Clinical Profile and Laboratory

CLINICAL PROFILE AND LABORATORY CORRELATES OF DEEP VENOUS THROMBOSIS: THE PREDICTABILITY OF POINT OF CARE D- DIMER TESTING AMONG ADULTS IN AMINU KANO TEACHING HOSPITAL, KANO.

A DISSERTATION SUBMITTED TO THE NATIONAL POST GRADUATE MEDICAL COLLEGE OF NIGERIA IN PARTIAL FULLFILMENT OF THE REQUIREMENTS FOR THE AWARD OF FELLOWSHIP OF THE COLLEGE IN INTERNAL MEDICINE.

FACULTY OF INTERNAL MEDICINE

(SUBSPECIALTY: CLINICAL HAEMATOLOGY)

ABDULLAHI MUSBAHU

DEPARTMENT OF INTERNAL MEDICINE

AMINU KANO TEACHING HOSPITAL

KANO

MAY 2017

CERTIFICATION

We certify that we supervised the project titled Clinical profile and laboratory correlates of Deep Venous thrombosis: The predictability of point of care D-dimer testing in adult patients in Aminu Kano Teaching Hospital, as part of the part II examination requirement of the National Postgraduate Medical College of Nigeria.

First supervisor`s Name: DR. BAFFA ADAMU GWARAM

Year of Fellowship…………….………………………………………………

Signature and Date………………..……………………………………………

Second supervisor`s Name: DR. ABDULHAMID ISA DUTSE

Year of Fellowship………………………………...……………………………

Signature and Date………………………………………………………………

DECLARATION

The dissertation titled “Clinical profile and laboratory correlates of Deep Venous thrombosis: The predictability of point of care D-dimer testing in adult patients in Aminu Kano Teaching Hospital” was conducted in the department of Medicine, Aminu Kano Teaching Hospital by Dr Musbahu Abdullahi.

Head of Department;

Name: PROF. A.A. SAMA`ILA

Signature and Date:..….………………………………………………………..

Declaration/Attestation

I declare that I conducted the above titled project according to the stated study protocol as part of the requirements for the award of Fellowship of the National Postgraduate Medical College of Nigeria.

Candidate`s Name: MUSBAHU ABDULLAHI (AF/009/12/115/927)

Signature…………………………………………………………………………

Dedication:

This work is dedicated to my late father, Alh Abdullahi Aliyu Sumaila and my mother, Haj

Saude A Aliyu whose support, guidance and encouragement have seen me through life. It is also dedicated to my siblings, Aliyu, Ahmed, Yusuf, Aminu, Rabi and late Abdullahi for being an indispensible pillar of support in my life. I also dedicate this work to my wife, Rabi for the patience, encouragement and support.

Acknowledgement:

My appreciation goes to all my teachers in the department of medicine, especially Dr

Abdulhamid Isa Dutse who provided immense academic, clinical and general guidance and training throughout my residency training, despite his tight schedule. I am particularly indebted to my teacher, Dr Baffa Adamu Gwaram, who saw to my training and provided invaluable academic, practical and social support at all times. He was ever present at times of need and patient with my shortcomings. I would like to appreciate Prof M.M.Borodo for his much needed fatherly guidance and inputs in completing my training and this work. I would also like to thank Prof K.M. Karaye for his contributions towards a successful training and this work.

My appreciation also goes to my fellow resident doctors who provided me with an invaluable support during my residency training.

I would like to appreciate my family members, especially my mother, siblings, and wife for the patience, encouragement and support.

I also thank all the numerous people that contributed toward the success of this study which time and space may not permit me to mention. Finally, and above all, I thank the Almighty,

Allah with whom all is achievable and without whom nothing is accomplished.

TABLE OF CONTENTS

Title page i

Certification ii

Declaration iii-iv

Dedication v

Acknowledgement vi

Table of contents vii-x

List of tables xi

List of figures and picture xii

Abbreviations xiii

Abstract xvi

1.0 Introduction 1

1.1 Aims 3

1.2 Objectives 3

1.3 Justification for the study 4

1.4 Ethical Consideration 4

1.5 Research question 5

1.6 Relevance of the project to the discipline 5

2.0 Literature review 6

Introduction 6

Epidemiology 6

Risk factors 6

Clinical features 7

Investigations 11

Treatment 13

3.0 Methodology 14

3.1 Study area 14

3.2 Study population 14

3.3 Sample size determination 15

3.4 Inclusion and exclusion criteria 16

3.5 Study design and procedure 17

3.5.2 Study period 19

3.5.3 Data collection tools 19

3.5.4 Blood sample collection 20

3.5.5 Sample transportation and storage 20

3.5.6 Laboratory tests 21

1 D-dimer 21

2 Plasma VWF antigen 22

3 Blood grouping 24

4 Full Blood count 25

3.5.7 Quality control 25

3.5.8 Biosafety standard 26

3.6 Data Analysis 26

3.7 Incentives/benefits to the study population 27

4.0 Chapter four 28

4.0 Results 28

4.1 Socio demographic characteristics of participants 28

4.2 Clinical risk factors of DVT in participants 31

4.3 Blood groups of the study population 40

4.4 D-dimer levels of the study population 41

4.5 vWF antigen levels of the study population 42

4.6 other laboratory results 45

4.7 Doppler ultrasound features of the study population 47

4.8 Reliability of D-dimer 48

4.9 Relationship between risk factors and DVT 49

5.0 Discussion 52

6.0 Conclusion and Recommendations. 66

References 68

Appendix one: Proforma/Questionnaire 78

Appendix two; Consent form 83

Appendix three: Ethical clearance 87

LIST OF TABLES Page No:

Table 4.1: Socio demographic characteristics of study participants 41

Table 4.2: Clinical profile of the study participants: risk factors 44

Table 4.3: Causes of immobility among participants 45

Table 4.4: Clinical findings of the affected limb 48

Table 4.5: Wells’ score of the subjects 49

Table 4.6: Blood group distribution among participants 50

Table 4.7: D-dimer in the various Wells score risk category 51

Table 4.8: Positive D-dimer levels in the various blood groups. 52

Table 4.9: Plasma vWF antigen levels in the various blood groups 54

Table 4.10 Plasma vWF antigen levels according to D-dimer levels of the study participants 54

Table 4.11 Doppler ultrasound findings in study subjects 55

Table 4.12: True positives and negatives, and False positives and negatives of D-dimer test 56

Table 4.13: positive D-dimer values among subjects 58

Table 4.14: Positive D-dimer values among study participants 59

LIST OF FIGURES Page No.

Figure 3.1: COBAS® Roche cardiac D-dimer portable reader and D-dimer testing Kit 22

Figure 4.1: Age distribution of study participants 40

Figure 4.2: BMI of study participants 47

Figure 4.3: Distribution of VWF antigen levels in study cases and controls 53

ABBREVIATIONS

AKTH: Aminu Kano Teaching Hospital

APS: Antiphospholipid syndrome

APPT: Activated Partial Thromboplastin Time

BMI: Body Mass Index.

CAD: Coronary Artery Disease

CLD: Chronic Liver Disease

CD4: Cluster of differentiation 4

CTPH: Chronic Thromboembolic Pulmonary Hypertension

CMV: Cytomegalovirus

CV: Contrast Venography

CVD: Cerebro Vascular disease

DIC: Disseminated Intravascular Coagulopathy

DM: Diabetes mellitus

DVT: Deep Venous Thrombosis

ELISA: Enzyme-linked immunosorbent assay

HDL: High Density Lipoprotein

HIV: Human Immunodeficiency Virus

HRT: Hormone Replacement Therapy

IBD: Inflammatory Bowel Disease

ICU: Intensive Care Unit

INR: International Normalised Ratio

LDL: Low Density Lipoprotein

MRI: Magnetic Resonance Imaging.

NCEP-ATP III:National Cholesterol Education Program-Adult Treatment Panel III

NPV: Negative predictive value

OCP: Oral Contraceptive Pills

PTB: Pulmonary Tuberculosis

P.E: Pulmonary Embolism

PPV: Positive Predictive Value

SVD: Superficial Venous Dilation

TAFI: Thrombin Activatable Fibrinolysis Inhibitor

TB: Tuberculosis

TGs: Triglycerides

USS: Ultrasound scan vWF: von Willebrands factor

VTE: Venous thromboembolism

SUMMARY

Deep vein thrombosis (DVT) is a major cause of morbidity and mortality especially in hospitalized patients. This study examines the clinical profile and some laboratory correlates of DVT in the study environment. It also explores the possibility of using the Roche point-of- care D-dimer test as an alternative to Doppler USS in the diagnosis of DVT, which is cheaper and easier to use, with less technical expertise and faster turnaround time.

This descriptive, cross-sectional study of consenting adult patients with clinical risk factors suggestive of DVT was carried out at the out-patient clinics and various wards and emergency units of AKTH, Kano. Diagnosis of DVT was established or ruled out using the gold standard, Doppler ultrasound scan. Forty patients with DVT and forty age- and sex- matched controls without DVT were recruited following informed consent. The socio- demographic and clinical characteristics of the patients and the risk factors associated with

DVT were obtained using a structured questionnaire. Weight (Kg) and height (m) were obtained to calculate the BMI, and both limbs circumference were measured. Venous blood

(9ml) was obtained to determine the D-dimer levels using the Roche cardiac D-dimer portable reader, blood group type, and plasma vWF antigen levels. Data was analysed statistically using SPSS version 20.0 to check for true associations. The sensitivity, specificity, Negative Predictive Value (NPV), Positive Predictive Value (PPV) of D-dimer in the diagnosis of DVT was determined. P-values ≤0.05 was used to define statistical significance.

Forty subjects and 39 age and sex-matched controls were recruited for the study. Their mean age was 47.8 ±11.8 years for the subjects and 48.3±9.8 years for the controls (p = 0.8384).

There were 16 males (40%) and 24 females (60%) amongst the subjects and 16 males and 23 females amongst the controls, with a male to female was 1: 1.5 in each arm. The sensitivity and NPV of the D-dimer test was determined to be 87.5% and 85.29% respectively, while the specificity and PPV were 72.50% and 85.29% respectively. History of surgery was obtained 15 among 17 (42.5%) subjects and 6 (15%) controls (p = 0.0135), 14 (35%) subjects had a history of HIV compared to 5 (12.5%) controls (p = 0.0355), while history of immobility was obtained in 21 (52.5%) subjects compared to 11 (28.2%) controls (p = 0.0399). History of air travel/long distance journey was obtained among 15 (37.5%) subjects and 6(15%) controls (p

= 0.0421). There was no significant statistically significant difference between the subjects and controls in the history of diabetes mellitus, cancer, cigarette smoking, radiotherapy, preceding trauma, family history of deep venous thrombosis, pregnancy, use of Oral

Contraceptive Pills (OCP), and femoral venous access, however, among the subjects, 67.5% had clinically overt DVT. Other clinical features observed to be statistical significant between subjects and controls included hypertension (21; 52.5% and 10; 25.6%, respectively; p = 0.0217) and obesity (9; 22.5% and 6; 15%, respectively; p = 0.0460). A Wells’ score of

≥4 was observed among 21 (52.5%) subjects. The mean D-dimer was observed to be statistically significant between the subjects (0.655 ± 0.24µg/mL) and controls (0.313 ±

0.15µg/mL; p = 0.0001); and between subjects (0.7 ± 0.22µg/mL) and controls (0.56 ±

0.05µg/mL) with a positive D-dimer values (p = 0.0435). Controls with positive or negative

D-dimer had values that were not statistically significant numerically. Amongst the risk factors assessed, a significant difference was obtained between subjects and controls for non-

O blood groups (p = 0.025), D-dimer levels (p = 0.044), plasma vWF antigen levels (p =

0.037).

This study showed that DVT is commoner among females, middle aged and elderly individuals. Half of the subjects with DVT presented with a high Wells’ score, which was found to be positively related to the D-dimer values. Elevated D-dimer levels, non-O blood groups and high vWF antigen levels were observed to be important risk factors of DVT in the study environment. Point of care D-dimer test can be used to safely rule out the presence of a new thrombus in patients with suspected DVT.

CHAPTER ONE

1.0 INTRODUCTION

A thrombus is a “blood clot in the cardiovascular system formed during life from the constituents of blood” and thrombosis is “the formation or presence of a thrombus”.1

Thrombosis and its attendant complications represent a spectrum of important disorders that constitute a rising morbidity, mortality and cost of health care.2 Pulmonary embolism (PE), a complication of deep venous thrombosis (DVT) is an important cause of maternal mortality in western countries.3

Thrombus formation may occur in arteries and veins but differ in their pathophysiology.4,5,6,7

While arterial thrombi occur in relatively damaged vessels and are rich in platelets with minimal fibrin, venous thrombi occur in relatively preserved vessels, and are rich in red blood cells and fibrin with minimal amount of platelets.3,4,5,6 Venous thrombosis may occur in the deep veins of the limbs presenting as DVT with consequent embolisation to the lungs resulting in pulmonary embolism (P.E).3,7 From the above it can be seen that venous thromboembolism (VTE) is a spectrum of thrombotic disorders presenting as DVT and P.E.

Hospital based studies reported a DVT incidence of 20-35% in western countries, 9.6% in

Sudan, and 12% in Malaysia.8,9,10 The incidence of post-operative DVT in a study carried out among 450 consecutive patients that had elective surgery in Nigeria was 2.2%.11

The risk factors for DVT that may be described as “acquired” include previous DVT, surgery, immobilization, obesity, pregnancy, use of oral contraceptives pills, cancer, and air travel.4,

5,6,7,12 A number of inherited risk factors are associated with an increased risk of DVT especially in the young and in unusual locations.4,5,6,13,14,15 But since the prevalence of these abnormalities are low (5%) in the population, development of DVT in the general population is not usually attributed to these factors. These include Factor V Leiden mutation, 17

Antithrombin deficiency, Protein C deficiency, Protein S deficiency, dysplasminogenemia, dysfibrinogenemia, increased levels of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and elevated levels of factor VIII, IX, XI.4,5,6,14,15,16 Individuals with a Non-O blood group have also been found to have a higher VTE risk.17

Wells’ scoring system is the first model to be evaluated in the assessment of out-patients with

DVT and is one of the most validated clinical risk assessment scales.4,5,6,12 It classifies patient’s history, symptoms and signs into two sub groups: major and minor and stratifies patients into low, intermediate and high risk categories (pretest probability).4,5,6,18

Doppler ultrasound is now the investigation of choice used in the diagnosis of DVT. It is

100% sensitive and 98% specific in detecting symptomatic proximal DVT and 94% sensitive and 75% specific for detecting distal DVT, but less sensitive among asymptomatic patients with DVT.4,5,6,13 The main advantages of Doppler ultrasound scan are its low cost, non invasiveness, reproducibility, portability of the machine, and that it can be carried out as a bedside procedure.5,6,19 However, the long time taken and the expertise needed to carry out the procedure are some of its setbacks.

Another investigation that is important in the management of DVT is D-dimer which measures the degradation product of cross-linked fibrin and is the first objective test in suspected DVT patients with a low pre-test probability, although it has a low specificity (and thus a positive D-dimer result is not very useful).5,6,20 D-dimer cut off value in most studies is

0.5µg/ml and so if the detected value of D-dimer is less than this, DVT can be safely ruled out.5,6,21

The first step in the diagnosis of DVT is to stratify the patients into high, intermediate, or low risk categories using a validated clinical model using the Wells’ scoring system, and DVT can be excluded in out-patients with low pretest probability and negative D-dimer.4,5,6,20

D-dimer is believed to be a useful adjunct in the diagnosis of DVT, and studies have been conducted to establish its role as a useful cost and clinically effective and available alternative to Doppler ultrasound scan in emergency and late night hours in some western hospitals.22,23

1.1 AIM:

To enhance early detection of DVT by determining clinical and other laboratory correlates of

D-dimer and the usefulness of a point of care D-dimer device.

1.2 OBJECTIVES

The specific objectives of the study are to

1.determine the clinical profile of adult patients with DVT in Aminu Kano Teaching

Hospital, Kano;

2.determine the ABO blood group, D-dimer and von Willebrands Factor (vWF) levels

in adult patients with DVT and controls;

3.assess the reliability of point of care (POC) D-dimer test in the diagnosis of DVT;

and

4.evaluate the relationship between the measured parameters with point of care D-

dimer levels in patients with DVT and controls.

1.3 JUSTIFICATION

There is an increasing number of patients diagnosed with DVT in developing

countries, the majority of whom require long term treatment with consequent

increase in the economic and financial burden on the community and its poorly

financed health sector.2 Although there are some reports on the prevalence and

clinical profile for the development of DVT in Nigeria, the existing data is

rudimentary and a study of this nature has not been conducted to my knowledge. 19

Doppler ultrasound scan, an acceptable method of diagnosing DVT is not readily

available in many centres in Africa due to unavailability of skills and cost of

equipment. Some studies in the western world have examined the use of D-dimer

as an alternative to Doppler ultrasound scan for the diagnosis of DVT in the

emergency room after routine working hours, when routine Doppler ultrasound

scan is not available. However such possibilities have not been explored in the

study area. Therefore, this study aims to fill this gap as well as contribute to the

interest and knowledge of DVT.

1.4 ETHICAL CONSIDERATION

Approval for the study was obtained from the Ethical Committee of Aminu Kano

Teaching Hospital and informed consent was obtained from each participant.

Patients who were found to have abnormal results were managed or referred

appropriately.

1.5 RESEARCH QUESTIONS

1) Point of care D-dimer measurement may be used as an alternative to Doppler

ultrasound for diagnosing DVT.

2) There is a positive relationship between non-O blood group, vWF and DVT.

1.6 RELEVANCE OF THE PROJECT TO THE PRACTICE OF THE DISCIPLINE

1) The role of point of care D-dimer testing in the diagnosis of DVT in the study population was determined. This could potentially reduce the financial cost and level of technical expertise needed to confirm the diagnosis of DVT, especially during odd hours (non working).

2) The clinical profile of adult patients with DVT in the study population was

described.

3) Some laboratory correlates of DVT in the study population were characterized.

CHAPTER TWO

LITERATURE REVIEW

First description of DVT was by Sushruta around 600-900BC which he documented in his

Indian traditional medicine book Shushruta samhita.24 Some records suggestive of a thrombotic disorder was found on Eber-papyrus dating from 1550BC.25

The first description of subclavian venous thrombosis was in 1590, Henry IV of Nevarra

(1553-1610) King of France was said to have used his sword hand so much that he developed an excruciatingly painful swelling after the battle of Ivory and could not use his hands for weeks.26 Venous thrombosis of the inferior vena cava was first described by Schenk in

1644.25

Present theory/pathophysiology of vascular thrombosis has its origins in 1840 when the

German pathologist Rudolf Virchow observed the high frequency of post partum thrombosis.26 He deduced that the major cause of thrombosis are at least one of the following three factors-Alterations in blood flow (stasis), alterations in the blood composition

(hypercoagulability) and alteration in vessel wall. These factors are otherwise called

Virchows’ triad.26

Armand Trousseau described an association between VTE and abdominal malignancy in the

1865.14

The incidence of DVT is not really known. This is largely because it is easily missed in most cases, and because large community or regional data are lacking. Most epidemiological studies described the incidence of DVT among hospitalized patients, who have a higher risk of developing DVT. The incidence depends on the specific population being studied and the sensitivity and specificity of the diagnostic method used.5,16 While some hospital based studies reported an incidence rate of 20-35% in western countries, the incidence in Sudan was

9.6% and 12% in Malaysia.8,9,10 A retrospective study in southern India observed a high incidence of 1.79/1000,19 while in two hospital studies in Nigeria, DVT was seen in 0.6% and

2.2% of cases.11,27

The incidence of severity of DVT is ethnicity related, with studies reporting differences in different races and ethnic groups. Although DVT is commoner among Caucasians globally, incidences are higher among African-Americans than among USA Caucasians by about 25%,

22 but lower among Asians, Pacific Islanders and Hispanics than in the Caucasians.28

Age is an independent risk factor for DVT.4, 5,6,7,13, 29 Deep venous thrombosis is rare in infancy and childhood, but there is a sharp increase during the fifth decade of life.4,5,6,30,31,32 It is rarely seen in infants and children in the absence of iatrogenic causes.4,5,12 The incidence increases from about 1 in 10,000 young adults to 1 in 100 elderly.4The age and sex adjusted incidence of VTE for those 15 years of age and older is 149/100,000.3

The low incidence in children may be due to a low capacity to produce thrombin, increase capacity of alpha-2 macroglobulin to inhibit thrombin and enhance anti thrombin potential of vessel wall.3,4,6,7,12,20

A combination of risk factors have been suggested as the reason for a higher risk of DVT in the elderly such as innate biological changes and may be to a lesser extent, increased and repeated exposure to VTE risk factors, decrease mobility, increasing presence of other illnesses predisposing to thrombosis, increase in coagulation potential, degenerative vascular damage or some combination of these factors.4,6,12,24

The incidence of DVT is higher in females likely due to the use of Hormone Replacement

Therapy, Oral Contraceptive Pills (OCP), pregnancy and peuperium, although some studies did not show any gender variation.3,4,5,6,14, 30,31

Use of Oral contraceptive pills (OCP) and hormone replacement therapy (HRT) are associated with increased risk of DVT.14,15 There is a 2-4-fold increase risk of DVT for patients using second generation OCP and a 3-8-fold risk for those using third generation

OCP.4,12,24 Another study reported the incidence of DVT in those taking OCP to be 2-8-fold higher.13 Relative risk of VTE in women on HRT was 2.1, and this is highest in the first year of use.12,13,15 This is believed to be due to decrease sensitivity to activated protein C.4,5,6,7,12

Pregnancy is an independent risk factor for DVT increasing the risk by 5-fold.4,5,6,7,12

Pueperium is also a proven important risk factor for DVT, with a 20-fold increase risk during

23 peuperium.5,7,12,15,21,24 A study found the incidence of DVT in the peuperium to be

61/100,000.17

Surgery is an important acquired risk factor of developing DVT, accounting for 24% of all

VTE cases.4,5,6,13, 31 Surgery in the preceding 45-90 days confers a 4-22% increase risk of

VTE.3 Factors that determine risk of VTE in surgical patients are age more than or equals to

65years, sex, presence of active cancer, type of surgery, neurological disease, radiation and previous DVT.4,5,6,12,24

Lower extremity surgery especially orthopedic surgery carries the highest risk of all surgeries.4,5,6,10,15,28,29 This is believed to be as a result of interaction by multiple risk factors including immobility, vessel injury, activation of coagulation factors etc. The rates of proximal DVT following Total hip replacement surgery, knee joint replacement and hip joint fracture surgery are estimated to be 23-36%, 9-20%, and 17-36% respectively.33

Major elective surgery confers about 16% risk of developing lower extremity DVT. Vascular surgery, without the use of thromboprophylaxis account for 18% of DVT, with the incidence dropping to 10% after adequate prophylaxis.10

Prevalence of DVT after neurosurgery is 13%, with the risk being particularly high (21.32%) in patients with glioma and persists for a year or more.8,12,15

General abdominal and other surgeries have been reported to confer added risk of developing

DVT. About 20-30% of patients undergoing elective major surgery in a North American trial were found to have DVT using serial 125I FLS and contrast venography.33 For unexplained reasons, North Americans trials reported the incidence of DVT to be one half that of

European studies.41 Patients with malignant disease undergoing surgery have a higher incidence of DVT than those without malignant disease.41 Likewise, patients that had

Urologic surgery, vascular surgery and some major gynaecologic surgeries were reported to 24 have an incidence of 41%, 23-34%,and 17.5% respectively.34,35,36 This figure was reportedly higher in those with associated malignancy, previous DVT and radiotherapy. 37

Type of Anesthesia has been reported to increase the risk of developing DVT. Seventy five percent (75%) of patients with hip fracture surgery that had general anesthesia were reported to develop DVT compared to 40% with sub arachinoid block.38 Likewise, for Urologic procedures, 12% of patients with retropubic prostatectomy and lumbar epidural analegesia were reported to develop DVT, compared to 52% that had general anesthesia.39

Trauma and fracture to various body parts also increase DVT risk, as a result of multiple risk factors, making interpretation of such data difficult.14

A large study in a regional trauma centre in Toronto showed that 201 out of 349 patients enrolled (58%) had DVT by Contrast Venography (CV), but only 3 had clinical features of

DVT. The same study showed that among patients with lower extremity fracture, 69% developed DVT, while 50% of patients with chest, face and abdominal trauma had DVT. A number of independent risk factors that increase the risk of developing DVT in trauma patients have been reported, including older age, blood transfusion, surgery and fracture

(femur, tibia, spinal cord injury).40

The incidence of DVT using routine screening with duplex ultrasonographic scanning in the absence of prophylaxis varies within 6-27% in patients with burns.34

Neurological disease with extremity paresis confers a higher risk of developing DVT, with the paralysed limb of patients with Cerebro Vascular Disease (CVD) having a 42-60% risk.4,5,6,7,12,14,15,31 DVT in CVD patients in a tertiary centre in Northeastern Nigeria was found to be much lower with an incidence of 0.6%, which may be due to the unavailability of diagnostic tools for DVT.27

Hospitalization for acute medical illness and Nursing home confinement is associated with

60% increase VTE risk.3,28,31,41 Nursing homes increase VTE risk by 10%. About 10% of all hospital in-patient deaths is due to PE, and In most cases it was not suspected before death.3,4,5,15 Acutely ill medical patients have an incidence of symptomatic VTE of 3.4-

6.6%.10,12,29Autopsy studies found DVT in 15% and 80% of those bedridden for less than and greater than one week respectively.14

Patients admitted into Intensive Care Unit (ICU) were reported to have a higher risk of developing DVT, although they represent a heterogeneous group with different diseases, rendering interpretation of incidence rates difficult. In a prospective trial with 100 medical

ICU patients, 33 develop DVT, despite 58% of them being on prophylaxis.42 Interestingly, the study did not obtain any difference in age, diagnosis of cancer, recent surgery or duration of hospitalization between patients with and without DVT.

Immobilization is also a proven risk factor for deep venous thrombosis.11,15,52 Autopsy studies found that 15% of patients bedridden for less than a week develop DVT compared to 80% of those bedridden more than a week. Likewise a study found that those bedridden for non surgical illness for between 2-8 days have 13% risk of developing DVT.

Active cancer with or without chemotherapy has been found to be associated with a 5-fold increase risk of VTE. 3,4,5,6,7, 13, 14 Community studies put the incidence of cancer related VTE at 15-29%.3, 16 Several factors are believed to contribute to the increased risk of VTE in cancer patients. These are increased coagulation activity, compression of veins by solid masses, a combination of hospitalization, surgery and chemoptherapy.4,5,6,7,12

Transvenous pacemakers and Central venous catheters also increase the risk of DVT. Central venous catheters represent an important risk factor of developing DVT in children. About 2/3 of children with central venous catheters for Total Parenteral Nutrition and antineoplastic

26 chemotherapy develop deep venous thrombosis32. Upto 60% of patients with indwelling devices develop various complications including venous thrombosis.7,32

Obesity, with a Body Mass Index (BMI) of more than 30kg/m2 is associated with a 2-3-fold increase in DVT and PE.3,4,5,6,28 Likewise, waist circumference and waist-hip ratio has been found to be independent risk factors for developing VTE.3,4,12Abnormal lipid profile with a high cholesterol and low HDL (inverse relationship), hypertension, Diabetes mellitus and high waist-hip ratio are also associated with a higher risk of developing DVT.3,4,5,28

Deep venous thrombosis is 2-10 times commoner among patients with Human Immune deficiency Virus (HIV), with an incidence of 0.25-0.96% in clinical studies and 17% on autopsy.16,22, 43 Severe Pulmonary tuberculosis is often complicated by DVT in 3-4% of patients because of the association between inflammation and haemostatic changes that results in a hypercoagulable state.22,44.

Hyperhomocysteinemia from Folate or Vitamin B12 deficiency is associated with tendency to thrombosis. However there is no significant difference in the prevalence of DVT by correcting Homocysteine levels with Folate, Cyanocobalamin and Pyridoxine, and thus

Homocysteine is not routinely tested in patients with DVT. 28

Antiphospholipid syndrome is an acquired thrombophilic disorder characterised by arterial and venous thrombosis, recurrent miscarriages, elevated Antiphospholipid antibodies and or

Lupus anticoagulant and confers a higher risk of developing DVT.4,5,6,16

A number of Inherited risk factors, like Antithrombin deficiency, Protein C and S deficiency, dysplasminogenemia, and dysfibrinogenemia; are associated with increased risk of DVT especially in the young and in unusual locations.4,5,6,7,13,14,15,16 But since the prevalence of these abnormalities are low (5%) in the population, development of DVT in the general population is not usually attributed to these factors.4,5,6,14 27

Individuals with type ‘O’ blood group have 30% lower vWF levels, a coagulation factor VIII carrier which prevents it from degradation.17 Individuals with a non-O blood group have nearly 2-fold higher VTE risk, because the higher vWF levels prevents coagulation factor

VIII from degradation which confers a higher tendency for thrombosis.4,5,12,17

Any form of travel that lasts for four hours or more double the risk of developing DVT for several weeks following the travel.4,5,6,12, 28 The risk is even higher if other risk factors are present4,12,28 Air travel of more than six (6) hours increases this risk most significantly.12,15

Smoking is associated with increased risk of DVT because of increased inflammation, blood viscosity, and is a potent risk factor for a number of diseases (cancers, CVD, Coronary artery disease) which are associated with increased risk of DVT.45

Deep Venous Thrombosis is 10-15% higher during winter, likely due to increased hospital admissions for other illnesses and reduced physical activity.30 Varicose veins and Superficial vein thrombosis confers an increased risk of DVT.15

Unprovoked DVT, in which no risk factor is identified occurs in 30-50% of patients.3,4,5,6

Previous DVT increases the risk of having another DVT and is the single most important risk factor.4,5,6,15,46

DVT may be asymptomatic in about 50% of patients.4,12 However only about 25% of patients who present with compatible symptoms have DVT confirmed on objective testing.12,20

Common symptoms that are associated with DVT include Pain in the affected limb due to vein wall inflammation and venous distension, redness and warmth due to vein wall inflammation and shunting of blood from obstructed deep vein to superficial veins, and swelling is mainly due to venous out flow obstruction.4,5,6,7,12

Common signs include tenderness, warmth, erythema, cyanosis, pedal oedema (usually

28 pitting), palpable cord (palpable thrombosed vein), superficial venous dilatation

(SVD)4,5,6,7,12. Some important clinical examination signs associated with DVT although some have questionable clinical use due to risk of dislodgement of thrombus are humans sign, Laurels sign and Lowenbergs sign.4,5,6,7,12

Homans sign is present if sudden dorsiflexion of ankle joint with knee flexed to 300 produces discomfort in the upper calf.5,6,21,24,25 Laurels sign denotes worsening of pain along the course of thrombosed vein by coughing or sneezing.6,24,25 Lowenbergs sign is positive if after inflation of sphygmomanometer cuff around the calf, pain is experienced in affected calf at a lower pressure than the unaffected calf.25

Deep venous thrombosis need to be differentiated from other clinically conditions that may present with similar clinical findings like cellulitis, arterial occlusion, superficial thrombophelebitis, neuropathy, lymphoedema, varicose veins, chronic venous insufficiency, arthritis.4,5,6,7,12,21,24,40 The most common differential diagnosis found in some studies are muscle related (40%), cellulitis (3%), leg swelling in paralysed leg (9%), venous reflux(8%), lymphatic (8%), bakers cyst (5%), unknown (26%).4,5,6,7,12,24,25

Because of the clinical and economic importance of DVT, accurate and timely diagnosis and treatment is important, and has been demonstrated to reduce the severity of symptoms, progression of disease, and its complications especially PE and its attendant mortality.47,48

Equally important reason for accurate diagnosis of DVT is the potential financial, psychological and medical implication of a wrong diagnosis. Patients mislabeled as having

DVT may be subjected to unnecessary hospitalization and long term anticoagulation with its associated risk of bleeding, and its consequent financial cost.49,50As patients with a previous

DVT are at a higher risk of developing subsequent DVT, they will be subjected to an unnecessary anxiety whenever they develop a limb swelling that mimic DVT. Likewise, they

29 will also be subjected to unnecessary prophylactic anticoagulation whenever they have an added risk of developing DVT like, pregnancy or prolonged air travel.

The symptoms of DVT mentioned above are very common in the general population and there are many clinical conditions that may present with a set of such symptoms. Various studies have attempted to validate the use of a set of clinical characteristics that will enable a physician to differentiate DVT from other non vascular conditions that mimic DVT. These pre test probability estimation of the likelihood of DVT and a subsequent investigative procedures increase the likelihood of accurate diagnosis, judicious use of diagnostic resources, and appropriate treatment of DVT.

Due to the clinical similarities of DVT to other mimics, it is important to have a clinical model to help assess the clinical likelihood of DVT to help in reducing the risk and cost of confirmatory investigations.4,5,6,7,12

Crandon prediction rule for gynaecological surgery patients was developed in 1980.51It uses a number of clinical and laboratory parameters including Height, weight, age, hospital length of stay before surgery, smoking habits, pre operative Haemoglobin levels, varicose veins, history of DVT, nature of surgery, presence of malignancy, and other laboratory measures reflecting coagulation status. The most sensitive parameters were reported to be Euglobin

Lysis time (ELT), age, varicose vein, fibrin-related antigen, and overweight. It has a reported

Sensitivity of 90%, specificity of 87%, PPV of 56%, and NPV of 98%.51

Its major shortcomings are the use of blood test that is not widely available, restricted to surgical population and was only validated on small number of patients. The patients that were negative for FLS did not undergo CV.

Clarke-pearson was another clinical prediction score that was validated on a small number of gynaecological patients with reported important parameters as anesthesia >300 minutes, age, 30 prior DVT, race, oedema, and severe varicose veins. 37

Lowe and Sue-ling are two prediction rules that were tested among abdominal surgery patients. Lowe uses age, weight, height and sex as its parameters, and has a reported

Sensitivity of 90%, with a low specificity of 52%, which is likely due to the effects of unmeasured risk factors.51

Sue-ling utilizes Age and ELT, and has a Sensitivity of 93% and specificity of 83%.52 Its widely credited for its simplicity. However ELT not readily available in most centres and it was validated among a small population size.

The Rogers and Caprini risk assessment models have recently been validated, especially in surgical patients. The Caprini risk assessment model utilizes a combination of clinical and laboratory risk factors, with different severity of each assigned a numerical weight. It stratifies the risk factors into one-point, two-point, three-point and five-point scores depending on their severity.53 These factors are age, surgery, BMI, leg swelling, varicose veins, pregnancy, post partum, history of spontaneous abortions, OCP, sepsis, COPD, pneumonia, Acute myocardial infarction, CCF, inflammatory bowel disease, cancer, lupus anticoagulant, elevated serum Homocysteine, etc. The Rogers assessment score utililses factors like type of surgery, anaesthetic score (ASA), sex, cancer, electrolytes etc.54

Prediction rules tested among general patients include Vine, Landefeld, and Wells’.55,56,57

One of the most validated clinical risk assessment scales is the Wells’ scoring scale.5,6,18

It was developed in 1995 in three centres in Canada and Italy. Patients with a 1st episode of

DVT were recruited for the trial. However, those with a recurrent DVT, suspected PE, pregnancy, anticoagulation, those that could not tolerate dye were excluded. It reported similar accuracy in all three centres despite difference in incidence rates. It is credited with its ease of practical application, readily available parameters, and could be done with non 31 invasive tests to improve efficacy. However, other risk factors not included could be as important or even more as those used. No multivariate analysis, thus not known whether the clinical predictions are collinear, interact with one another or are acting as confounders in the association between unmeasured predictions and DVT.

Wells’ score classifies patient’s symptoms and signs into two sub-groups:

MAJOR:

 Active cancer

 Paralysis, paresis, recent cast

 Recent immobilization or surgery

 Tenderness along deep vein distribution

 Swollen thigh and calf (measured >3cm difference between limbs)

 Family history of deep venous thrombosis

MINOR:

 Recent trauma

 Pitting oedema in symptomatic leg.

 Dilated superficial vein in symptomatic leg

 Hospitalization in the past 6 months.

 erythema

Interpretation:

 high probability:

o 3 or more major/2 major+ 2 or more minor with no alternative diagnosis

 low:

o 1 major + at least 1 minor with no alternative diagnosis or 32

o 2 or more minor with no alternative diagnosis.

 moderate probability: all other combinations.

However, clinical prediction scores are still not reliable.4 Objective diagnostic methods needed. There are various investigative modalities available for objectively assessing

DVT.4,5,6,7,12,58

Contrast venography (CV) is the gold standard for the diagnosis of DVT but has some short comings, mainly its costs, invasiveness and complications. 4,5,6,7,12,58 Experienced radiologist, non ionic contrast medium with low osmolality should be used to reduce SE, endothelial damage, post phlebographic DVT.4

Doppler ultrasound scan is now considered the most reliable widely available tool for the objective diagnosis of DVT in the clinical setting. 4,5,6,7,12 It employs the use of high frequency ultrasound waves to determine the blood flow, and thus obstruction within a blood vessel. Various modifications or adjunct are used to improve on the reliability of Doppler ultrasonography for the detection of a vascular clot. Compression ultrasound scan is used to demonstrate a non compressible clot within a vein. However, it has a poor visibility of pelvic veins, and is difficult to differentiate a new clot from a recurrent thrombus. Colour duplex ultrasound scan has a sensitivity and specificity similar to CV, and is good at detecting proximal DVT. Deep Venous Thrombosis can be safely excluded in patients with a low clinical probability score and a negative Doppler ultrasound scan. Those with a moderate clinical probability score and a negative ultrasound scan result should have a repeat Doppler ultrasound within a week. Likewise, those with a high pre test clinical probability score and a negative Doppler ultrasound scan should have a repeat Doppler ultrasound scan or a CV.

Impedence plethysmography is non invasive, cheap, easier to perform, with no side effects compared to contrast venography. 4,5,6,7,12,58 They are however, not able to visualize the entire

33 venous system, not widely available and are also dependent on the experience of the observer. In case of a negative result, serial testing is required in order to confirm.

125I fibrinogen is sensitive to calf and low proximal DVT but not to high proximal

DVT.4,5,6,7,12,58

Fibrin Degradation Product and technetium Red Blood Cell scan are markers of ongoing thrombosis, but with a poor test performance compared to above.4,5,6,7,12,58

D-dimer measures the degradation product of cross-linked fibrin and is the first objective test in suspected DVT patients with a low pre test probability.4,5,6,20 It has a high negative predictive value and can thus be used to rule out the presence of an acute thrombus however, it lacks specificity therefore a positive D-dimer result is not useful.4,5,6,20 D-dimer cut off in most studies is 0.5µg/ml.5,21 If the detected value of D-dimer is less than this value, DVT can be safely ruled out, however, the sensitivity and specificity of the D-dimer test depends on the method employed, with a marked variation in the values between the different methods. A large study involving 113 patients in Aalborg that tested the reliability of three different D- dimer test methods reported VIDAS New and Auto Dimer have sensitivities of 90% and

88%, specificities of 42% and 44%, and NPV's of 85% and 83%, respectively. The Nycocard

D-dimer assay reported a contrasting figures with sensitivity of 63%, specificity of 67% and

NPV of 71%.59,60

Commercially available assay methods have a varying sensitivity of between 85-95% with the ELISA method being the most sensitive.20,59,61

One of the most validated commercially available test methods uses a quantitative immunological test for the detection of D-dimer in heparinised venous blood. The test uses a gold-labeled and a biotynlated antibodies against the D-dimer structure element. It uses

150µL of venous blood, and has a measuring range of 0.1-4µg/mL. The test has good repeatability with a variation coefficient of less than 11% in most studies and sensitivity of 34

90%.59,62

D-dimer is elevated in the setting of acute thrombosis and may however be elevated in other conditions like pregnancy, post partum period, previous DVT, malignancy and infections.20

False positive D-dimer may also be found in the elderly, conditions associated with inflammation, and also higher with gestational age and complicated pregnancy (preterm labor, abruption placentae, gestational hypertension).61

False negative D-dimer test may occur in heparin use, late presentation (symptoms of more than 2 weeks), and below knee DVT.61

Due to the wide variation of recorded D-dimer levels in different disease conditions mentioned above, some researchers have proposed cut-off D-dimer values for specific condtions.63

Although Doppler ultrasound is now the preferred choice of diagnostic tool because of its acceptable sensitivity and specificity coupled with its non invasiveness, it has some major shortcomings. These are non availability in most centres, cost, inter observer dependence on interpretation and non availability outside of normal hospital working hours, even where available. D-dimer is believed to be a useful adjunct in the diagnosis of DVT, and studies have been conducted to establish its role as a useful cost and clinically effective and available alternative to Doppler ultrasound scan in emergency and late night hours in some western hospitals.22

The use of D-dimer assays reduces the need for Doppler ultrasound scan in most studies by about 7.6% in selected patients and 21% overall for general patients.27

In a study to evaluate the use of D-dimer as an alternative diagnostic tool involving 530 controls and 556 patients, use of D-dimer testing resulted in a significant reduction in the use of ultrasound scan from a mean of 1.34 test per patient in the control group to 0.78 in the D- dimer group (p = 0.008) and 39% of patients in the D-dimer group did not require ultrasound 35 scan. 62

In a large multi centre randomized control trial in Canada on the use of selective D-dimer testing for the diagnosis of first episode of DVT showed a reduction in the proportion of patients who require ultrasound scan by a total of about 7.6%.23

Decision to treat and with what to treat depends on the type, site and extent of the thrombosis.4,5,6,7,12,14,64,65 Duration of anticoagulation is three (3) months, which may be doubled or made lifelong depending on the presence of ongoing risk factors (e.g. malignancy, recurrence of DVT, thrombophilia).4,5,6,7,64

Treatment entails the use of anticoagulant therapy, which promotes endogenous fibrinolysis mediated recanalisation of the blood vessel.4,5,6,7,12 If there is no contra indication, the combined use of heparin for prompt anticoagulation effect and an oral vitamin a antagonist/Coumarin eg Warfarin is advocated. Other treatment modalities include possible thrombolysis, insertion of IVC filters, and in rare situations, the use of antiplatelet drugs.4,5,6,7,12

Parentral Heparin therapy seeks to rapidly abrogate thrombin generation, prevent thrombus extension, and serves as a bridge to oral anticoagulation. May also be used as a single therapy in situations whereby Warfarin is contra indicated. Low Molecular Weight Heparin is easier to administer and is safer than unfractionated Heparin, and it does not require frequent monitoring in order to prevent unwanted side effects. The activity of UFH is monitored using aPPT while LMWH is monitored using factor Xa levels. However, the disadvantages of

Heparins generally are the parenteral route of administration, high cost (expensive), potential

Heparin-induced thrombocytopenia, and osteoporosis when used for a prolonged period of time.4,5,6,7 There is always the possibility of bleeding, as with all anticoagulants. Warfarin is relatively very cheap, and has an added advantage of oral route of administration. Thus it has

36 the economic advantage of shorter hospital stay, low cost of therapy, and oral and self administration. Its activity level must however be monitored closely with PT/INR, and has a narrow therapeutic index with a very high level of drug-drug interactions (including to herbal preparations and multi vitamins) and drug-diet interaction.4,5,6,7,12 Warfarin is also contra indicated in pregnancy, due to the risk of teratogenicity (fetal Warfarin syndrome). Other side effects of Warfarin use include Skin necrosis, and potential limb gangrene.4,5,6,7,12

It is important to use the appropriate dose of anticoagulant medications as under dosing of anticoagulation may lead to the recurrence of VTE.4 Weight based LMWH dosing regimen are commonly used in the treatment of VTE. A dose of 1mg/kg/12 hours or 1.5mg/kg daily is commonly utilized.5,12 Dalteparin is given as 200 IU/Kg (maximum ≤18,000IU) daily, while

Tinzaparin is given 175 IU/kg daily.4,5,12

Anticoagulation is contra indicated if there is a recent major surgery, GIT bleeding, Neuro axial bleeding, CVD, trauma, thrombocytopenia, and CKD.4 A Creatinine clearance of <30%, leads to a ≥25% reduction in clearance of LMWH from circulation.4,5 Low Molecular Weight

Heparin (LMWH) is also not suitable for the morbidly obese.4

The use of Warfarin alone as an initial anticoagulant is not advocated because of the theoretical hypercoagulability state it confers as a result of simultaneous inhibition of the natural anticoagulants Protein C and protein S, which have a shorter half life than the coagulation factors.4,5

The use of Heparin and Warfarin are overlapped for a minimum of 4 days or until the target

INR of between 2.0 and 3.0 is achieved.4,5,6,7 Early overlap reduce the risk of heparin induced thrombocytopenia and reduces hospital stay.4

The goals of therapy for a proximal DVT are to restore venous patency, prevent embolisation, prevent thrombi extension, prevent early and late recurrence, and prevent Post Thrombotic 37

Syndrome (PTS).4,5

Treatment goals of acute PE are the same as for acute proximal DVT, and are mostly an in- patient treatment.4,5 However, outpatient treatment options are under investigation. IVC is indicated only if anticoagulation is contra indicated (cardiac and pulmonary disease).

The goal of treatment of a distal DVT is to prevent proximal conversion/extension of the thrombus.4,5,12 Some centers usually reserve anticoagulation for distal DVT that has started to propagate.4,7 Patients are observed with a 2 to 3 weekly Doppler USS without any anticoagulation. Anticoagulants are commenced if the clot shows evidence of propagation.

The potential risk versus the benefits of anticoagulation is assessed on an individual patient basis. While some other physicians advocate the commencement of treatment from the onset.

Inferior vena caval filters are another treatment modalities that seek to prevent the embolisation of a proximal DVT to the pulmonary circulation.4,5 It may be temporary and removable, which are placed for a short period of time to prevent embolisation especially when anticoagulation is contra indicated or may be permanent filter, which are left in place for life. Inferior vena caval filters reduce the risk of PE in the short term, however, in the long term; it may confer increased risk of PE.

Temporary IVC (retrievable) filters are preferred to permanent IVC filters, which will require lifelong anticoagulation.4,5,6,7 IVC filter not recommended for calf DVT.4

The use of thrombolytic therapy to lyse a large occluding clot is indicated especially in the setting of Phlegmasia Cerulea Dolens, where there is a risk of imminent critical limb ischemia, necrosis and gangrene.4,5,6,7,12,21,23 It provides an immediate recanalisation of the affected blood vessel, symptom resolution and relieves venous compression examples May thurner syndrome or venous webs. It also improves health-related quality of life. It is also indicated in the setting of extensive Ilio-femoral DVT in the young and in massive PE with 38 cardiovascular compromise.

Here, it provides for a rapid thrombolysis, early improvement of pulmonary blood flow, and improvement of right ventricular function. A number of agents can be used in thrombolytic therapy including Streptokinase and tissue Plasminogen activator e.g. Alteplase. Their major side effects are the major haemorrhage in 4-22% of patients.12

Untreated DVT may have a number of outcomes, including a potentially fatal pulmonary embolism, spontaneous resolution, post thrombotic syndrome, paradoxical emboli with a possible attendant arterial emboli including CVD.4,5,6,7,12,21,23 It may also have a recurrence, as a previous DVT is the single most important risk factor for having another DVT.4

Propagation of a clot is another complication that may occur. Calf DVT is considered a separate disease entity to a proximal DVT. About 15-25% of calf DVT may propagate and convert to a proximal DVT.21,23 Symptomatic and asymptomatic calf DVT carry the same risk of proximal propagation, and thus should be treated the same. Propagation usually occurs within two weeks of onset.4

Pulmonary embolism (P.E), a potentially life threatening complication of DVT may occur in approximately 50% of proximal DVT and rarely in distal DVT may be associated with clinically insignificant PE in 20%.4,5 The all-cause mortality for treated PE is reported to be

11% at two (2) weeks, and 17% at three (3) weeks.12

Depending on the size of the clot, PE may lead to difficulty in breathing, respiratory arrest, cardiac arrhythmias or cardiac arrest. Smaller emboli may be asymptomatic, while small diffuse showers of emboli may lead to chronic pulmonary thromboembolic disease, pulmonary hypertension and right heart failure.4,5,12 Long term complications of DVT include post thrombotic syndrome, leg ulceration.

Due to the potential morbidity and mortality associated with VTE diseases, prevention has 39 become an important integral part of the management process. Various guidelines have been advocated for various categories of patients, especially for those on hospital admission, since fatal PE is reported to be the most common cause of hospital deaths. Factors that increase the risk of fatal PE in hospitalized patients are age, immobility, CVD, paralysis, previous VTE, active cancer/treatment, major surgery, (abdominal, pelvic, lower limbs), trauma (pelvis, hip, leg), Obesity, varicose vein, low LVEF, central venous catheter, Inflammatory Bowel

Disease (IBD), lobar pneumonia, nephritic syndrome, pregnancy, OCP (estrogen) therapy.4,5,6,7,12 Development of DVT among medical patients is reported as 14.9% within 2 weeks of admission.4,5,12 This reduces to 5.5% with a prophylactic once daily LMWH.4,5,12

Apart from pharmacological methods of prevention (which increases the risk of major haemorrhage in susceptible individuals), various non pharmacological modalities are now available, including Intermittent Positive Compressions, Thrombo-embolic deterrent (TED) stockings, etc.12

CHAPTER THREE

3.0 METHODOLOGY

3.1 STUDY AREA

The study was conducted at Aminu Kano Teaching Hospital (AKTH), Kano, Northwest

Nigeria, that lies on latitude 110 151 and longitude 80 291. The hospital was established in

1988 and serves population of about nineteen (19) million people mainly from the states of

Kano, Jigawa and Katsina based on 2006 population census.66 It provides primary, secondary and tertiary health care services.

Aminu Kano Teaching Hospital has a capacity of 800 beds. It has several clinical departments including Internal medicine, family medicine, Surgery including Orthopaedics,

Obstetrics & Gynecology, Pediatrics and Haematology that run specialist out-patient clinics and emergency services.67 It has well equipped laboratories including haematology and blood transfusion, Chemical pathology, Medical Microbiology and Histopathology.

3.2 STUDY POPULATION

The study population comprised all adult patients with clinical and radiological features suggestive of DVT in Aminu Kano Teaching Hospital. Age and sex-matched controls for each patient were selected from the respective departments as the patients.

3.3 SAMPLE SIZE DETERMINATION

The minimum sample size was determined based on the incidence of DVT of 2.2% using the

Yamanes statistical formula for calculating sample size in a study population <10,000.11,68

n = Z2pq

n=sample size

Z=95% confidence interval equaling to 1.96, and the tolerable sampling error (0.05)

Prevalence of the disease in the population

q=1-p

d=tolerable sampling error (0.05)

Z2=3.8416

P=0.022

q=0.98

d2=0.0025

(3.8416 x 0.02 x 0.98)/0.0025

Using the prevalence of deep venous thrombosis of 2.2%, this gave a sample size of 33

patients.11 A 10% attrition rate was used, giving a total of 36.3. The sample size was

increased to 40 for ease of sampling and calculation.

All patients with suspected DVT that have satisfied the inclusion criteria were recruited

consecutively until the sample size was achieved.

Thirty nine (39) Age and sex- matched controls were selected for each case from the

respective departments.

3.4 INCLUSION CRITERIA/EXCLUSION CRITERIA

3.4.1 INCLUSION CRITERIA FOR SUBJECTS

 Adult patients (age 18 years and above) accessing care in Aminu Kano

Teaching Hospital. 42

 Patients with a minimum Wells score of “low risk” category.

3.4.2 EXCLUSION CRITERIA FOR SUBJECTS

 Chronic deep venous thrombosis.

 Any patient already commenced on therapeutic anticoagulation.

3.4.3 INCLUSION CRITERIA FOR CONTROLS

1. Patients aged of 18 years and above.

2. Patients who are seen at the outpatient clinics and wards of AKTH without clinical

and/or radiological evidence of deep venous thrombosis and were never diagnosed

with deep venous thrombosis in the past.

3. Patients that are Age- and sex- matched with the cases, selected from the same

department as the subjects

3.4.4 EXCLUSION CRITERIA FOR CONTROLS

1.Include all the exclusion criteria for subjects

2.patients with deep venous thrombosis

3.5 STUDY DESIGN AND PROCEDURE

The study was a cross sectional comparative study to determine the clinical profile and laboratory correlates of DVT, and the reliability of D-dimer test among adult patients attending Aminu Kano Teaching Hospital, Kano.

Consecutive patients that satisfied the inclusion criteria were recruited from various patient care points in the Hospital which included the General Outpatient Department, Accident and

Emergency, Haematology Daycare Unit, Radiology and the outpatient clinics and wards of the departments of Medicine, Surgery Obstetrics and Gynaecology. The doctors providing care were informed about the study and the contact mobile telephone number of the 43 investigator was provided so that he could be contacted when patients with features suggestive of DVT are seen. A reminder notice was also pasted on respective departmental notice boards and service points.

Written Informed consent was obtained using a consent form designed for this study

(Appendix 2). Consenting adult patients presenting with features suggestive of DVT were first screened using the Wells clinical prediction score (inclusion criteria).

Consenting adult patients with similar ages and sex to the study participants that satisfy the inclusion criteria but that did not have clinical features suggestive of deep venous thrombosis were recruited in the respective patient care points of AKTH, to serve as control group.

All the patients had relevant data collected using an interviewer-administered questionnaire designed for this study to assess the clinical profile of DVT (Appendix 1). The questionnaire has five (5) sub sections. Section one (1) will be used to get the necessary biodata of the respondents, section two (2) the relevant medical history, section three (3) will be used to document the relevant physical examination findings, section four (4) the relevant laboratory and Doppler Ultrasound findings, and section five (5) is the conclusion.

Doppler ultrasound scan was performed and reported by an experienced Consultant

Radiologist, with the researcher observing. The Doppler ultrasound scan machine used is the

Mindray DP 8800 ultrasound machine. All patients in the case- and control groups underwent

Doppler ultrasound scan. In case of a negative result, the Doppler ultrasound was repeated for a minimum of two (2) times before the test was recorded as negative. Two (2) experienced radiologist performed all the Doppler ultrasound to reduce inter observer bias.

3.5.2 STUDY PERIOD

This research work was commenced in May 2016 and completed in November 2016.

3.5.3 DATA COLLECTION TOOLS

The following are the tools used for the collection of data during the study.

1. Pre-tested questionnaires. A copy is attached as appendix I.

2. Sample collection syringes

3. Sample containers: Lithium heparin, plain, EDTA, Flouride oxalate

4. Mindray DP 8800 ultrasound machine.

5. COBAS® Roche cardiac D-dimer portable reader

6. Thermo Scientific PierceTM Human ELISA kit

7. BIORAD microplate reader model PR 3100 TSC and washer

8. Ceramic tiles

9. Blood group serology anti-sera: Anti-A, anti-B, anti-D

10. Mindray 2800 Haematology autoanalyser

11. Measuring tape

12. Weighing scale (RGZ-120 Health Scale).

13. Stadiometer (RGZ-120 Health Scale).

14. Sphygmomanometer.

3.5.4 BLOOD SAMPLE COLLECTION

Venous blood sample was obtained for the measurement of the serum D-dimer levels, vWF levels, ABO and Rhesus blood grouping, Full blood count, urea/electrolytes/Creatinine,

Fasting Blood Sugar, lipid profile, and HIV serology.

A suitable peripheral vein was identified in the antecubital fossa, wrist, or forearm. Universal safety techniques for the collection and handling of blood samples were adhered to throughout the process of handling the blood samples.

About 10ml of venous blood was collected and 3ml each was expelled into a lithium heparin bottle and EDTA container, respectively. Two (2) ml of blood was expelled each into a plain and Flouride oxalate bottles respectively. The tubes were then closed with their respective stoppers, properly labeled and mixed.

3.5.5 SAMPLE TRANSPORTATION AND STORAGE:

The blood samples were transported immediately to the laboratory where the D dimer test was conducted by the researcher using the COBAS® Roche cardiac D-dimer portable reader using the blood sample collected in a Lithium heparin sample bottle. The remaining blood sample was transported to the chemical pathology laboratory for analysis of

Urea/electrolytes/Creatinine and lipid profile. The blood sample for blood glucose was transported in the Flouride Oxalate bottle to the laboratory where it was analysed immediately.

The ABO and Rh blood group was determined using tile technique that was performed by the researcher using the sample in the plain bottle. The remaining sample in the plain bottle was used for HIV screening and then centrifuged, separated, and the serum stored at a temperature of between -200C until all samples have been collected for the measurement of the serum

Von Willebrands Factor (vWF) level.

3.5.6 LABORATORY TESTS:

1. D-dimer.

Test principles:

It is a quantitative immunological test for the detection of D-dimer in heparinised venous blood for use with the Cobas h 232 instrument. The test contains two monoclonal antibodies against fibrin degradation products which contain the D-dimer structure element. One of the antibodies is gold-labeled, the other biotynlated. The antibodies form a sandwich complex with D-dimer in the blood. Following removal of erythrocytes from the sample, plasma passes through the detection zone in which the gold labeled D-dimer sandwich complexes accumulate and the positive signal is displayed as a reddish line (the signal line). Excess gold labelled antibodies accumulate along the control line, signaling that the test was valid. The intensity of the signal line increases in proportion to the D-dimer concentration.

The optical system of the instrument detects the two lines and measures the intensity to a quantitative result and shows it in the display. It uses 150µL of venous blood, and measuring range of 0.1-4µg/mL.

Test procedure:

 The researcher activated the COBAS® Roche cardiac D-dimer portable reader.

 The patients initials, date and time were then be properly imputed.

 The Roche D-dimer test strip was inserted into the D-dimer portable reader when the

machine prompted.

 A few minutes after this, the machine prompted the researcher to apply the

heparinised venous blood sample on a specific point on the test strip.

 After the application of the blood sample, the D-dimer portable reader processed the

test and the result automatically within 8 minutes.

 The reference level of D-dimer is less than 0.5 µg/mL.

COBAS® Roche cardiac D-dimer portable reader and D-dimer testing Kit.

2. vWF assay (ELISA method)

Principle of the method:

The Thermo Scientific™ Pierce™ Human vWF ELISA is a solid-phase, sandwich-type enzyme-linked immunosorbent assay (ELISA). An antibody specific for von Willebrand factor (VWF) has been coated onto the wells of the microtiter strips provided. Samples, including standards of known von Willebrand factor (VWF) content, control specimens, and unknowns, are pipetted into these wells, followed by the addition of a biotinylated second antibody. During the first incubation, the von Willebrand factor (vWF) antigen binds simultaneously to the immobilized (capture) antibody on one site, and to the solution-phase biotinylated antibody on a second site. After removal of excess second antibody, streptavidin-

48 peroxidase (enzyme) is added. It binds to the biotinylated antibody to complete the four- member sandwich. After a second incubation and washing to remove all unbound enzyme, a substrate solution is added, which is acted upon by the bound enzyme to produce color. The intensity of this colored product is directly proportional to the concentration of von

Willebrand factor (vWF) present in the original specimen.

Assay Procedure:

The test was performed by a qualified Chemical Pathologist with the active participation of the researcher.

 All reagents and samples were brought to room temperature (18 - 25ºC) before use.

 All standards and samples were run at least in duplicate.

 100μL of each standard and sample were added into appropriate wells, which was

then covered and incubated for 2.5 hours at room temperature or over night at 4ºC

with gentle shaking.

 The solution was then discarded and washed (by filling each well with Wash Buffer

(300μL) using a multi-channel Pipette) 4 times with 1X Wash Buffer. Complete

removal of liquid at each step was ensured for good performance.

 After the last wash, any remaining Wash Buffer was removed by decanting.

 The plate was inverted and blotted against clean paper towels.

 100μL of 1X prepared biotinylated antibody was then be added to each well, and then

incubated for 1 hour at room temperature with gentle shaking.

 The solution was then discarded and the wash step was then repeated.

 100μL of prepared Streptavidin-HRP solution was then added to each well and

incubated for 45 minutes at room temperature with gentle shaking.

 The solution was then discarded and wash step repeated. 100μL of TMB Substrate

was then added to each well, incubated for 30 minutes at room temperature in the dark

with gentle shaking.

 The plate was evaluated within 30 minutes of stopping the reaction.

 The absorbance is then measured on an ELISA plate reader set at 450nm and 550nm.

To correct for optical imperfections in the microplate, 550nm values was substracted

from 450nm values.

Calculation of Results:

The standard curve was generated by plotting the average absorbance (450nm minus 550nm) obtained for each Standard concentration on the vertical (Y) axis vs. the corresponding vWF concentration on the horizontal (X) axis.

Results was calculated manually using graph paper.

The amount of vWF in each sample was determined by interpolating the vWF concentration

(X axis) to the absorbance value (Y axis).

When the sample was diluted, the interpolated value obtained was multiplied by the dilution factor to determine the amount of vWF in the sample.

3. Blood grouping:

ABO cell grouping using a tile technique:

 The researcher prepared a 20-30% of the patients’ red cell suspension by adding 5

drops of the patients packed red cells to 20 drops of saline.

 A white ceramic tile was divided into four (4) zones, labeled 1-4, and named A, B, D,

and control respectively.

 One volume of patients 20-30% red cells was pippetted into zones 1,2 and 3 on the

tile.

 One volume of 20-30% red cell suspension of a known blood type was pippetted onto

zone 4, as control and mixed with the appropriate antibody.

 One volume of anti-A and anti-B was pippetted onto zones 1 and 2 respectively.

 One volume of anti-D was pippetted onto zone 3.

 The contents on each zone were then mixed using a small clean piece of applicator

stick for each.

 The tile was then rocked gently from side to side, looking for agglutination.

 Agglutination if present, and confirmed by viewing under the microscope, represented

a positive result.

 The results were then recorded after about two minutes.

4. Full Blood Count:

This was performed by the researcher using a Mindray 2800 Haematology autoanalyser in the

Clinical haematology research laboratory of the department of medicine, AKTH.

3.5.7 QUALITY CONTROL

The following standards were observed in order to obtain a highly qualitative data:

After collection, blood samples were stored at -200C until the time of analysis.

The storage temperature was checked daily.

All reagent kits were assessed for validity prior to use. (The expiry dates were checked and they were kept at the recommended storage temperature).

Only freshly prepared reagents were used.

All pipettes that were used for laboratory analysis were calibrated using gravidimetric method before use.

Blood samples were transported immediately after collection to the laboratory where the D 51 dimer test was conducted by the researcher using the COBAS® Roche cardiac D-dimer portable reader

3.5.8 BIOSAFETY

Ensuring safety in all laboratory processes was always a priority. The WHO biosafety protocol for the handling of blood products was adhered to.69 Full length laboratory coats with disposable fluid resistant apron were worn along with gloves, goggles, and mask.

3.6 DATA ANALYSIS

All data generated was collated, checked and analysed using computer based statistical package for social sciences (SPSS) version 20.0. Qualitative data were presented as proportions and percentages. Quantitative data were presented as means and standard deviation. Comparison of the means was done using student T- test while comparison of proportion was by Pearson’s χ2. A confidence interval of 95% was used, and a p-value of ≤

0.05 was considered significant.

Factors found to be strongly associated with DVT were entered into a logistic regression model to adjust for confounding.

Sensitivity is the probability of testing positive when the disease is present. Sensitivity of detecting DVT was calculated for the D-dimer method using Doppler ultrasound as gold standard with the following formula:

Sensitivity: TP/ (TP+FN)

Specificity, probability of being tested negative when the disease is absent, was calculated using the following formula:

Specificity = TN/N=TN/FP+TN 52

Positive predictive value=TP/TP+FP

Negative predictive value=TN/TN+FN

Where

FN= false negative: incorrectly rejected, TN=true negative: correctly rejected, FP=false positive: incorrectly identified, TP=true positive: correctly identified

3.7 INCENTIVES/BENEFITS TO THE STUDY POPULATION

1.The Doppler ultrasound scan, D-dimer, vWF assay, ABO blood grouping were done at no cost to the patients.

2.This study described the clinical profile and some laboratory correlates of DVT and the role of D-dimer point of care testing in the diagnosis of DVT thus help in better management of the patients.

CHAPTER FOUR

4.0 RESULTS 53

A total of 40 consecutive patients that satisfied the inclusion criteria with a positive Doppler ultrasound scan for DVT were recruited from the various clinical service delivery points of

Aminu Kano Teaching hospital, Kano from May 2016 to November 2016. Thirty nine (39) age and sex matched patients without DVT were also recruited to serve as controls.

4.1 SOCIO DEMOGRAPHIC CHARACTERISTICS OF THE STUDY SUBJECTS

The age distribution of the study participants is depicted in Figure 4.1, with a mean (±SD) age of 47.8±11.8 years for the subjects and 48.3±9.8 years for the controls (p = 0.8384). The ages of the study participants ranged between 26 and 69 years, with modal age group of 46-

50 years. As shown in Table 4.1 majority of the study patients are females with female: male ratio of 1.5:1. Most of the subjects were employed, out of which 13(32.5%) were engaged in

Business and 11 (27.5%) were civil servants. Among the control group 56.4% were gainfully employed, while 43.6% were unemployed. Majority of both cases and control were married.

Figure 4.1: Age distribution of the study participants

Age distribution of the study participants 10

SUBJECTS Frequency CONTROLS 4

0 26-30 31-35 36-40 41-45 46-50 51-55 56-60 Above 60 Age group (p = 0.8384)

Table 4.1: Some Socio demographic characteristics of the study population.

SOCIO-DEMOGRAPHIC VARIABLES SUBJECTS CONTROLS P-value

VARIABLES n=40( %) n=39(%)

SEX MALE 16(40) 16(41.0) 1.000

FEMALE 24(60) 23(59.0) 1.000 TOTAL 40(100) 39(100) 1.000

OCCUPATION PRIVATELY 13(32.5) 10(25.6) 0.6438

EMPLOYED

CIVIL SERVANTS 11(27.5) 12(30.8) 1.000

UNEMPLOYED 16(40.0) 17(43.6) 1.000

TOTAL 40(100) 39(100) 1.000

MARITAL STATUS MARRIED 24(60) 19(47.5) 0.7047

NON MARRIED 11(27.5) 14(35) 0.6488

WIDOW(ER) 5(12.5) 7(17.5) 0.7582

TOTAL 40(100) 39(100) 1.000

*Statistically significant

4.2 CLINICAL PROFILE OF THE STUDY PARTICIPANTS

The clinical characteristics of the study participants are shown in Table 4.2. History of surgery was obtained among 17 (42.5%) of subjects compared to 6 (15.4%) controls, with a statistically significant difference (p = 0.0135), history of HIV was recorded among 14 (35%) subjects and 5 (12.8%) controls with a statistically significant difference (p = 0.0355), while history of immobility of more than 3 days was obtained among 21 (52.5%) subjects and 11

(28.2%) of the controls with a statistically significant difference (p = 0.0399). The history of

Air/long distance travel was obtained among 15 (37.5%) of the subjects and 6 (15.4%) of the controls, with a statistically significant difference (p = 0.0421), while the history of other medical illnesses was obtained among 23 (57.5%) of subjects and 13 (33.3% ) controls (p =

0.0431).

The history of Diabetes mellitus was recorded 15 (37.5%) subjects and 7 (17.9%) controls (p

= 0.0797), while history of cancer was recorded in 9 (22.5%) subjects and 4 (10.3) controls (p

= 0.2253). Cigarette smoking was recorded among 9 (22.5%) of the subjects and 5 (12.8%) of the controls (p = 0.3771), while a history of radiotherapy was obtained in only 2 (5%) subjects and none of the controls (p = 0.4937). History of trauma was obtained in 3 (7.5%) subjects and 2 (5.1%) controls (p = 1.000), family history of DVT was obtained in 2 (5%) of subjects and 1 (2.6%) controls (p = 1.000). History pregnancy was recorded among 9(37%) subjects and 6 (26.1%) controls (p = 0.5657), while history of OCP use was obtained among

8 (33%) subjects and 7 (30.4%) controls (p = 1.000).

A record of hypertension was recorded among 21 (52.5%) subjects and 10 (25.6%) controls

(p = 0.0217), and obesity was documented among 9 (22.5% subjects and 6 (15.4%) controls

(p = 0.5657). Six (15%) subjects had a femoral venous catheter in situ prior to onset of symptoms compared to 5 (12.8%) controls (p = 1.000).

As shown in Table 4.3, the reason for immobility among the study participants was osteoarthritis in 4 (19%) of the subjects and 3 (27.3%) of the controls (p = 0.6857). 57

Paraplegia is the cause of immobility in 1 subject, while the majority of subjects and controls had other medical illnesses, which included acute severe malaria, acute exacerbation of

Peptic ulcer disease, diarrheal disease, Urinary tract infection, Community acquired pneumonia, typhoid fever, Diabetic ketoacidosis, and Acute Kidney Injury.

The acute medical illnesses listed above constituted 16 of the cases while the other cases were CCF and CVD, which constituted 30.4%. While majority of the control group had malaria 3(23.1%), PUD 3(23.1%), CCF 2(15.4%) and typhoid fever 2 (15.4%).

Table 4.2: Clinical profile of Subjects and controls: clinical risk factors

VARIABLE Subjects (n=40) Controls (n=39) p-value

Frequencies (%) Frequencies (%)

HISTORY

Surgery 17(42.5) 6(15.4) 0.0135*

HIV 14(35) 5(12.8) 0.0355*

Immobility 21(52.5) 11(28.2) 0.0399*

Air travel 15(37.5) 6(15.4) 0.0421*

Other medical illness 23(57.5) 13(33.3) 0.0431*

Diabetes mellitus 15(37.5) 7(17.9) 0.0797

Cancer 9(22.5) 4(10.3) 0.2253

Cigarette smoking 9(22.5) 5(12.8) 0.3771

Radiotherapy 2(5) 0(0) 0.4937§

Trauma 3(7.5) 2(5.1) 1.000§

Family history of DVT 2(5) 1(2.6) 1.0000§

Pregnancy among females 9(37) 6(26.1) 0.5657

OCP use among females 8(33) 7(30.4) 1.0000

Femoral IV line 6(15) 5(12.8) 1.000

PHYSICAL EXAMINATION MEASUREMENT

Hypertension 21(52.5) 10(25.6) 0.0217*

Obesity 9(22.5) 6(15.4) 0.5657

*significant §Fishers exact test

Table 4.3: Causes of immobility among Subjects

Variable Subjects Controls p-value

n=21 (%) n=11(%)

Paraplegia 1(4.76) 0(0) 1.000

Osteoarthrits 4(19) 3(27.3) 0.6857

Acute medical illness 16(76.19) 8(72.7) 1.000

*Statistically significant

The distribution of the Body Mass Index (BMI) of the study participants is depicted in Figure

4.2. Obesity (BMI>30Kg/m2 was recorded among 9 (22.5%) subjects and 6 (15%) controls, while 7 subjects and 5 controls were overweight (BMI between 25 and 30 Kg/m2). BMI of less than 20Kg/m2 was recorded among 11 subjects and 4 controls, with 13 subjects and 25

60 controls having a normal BMI (20-25Kg/m2). The mean BMI measured was

25.05(±6.21Kg/m2) for subjects and 23.39(±4.06) for the controls, p = 0.1648. However, the mean BMI for those that are obese (BMI >30Kg/m2) was 33.99(±2.38) and 31.78(±0.58) for the subjects and controls, respectively p = 0.0460.

Three (7.5%) subjects had significant inguinal lymph node enlargement, 4(10%) had intra abdominal masses/lymph node, and 5(12.5%) had intra abdominal organ enlargement. The mean systolic blood pressure was 139.45(±18.31) mmHg in subjects and 128.82(±15.49) mmHg in the controls (p = 0.0068). The mean diastolic blood pressure was 87.55(±14.50) mmHg in subjects and 84.26 (±12.64) mmHg in the controls (p = 0.2862).

As shown in Table 4.4, 29(72.5%) of the subjects had a differential limb swelling of >3cm,

33(82.5%) had pain, 26(65%) had discolouration, and 21(52.5%) had warmness on the affected limb. Almost half the subjects presented within 3 days of onset of symptoms and about one-quarter presented after one week.

The Wells’ score of the subjects is shown in Table 4.5. About half of the subjects 22(55%) had a Wells’ score of 3-4, 11(27.5%) had a Wells’ score of ≥5, while 7(17.5%) had a Wells’ score of 1-2.

Figure 4.2: Body Mass Index (BMI) of the study participants

Body Mass Index of the study participants 30

Subjects Frequency Controls

0 <20 20-25 25-30 >30 BMI (Kg/m2) p=0.1648

Table 4.4: Clinical features of affected limb

VARIABLE n(%)

Duration of symptoms 1-3 days 19(47.5)

4-7 days 12(30)

>7 days 9(22.5)

Swelling 29(72.5)

Tenderness 33(82.5)

Discolouration/redness 26(65)

Warmth 21(52.5)

Table 4.5: Wells’ score among subjects

Sex WELLS’ SCORE n=40(%) Male Female n=16(%) n=24(%)

1 7(17.5) 2(12.5) 5(20.8)

2 11(27.5) 2(12.5) 9(37.5)

3 9(22.5) 4(25) 5(20.8)

4 5(12.5) 3(18.8) 2(8.3)

≥5 8(20) 5(31.3) 3(12.5)

4.3 BLOOD GROUPS OF THE SUBJECTS AND CONTROLS

The blood groups distribution of the study population is shown in Table 4.6. Majority of the subjects had non-O blood groups (67.5%) in contrast to the control group that majority have an ‘O’ blood groups (60%). A statistically significant difference was found between ‘O’ and non-O blood groups among the study population (p = 0.025).

Table 4.6: Blood groups of the study participants

BLOOD GROUP SUBJECTS CONTROLS

n=40(%) n=39(%)

“O” 13(32.5) 23(59)

“A” 12(30) 7(17.9)

“B” 10(25) 6(15.4)

“AB” 5(12.5) 3(7.7)

TOTAL NON”O” BLOOD GROUPS 27(67.5) 16(41) p=0.025 χ2=12.604

4.4 D-DIMER LEVELS OF THE SUBJECTS AND CONTROLS 65

D-dimer value of >0.5µg/mL was provided by the manufacturer as cut-off value for positive

result. Majority of the subjects had a positive D-dimer result 35 (87.5%) compared to 11

(27.5%) controls. The mean D-dimer was higher among the subjects (0.655±0.24µg/mL) than

among the controls (0.313±0.15µg/mL), with a statistically significant difference (p <

0.0001). Likewise among those with a positive D-dimer values, there was a statistically

significant difference between the subjects and controls (p = 0.044).

Table 4.7 shows the D-dimer levels among the various Wells’ score readings of the subjects.

The mean (±SD) D-dimer values is higher in those among subjects with a Wells’ score of ≥5,

with a an observed value of 0.92 (±0.35)µg/mL. There was a statistically difference in the D-

dimer levels between the various Wells’ score categories (p = 0.001).

Table 4.8 compares the D-dimer and blood groups of the study participants. A statistically

significant relationship was found between non -O blood groups and positive D-dimer levels

of the study participants (p = 0.0001).

Table 4.7: Mean (±SD) D-dimer among subjects with different Wells’ score

Wells’ score Mean (±SD) µg/mL n=35(%)

1-2 0.68571(±0.10995) 14 (40)

3-4 0.57692(±0.08321) 13(37.1)

≥5 0.925(±0.34949) 8(22.9) p = 0.001

Table 4.8: Positive D-dimer (>0.5µg/ml) levels in the various blood groups

D-dimer Non-O Blood group ‘O’ blood group

Subjects n=35(%) 27(77.1) 8(22.9)

Controls n=11(%) 11(100) 0(0) p = 0.0007 χ2=1.661

4.5 vWF ANTIGEN LEVELS OF THE SUBJECTS AND CONTROLS

Figure 4.3 depict the distribution of plasma vWF antigen levels among the Subjects and controls. The mean vWF antigen is 117.35±21.78 IU/dL among the subjects and

106.7±23.17 IU/dL among the controls. A statistically significant difference was found in the vWF antigen levels between the subjects and controls (p = 0.037).All the subjects had a serum vWF antigen levels within the reference range (50 and 200 IU per dL), with a range of

87 IU per dL and 158 IU per dL. The control group had a serum vWF antigen level range of

38 IU per dL to149 IU per dL.

Additionally, as shown in Table 4.9, the mean (±SD) vWF antigen level is higher among subjects with a non -O blood groups than those with “O” blood groups, 112.30 (±19.11)

IU/dL and 95.81(±23.88)IU/dL respectively. A statistically significant difference was observed in the mean value of vWF antigen between the two groups (p = 0.0169).

The relationship between vWF antigen levels and D-dimer is shown in Table 4.10. Although the mean vWF antigen level among the subjects was higher among those with a negative D- dimer than those with a positive D-dimer, and there was no statistically significant difference between the two groups (p = 0.163). The mean vWF antigen level was however, statistically significantly higher among the subjects than controls (p = 0.0045).

Figure 4.3: Distribution of plasma vWF antigen levels in the study subjects and controls (IU/dL)

15 Frequency

0 30-40 51-60 71-80 81-90 91-100 101-110 111-120 121-130 131-140 141-150 151-160 vWF antigen levels (IU/dL) p=0.037

Table 4.9: Mean (±SD) plasma vWF antigen levels (IU/dL) in different blood groups for subjects and controls

Blood group Subjects (n=40) Controls (n=39) p-value

Non”O” 112.30(±19.11) 95.81(±23.88) 0.0169

O 127.85(±23.95) 113.88(±20.02) 0.0696

p-value 0.0326 0.0146

Table 4.10: Mean plasma vWF antigen levels (IU/dL) according to D-dimer levels of the study participants

D-dimer Subjects (n=40) Controls (n=39) p-value

High (>0.5µg/ml) 115.54(±20.86) 92.36(±26.92) 0.0045

Normal (<0.5 µg/ml) 130.0(±24.44) 112.13(±19.43) 0.0774

p-value 0.1631 0.0147

4.7 DOPPLER ULTRASOUND FEATURES OF SUBJECTS

The Doppler ultrasound findings of the sudy subjects is shown in Table 4.11, with proximal 69

DVT recorded among 27(67.5%) individuals and distal DVT observed among 13 (32.5%).

Table 4.11: Doppler ultrasound features of the Subjects

Variable n=40(%)

Proximal DVT 27(67.5)

Distal DVT 13(32.5)

4.8 SENSITIVITY AND SPECIFICITY OF D-DIMER TEST

Table 4.12: True positives and negatives, and false positives and negatives for D-dimer

70 among study population.

Positive D-dimer Negative D-dimer

n=46 n=34

Subjects 35 (TP) 5 (FN) 40

Controls 11 (FP) 29 (TN) 39

KEY:FN= false negative: incorrectly rejected, TN=true negative: correctly rejected, FP=false, positive: incorrectly identified, TP=true positive: correctly identified.

Table 4.12 shows the frequencies of true and false positives, and true and false negative results of the D-dimer test. The Sensitivity of detecting DVT was calculated for the D-dimer method using Doppler ultrasound as gold standard with the following formula:

Sensitivity= TP/ (TP+FN)= [ 35/ (35+5)]=87.50%.

Specificity was calculated using the following formula:

Specificity = TN/N=TN/FP+TN=[29/ (11+29)]= 72.50%.

Positive predictive value=TP/TP+FP= [35/ (35+11)]= 76.09%,

Negative predictive value=TN/TN+FN= [ 29/(5+29)]= 85.29%.

Diagnostic accuracy: 80%.

Likelihood ratio of a positive test: 3.182

Likelihood ratio of a negative test: 0.1724

4.9 RELATIONSHIP BETWEEN THE MEASURED PARAMETERS AND D-DIMER

AMONG SUBJECTS

Table 4.13 shows that among subjects, the following risk factors showed a statistically significant relationship with D-dimer: HIV (p = 0.0426), air/long distance travel (p = 0.0564),

71 cancer (p = 0.0061), family history of DVT (p = 0.0128), pregnancy (p = 0.0061), femoral IV line (p = 0.0001), and obesity (p = 0.0002). There was no statistically significant relationship between D-dimer and the risk factors among the controls.

Table 4.14 shows a statistically significant relationship between surgery (p = 0.0126), immobility (p = 0.0392), air/long distance travel (p = 0.0406), pregnancy among females (p =

0.0307), OCP among females (p = 0.04609) and hypertension (p = 0.0210), between subjects and controls with a positive D-dimer values. Linear regression did not observe any statistically significant relationship between D-dimer with plasma vWF antigen levels (p =

0.0986; r2 = 0.01), systolic blood pressure (p = 0.9693; r2 = 0.00), diastolic blood pressure (p

= 0.4989; r2 = 0.01), and BMI (p = 0.4657; r2 = 0.01).

Table 4.13: Positive D-dimer levels (>0.5µg/mL) among subjects

VARIABLE POSITIVE NEGATIVE P-Value

n(%) n(%)

Surgery 14(40) 3(60) 0.6340

HIV 10(28.5) 4(80) 0.0426*

Immobility 20(57.1) 1(20) 0.1723

Air travel 11(31.4) 4(80) 0.0564*

Other medical illness 21(60) 2(40) 0.6340

Diabetes mellitus 14(40) 1(20) 0.6330

Cancer 5(8.6) 4(80) 0.0061*

Cigarette smoking 8(22.9) 1(20) 1.000

Radiotherapy 2(5.7) 0(0) 1.000

Trauma 2(5.7) 1(20) 0.3376

Family history of DVT (0) 2(40) 0.0128*

Pregnancy among females 5(8.6) 4(80) 0.0061*

OCP use among females 6(17.1) 2(40) 0.2568

Femoral IV line 1(2.9) 5(100) 0.0001*

Hypertension 18(51.4) 3(60) 1.000

Obesity 4(11.4) 5(100) 0.0002*

Non-O blood group 22(62.9) 5(100) 0.1540

*Statistically significant Fisher exact T test

Table 4.14: Positive D-dimer (0.5µg/ml) values among study participants

VARIABLE SUBJECTS CONTROLS P-VALUE n(%) n(%) Surgery 14(40) 2(18) 0.0126*

Immobility 10(28.5) 1(9) 0.0392*

Air travel 20(57.1) 4(36.4) 0.0406*

Diabetes mellitus 11(31.4) 1(9) 0.0784

HIV 21(60) 2(18) 0.1610

Cancer 14(40) 3(27.3) 0.2247

Cigarette smoking 5(8.6) 2(18) 0.3781

Radiotherapy 8(22.9) 1(9) 0.4936

Trauma 2(5.7) 0(0) 1.0

Family history 2(5.7) 1(9) 1.0

Pregnancy (0) 0(0) 0.0307*

OCP use 5(8.6) 2(18) 0.04609*

Hypertension 6(17.1) 2(18) 0.0210*

Obesity 1(2.9) 1(9) 0.5679

Non-O blood group 18(51.4) 5(45.5) 0.1689

Femoral IV line 4(11.4) 3(27.3) 1.0

*Statistically significant

CHAPTER FIVE.

5.0 DISCUSSION

Deep venous thrombosis is recognized as an increasing cause of mortality and morbidity among patients, and contributes to a rising cost of healthcare services. Its management requires timely diagnosis and prompt commencement of treatment.

The study described the clinical and some laboratory characteristics of patients with deep venous thrombosis, and assessed how these characteristics relate to the risk of developing

DVT. It also assessed the predictability of using the point of care D-dimer in the diagnosis of

DVT among adult patients in Aminu Kano Teaching Hospital, Kano.

5.1 SOCIO DEMOGRAPHIC CHARACTERISTICS OF THE STUDY POPULATION

The majority of subjects studied with DVT were middle aged and elderly (Table 4.1). This result indicate a high frequency of DVT in the fifth decade of life, which is in keeping with various studies that showed that increasing age is an independent risk factor for DVT.

4,5,6,7,13,29 Although the exact mechanism directly associating age with incidence of DVT is not known, there have been several hypothesis on this regard. These include innate biological changes and may be to a lesser extent, due to increased and repeated exposure to VTE risk factors, decrease mobility, increasing presence of other illnesses predisposing to thrombosis, increase in coagulation potential, degenerative vascular damage or some combination of these factors.12,28 The low incidence in children may be due to a low capacity to produce thrombin, increase capacity of alpha-2 macroglobulin to inhibit thrombin and enhance anti thrombin potential of vessel wall.65

Majority of the patients involved in the study were females. This may indicate that DVT is commoner among females, which is similar to findings in many studies that the incidence of

DVT is higher among females than males3,4,5,6,14,30,31, although there are some studies that did not observe any significant difference. 4,6,30,31

More than half of the study subjects were civil servants or privately employed engaged actively in office work with less ambulation and more travel, which may have accounted for the higher incidence.

5.2 PREDICTABILITY OF D-DIMER IN THE DIAGNOSIS OF DVT AMONG THE

STUDY POPULATION.

Sensitivity of D-Dimer test to DVT in this study was 87.50% (Table 4.12). Sensitivity of a 75 test is the probability that a test result will be positive when the disease is present (true positive rate). Therefore the D-dimer method showed positive 87.50% of time in patients with DVT. Specificity of D-Dimer test to DVT disease was 72.50%. Specificity of a test is the probability that a test result will be negative when the disease is not present (true negative rate). The D-dimer method showed negative in 72.50% times among those without DVT. A

Positive Predictive Value of 76.09% was observed. Therefore, among patients that test positive for D-dimer, only 76.09% actually do have DVT. A Negative Predictive Value of

85.29% was observed in this study. Therefore, among those that test negative for D-dimer,

85.29% actually do not have DVT. The diagnostic accuracy observed was 88.75%.

These are also similar to findings in other studies in different parts of the world.

4,5,6,20,21,59,61,62A study involving 68 in-patients in Turkey demonstrated similarly high levels of sensitivity and NPV of the D-dimer test ( 95.2% and 96.2% respectively), but a much lower levels of specificity and PPV(55.3% and 48.7% respectively).70 Some other studies reported varying sensitivities of between 94% to 100%.71 The result in this study is also similar to studies using the same point of care D-dimer machine, which obtained a specificity of 60.8% but a higher sensitivity of 96.9%.59,60 These different values recorded might be because of the lower sample size in our study in comparison to the 783 used in the study using the same D-dimer machine, and the different laboratory method used in the other studies in the other studies.

Some studies have reported a much lower PPV of 14.1% (95% CI, 7.95% - 99.9%) and a

NPV of the D-dimer test of 99.1 %. 62

However, the sensitivity and specificity of the D-dimer test depends on the method employed, with a marked variation in the values between the different methods. A large study involving 113 patients in Aalborg that tested the reliability of three different D-dimer test

76 methods reported VIDAS New and Auto Dimer have sensitivities of 90% and 88%, specificities of 42% and 44%, and NPV's of 85% and 83%, respectively. The Nycocard D- dimer assay reported a contrasting figure with sensitivity of 63%, specificity of 67% and

60 NPV of 71%. The Auto dimer, which uses the same principle as the Cobas H232 machine that was used in our study, showed comparable findings, but with a much lower specificity rate. However the Nico D-dimer assay reported much lower values.

Due to the common factors that affect the level of D-dimer, some studies have attempted to adjust for these variations. A study involving 78 patients that had hip and knee joint replacement surgeries and absent DVT (using Doppler ultrasound), demonstrated significantly raised D-Dimer levels in all patients at all measurements during the first week.

Levels after total knee replacement were higher than after total hip replacement, and levels rise and fall according to the duration of time after surgery. Comparison was made with an age-matched group who had a proven DVT and no difference in D-dimer levels between patients with or without a DVT was observed.63 Similar findings have prompted many researchers to propose different cut off value for D-dimer to serve as baseline level for the diagnosis of VTE in different disease conditions, procedures, duration of illness etc.

Similarly, studies have demonstrated significant reduction in the use of ultrasonography, from a mean of 1.34 tests per patient in the control group to 0.78 in the D-dimer group (P =

0.008) on serial measurements of D-dimer levels.62 Selective D-dimer testing based on patient risk category (e.g. Wells’ score), which was what was employed in our study, reduced the proportion of patients who required D-dimer testing by 21.8% and ultrasonography by

7.6%, respectively, with no difference in patients diagnosed with a venous thromboembolic even.72

5.3 CLINICAL PROFILE OF THE STUDY POPULATION

Surgery was observed to be statistically significant between the subjects and controls (p =

0.01; Table 4.2). Reports have shown high incidences of DVT among patients that had surgery within the previous three months.3,4,5,6,13,31 Although care should be taken in interpreting such findings because most of the study subjects had other risk factors that are established risk factors of DVT, example age more than or equals to 65years, female sex, presence of active cancer, type of surgery, type of anesthesia, neurological disease, radiation and previous DVT.15,65 However, multivariate analysis did not show any statistically significant difference between surgery and DVT. This could be explained by the paucity of data in our study on the type of surgery, type of anesthetic used, even though all of them had the surgery within the previous three months.

Human immune deficiency virus infection was observed to be almost three times commoner in the study group, with a statistically significant relationship between subjects and controls

(p = 0.04; Table 4.2). Human immune deficiency virus is a well documented independent risk factor for DVT, with some studies reporting a 2-10 times higher risk of DVT among patients with HIV, and an incidence as high as 17% on autopsy.16,22,43

Immobility featured prominently among the study participants, with a statistically significant relationship between both immobility and other medical illness between cases and controls (p

= 0.04 and p = 0.04 respectively). This is not surprising as about 70% of the reason for immobility was caused by other medical illness in our study. This is similar to findings in studies in Europe and North America that patients bedridden have an increased risk of developing DVT. ,3,4,5,14,15,27,28,31,41,73 This can be obviously be explained by the higher sample size of this study. A study in a tertiary hospital conducted in North eastern part of Nigeria found a low incidence (0.6%) of DVT among immobilised CVD patients, which was attributed to diagnostic difficulty in the low resource setting the research was conducted .27

History of air travel that lasted more than 4 hours or long distance land journey (more than six hours) within the week preceding the onset of symptoms was observed to be significant.

A statistically significant relationship was observed in our study between Air/long distance travel among the two groups (p = 0.0421). However, no statistically significant difference was observed after multivariate analysis. This is similar to findings in other studies that any form of travel that lasts for four hours or more double the risk of developing DVT for several weeks following the travel.4,5,6,12, 28 Many factors have been attributed to the increased risk of developing DVT due to air travel including relative hypoxia, reduced barometric pressure, low humidity, dehydration from consumption of diuretic beverages (coffee, Alcohol) etc.4,6

A statistically significant difference was observed between cases and controls with hypertension (p = 0.02), although there was difference in the diabetes mellitus patients (p =

0.08). This is similar to studies that have demonstrated a higher risk of developing DVT among patients with hypertension and diabetes mellitus.3,4,5,28 However, studies conducted in

Taiwan and South Korea did not reveal any statistically significant relationship between hypertension and DVT.74,75

Cancer was observed in nine patients in the case group but only two patients reported a history of radiotherapy. No statistically significant relationship was obtained cancer and radiotherapy with DVT (p = 0.2253 and p = 0.4937 respectively). Active cancer with or without chemotherapy/Radiotherapy has been found to be associated with a 5-fold increase risk of VTE. 3,4,5,6,7, 13, 14 These findings should however be interpreted with caution because most of these patients also have a combination of associated non-cancer related risk factors of

DVT like hospitalization, surgery and chemoptherapy.14. A possible explanation to the insignificant relationship between DVT and radiotherapy might be because radiotherapy services are not available in the vicinity.

In Northwestern Nigeria, 3% of the population was reported to indulge in cigarette smoking.63 However, no statistically significant relationship was observed between cigarette smoking and DVT (p = 0.38) table. This is in contrast to studies from the west that showed a relationship between high cigarette smoking and DVT. 3,4,13,45. This could be explained by the low level of cigarette smoking among females in Kano77, which constituted the majority of the study participants (60%).

Our study did not demonstrate any significant relationship between family history of DVT and DVT (p = 1.00). This is in contrast to findings in western world where a positive family history is an important risk factor of DVT, largely due to inherited thrombophilias.4,12 This is in contrast to studies that show a lower incidence of inherited thrombophilias and DVT among black Africans.9,11,27 Another possible explanation of this difference may be because of poor health seeking behavior and a possible low level of awareness of DVT among the general population in the study area.

One-third of the females with DVT were pregnant compared to about one-quarter females in the control group. The high incidence of DVT among pregnant females of the study participants is similar to findings of a higher DVT incidence among pregnant women in other parts of the world. Some studies have found a 5-fold higher risk of developing DVT among pregnant females.12,65 However, there was no statistically significant relationship between pregnancy and DVT in our study (p= 0.5657; Table 4.2). This might be because of the relatively smaller sample size in our study, and because of the poor health seeking behavior among females in the study area.78

Use of oral contraceptive pills was low in both the case and control groups (Table 4.2). The low prevalence of OCP use in this study population may be because of the low utilization of

OCPs reported among women in Northern Nigeria79 compared to developed countries like the

USA were about 70% of females in the reproductive age groups make use of OCPs, which was attributed to cultural factors.80 Studies in the western world found a higher incidence of

DVT among women using OCPs. 12,15,31,65 This study did not find any statistically significant difference in the use of OCP between cases and controls (p=1.000). This might be because of the varying relative risk of developing DVT with the different formulations and contents of the OCPs, with a lower relative risk of developing DVT and PE with second generation OCPs and pills containing lower dose of Levonorgestrel and Ethinylestradiol.81,82,83 Most of the study participants could not identify the type or formulation of the OCP they used. The reported poor pharmaceutical quality of medications in the study area might also account for

84,85 this difference.

Obesity (BMI >30mg/m2) was observed to be higher in the study participants, compared to individuals in the control group, although there was no statistically significant relationship between obesity and DVT among the study participants (p = 0.5657). Likewise the mean

BMI for those that were obese was statistically significantly higher among subjects than controls (p = 0.046). Many studies have found as much as a 2-3-fold increase in DVT and PE among individuals with a BMI of >30mg/m2.3,4,5,6,28 However, a study conducted in South

Korea did not find any statistically significant relationship between obesity and DVT even though the study was conducted among elderly patients.74

There was no statistically significant difference between the study subjects and controls with respect to femoral IV cannulation, and also no relation was found with DVT. Studies indicate a higher incidence of DVT among patients with central venous catheters for various procedures.18,31 The absence of relationship in our study could be explained by the fact that femoral venous catheter use was observed in 6 (15%) patients in the case group, which is almost similar to 5 (12.5%) individuals in the control group.

Majority of the DVT cases presented with limb swelling, pain and discolouration of the affected limb, which is similar to findings in other studies that mentioned the common clinical presentation as pain, in the affected limb due to vein wall inflammation and venous distension, redness and warmth.4,12,15 There is no statistical significance was observed between the symptoms and DVT. Majority of the subjects presented with a moderate and high Wells’ score (Table 4.5), which is similar to findings reported in the literature.4,5,7,12

5.4 BLOOD GROUP, PLASMA vWF ANTIGEN AND D-DIMER LEVELS

Studies on the ABO blood group of blood donors in Kano indicate that majority of blood donors have blood group “O”, and thus, may explain the higher “O” blood group among the control group reported in this study.86 A statistically significant relationship was found between non-O blood group and DVT (p = 0.025), which is similar to other studies that found a higher incidence of DVT among those with non-O blood group. 87,88

Several studies also reported similar findings of a higher incidence of DVT among patients with a non-O blood group. A large study involving 49,373 healthy blood donors reported a significantly higher frequency of non-O blood group in 369 patients with a diagnosis of deep vein thrombosis (70.6% vs 53.9%, p<0.001).89 In a case-controlled study involving 301 patients with a first time VTE, blood group ‘O’ was confirmed to be less represented among

VTE patients than among controls (25% vs 43%), and group ‘O’ subjects had lower concentrations of both FVIII and VWF as compared to those of non-O individuals.88A large study, the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, involving more than 1,500 study participants, reported a significantly higher risk of VTE among non-O blood type carriers than that among those with ‘O’ blood type.89 A large Italian case-control study involving 1424 study participants found that having a non-O blood group increased the risk of deep vein thrombosis by 2.2 times over that of individuals with group ‘O’. 90

Blood group is among the factors that affect the vWF levels, which accounts for 30% of variation in plasma vWF.91 Studies among normal healthy subjects have observed a 25%-

35% lower vWF levels in individuals with blood group ‘O’, than in those with non-O blood group.92,93,94 This is similar to the findings of this study that showed a higher mean vWF antigen level of 123.16±22.2IU/dL in the DVT group compared to the 109±26.71IU/dL in the control group. The relationship between vWF antigen levels and DVT is believed to be related to non-O blood group as discussed above.

However, no cut off value of the serum vWF antigen has been agreed as a definitive level that confers a higher risk for DVT, rather, a cut off point for each particular blood group antigen was proposed.95 Several studies have thus suggested a blood group-specific reference ranges for the diagnosis of von Willebrands disease (VWD).93,94,95

Furthermore a statistically significant relationship was found between Blood group and vWF levels (p = 0.013). These findings are similar to reported findings in other studies and literature. 88,96 A study in Calabar, South-South Nigeria observed a lower mean VWF antigen levels in individuals with ‘O’ blood group compared to all the other ABO blood group types.

And a comparison of the mean vWF Antigen levels of the various ABO groups showed that the differences between their means were statistically significant.97

Majority of the subjects had a D-dimer level greater than 0.50µg/mL, in sharp contrast to the control group, in which only 11 (27.5%) individuals had D-dimer levels above 0.5µg/mL.

The cut-off value of 0.5µg/mL was chosen based on the recommendation of the manufacturer and other studies.59,76 The mean D-dimer levels was also twice as high in the subjects compared to the control group. Statistical analysis revealed a significant difference between the subjects and controls (p < 0.0001). Among those with a high (positive) D-dimer values, there was a statistically significant relationship between the subjects and controls (p =

0.0435). These findings are similar to other studies that reported a higher mean D-dimer level among patients with DVT.60,62,65,70,72,76

The mean D-dimer was observed to be higher among subjects with a Wells’ score of ≥5 than among those with a lower Wells’ score, with a statistically significant difference observed between the mean D-dimer values in the different Wells’ score categories (Table 4.7; p =

0.001).This is similar to findings in some studies that demonstrated D-dimer values to confer a higher risk of developing DVT, and the levels of D-dimer to be proportionate to the Wells’ score.98,99 D-dimer is an established marker of thrombosis and is used as a screening test for the diagnosis of acute thrombotic states.4,6,7,12

Statistical analysis observed significant relationship between D-dimer and non-O blood group

(p = 0.001). Although studies establishing a direct relationship between D-dimer levels with non-O blood group were not found, it is likely that the high value of D-dimer obtained in those with a non-O blood group is indirectly related to the higher mean values of D-dimer among recorded among patients with DVT, which majority have a non-O blood group.

There was no statistically significant relationship between the means of vWF antigen between those with a positive D-dimer (110.0±24.29IU/dL) and those with a negative D-dimer test

(114.8±12.12IU/dL) D-dimer and vWF levels (p = 0.362) observed in our study. This finding is similar to the reported findings by Bombeli et al,100and Jenkins el al101 that there was a statistically significant relationship between DVT, and factor VIII and vWF antigen levels but not with other fibrinolysis or other endothelial cell derived coagulation proteins.

5.6 SCOPE AND LIMITATION OF THE STUDY

The research aimed to study the clinical profile of adult patients with deep venous thrombosis in AKTH. It also aimed to study some laboratory factors associated with deep venous thrombosis and their relationship with D-dimer, and to evaluate the reliability of using a point 84 of care testing of D-dimer in the diagnosis of deep venous thrombosis.

The study only examined the reliability of a single point of care test machine, Cobas H232, and results obtained were not compared with the D-dimer ELISA assays, which are considered the gold standard for the investigation of DVT. Patients with previous DVT were excluded in the study; the result may not be applicable to them.

5.7 CONFLICT OF INTEREST

I declare that I have no conflict of interest in the utilization of the COBAS® Roche cardiac

D-dimer portable reader or the kit in the conduct of this study.

6.0 CONCLUSIONS AND RECOMMENDATIONS.

CONCLUSIONS:

This study showed that DVT is commoner among females, middle aged and elderly individuals in the study area.

Majority of the patients with DVT presented with affected limb swelling, pain, and discolouration.

Majority of the patients presented with a “moderate” to “high” risk Wells’ score.

D-dimer was observed to be higher with those with a Wells’ score of >5 (High risk).

It was observed that the mean serum vWF antigen level was significantly higher among patients with a non-O blood group.

Elevated D-dimer levels, non-O blood group and vWF antigen levels from various causes were observed to be important risk factors of DVT in the study environment.

Point of care D-dimer test can be used to safely rule out DVT in patients with suspected

DVT.

RECOMMENDATIONS:

Based on the findings of this study, the following are recommended:

1. All patients presenting with suspected DVT should be screened with a point of care D-

dimer test to rapidly make a diagnosis and commence treatment.

2. All patients presenting with features of suspected DVT and high Wells’ score should be

properly evaluated for DVT.

3. Point of care D-dimer can be used to rule out DVT in such patients.

4. Clinicians especially Haematologists should be encouraged to conduct more studies with

a view of establishing local characteristics of DVT patients and determine the factors

determining the outcome of DVT in the local environment.

5. Clinicians and Haematologists should be encouraged to conduct more studies to

establish clinical and laboratory factors to use in a guideline for better risk stratification

of patients with suspected DVT.

6. Clinicians and Haematologists should be encouraged to conduct more studies to

determine the prevalence and nature of inherited thrombophila in the local environment.

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APPENDIX 1: PROFORMA

CLINICAL PROFILE AND LABORATORY CORRELATES OF DEEP VENOUS

THROMBOSIS: THE RELIABILITY OF POINT OF CARE D-DIMER TESTING AMONG

ADULTS IN AMINU KANO TEACHING HOSPITAL, KANO.

QUESTIONNAIRE CODE: DATE:

Section One: Biodata

Name:______Age:______

Gender:______Hospital No.:______Tribe:______

Address:______Occupation:______

Section Two: History:

Were you ever diagnosed and /or treated for cancer? YES/NO

Do you have active cancer? YES/NO

If yes, type/site of cancer:______

History of recent Radiotherapy : YES/NO

Smoking YES/NO

Surgery in past 6 months: YES/NO

Othorpaedic surgery in the past 6 months: YES/NO

Hip surgery in past 6 months: YES/NO

Knee surgery in past 6 months: YES/NO

Pelvic surgery in past 6 months YES/NO

Type of anaesthesia used GA/LOCAL

Congestive cardiac failure: YES/NO

COPD: YES/NO

Liver disease: YES/NO

Diabetes mellitus: YES/NO

Medications you currently take:______

PAST STROKE: YES/NO

If yes, limb affected;…………………………………………………………..

PRESENT stroke: YES/NO

Use of Oral contraceptive pills: YES/NO

Hormonal replacement therapy: YES/NO

Are you currently pregnant (if female): YES/NO

If yes, Gestational Age:…………………………………………………

LAST CHILD BIRTH/DELIVERY

History of previous pregnancy/miscarriages:______

Relevant family history:______

Relevant past or family history of coagulation disorders:______

Current medical illness/symptoms:______

Duration of presenting symptoms:______

Swelling noted by patient:______

Duration of swelling:______99

Presence of pain: YES/NO

Duration of pain:______

Redness noted by patient:______

Duration of redness:______

Leg trauma in last 30 days:______

Immobilized a day or more in the last 30 days?______

Number of days immobilized in the last 30 days:______

HIV status (if previously tested):______

Section Three: (official)

General Physical Examination:

Height:______Weight:______BMI:______Waist-Hip ratio:

Respiratory distress: Painful distress: Temperature:

Pallor: Jaundice: Petechiae:

Lymphadenopathy

Cardiovascular system:

Pulse rate: Blood pressure: Jugular venous pulse:

Heart apex beat: Parasternal heave: Heart sounds:

Respiratory system:

Respiratory rate: Breath sounds:

Abdomen:

Swelling: Organs palpable: 100

Central nervous system:

Consciousness/GCS: Signs of meningeal irritation: Motor system:

Status localis:

Any sign noted by examiner:______

Tenderness on palpation:______

Pitting oedema:______

Non-piting oedema:______

Erythema:______

Superficial venous dilation:______

Warmth:______

Palpable cord:______

Lower limb circumference:______

Wells Score:

Section four: laboratory/ radiology.

(a) Haematology

D dimer levels(µg/mL): ABO/Rh blood group: HB level(g/dl):

Platelet count: WBC count:

(b) Chemical Pathology vWF lebels(ng/mL): Urea: Creatinine:

Serum Potassium Serum HCO3 Serum sodium

Serum total cholesterol Serum TGs Serum LDL

Serum HDL Serum Fasting plasma glucose

HIV status: 101

(d) Radiology

Positive Doppler uss for an acute DVT:______YES/NO

Appendix two: Patient information form and Consent form:

Subject information Sheet and consent form

Dear Sir/ Madam,

My name is Dr Musbahu Abdullahi, I am a resident doctor in the Department of Medicine,

Aminu Kano Teaching Hospital, Kano.

Purpose of the study: the reason we are carrying out this study is to assess the clinical profile and laboratory correlates of DVT and the reliability of point of care D-dimer testing among adult patients.

Process: The study will involve asking you about the symptoms you felt during the course of your illness, past medical history, medication history and family history, using a form called questionnaire. A physical examination and blood test (5ml of blood drawn form a vein) will be performed by me. It will take about 15 minutes to fill the form. Your honest responses to the questions will be appreciated.

Participation: You are free to participate or decline to take part in this study. Your non- participation will in no way affect the care you receive in this hospital. We will however, greatly appreciate your cooperation in responding to the survey and taking part in the study.

Confidentiality: I wish to assure you that all the information you give will be treated with utmost confidentiality. That is your name is not required on the questionnaire.

Risk/Benefit: There is no risk involved in participating in this study. You are however, given an opportunity to contribute to the knowledge and better clinical care delivery on Deep venous thrombosis in this environment.

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CONSENT FORM

CLINICAL PROFILE AND LABORATORY CORRELATES OF DEEP VENOUS

THROMBOSIS: THE RELIABILITY OF POINT OF CARE D-DIMER TESTING AMONG

ADULTS IN AMINU KANO TEACHING HOSPITAL, KANO.

Mr/Mrs……………………………………………………..of

No……………………………….

I understand that I am volunteering on this project as a subject/control.

I can withdraw from the study without being discriminated against in any way.

The results of the tests will be explained to me and I will be given the opportunity for treatment, if necessary.

I hereby consent to participate in this project

Signature of participant:……………………. Right thumb print:………

Date:……………………………………….. Tel No:…………………..

Name of witness:…………………………….

Signature:………………….

Telephone number of witness:…………………

Signature of the Researcher………………………..

Date……………………………………………….

Thank you for your cooperation. 103

Hausa translation of the subject information sheet and consent form

Takardar bayani da amincewar shiga bincike

Barkanmu Malan/Malama,

Sunana Dr Musbahu Abdullahi, Ni Likita ne mai kwaraiwa a sashin kula da marassa lafiya na bada magani na asibitin koyarwa na Aminu Kano.

Amfanin binciken: babbab amfanin wannan binciken shine asan yanayin jikin masu cutar dunkulewar jinni a kafa, kuma a gwada amfanun da nagartar na`urar gwajin je da gidanka na

D-dima (D-dimer) wajen gano cutar.

Yanda za ayi: Yanayin wannan binciken yana kunshe da tambayoyi da za ayi day a danganci yanayin da cutar ta fara kama ka/ki, yanayin abubuwan dake damun ka/ki, iri irin rashin lafiya da ka/ki kayi a baya, wasu iri irin rashin lafiya da `yan uwa na jini sukayi ko su keda.

Duka wadannan tambayoyi na kunshe a jikin wata takarda daukar bayane. Daga bisani ne za`a duba sassa daban daban na jikin ka/ki dangane da ita wannan cuta, kuma a dauki mil biyar na jinni domin gwajin da nayi bayani a sama. Dukan wannan muna sa rai bazai wuce minti 15 ba. Na kasance mai godiya da saran za ka/ki bayar da cikakken bayani dangane da tambayoyin da aka tambaya.

Shiga binciken: ka sani cewa ka/ki na da dammar shiga ko kin amincewar shiga wannan bincike. Kuma rashin shiga wannan bincike bazai canja yanayi ko ingancin kulawa da za`a ba ka/ki ba. Amma zanyi matukkar farin ciki da godiya idan za ka/ki amince shiga wannan bincike.

Sirri: ina mai tabbatar muku da cewa dukan bayanai da zaku bamu zasu kasance na sirri zakanin ku damu. Sannan sunan ka/ki bazai kasance a takardar daukan bayanan ba.

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Illa ko samun karuwa: Babu wani abin illa da zai biyo baya domin kasancewar ka/ki a wanna bincike. Amma wannan wata dama ce ta ka/ki domin bada gudunmuwa wajen binciken ilimi da kuma samo hanyoyi mafi nagarta wajen bada kulawa na cutar dunkulewa jinni a wannan yankin.

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Takardar amincewar shiga bincike

Barkanmu da warhaka,

Sunana Dr Musbahu Abdullahi, na sashin kula da marassa lafiya nashan magani, na asibitin koyarwa na Aminu Kano. Ina gudanar da binkice domin sanin yanayin jikin masu cutar dunkulewar jinni da kuma gano nagartar na`urar tafi d agidanka na D-dima (D-dimer) wajen gano cutar.

YANAYIN JIKI DA TARE DA DANGANTAKAR SINADAREN JINNI NA CUTAR

DUNKULEWAR JINNI: NAGARTAR GWAJIN TAFI DA GIDANKA NA D-DIMA A

MANYA A ASIBITIN KOYARWA NA AMINU KANO.

Ka.ku sani cewa:

1. Shiga binciken ganin dam ace.

2. Za ka/ki iya ficewa daga binciken duk lokacin da ka/ki ke so.

3. Za ayi muku bayanin sakamakon binciken.

4. Idan aka samo kunada wata rashin lafiya, za`a baku dammar neman magani.

5. Babu wata illa ko mataki da za`a dauka a kan wanda yaki amincewa ya shiga

binciken.

Idan ka/kin amince da shiga wannan bincike, saka hannu a kasa:

Saka hannun mai shiga bincike:…………………………………………….

Hoton babban danyatsan dama:…………………………………………..

Kwanan wata:……………………………………………………………………….

Saka hannun mai bincike:……………………………………………………..

Kwanan wata:………………………………………………………………………. 106

Nagode.

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