapter 11

Table 11.1 Point of care devices available and their characteristics.

Chapter 12

Table 12.1 Current approved indications for DOACs from FDA, EMA and Health Canada.

Table 12.2 Specific laboratory assays that can be used to more accurately measure drug levels.

Chapter 13

Table 13.1 Extremity signs and symptoms of post‐thrombotic syndrome.

Table 13.2 Signs and symptoms of Phlegmasia Cerulea Dolens.

Table 13.3 Contraindications to catheter‐directed thrombolysis.

Chapter 14

Table 14.1 Professional medical society practice‐based guidelines for IVCF indications.

Table 14.2 Summary of randomised controlled trials of IVCFs.

Chapter 15

Table 15.1 Risk factors for venous thromboembolism in pregnancy and the puerperium (from RCOG Green‐top Guideline No. 37a).

Table 15.2 Prevalence and pregnancy risk of VTE with different heritable thrombophilias.

Table 15.3 Suggested LMWH doses for antenatal and postnatal VTE prophylaxis.

Table 15.4 Estimated radiation doses associated with investigations for VTE.

Table 15.5a Therapeutic dose (treatment dose) of enoxaparin.

Table 15.5b Therapeutic dose (treatment dose) of tinzaparin.

Chapter 16

Table 16.1 A list of common paediatric risk factors for thrombosis.

Chapter 17

Table 17.1 Dosing schedules of different LMWHs in treatment and secondary prevention of CAT.

Table 17.2 Summary of ISTH SCC haemostasis and malignancy guidance for challenging cases.

Table 17.3 Khorana score for risk of developing VTE during chemotherapy.

Chapter 18

Table 18.1 Summary of key points for the treatment of VTE with anticoagulant therapy.

Table 18.2 The pharmacokinetic profiles of the newer anticoagulant agents compared to enoxaparin.

Chapter 22

Table 22.1 Risk factors for venous access‐associated upper extremity deep vein thrombosis (Joffe and Goldhaber, 2002; van Rooden

et al

., 2005; Hull

et al

., 1981).

Chapter 23

Table 23.1 Risk factors for splanchnic vein thrombosis.

Table 23.2 Risk factors for renal and ovarian vein thrombosis.

Chapter 24

Table 24.1 Retinal vein occlusion risk factors and associations.

Table 24.2 Retinal artery occlusion risk factors and associations.

Chapter 25

Table 25.1 Villalta score.

Table 25.2 CEAP classification – patients are assigned a value for each category C, E, A and P. For example, a typical PTS patient would score C

4B

E

S

A

D

P

O

.

Table 25.3 Venous clinical severity score.

Chapter 27

Table 27.1 Risk factors for recurrent VTE following a first unprovoked VTE.

Table 27.2 Clinical prediction rules for recurrent VTE following unprovoked first VTE.

Chapter 28

Table 28.1 Summary of key trials. See text for details.

Chapter 30

Table 30.1 Performance of diagnostic test in patients with suspected distal DVT.

Table 30.2 Major and minor risk factors for IDDVT extension or recurrence.

List of Illustrations

Chapter 01

Figure 1.1 VTE risk increases with age. Taken from UK VERITY (Venous Thromboembolism registry).

Figure 1.2 Risk factors for VTE. Taken from UK VERITY (Venous Thromboembolism registry).

Figure 1.3 Rates of different cancers in the non‐VTE and VTE population; odds ratios for different types of cancer. Taken from UK VERITY (Venous Thromboembolism registry).

Figure 1.4 Risk assessment for VTE in cancer patients.

Chapter 05

Figure 5.1 Diagnostic algorithm for deep vein thrombosis. DVT – deep vein thrombosis; HS – high sensitivity; US – ultrasonography.

Figure 5.2 Diagnostic algorithm for pulmonary embolism. HS – high sensitivity; PA – pulmonary angiography; PE – pulmonary embolism; US – ultrasonography; V/Q scan – pulmonary ventilation/perfusion scan.

Figure 5.3 Generation of fibrin/fibrinogen degradation products (FDPs) and D‐dimer.

Figure 5.4 Diagnostic algorithm for recurrent deep vein thrombosis. DVT – deep vein thrombosis; HS – high sensitivity; US – ultrasonography.

Figure 5.5 Mechanism of action of the leading anticoagulant drugs. F – factor; LMWH – low molecular weight heparin; VKAs – vitamin K antagonists.

Figure 5.6 Laboratory assessment of the leading anticoagulant drugs. APTT – activated partial thromboplastin time; dRVVT – dilute Russell viper venom time; dTT – dilute thrombin time; ECT – ecarin clotting time; FXa – activated factor X; LC‐MS/MS – liquid chromatography tandem mass spectrometry; LMWH – low molecular weight heparin; PT – prothrombin time; UFH – unfractionated heparin; VKAs – vitamin K antagonists.

Chapter 07

Figure 7.1 Flowchart in patients with suspected PE, classified as high‐risk patients (modified from Konstantinides

et al

., 2014). CTPA – computed tomography pulmonary angiography; RV – right ventricle; PE – pulmonary embolism.

Figure 7.2 Flowchart in patients with suspected PE, classified as non‐high‐risk patients (modified from Konstantinides

et al

., 2014). CTPA – computed tomography pulmonary angiography; PE – pulmonary embolism.

Chapter 09

Figure 9.1 Algorithm for managing DVT as an outpatient.

Figure 9.2 An algorithm to guide the decision for managing PE as an outpatient.

Chapter 10

Figure 10.1 Counselling form used by GCAS when commencing patient on Vitamin K antagonist.

Figure 10.2 GCAS risk assessment form for patients requiring domiciliary visits for INR testing.

Figure 10.3 GCAS protocol outlining patient and GCAS responsibilities, and signed agreement form for INR self‐testing.

Chapter 11

Figure 11.1 Calibration of a new reagent using reference thromboplastin.

Figure 11.2 Comparison of three INR tests performed on the same patient on the same day: (a) shows results which are accurate and precise; (b) shows results that are inaccurate but precise; (c) shows inaccurate and imprecise results.

Chapter 13

Figure 13.1 Initial venogram via a popliteal vein catheter, demonstrating acute thrombus in the femoral vein with increased flow through deep perforator branches, and the greater saphenous vein (GSV).

Figure 13.2 Follow‐up venogram after 12‐hour CDT rt‐PA infusion demonstrates minimal residual thrombus with preferential flow through the femoral vein and decreased flow through perforators. The GSV is no longer visualised.

Figure 13.3 Venogram through popliteal catheter demonstrates acute thrombus in the popliteal and femoral vein.

Figure 13.4 Venogram after overnight CDT rt‐PA infusion demonstrates complete thrombus resolution.

Figure 13.5 Pelvic venogram through right femoral catheter demonstrates acute on chronic thrombus extending to the IVC filter. Contrast surrounds the acute thrombus in the IVC and right iliac veins.

Figure 13.6 Left pelvic venogram through left common femoral vein catheter, collateral veins due to acute on chronic thrombus of the left iliac system.

Figure 13.7 Overnight, CDT dissolved acute thrombus. However, there was residual high grade thrombus so, therefore, stenting of the iliac veins and IVC was performed. The final angiogram demonstrates anatomic flow without stenosis.

Chapter 15

Figure 15.1 Virchow’s triad in pregnancy.

Figure 15.2 Obstetric thromboprophylaxis risk assessment and management.

Figure 15.3 Common and important causes of chest pain and breathlessness in pregnancy.

Figure 15.4 Investigation algorithm for DVT in pregnancy.

Figure 15.5 RCOG diagnostic algorithm for PE in pregnancy.

Chapter 16

Figure 16.1 Virchow’s triad explains the pathophysiology underlying the majority of thrombosis in children.

Chapter 17

Figure 17.1 Risk factors for cancer‐associated thrombosis.

Chapter 18

Figure 18.1 Relationship between lean body weight (LBW) and drug clearance, as stipulated by Han

et al

. (2007). Patients to the right of the vertical dashed line are obese (>30 kg/m

2

). The linear relationship between clearance and LBW is shown by the LBW (solid curve) and clearance graphs (dotted curve) running parallel to each other.

Chapter 22

Figure 22.1 (a) Suggested diagnostic algorithm for suspected upper extremity DVT.

Chapter 23

Figure 23.1 Suggested anticoagulant therapies for the acute‐phase SVT in different situations.

Chapter 26

Figure 26.1 Suggested algorithm for stepwise approach in evaluation, diagnosis and management of CTEPH.

Figure 26.2 (a) Proximal vessel narrowing in right upper lobe (solid white arrow) and on lateral view, intimal irregularities anterior right lower lobe vessel (open white arrow). (b) Segmental level narrowing left upper lobe arteries (open black arrow), with what appears to be ‘web’ narrowing of proximal left descending PA. That on lateral view was the lingula artery (solid black arrow); the left descending PA was completely occluded beyond the lingula. These angiographic findings are consistent with organized thromboembolic disease.

Figure 26.3 Suggested algorithm for treatment approaches for patients with CTEPH.

Chapter 27

Figure 27.1 Conceptual framework for risk of recurrent VTE following provoked and unprovoked first VTE.

Figure 27.2 Cumulative rates of VTE recurrence‐free survival according to DASH score.

Chapter 31

Figure 31.1 VTE risk assessment tool for medical and surgical inpatients (excluding orthopaedics, obstetrics and gynaecology)

Figure 31.2 VTE risk assessment for obstetric patients, using a points system.

Figure 31.3 Proposed risk assessment and preventative measures in travellers.

Chapter 32

Figure 32.1 Aims of National VTE Exemplar Centres in England.

Figure 32.2 Essential criteria for VTE Exemplar Centres.

Figure 32.3 e‐learning modules available in England.

Chapter 33

Figure 33.1 An effective path to follow when planning an RCA.

Figure 33.2 Team structure.

Guide

Cover

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Handbook of Venous Thromboembolism

Edited by

Jecko Thachil, MBBS, MD, MRCP, FRCPath

Consultant Haematologist,Department of Haematology, Manchester Royal Infirmary,Manchester, UK

Catherine Bagot, BSc, MBBS, MD, MRCP, FRCPath

Consultant Haematologist,Department of Haematology, Glasgow Royal Infirmary,Glasgow, UK

This edition first published 2018© 2018 John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data

Names: Thachil, Jecko, editor. | Bagot, Catherine, editor.Title: Handbook of venous thromboembolism / edited by Jecko Thachil and Catherine Bagot.Description: Chichester, West Sussex ; Hoboken : John Wiley & Sons, 2018. | Includes bibliographical references and index. |Identifiers: LCCN 2017039383 (print) | LCCN 2017040998 (ebook) | ISBN 9781119095590 (pdf) | ISBN 9781119095583 (epub) | ISBN 9781119095576 (cloth)Subjects: | MESH: Venous ThromboembolismClassification: LCC RC697 (ebook) | LCC RC697 (print) | NLM WG 610 | DDC 616.1/45–dc23LC record available at https://lccn.loc.gov/2017039383

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List of Contributors

William R. Auger, MDUniversity of California, San Diego, USA

Catherine Bagot, BSc, MBBS, MD, MRCP, FRCPathConsultant Haematologist, Department of Haematology, Glasgow Royal Infirmary, Glasgow, UK

Rebecca Barton, MBBS, BBioMedScDepartment of Clinical Haematology, Royal Children’s Hospital, Melbourne, Australia

Enrico Bernardi, MD, PhDDepartment of Emergency and Accident Medicine, Hospital of Conegliano, Italy

Karen Breen, MD, MRCPI, FRCPathDept of Thrombosis, St.Thomas’ Hospital, London

Andrew Busuttil, MD, MRCSAcademic Section of Vascular Surgery, Charing Cross Hospital, Imperial College London, UK

Giuseppe Camporese, MDUnit of Angiology, Department of Cardiac‐Thoracic‐Vascular Sciences, University Hospital of Padua, Italy

Lana A. Castellucci, MD, MScDepartment of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

Yen‐Lin Chee, MBChB, MRCP, PhD, MRCPathConsultant Haematologist, Department of Hematology‐Oncology, National University Cancer Institute, Singapore

Marco Das, MD, PhD, MBADepartment of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands

Alun H. Davies, MA, DM, DSc, FRCS, FHEA, FEBVS, FACPhAcademic Section of Vascular Surgery, Charing Cross Hospital, Imperial College London, UK

Kerstin de Wit, MBChB, BSc, MSc, MDDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada

C.E.A. Dronkers, MDDepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands

Emmanuel J. Favaloro, BSc (Hons), MAIMS, PhD, FFSc (RCPA)Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia

David Fitzmaurice, MBChB, MRCGP, MD, FRCGPProfessor of Cardiorespiratory Primary Care, University of Warwick, Coventry, UK

Lauren Floyd, MBBS, MRCPCore Trainee, Manchester Royal Infirmary, Manchester, UK

Massimo Franchini, MDDepartment of Hematology and Transfusion Medicine, C. Poma Hospital, Mantova, Italy

Emma Gee, BScNurse Consultant, Thrombosis and Anticoagulation, King's College Hospital NHS Foundation Trust, London, UK

Francesca Gianniello, MDA. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda ‐ Ospedale Maggiore Policlinico, Milan, Italy

Carlos J. Guevara, MDInterventional Radiology Section, Mallinckrodt Institute of Radiology, Washington University in St. Louis, USA

Paul Hahn, MD, PhDDepartment of Ophthalmology, Duke University Medical Center, Durham

Dan Horner, BA, MBBS, MD, PgCert, MRCP (UK) FCEM FFICMConsultant in Emergency Medicine and Intensive Care, Salford Royal NHS Foundation Trust, Manchester, UK

M.V. Huisman, MDDepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands

Francesca Jones, MBBS, MRCP, FRCPathHaematology consultant

Department of Haematology, University Hospital Coventry and Warwick, NHS Foundation Trust, UK

David Keeling, BSc MD FRCP FRCPathConsultant Haematologist, Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals, Oxford, UK

Dianne Patricia KitchenPoint of Care, UK NEQAS for Blood Coagulation, Sheffield, UK

F.A. Klok, MD, PhDDepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands

Dawn Kyle, BSC, RGNTeam Leader, Glasgow and Clyde Anticoagulation Service, Glasgow, UK

Kathryn Lang, MBBS, MRCP(UK) King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London

Will Lester, MBChB, BSc, FRCP, FRCPath, PhDHaematology Consultant

Department of Haematology, University Hospital Birmingham NHS Foundation Trust

Giuseppe Lippi, MDSection of Clinical Biochemistry, University of Verona, Verona, Italy

Molly W. Mandernach, MD, MPH, FACPUniversity of Florida College of Medicine, Gainesville, Florida, USA

Ida Martinelli, MD, PhDA. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda ‐ Ospedale Maggiore Policlinico, Milan, Italy

Paul Monagle, MBBS, MD, MSc, FRACP, FRCPA, FCCPDepartment of Clinical Haematology & Department of Paediatrics, University of Melbourne Royal Children’s Hospital, Victoria, Australia

Kathy Macintosh, BScTeam Leader, Glasgow and Clyde Anticoagulation Service, Glasgow, UK

Alison MoughtonAnticoagulant Nurse Specialist

Department of Haematology, University Hospital Birmingham NHS Foundation Trust

Simon Noble, MBBS, MD, FRCPDivision of Population Medicine, Cardiff University, Cardiff, Wales

Serena M. Passamonti, MD, PhDA. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda ‐ Ospedale Maggiore Policlinico, Milan, Italy

Jignesh Patel, BSc(Hons), MSc, PhDInstitute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London & King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, UK

Demosthenes G. Papamatheakis, MDUniversity of California, San Diego, USA

Catherine Nelson Piercy, PhD, FRCP, FRCOGProfessor of Obstetric Medicine, Women’s Health Academic Centre, Guy’s and St Thomas’ Foundation Trust, London, UK

Anita Rajasekhar, MD, MSUniversity of Florida College of Medicine, Gainesville, Florida, USA

Gill Parmilan, MBBS, MRCPCore Trainee, Manchester Royal Infirmary, Manchester, UK

Peter E. Rose, BSc(Hons), PhDConsultant Haematologist, Warwick Hospital, South Warwickshire Foundation Trust, UK

Linda Smith, RGN/BSCTeam Leader, Glasgow and Clyde Anticoagulation Service, Glasgow, UK

Scott M. Stevens, MDDepartment of Medicine, Intermountain Medical Center, Murray, Utah, and Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

R. Campbell Tait, MBChB, FRCPSG, FRCPathHonorary Professor of Haemostasis and Thrombosis, Department of Haematology, Glasgow Royal Infirmary, Glasgow, UK

Jecko Thachil, MBBS, MD, MRCP, FRCPathDepartment of Haematology, Manchester Royal Infirmary, Manchester, UK

Suresh Vedantham, MDInterventional Radiology Section, Mallinckrodt Institute of Radiology, Washington University in St. Louis, USA

Henry G. Watson, MD, FRCP, FRCPathConsultant Haematologist and Honorary Professor of Medicine, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, Scotland, UK

Christian Weimar, MDDepartment of Neurology and Stroke Center, University Duisburg‐Essen, Germany

Joachim E. Wildberger, MD, PhDDepartment of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands

Scott C. Woller, MDDepartment of Medicine, Intermountain Medical Center, Murray, Utah, and Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

Wenlan Zhang, MDDepartment of Ophthalmology, Duke University Medical Center, Durham

Foreword

Venous thromboembolism (VTE) is ubiquitous in both primary and secondary care, and therefore, having a clear understanding of the presentation, diagnosis and treatment of this condition is important. However, remaining up to date with this rapidly changing field is a challenge for the non‐expert.

Over the last 20 years, the management of VTE has undergone a paradigm shift. Investigation and diagnosis of Deep Vein Thrombosis (DVT) and, in recent years, pulmonary embolism (PE), has moved from an in‐patient setting into well‐defined out‐patient pathways. Warfarin, the mainstay of treatment for venous thrombosis for over 70 years, is rapidly being replaced by use of direct oral anticoagulants, a new class of drugs which have their own characteristics and challenges. Finally, when once all patients would have received six months of anticoagulation following a VTE, patients are now risk‐stratified, using a combination of both laboratory and demographic markers, demonstrating that a single duration of anticoagulation cannot be universally applied.

In addition to changes in VTE management, the prevention of VTE in hospital inpatients has become paramount in recent years, with the realisation that a significant number of thromboses occur as a result of hospital admission. Prevention strategies have reached the top of national health agendas, and remain a significant focus of safe patient care. Implementing effective VTE prevention strategies can be a significant challenge for healthcare professionals who may not have a primary role in VTE.

The purpose of this book is to provide all healthcare professionals involved in VTE with an easy‐to‐use tool, written by experts in the field, which summarises the most effective strategies for VTE investigation, diagnosis, management and prevention. We hope it can also be a practical reference for all those involved in the care of patients with VTE, both in its treatment and prevention.

Dr Catherine Bagot, Consultant Haematologist, Glasgow, UKDr Jecko Thachil, Consultant Haematologist, Manchester, UK

Section IClinical Overview

1Risk Factors for Venous Thromboembolism

Peter E. Rose

Consultant Haematologist, Warwick Hospital, South Warwickshire Foundation Trust, UK

Introduction

There are many risk factors reported to increase the risk of venous thromboembolism (VTE), as shown in Table 1.1.

Table 1.1 Risk factors for venous thromboembolic disease.

Patient Related

Additional factors

Increasing age

Surgery within 90 days

Previous history VTE

Lower limb cast

Family history 1st degree relative

Hospital stay > 3 days

Thrombophilia

Cancer in past six months/ongoing disease

Pregnancy

Medical comorbidities

Obesity > 30 kg/m

2

Extended travel

Smoking/alcohol/substance abuse

Medication related

Large national registries for VTE patients have helped to elucidate and quantify the relative risk of individual factors. The risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE) are largely similar, as DVT and PE represent a spectrum of the same disease process. There is also some overlap between venous and arterial thrombotic risk, with age, smoking and obesity common to both, although they are much more important factors in arterial disease. Part of this may be an indirect association – for example, smoking increases cancer risk, and hence VTE, while medical in‐patients with heart failure have a marked increase in risk for pulmonary embolism. Figure 1.1 shows the increasing rate of VTE with age, from the UK VTE registry, VERITY. Overall, the risk for VTE is increasing, with an ever aging population, receiving multiple medications many of which increase thrombotic risk, particularly in the field of cancer medicine.

Figure 1.1 VTE risk increases with age. Taken from UK VERITY (Venous Thromboembolism registry).

The most important risk factors for VTE are a history of previous VTE, recent surgery, hospital in‐patient stay and cancer. While there is much comment around factors such as long‐haul travel and inherited risk factors for VTE, these represent less common and less important factors. In general the more risk factors present, the greater will be the cumulative risk for VTE.

Previous VTE

For patients with a known history of VTE, it is important to identify if the previous event was provoked, in association with temporary risk factors, or unprovoked. The risk of recurrence is less than 3% if provoked, but is near 10% in unprovoked VTE within 12 months of discontinuing anticoagulant therapy. It can be difficult to determine what is and is not provoked; for example, a DVT post orthopaedic surgery is clearly provoked, while a female on the combined pill preparation for three years without previous thrombosis is not necessarily a provoked event. A VTE within three months of starting the pill however, would be provoked.

Provoking factors can be further divided into surgical, with a recurrence rate of 1% within 12 months of treatment, and non‐surgical factors, with a 6% risk in this time period. For patients with unprovoked VTE, the risk persists with time, with 40% recurrence within ten years. For a cohort of young male patients presenting with unprovoked PE, there is a 20% risk of recurrence of PE within 12 months which persists, making recurrence almost inevitable.

Surgery

Pulmonary embolism remains the most widely reported preventable cause of death in patients undergoing surgery. It is the most common cause of death within 30 days of surgery, with 40% of VTE events occurring later than three weeks post operatively. Even for low‐risk general gynaecological abdominal surgery for non‐malignant disease, the risk for VTE extends up to at least 90 days post‐surgery. Previous autopsy studies in surgical patients report VTE to be present in 5–10% of cases. Surgery, therefore, requiring general anaesthesia for over one hour, is a major risk factor for VTE. Surgical risk is compounded by many concomitant medical risk factors – for example, a further doubling of risk in cancer surgery. See Table 1.2.

Table 1.2 Surgical risk factors for VTE.

Personal

Surgical

Age > 60

Prolonged anaesthesia

Medical comorbidities

Major trauma

Previous VTE

Lower limb surgery

Thrombophilia

Major abdominal surgery

Obesity

Cancer surgery

Post‐operative admission to ITU

Bariatric surgery

Orthopaedic Surgery

Patients undergoing lower limb surgery are among the highest risk patients (odds ratio > 10), and this includes total hip and knee arthroplasty, hip/leg fractures, major orthopaedic trauma and spinal surgery. With improved surgical procedures and shorter time for anaesthesia, there is some recent risk reduction. The risk for VTE partly relates to prolonged stasis associated with immobility, and the release of tissue fragments of collagen and fat, which can directly activate coagulation factors. Furthermore, direct blood vessel damage during retraction of soft tissues can act as a nidus for thrombus formation.

Lower limb immobilisation in casts, with or without surgery, increases the risk of VTE. The prevalence of lower limb injury‐related DVT with cast immobilisation is reported to occur in 4–40% of cases. Further confirmation of the importance comes from studies using chemical thromboprophylaxis, which results in a 50% reduction in DVT rate. On this basis, NICE guidance recommends that all patients with lower limb immobilisation should be assessed for chemical thromboprophylaxis.

Other Surgeries

Other high‐risk surgery includes major abdominal procedures, particularly in cancer patients. Evidence confirming the importance of general surgery as a major risk factor for VTE is provided from studies evaluating the efficacy of thromboprophylaxis. For example, a systematic review of cancer patients undergoing surgery showed a reduction in VTE events from 35% to 13% in patients receiving pharmacological thromboprophylaxis.

Additional risk factors for thrombus and surgery include the increasing use of indwelling venous catheters and filters for prolonged periods of time in the post‐operative period. It is estimated that 14% of patients undergoing cardiac surgery without thromboprophylaxis develop VTE. As many of these patients are already on antiplatelet or anticoagulant therapy, the true risk associated with surgery is difficult to assess. Similarly, the risk with vascular surgery, while increased, is difficult to quantify in a largely elderly group with reduced mobility, on anti‐platelet therapy and often with comorbidities. A careful VTE risk assessment is needed for all patients undergoing surgery, particularly where this involves general anaesthesia and prolonged hospital admission, evaluating the bleeding risk due to the procedure against the reduction in thrombotic events.

Hospitalised Medical Patients

Approximately 70–80% of fatal hospital acquired thrombosis (HAT) occurs in medical patients. Venous thrombosis is increased in most acute medical conditions, necessitating hospital admission. The risk of VTE is also increased in a number of chronic medical disorders (see Table 1.3). Medical inpatients are usually elderly, often with several conditions to compound VTE risk.

Table 1.3 Medical conditions with increased risk of VTE.

Acute

Chronic

Congestive heart failure

Disorders of mobility (mechanical/ neurological)

Respiratory failure

Nephrotic syndrome

Severe infection/ sepsis

Sickle‐cell disease

Rheumatological conditions

Paraproteinaemia

Inflammatory bowel disorders

Paroxysmal nocturnal haemoglobinuria

Stroke

Bechet’s disease

Cancer

Porphyria

Stroke patients, whether due to ischaemic or haemorrhagic events, are at increased risk of VTE, with a wide range of estimates reported, namely, 15–60%. Prevention with chemical thromboprophylaxis is dependent on safety, with haemorrhagic risk often high. In the absence of haemorrhage, the presence of additional factors, such as severity of immobilisation and comorbidities, are important for risk assessment. Acute respiratory infection in hospitalised patients is a particularly high risk for VTE. Other medical conditions included in clinical trials for thromboprophylaxis in medical patients include congestive heart failure, respiratory failure, acute rheumatological and inflammatory bowel disorders.

Clinical studies have shown the risk of DVT to be between 4–5%, with mortality at 90 days 6–14%. Congestive heart failure patients commonly develop DVT in the absence of thromboprophylaxis, affecting 20–40% of patients, with a similar risk for medical intensive care patients. All hospitalised medical inpatients, therefore, require a risk assessment for VTE in order to reduce morbidity and mortality from HAT.

Several chronic medical conditions carry an increased life‐time risk of VTE. Rheumatological disorders such as systemic lupus erythematosus, particularly associated with the anti‐phospholipid syndrome, are pro‐thrombotic conditions. Inflammatory bowel disease is associated with a 2–3 fold increased VTE risk. Less common medical conditions at high risk include Bechet’s disease, nephrotic syndrome, sickle cell disease, and some porphyrias. Paroxysmal nocturnal haemoglobinuria, while rare, is complicated by thrombotic problems in over 50% of cases. Medical treatments may also be associated with VTE, with hormone therapies and erythropoietin being common examples. These medical conditions should evoke a high index of suspicion for VTE, particularly in those with a previous proven event.

Cancer Associated Thrombosis (CAT)

Twenty percent of all VTE cases occur in patients with cancer (those diagnosed within the previous six months or with ongoing disease or treatment for cancer). VTE is the second most common cause of death in cancer patients, and is associated with a very poor prognosis. Nearly 50% of cancer patients die within six months of developing VTE. CAT has a different pathogenesis, a different additional risk profile, and requires different management from non‐cancer VTE. CAT is often undiagnosed, as it is found in 50% of cancer patients at autopsy. Important risk factors need to be considered for CAT, including the tumour site and the presence of metastatic disease. These risk factors are shown in Table 1.4 below.

Table 1.4 Risk factors for cancer‐associated VTE.

All cancer patients

Cancer patients receiving chemotherapy

Site of tumour high/intermediate/low risk

Platelets > 350 × 10

9

/l

Metastatic disease

Haemoglobin < 100 g/l

Surgery

White blood count > 11 × 10

9

/l

Chemotherapy

BMI > 35 kg/m

2

Radiotherapy

High D‐dimer

Hormone treatment

High serum P‐selectin

Anti‐angiogenic therapy

Indwelling venous catheter

Tumour sites with the highest thrombotic risk include pancreas, brain, stomach and lung. Rare tumours, such as head and neck plus endocrine, are also high risk for CAT – see Figures 1.2 and 1.3 from the UK VERITY registry.

Figure 1.2 Risk factors for VTE. Taken from UK VERITY (Venous Thromboembolism registry).

Figure 1.3 Rates of different cancers in the non‐VTE and VTE population; odds ratios for different types of cancer. Taken from UK VERITY (Venous Thromboembolism registry).

While breast and prostatic cancer are the most commonly seen malignancies in patients presenting with CAT, this is due to their increased prevalence, with overall moderate to low risk, respectively, for these sites. The risk of VTE is greatly increased in the presence of metastatic disease, with increased tumour burden an important factor in promoting the pro‐thrombotic state. This is illustrated in breast cancer, where the risk for localised Stage 1 disease not requiring adjuvant treatment for VTE is low, but increases 15 fold for those with Stage 4 disease requiring chemotherapy.

There is also a 28 fold increase in CAT patients with haematological malignancy, compared with population controls. This figure not only reflects the underlying pro‐thrombotic state, but also the intensity and need for several modalities of treatment. Nearly all modalities of treatment increase the thrombotic risk in cancer patients. Many chemotherapeutic agents increase damage to the vascular endothelium, while radiotherapy also increases VTE. Many adjuvant treatments, such as hormone therapy, anti‐angiogenic agents such as thalidomide, lenalidomide and anti‐ VEGF therapy, are associated with high risk for thrombosis. The use of indwelling lines for prolonged venous access, together with the additional risk where surgery is needed, all contribute to CAT. Supportive therapies, such as G‐CSF, erythropoietin and even blood transfusion, have been reported to increase VTE risk.

The presence of malignancy appears such a significant risk factor for VTE that the risk profile is very different from non‐cancer patients with VTE. In one large registry study, factors such as personal history of VTE, Thrombophilia, IV drug abuse and smoking were only significantly raised in non‐cancer patients, with medical in‐patient stay with immobilisation for more than three days in the last four weeks more common in CAT patients. In many, CAT is asymptomatic with increasing numbers of cases identified, due to improved imaging techniques. All cancer patients, as part of the multi‐disciplinary treatment assessment at presentation, should have an appraisal of VTE risk in order to reduce the very high mortality with CAT. See Figure 1.4.

Figure 1.4 Risk assessment for VTE in cancer patients.

Pregnancy

Pregnancy is a pro‐thrombotic state from the first trimester onwards, and is associated with a 4–5 fold increase in risk for VTE. The highest risk period is in the immediate eight weeks post‐partum, with a 20 fold increased risk. The prevalence of all thrombotic events in pregnancy is two per 1000 deliveries, with 80% venous and 20% arterial. It is suggested that the pro‐thrombotic state has evolved to reduce the haemorrhagic complications with childbirth. VTE accounts for approximately 10% of all maternal deaths, and is the most common cause in the western world. The risk of VTE increases with maternal age and multi‐parity, and is higher in black females. The risk factors are shown in Table 1.5.

Table 1.5 Pregnancy and risk factors for VTE.

Patient‐related

Additional factors

Increasing age > 35

Caesarean section

Previous VTE

Dehydration (hyperemesis)

Multi‐parity

Pre‐eclampsia

Varicose veins

Previous fertility treatment

Thrombophilia

Puerperal sepsis

Ethnicity (> Afro‐Caribbean)

Ante‐partum haemorrhage

Obesity

Smoking

The clinical presentation is usually with an extensive clot in the proximal veins of the left leg. The predilection for the left leg is due to narrowing of the left common iliac vein, as it compresses between the lumbar vertebral body and right common iliac artery. There have also to be additional mechanical or hormonal factors in pregnancy to affect this change.

Reduced venous flow in pregnancy is multi‐factorial, with hormones mediating a reduction in venous tone and increased risk of varicosities. This is abetted by the expanding uterus and reduced mobility. The higher risk post‐delivery is the result of increased tissue and vessel damage. A number of coagulation factors are significantly increased, including factors V, VIII, IX, XI and fibrinogen. There are changes in the natural anticoagulant free protein S, which reduces throughout pregnancy due to increased levels of binding protein C‐4b, increasing thrombotic risk. Reduced fibrinolysis with increased levels of plasminogen activator inhibitors (PAI‐1) and (PAI‐2), is also seen in pregnancy. PAI‐2 is produced in the placenta, and markedly increases in the third trimester. All of these changes contribute to the pro‐thrombotic condition.

There are several additional risk factors to increase VTE in pregnancy. A personal history of VTE increases the risk by a further 3–4 fold. Dehydration and hyperemesis can be an important factor from early in pregnancy. Surgical intervention, with caesarean section, post‐partum haemorrhage and puerperal sepsis, all increase thrombotic risk. While pregnancy can be considered an acquired form of thrombophilia, the risk for VTE increases further in the presence of a heritable thrombophilia. The risk varies dependent on the thrombophilia but, for those homozygous for Factor V Leiden or the Prothrombin mutation, there is a 30 fold increase in risk, while heterozygosity is associated with a 6–8 fold increase.

Patients with anti thrombin deficiency are high risk, with 50% risk for VTE in pregnancy. Protein C and S deficiency are reported to increase risk during pregnancy by 3–10% and 0–6%, respectively, with higher risk post‐partum between 7–20%. Patients with thrombophilia, particularly with a proven history of VTE, would require specialist input to assess management.

Those who become pregnant as a result of fertility treatment have an added risk of VTE, sometimes presenting with thrombosis at unusual sites, resulting in subclavian and/or jugular vein thrombosis. A proper risk assessment for VTE in pregnancy is therefore essential, in order to avoid preventable morbidity and mortality. Combined assessment at an obstetric and haematology clinic is needed for patients at high risk, particularly those with a previous history of VTE.

Combined Oral Contraceptive Use

The highest risk period for VTE in users of the combined oral contraceptive (COC) is in the first few months of starting. The individual risk for VTE is very low but, as there are over 100 million users of reproductive age, it has an important impact on the incidence of VTE. The incidence in non‐COC users is reported to be 0.16 per 1000 person years, while the relative risk in COC users compared to non‐users is reported, in a Cochrane database study, to be 3.5. Similar to pregnancy, there are increased levels of several coagulation factors, and reduced levels of some natural anticoagulants in particular protein S. These changes have been reported to be more pronounced in some COC preparations than in others, most notably third generation COCs.

While all COC preparations increase VTE risk to some extent, studies have identified the dose of ethinylestradiol to be critical, with an important risk reduction in the dose from 150 to 30 micro grammes. The thrombotic risk is also dependent on the progestogen used in the preparation. Changes in the progestogen component have been made to try to reduce side‐effects of COCs. Second‐generation, from the 1970s, and third‐generation COCs, together with further preparations, have had varying VTE risk outcomes. Overall, the most recent Cochrane review still reported the second‐generation COC with 30 microgrammes of ethinylestradiol and levonorgestrel to have the lowest risk for VTE.

For all COC users of low‐dose ethinylestradiol in combination with either gestodene, desogestrel, cypropterone acetate or drospinerone, the risk of VTE is 50–80% higher than with the second‐generation COC. More recent studies, with the exception of norgestimate, also confirm the risk to be higher for the newer drug preparations. To date, there is limited information on the progestin‐only contraceptive, although a recent meta‐analysis concluded that VTE risk is not increased.

For postmenopausal women, increasing age is an important compounding factor and, for those taking hormone replacement therapy, there is a 2–5 fold increased risk for VTE. This risk is highest in the first 12 months of starting, when the risk is increased six‐fold. The risk varies by preparation, but is higher in oestrogen‐progestin preparations and increases with higher oestrogen dose. There is also a significant difference dependent on the mode of delivery, with transdermal patches safer. Overall, the risk, particularly when there are additional co‐morbidities, needs to be assessed when considering optimal therapy.

Family History of VTE and Thrombophilia

A family history of an unprovoked VTE in a first‐degree relative is associated with an additional risk for VTE. Screening for a significant heritable thrombophilia in patients with a proven history will, however, fail to identify an abnormality in nearly 50% of cases. The increased VTE risk remains, whether or not the screen is positive. For younger patients with an unprovoked PE, a thrombophilia screen should be considered if it is planned to stop anticoagulant treatment. This would also be the case where there is a known high‐risk thrombophilia in a first‐degree relative and the patient is due to be exposed to additional risk factors.

Heterozygosity for Factor V Leiden can be identified in approximately 5% of people in the UK. It carries only a two‐fold risk for VTE, and is the most commonly found abnormality in studies where thrombophilia screening has been undertaken in proven VTE patients, present in 30% of cases. For very rare cases homozygous for Factor V Leiden, the risk of VTE increases nearly 80 fold. The absolute risk for non‐COC users heterozygous for Factor V Leiden is 35 per 100 000, rising to 285 per 100 000 for COC users. To put this in context, it compares to an absolute risk with fracture of femur of 6000 per 100 000. Overall, the risk of COC usage is not an absolute contraindication in carriers of Factor V Leiden, as the risk would be higher if pregnant. If known, it should, however, be part of the discussion around the most appropriate and safest form of contraception.

Overall, the risk of a first DVT in carriers of Factor V Leiden or Prothrombin gene mutation, and those with increased levels of FVIII, is under 0.5% per year, not high enough to warrant consideration for thromboprophylaxis.This is particularly the case as there is no difference in recurrence rate to patients with first DVT who have not had thrombophilia testing. Higher VTE risk is seen in deficiency of the natural anticoagulants protein C, protein S and antithrombin. The annual risk for VTE is reported as between 1.5 and 1.9%, with a recurrence risk at five years of 40%. The risk with deficiency of these factors in pregnancy, as previously discussed, is significantly higher and warrants expert input. While high levels of other coagulation factors, FIX, FXI and hyperhomocysteinaemia, have been reported to increase VTE risk, they are not independent risk factors and are usually seen in association with increased FVIII. The combination of two or more thrombophilia factors would increase risk, and would require further expert input.

Obesity

A strong association between obesity and VTE has been reported. In a large population‐based study, DVT risk increased with BMI, showing a hazard ratio of 1.3 in those overweight, 1.8 in moderate obesity, and 3.4 in severe obesity, compared with normal‐weighted individuals. The risk is present for both males and females. Obese women using the COC, however have been reported to have a 24 fold increased VTE risk, compared with non‐obese females not taking a COC.

Obesity risk for VTE is also increased in combination with a heritable thrombophilia – for example, it is associated with an eight‐ and seven‐fold risk with heterozygosity for Factor V Leiden and Prothrombin 20210A mutations, respectively. For those with concomitant medical problems, the risk is high, as is the risk associated with bariatric surgery. Of the measures to quantify obesity, it is reported that waist circumference in males, and hip circumference in females, equate best with VTE. This contrasts with arterial and myocardial risk, in which waist‐hip and waist to height are better measures. This emphasises differences in body fat distribution for venous and arterial disease and, perhaps, a different underling cause. Obesity has been suggested to correlate with increased thrombin generation in females with VTE, with increased fibrinogen and prothrombin associated with a pro‐thrombotic state. Overall, the cause, independent of reduced mobility, still needs to be defined.

Travel

Extended travel is associated with an increased risk of venous thrombosis. The most compelling evidence relates to a study at Charles de Gaulle airport, where passengers diagnosed with acute pulmonary embolism were assessed in terms of distance travelled. For travellers of less than 5000 km, the event rate was 0.01 cases per million, compared with 4.8 cases per million for travel greater than 10 000 km. Overall there is a 2–4 fold increase in VTE events for air‐travellers for flights greater than four hours, compared with non‐travellers.

The absolute risk of a spontaneous VTE event within four weeks of flight is very low, at one per 4600 flights. The risk is increased with the frequency of flights within a short time frame, with a significant increase for two or more flights of over eight hours within six weeks. Additional risk factors are important, and can increase the event rate three‐fold. These include increasing age, obesity, recent surgery, recent VTE off anticoagulants, malignancy and pregnancy. The mechanism is likely to be multi‐factorial, but prolonged immobilisation resulting in venous stasis, and changes in air pressure, are most important. While dehydration in flight has been suggested as a risk factor, there is currently no body of evidence to support this.

In conclusion, a VTE episode occurring within eight weeks of extended flight can be considered to have a role in causation. Risk associated with car travel, bus or train is highest in the week after travel. The greatest risk is reported in those with a BMI of more than 30 kg/m2, those over 1.9 m tall, or those with Factor V Leiden.

Substance Abuse

There is a marked increase in risk for DVT in users of opioid drugs. The prevalence of previous DVT in opioid users is reported to be 14%, with an annual incidence rate of 3%. The rate increases with age, female use, sex‐worker status and intravenous administration. There is a high risk with iliac and femoral injection, often in combination with severe groin infection. High rates of venous leg ulceration (15%) are reported in young drug abusers which are usually chronic and recurring. Staphylococcus bacteraemia is a common problem with IV drug abuse and VTE; however, it is also a proven independent risk for VTE within 90 days of community acquired infection.

While moderate alcohol consumption has been suggested to reduce the risk of VTE, alcohol abuse and its associated medical complications increase the risk of DVT. The risk is increased, even in those without associated medical complications.

The magnitude of risk with smoking and VTE is much less than that seen with arterial disease. While VTE risk is small, smoking is very common, and is an additional risk factor for COC users and those with raised BMI. There is also a reported dose response relationship for smoking and VTE, with return to normal risk on discontinuation. The association is seen in patients with provoked and unprovoked VTE, and may be attributable to the reduced fibrinolysis, inflammation and raised viscosity seen in smokers.

Conclusion

VTE risk is multi‐factorial, and requires a careful clinical appraisal in order to reduce the unacceptable high rates of morbidity and death currently seen in clinical practice. Early intervention in high risk patients is essential, and it is to be hoped that greater awareness of the important risk factors for VTE can reduce the incidence of a largely preventable problem.

Further Reading

NICE clinical guidance CG92.

Venous thromboembolism: reducing the risk of venous thromboembolism in patients admitted to hospitals

.

www.nice.org.uk/guidance/ CG92

.

Testroote M, Stiger WA, Janssen L, Janzing MN (2014). Low molecular weight heparin for prevention of venous thromboembolism in patients with lower limb immobilisation.

Cochrane Database of Systematic Reviews

4

: CD00668.

Goldhaber SI, Turpie AG (2005). Prevention of venous thromboembolism among hospitalised medical patients.

Circulation

111

: 1–3.

Rogers MA, Levine DA, Blumberg N

et al

. (2012). Triggers of hospitalisation for venous thromboembolism.

Circulation

125

: 2092–99.

Watson HG, Keeling DM, Laffan M

et al

. (2015). Guideline on aspects of cancer‐related venous thrombosis.

British Journal of Haematology

170

(5): 640–8.

Klovaite J, Benn M, Nordestgaard BG (2015). Obesity as a causal risk factor for deep vein thrombosis; a Mendelian randomization study.

Journal of Internal Medicine

277

: 573–84.

De Bastos m, Stegman BH, Rosendaal

et al

. (2014). Combined oral contraceptives: venous thrombosis.

Cochrane Database of Systematic Reviews

3

(3): CD 010813.

Lijfering WM, Jan‐Leendert P, Brouwer P

et al

. (2009). Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study in absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives.

Blood

113

: 5314–532.

Watson HG, Baglin T (2011). Guidelines on travel‐ related venous thrombosis.

British Journal of Haematology

152

: 31–4.

VERITY (Venous thromboembolism Registry) (2007).

Fourth Annual Report

.

www.e‐dendrite verityonline.co.uk

.

2Management of Venous Thrombosis in the Lower Limbs

Dan Horner

Consultant in Emergency Medicine and Intensive Care, Salford Royal NHS Foundation Trust, Manchester, UK

Introduction

The annual incidence of deep vein thrombosis (DVT) throughout the developed world is approximately 1 : 1000 of the population. The condition carries significant morbidity in the form of embolisation, post‐thrombotic venous insufficiency, pain, swelling and decreased mobility. Short‐term mortality stands between 5% and 10% in most epidemiological studies. It is a condition that can range from a self‐limiting minor nuisance to the presenting feature of disseminated malignancy. As such, all cases should be carefully managed, and considerable thought given to the what, the where and the why of each case.