GRIGORE. T. POPA UNIVERSITY OF MEDICINE AND PHARMACY OF IAȘI [310235]
“GRIGORE. T. POPA” [anonimizat].DR.VICTORITA SORODOC
GRADUATE STUDENT: [anonimizat] 2016
ACKNOWLEDGEMENTS
This thesis would not have been complete without a special mention to the following people who helped me immensely throughout the working process.
[anonimizat].
I extend my heartfelt gratitude to Lec.Dr Victorita Sorodoc for her guidance and continuous support during the research period. [anonimizat], sincerity and motivation have deeply inspired me. She has taught me the methodology to carry out the research and to present the research works as clearly as possible. It was a great privilege and honor to work and study under her guidance. A [anonimizat].Spiridon hospital for their willingness to help in every possible situation.
For the ancestors who paved the path before me upon whose shoulders I stand. This is dedicated especially to my father Mr.Pravin Thanki and my mother Mrs.[anonimizat], prayers and mentorship in the completion of this work and also their sacrifices for educating and preparing me for my future.
Last but not least a big thank you to my friends for lending their helping hand in this venture and for their continuous supports throughout the working process. Thank you.
TABLE OF CONTENTS
ACKNOWLEDGEMENTS 2
1. TABLE OF CONTENTS 3
2. TABLE OF TABLES 5
3. TABLE OF FIGURES 6
4. ABBREVIATIONS 11
GENERAL PART 13
5. INTRODUCTION 14
6. HISTORY (BACKGROUND) OF DVT 15
7. EPIDEMIOLOGY 17
7.1. INCIDENCE 17
7.2. GENDER 17
7.3. AGE GROUP 17
8. PATHOPHYSIOLOGY OF DVT 18
8.1. STASIS OF BLOOD 19
8.2. CHANGES IN BLOOD VESSELS 19
8.3. HYPERCOAGULABILITY 20
9. HEMOSTASIS IN BRIEF 20
9.1. PRIMARY HEMOSTASIS (PLATELET ADHESION AND AGGREGATION) 20
9.2. SECONDARY HEMOSTASIS 21
9.3. FIBRINOLYSIS AND D-DIMER FORMATION 21
10. DIAGNOSIS OF DVT 23
10.1. CLINICAL DIAGNOSIS 23
10.2. CLINICAL ASSESMENT 25
10.3. LABORATORY INVESTIGATIONS(BLOOD ANALYSIS) 26
10.3.1. COMPLETE BLOOD COUNT 26
10.3.2. ADDITIONAL BLOOD TESTS 26
10.3.3. INFLAMMATORY MARKERS 26
10.3.4. D-DIMER AND OTHER FIBRIN DEGRADTION PRODUCTS 26
10.3.5. THROMBOPHILIA SCREENING 27
10.4. IMAGING TECHNIQUES 28
10.4.1. DOPPLER ULTRASOUND 28
10.4.2. CONTRAST VENOGRAPHY 30
10.4.3. OTHER IMAGING TECHNIQUES 31
11. DIAGNOSTIC ALGORITHM IN CLINICAL PRACTICE 32
11.1. LOW PRETEST PROBABLITY 32
11.2. HIGH PRETEST PROBABILITY 33
PERSONAL PART 34
12. AIMS AND OBJECTIVES OF THE STUDY 35
13. MATERIALS AND METHODS 35
14. RESULTS AND DISCUSSION 36
14.1. EPIDEMIOLOGICAL AND DESCRIPTIVE PARAMETERS 36
14.1.1. Gender 36
14.1.2. Age 37
14.1.3. Profession 38
14.1.4. Orthostatism 38
14.1.5. Settlement 39
14.1.6. Drug History 40
14.1.7. Pregnancy 40
14.1.8. Smoking 41
14.1.9. BMI 42
14.1.10. Days Of Hospitalization 43
14.1.11. Echocardiographic Findings 43
14.1.12. Doppler Ultrasound Findings 45
14.1.13. Blood analysis 53
14.1.14. Wells score 61
14.2. CORRELATIVE PARAMETERS 62
15. DISCUSSIONS 80
16. LIMITATIONS OF THE STUDY 84
17. CONCLUSIONS 85
18. BIBLIOGRAPHY 86
TABLE OF TABLES
Table 1: Wells score,a pretest probablity for DVT. 25
Table 2: Various Causes of Increased DD assay 27
Table 3: A table representing the statistical data regarding RDW-SD 55
Table 4: A table representing statistical data regarding NT-PRO BNP 57
Table 5: A Table representing the statistical data for CRP 58
Table 6: A table representing the statistical data regarding ESR 59
Table 7: A table representing the statistical data for Fibrinogen 60
Table 8: A statistical table representing the Male gender and the frequency of variable locations 64
Table 9: A table representing the statistical data for Female gender and the frequency of variable locations involved 65
Table 10: A table representing the statistical data regarding the limb involvement in Male gender 66
Table 11: A table representing the statistical data regarding the limb involvement in Female gender 67
Table 12: A table representing the correlational statistical data regarding the presence of thrombus and the wells score 74
Table 13: A table representing comparative statistics between the Wells score and DD analysis 75
Table 14: Chi square test comparing the nominals. 75
Table 15: A table representing the statistical data for DD and NT-PRO BNP 76
Table 16: A table representing the statistical collected for DD and RDW-SD 77
Table 17: A table representing the correlational Phi and Cramer’s V test performed for the nominals,V value of 0.232 and P value of 0.223 were found be inconclusive 77
Table 18: A table representing general comparative statistical data between ESR and CRP 78
Table 19: A table representing the correlational test of Phi and Cramer’s V test for the nominals.V values ≈1,in our study 0.555 and P values <0.05,in our study 0.008 are significant 78
Table 20: A table representing the general statistical data for CRP and Fibrinogen 79
Table 21: A table representing the correlational test of Phi and Cramer’s V test for the nominals.V values ≈1,in our study 0.756 and P values <0.05,in our study 0.000 are significant 79
TABLE OF FIGURES
Figure 1: The anatomy of the superficial and peripheral veins of the lower limb 14
Figure 2: A diagram illustrating formation of a blood clot in DVT and embolization to the general circulation 14
Figure 3: The illustrated manuscript depicting the first case of venous thrombosis. ClicheÁBiblioteÁque National de France, Paris. 15
Figure 4: Rudolf Virchow(1821-1902) 16
Figure 5: An image depicting the estimated average annual number of hospitalization with a diagnosis of DVT,PE or VTE by age and sex in USA between 2007-2009. 17
Figure 6: Virchows Triad 18
Figure 7:Virchows Triad in a nutshell 19
Figure 8: Primary Homeostasis at site of vessel injury. All rights reserved Casper Asmussen 20
Figure 9: Secondary Homeostasis (Plasma Coagulation).From Casper Asmussen, all rights reserved. 21
Figure 10: Fibrinolysis, From Casper Asmussen with all rights reserved 22
Figure 11: D-dimer formation. Fibrinogen consisting of two D domains separated by a central E domain. Thrombin cleavage of the fibrinopeptides results in the end-to-end association of D domains into a fibrin clot. During fibrinolysis, plasmin cleaves the cross linked fibrin into fibrin degradation products of which the D-Dimer is one of the resulting products. 22
Figure 12: A nurse performing the Homans sign in a suspected case of DVT . 23
Figure 13: A case of Phlegmasia Cerulea Dolens in a 85 year old woman with a newly diagnosed metastatic non-small-cell lung cancer causing a massive left femoropopliteal DVT which was confirmed by doppler ultrasonography. 24
Figure 14:A peculiar case of Phelgmasia Alba Dollens of the Right leg 24
Figure 15: An illustrated normal Doppler ultrasound of the Left Posterior Tibial vein from the radiology department of the second Medical Clinic Sf.Spridon 28
Figure 16: Doppler ultrasound of the CFV illustrating the presence of a thrombus in the second Medical Clinic Sf.Spiridon. 29
Figure 17: A Doppler ultrasound illustrating the presence of thrombus and flux abnormality in a case of complete thrombosis of the Femoral Vein in the second medical clinic Sf.Spridon. 29
Figure 18: A venogram demonstrating extensive DVT of the profound veins. Various filling defects are present throughout the venous system which are interpreted as thrombi. 30
Figure 19: CT Venography illustrating bilateral DVT,arrows indicate the exact location of the thrombus. 31
Figure 20: MRI in a patient with a recurrent popliteal DVT,arrow indicates the presence of Thrombus. 32
Figure 21: Diagnostic algorithm using D-dimer testing and ultrasound imaging in patients with suspected DVT. 33
Figure 22: Pie chart representing the difference in distribution of Gender 36
Figure 23: A pie chart representing the various age groups associated with DVT in our study 37
Figure 24: A pie chart illustrating the distribution of patients according to profession 38
Figure 25: A pie chart illustrating the distribution of patients with orthostatism 39
Figure 26: A pie chart illustrating the distribution of patients according to their settlement. 39
Figure 27: A pie chart representing the distribution of patients according to their medical drug history 40
Figure 28: A pie chart illustrating the distribution of patients according to pregnancy 41
Figure 29: A pie chart illustrating the distribution of 42
Figure 30:A histogram illustrating the distribution of BMI against the frequency of patients 42
Figure 31:A histogram illustrating the distribution of the number of hospitalized days against the frequency 43
Figure 32: A pie chart illustrating the distribution of patients with RA dilatation. 43
Figure 33:A pie chart illustrating the distribution of patients with RVH. 44
Figure 34: A histogram illustrating the grade of Tricupsid Regurgitation against the percent 44
Figure 35: A pie chart illustrating the distribution of the locations involved 45
Figure 36: A pie chart illustrating the precise limb involved in our study 45
Figure 37: A pie chart illustrating the percentage in Brachial vein involvement 46
Figure 38: A pie chart illustrating the percentage in IJV involvement 46
Figure 39: A pie chart illustrating the percentage in Subclavian vein involvement 47
Figure 40: A pie chart illustrating the percentage in Axillary vein involvement 47
Figure 41: A pie chart illustrating the percentage in CFV involvement 48
Figure 42: A pie chart illustrating the 48
Figure 43: A pie chart illustrating the percentage of PFV involvement 49
Figure 44: A pie chart illustrating the percentage of popliteal vein involvement 49
Figure 45: A pie chart illustrating the percentage of Peroneal Vein involvement 50
Figure 46: A pie chart illustrating the involvement of the ATV in percentage 50
Figure 47: A pie chart illustrating the percentage of involvement of PTV 51
Figure 48: A pie chart illustrating the percentage of Thrombus presence in our study 51
Figure 49: A pie chart illustrating the percentage of Collateral Circulation in our study 52
Figure 50: A pie chart illustrating the percentage of flux abnormality in our study 52
Figure 51: A pie chart analyzing the DD levels 53
Figure 52: A pie chart illustrating the analysis of FDP levels 54
Figure 53: A pie chart illustrating the analysis of WBC levels 54
Figure 54: A pie chart illustrating the Hb levels 55
Figure 55: A pie chart illustrating RDW-SD analysis 56
Figure 56: A pie chart illustrating INR analysis 56
Figure 57: A pie chart illustrating the analysis of NT-PRO BNP in blood 57
Figure 58: A pie chart illustrating the analysis for PLT 58
Figure 59: A pie chart illustrating CRP analysis 59
Figure 60: A pie chart illustrating the ESR analysis 60
Figure 61: A pie chart illustrating the analysis for Fibrinogen 61
Figure 62: A graph representing the Wells score against the percentage in our study 61
Figure 63: A graph representing the gender against the mean days of hospitalization 62
Figure 64 A graph representing the age groups against the mean days of hospitalization 62
Figure 65: A graph representing the Wells scores against the mean days of hospitalization 63
Figure 66: A histogram illustrating the mean days of hospitalization against the number of locations involved in our study 63
Figure 67 A graph illustrating the mean days of hospitalization against the orthostatism 64
Figure 68: A pie chart illustrating the percentage of variable locations involved for Male gender 65
Figure 69: A pie chart illustrating the percentage of variable locations involved for Female gender 66
Figure 70: A pie chart illustrating the percentage of precise limb involved in Male 67
Figure 71: A pie chart illustrating the percentage of precise limb involved in Female 68
Figure 72: A pie chart illustrating the age group 18-35 and the frequency of location involved 68
Figure 73: A pie chart illustrating the age group 35-50 and the frequency of locations involved 69
Figure 74:A pie chart illustrating the age group 69
Figure 75: A pie chart illustrating the age group >65 and the frequency of locations involved 70
Figure 76: A graph representing the correlation of Orthostatism and Gender with the percentage 70
Figure 77: A graph illustrating the correlation between age groups and orthostatism against the percentage. 71
Figure 78: A graph illustrating the correlational studies between the gender and the wells score against the frequency 72
Figure 79: A graph illustrating the correlational studies between age groups and wells score against the frequency 73
Figure 80: A bar chart illustrating the correlational studies between wells score and BMI against the frequency 73
Figure 81: A bar graph illustrating the correlational study between the wells score and the presence of thrombus against the frequency 74
Figure 82: A bar chart illustrating the correlational studies between DD and Wells score 75
Figure 83: A bar chart illustrating the correlation between DD and NT-PRO BNP against the frequency 76
Figure 84: A bar chart illustrating the comparative data between DD and RDW-SD 77
Figure 85: A bar chart illustrating the correlational data regarding ESR and CRP 78
Figure 86:A bar chart illustrating the correlational data between CRP and Fibrinogen 79
ABBREVIATIONS
APC-PCI Activated Protein C-Protein C Inhibitor complex
APTT Activated Partial Prothrombin Time
ATV Anterior Tibial Vein
BMI Body Mass Index
CFV Common Femoral Vein
COPD Chronic Obstructive Pulmonary Disease
CRP C-Reactive Protein
CT Computer Tomography
CTV Spiral-Multidetector-Row-CT-Venography
DD D-Dimer
DIC Disseminated Intravascular Coagulation
DVT Deep Vein Thrombosis
ESR Erythrocyte Sedimentation Rate
FDP Fibrin Degradation Products
FEU Fibrinogen Equivalent Units
FIX Factor IX, Factor IX
FVa Factor Va
FVIII Factor VIII
FX Factor X
FX Factor X
FXa Factor Xa, Factor Xa
FXI Factor XI
FXII Factor XII
Gp IIb Glycoprotein IIb
Gp111a Glycoprotein IIIa
GP1b Glycoprotien 1b
Hb Haemoglobin
Hct Haematocrit
HMW High Molecular Weight
IJV Internal Jugular Vein
INR International Normalized Ratio
MRI Magnetic Resonance Imaging
NT-PRO BNP The N-terminal Prohormone Of Brain Natriuretic Peptide
PAI Plasminogen Activator Inhibitor
PE Pulmonary Embolism
PFV Profound Femoral Vein
PLT Platelets
PMN Polymorphonucleated Cells
PT Prothrombin Time
PTV Posterior Tibial Vein
RA Right Atrium
RAD Right Atrial Dilatation
RBC Red Blood Cells
RDW-SD Red Blood Cell Distribution Width-Standard Deviation
RV Right Ventricle
RVH Right Ventricular Hypertophy
TAFI Thrombin Activatable Fibrinolysis Inhibitor
TAT Thrombin Antithrombin III Complex
TF Tissue Factor
t-PA Tissue Plasminogen Activator
VTE Venous Thromboembolism
WBC White Blood Cells
VWF Von Willebrand Factor
CHAPTER 1
GENERAL PART
INTRODUCTION
Deep Vein Thrombosis (DVT) is a condition marked by the formation of a thrombus (blood clot) within the lumen of profound veins of the limbs, predominantly favoring the lower limbs. It usually begins in the calf and propagates proximally to the popliteal, femoral and iliac veins. It is 10 times more common in the lower limbs compared to the upper limbs. Individuals experiencing their first DVT are at a high risk of recurrent episodes throughout their lives especially if the cause is idiopathic.
Thromboembolism is the dislodgment of the thrombus (when the portion of clot detaches loose) and travels in the bloodstream. The most serious complication of DVT is PE,the blood clot travels to the heart and then to the lungs thus causing a partial or complete obstruction of the pulmonary artery and its branches.PE is a serious life threatening complication accounting for 15 to 30% of patients diagnosed with lower limb DVT.DVT and PE are grouped together and commonly referred to as VTE (venous thromboembolism).Other potential complications of DVT include post thrombotic syndrome which appears as a late complication after a couple of years, recurrent DVT is very common and very rarely we could even find a paradoxical emboli.
HISTORY (BACKGROUND) OF DVT
The history of DVT goes as far as 2600 years B.C when a Chinese physician named Huan- Ti described how thrombus affects blood circulation. This transformation of liquid blood into solid form has fascinated observers for millions of years (3).According to Dexter &Folch-Pi (1974), the first well documented case of DVT is depicted in an illustrated manuscript written in the 13th century and currently preserved in Paris at the Bibliotheque Nationale(MS Fr 2829, Folio 87) (Fig 3).The description includes the case of a young man from Normandy named Raoul, aged 20 years who developed unilateral edema of the right ankle which extended up to the thigh. The left leg was in a good functional state. From the description it is clear that the young man developed a septic leg with ulceration and fistulation. At that time the great and popular surgeon Henri Du Perche advised him to wait and see. This conservative attitude during that time when surgery was the main approach to illness is now of common knowledge that in the treatment of DVT there is no room for surgical intervention.Raouls condition yet deteriorated further with exposure of bone from fistula and ulcers and development of gangrene.Raoul was advised to visit the tomb of Saint Louis, who was buried in the church of Saint Denis, where he spent several days confessing his sins and praying to the saint. Moreover he chose to collect the dust accumulating below the stone that covered the tomb and apply it to the fistulae and ulcers of his foot. The openings stopped running and were rejuvenated. He was first obliged to use crutches, but subsequently he could walk with a cane and was eventually able to dispose of all devices, even though his foot throbbed a little. Raoul was cured as described above in the year 1271 and was still alive and well in 1282. With our current knowledge, it is not certain that this was a bona fide case of venous thrombosis. Septic complications are not common features of this condition but, at that time, infections were much more prevalent than now. It is clear that, without its religious implications, this case would not have been reported in the manuscripts
The mordern understanding of pathophysiology of DVT is usually attributed to Rudolf Virchow in the mid 19th century who invented the Virchows Triad in an aid to understand the pathophysiology of venous thrombosis, the triad includes the vessel wall,blood flow and the constituion of the blood itself.Virchows triad remains a useful concept for clinicians and pathologists in understanding the contributors of thrombosis
Figure 4: Rudolf Virchow(1821-1902)
EPIDEMIOLOGY
INCIDENCE
Venous thromboembolism is a known major public health problem. An annual incidence of about 1 to 2 per 100 adults was established in the U.S.A.The precise number of individuals affected is unknown, although as many as 300,000 to 600,000 people could be affected annually in the U.S.A causing a high morbidity and mortality rate among the general population. It is estimated up to 60,000 to 100,000 deaths due to venous thromboembolism.
About 10 to 30% of the population dies within one month of diagnosis while sudden death is the first symptom in about 25% of patients who have a PE.The recurrence rate in 10 years is assumed to be in one third of the patients who have been previously diagnosed with a venous thromboembolism. Furthermore half of the patients with a previous DVT are known to experience long term complications. About two-thirds of patients manifest with DVT while one third manifest with PE with or without DVT.
GENDER
The rates are estimated to be slightly higher in males compared to females, the causes not well understood yet.
AGE GROUP
DVT is a disease of aging, with a low rate of around 1 per 10,000 annually before the age of 40 years and rising rapidly after the age of 45 years to an incidence of 5-6 per 10,000 till the age of 80.The morbidity impact of DVT on elderly seems to be more thus a higher mortality due to DVT is seen. Children and young adults rarely suffer from DVT.
Figure 5: An image depicting the estimated average annual number of hospitalization with a diagnosis of DVT,PE or VTE by age and sex in USA between 2007-2009.
PATHOPHYSIOLOGY OF DVT
In text three different types of veins have been described frequently. Superficial veins are made of the thick walled muscular layer and lie just beneath the skin as per their name, profound or deep veins are composed of thin walled muscles media. Both these types of veins have additional valves which permit unidirectional flow of blood to and back to the heart. Thus the valves readily open and close without coming into contact with the lumen of the veins, also allowing closure when the blood flows backwards preventing regurgitation. Furthermore the perforating veins permit one way flow of blood connecting the superficial and deep veins.
Generally the precise pathophysiology is not fully understood yet, however we owe a lot of this understanding to Virchow who postulated certain factors being valuable in the outcome of DVT.He concluded that the stasis of blood (1), the changes in blood vessels (2) and hypercoagulability (3)were the major factors responsible for the development of DVT.This is famously referred to, according to his understanding, as the “Virchow’s Triad”
Figure 6: Virchows Triad
STASIS OF BLOOD
This includes any phenomena that would interrupt the flow of blood. This happens when there is low blood volume and flow . Some of the many examples implicated here are venous stasis, long surgical operations, prolonged immobility e.g. on a long plane or car ride, bed ridden during hospitalization and varicose veins, effects of some medical therapy, severe conditions like shock or cardiac failure.
CHANGES IN BLOOD VESSELS
This phenomenon causes the irritation of the blood vessel and its vicinity. This is caused by any injuries or trauma to the endothelium arising from sheer stress or high blood pressure. Changes in the vessel wall may occur as a result of chemical trauma as in intravenous injections of a drug or due to mechanical trauma. The resulting endothelial cell damage predisposes to thrombosis. Post-operative venous thrombosis of the lower limbs may be a consequence of such mechanical trauma. During anesthesia, there is a loss of normal muscle tone and the weight of the limb in combination with a hard operating table may be sufficient to cause trauma to the venous endothelium. Thus, surgery itself appears to be a very potent stimulus for venous thrombosis.
Figure 7:Virchows Triad in a nutshell
HYPERCOAGULABILITY
This refers to the phenomena of blood coagulation. This includes any alterations in the composition of blood constituents. There are numerous implications listed in this phenomena, some of them include hyperviscosity,platelet aggregation, thrombophilia disorders (e.g.Antithrombin 3, Protein S, C deficiency) and plasma lipid profile may contribute to thrombosis. There is a strong co-relation between cigarette smoking and its effect on platelet function as it may have an effect on adhesion of platelets to the underlying vessel wall.
HEMOSTASIS IN BRIEF
This system contributes to essential body defense mechanism. It impedes both the loss of blood and the disturbance of the flow of blood, as well as providing repair of injured vessels and tissues consequently. The meaning of perfect homeostasis is no bleeding and no thrombosis. Three main stages of homeostasis have been described as follows:-
PRIMARY HEMOSTASIS (PLATELET ADHESION AND AGGREGATION)
Interaction between the damaged vascular wall, platelets and adhesive proteins leads to formation of a platelet plug. After vessel injury occurs, local vasoconstriction slows blood flow permitting platelets to adhere to the vessel wall.Thrombogenic components are exposed and clinging of platelets occurs through platelet receptors (GP1b) to the exposed collagen and to collagen bound (VWF).Thus the platelets change morphologically causing secretion of active substances.
Nearby thrombocytes are recruited, activated and aggregate by fibrinogen cross linking through binding between newly expressed fibrinogen receptors (Gp11b/Gp111a).Vessel injury also leads to activation of the coagulation cascade which subsequently follows.
Figure 8: Primary Homeostasis at site of vessel injury. All rights reserved Casper Asmussen
SECONDARY HEMOSTASIS
Traditionally, two separate pathways have been described, which are the extrinsic and the intrinsic pathway. These pathways meet at the level of factor X and the steps following after which result in the formation of thrombin, are common in both the pathways. Deficiencies in any of the coagulation active proteins in the pathways would delay the time of coagulation assay in vitro(PT for the extrinsic pathway and APTT for the intrinsic pathway respectively). It is moreover appreciated that coagulation occurs via a network of simultaneous interactions with regulation and modulation of these interactions during the generation of thrombin itself.
The physiological activation of coagulation however is mediated by TF. Circulating small levels of FVIIa bind to TF forming a complex which activates FX and FIX.FXa then binds to FVa forming a thrombin activating complex. The intrinsic factor way is initiated by contact factors FXII, HMWkinogen and prekallikrein which then activates FXI, FXI activates FIX which together with its cofactor (FVIII) can activate FX.Ultimately FXa acts on prothrombin to form thrombin
Figure 9: Secondary Homeostasis (Plasma Coagulation).From Casper Asmussen, all rights reserved.
FIBRINOLYSIS AND D-DIMER FORMATION
The main purpose of coagulation process is the formation of a stable fibrin plug or a thrombus which is regarded as a meshwork of fibers that seals a vascular injury. Thrombin is adequately generated and is able to cleave fibrinogen. Fibrinogen is converted into fibrin by enzymatic cleavage by thrombin. Tissue plasminogen activator (t-PA) converts plasminogen to plasmin which breaks down cross-linked fibrin to several fibrin degradation products, the smallest of which is D-dimer.Thrombin activatable fibrinolysis inhibitor (TAFI)prevents the formation of plasmin.Anti-plasmin and plasminogen activator inhibitor-1(PAI-1) inhibit plasmin and t-PA respectively.
Figure 10: Fibrinolysis, From Casper Asmussen with all rights reserved
Traces of products containing DD are detected in plasma of health individuals since 2-3% of fibrinogen is converted to cross linked fibrin and then degraded physiologically.
Figure 11: D-dimer formation. Fibrinogen consisting of two D domains separated by a central E domain. Thrombin cleavage of the fibrinopeptides results in the end-to-end association of D domains into a fibrin clot. During fibrinolysis, plasmin cleaves the cross linked fibrin into fibrin degradation products of which the D-Dimer is one of the resulting products.
DIAGNOSIS OF DVT
CLINICAL DIAGNOSIS
The clinical presentation of DVT includes swelling and tenderness of the affected limb,pain,warmth and redness or disclouration of the skin which are clasically represented as the signs of inflammation.Low grade fever can also be appreciated in some cases.Patients can also exhibit complications like superficial thrombophlebitis on presentation to the clinic,a palpable cordlike,tender vein is the most common finding. Alternatively DVT can be associated without any symptoms.Individual symptoms are neither sensitive nor specific for postive diagnosis.A full physical examination isnt known to be of any particular benefit in diagnosising DVT itself.
Homan sign is usually known to be positive in DVT,this test is performed by dorsiflexion of the affected limb elicits pain in the posterior calf.The mechanism ought to cause the pain is due to the exertion of traction of the posterior tibial vein. Nevertheless,it should be noted that this test is of little diagnostic value as other conditions have also been associated with a positive homans signs,examples include herniated intervertebral discs,calf muscle spasm,neurogenic leg pain,ruptured Bakers cyst and cellulitis among many other causes..Other signs including Pratts sign,Bancrofts sign and Lowenbergs sign have been found positive in patients with DVT but they are neither specific nor sensitive for diagnosis.
Figure 12: A nurse performing the Homans sign in a suspected case of DVT .
Rare presentations include phlegmasia cerulea dollens in which the patients present with extensive swollen and cyanotic leg due to massive iliofemoral thrombosis which could lead to a venous gangrene.
Figure 13: A case of Phlegmasia Cerulea Dolens in a 85 year old woman with a newly diagnosed metastatic non-small-cell lung cancer causing a massive left femoropopliteal DVT which was confirmed by doppler ultrasonography.
Phelgmasia alba dollens manifests as white colouration of the leg due to arterialspasm secondary to massive iliofemoral thrombosis,which is often mistaken for arterial occlusion.
Figure 14:A peculiar case of Phelgmasia Alba Dollens of the Right leg
The medical history of the patient is equally essential in current diagnosis of DVT.Certain conditions are known to be associated with DVT.These are reffered to as risk factors and include certain immunosurpresive medications,pregnancy,active cancer,recent history of a major surgical intervantion,oral contraceptive use,systemic infections smoking,thrombophilia and certain working conditions causing orthostatism among many others.
CLINICAL ASSESMENT
Based on the physical examination and medical history,the pretest possibility is the first step when DVT is suspected.Patients are classified into three different categories,namely low,intermediate and high by the evaluation of the final score.The frequently used score is the Modified Wells score.It includes the following parameters and each finding is awarded a point if present.The low category of patients have a score of 0,the moderate have a score of 1 or 2 and the high have a score of >3.The Wells score and its parameters are elaborated in the table below.
Table 1: Wells score,a pretest probablity for DVT.
The algorithm for the evaluation of suspected DVT will be disscussed further on the disertation after evaluating all the probable options for diagnosis in depth with the aid of the pretest probability using the Wells score just disscused above.
LABORATORY INVESTIGATIONS(BLOOD ANALYSIS)
COMPLETE BLOOD COUNT
A complete blood count includes various tests which are performed on daily basis such as RBC,WBC, thrombocyte count,Hb,Hct,RDW-SD and many more.Various studies have shown the relation of RDW-SD to DVT pathogenesis.
ADDITIONAL BLOOD TESTS
This category includes INR,NT-PRO BNP,coagulation profile markers such are PT,APTT and so on.Studies have elaboarted the association of NT-PRO BNP in DVT diagnosis
INFLAMMATORY MARKERS
Markers such as ESR,CRP and fibrinogen are of known value in DVT pathology.Previous studies have a shown a strong correlation between the process of thrombus formation and inflammation.
D-DIMER AND OTHER FIBRIN DEGRADTION PRODUCTS
As discussed in the earlier chapter,D-dimer is one of the easiest product of fibrinolysis to detect in blood.Monoclonal antibodies against the DD epitope are generated by immunization with purified DD which enables measurement of DD level in plasma or whole blood.The numeric results of DD assays are reported as either in DD concentration or FEU(fibrinogen equivalent units) i.e 2FEU=1 DD.
The available immunological techniques for DD detection in laboratory include ELISA,latex agglutination assays and whole blood agglutination assays.
DD has a high sensitivity but a very low specificity.DD is not a definete analyte but rather a group of cross linked FDP. The concentration could be increased in other pathologic or non pathologic conditions apart from DVT such as DIC, infections or inflammations, cancers, pregnancy, old aged individuals and trauma .False negative DD assays can be encountered in cases of small blood clots in calf veins, if the clot has matured over time and if the patient has a defective fibrinolytic process.
Other FDPs such asThrombin-Antithrombin III complex(TAT) and APC-PCI complex could be measured in the diagnosis of DVT.They are subjects of high interest among various researchers
Table 2: Various Causes of Increased DD assay
THROMBOPHILIA SCREENING
Thrombophilia is defined as a hypercoagulable state in which there is an increased tendency of blood clot formation.They are grouped as gentically acquired or inherited or acquired during the adult life.This screening is preserved for a certain population.Subjects that should undergo these tests include a VTE event under the age of 40,recurrent events of VTE or even late complications like thrombophlebitis,a thrombosis at a peculiar site like the abdomen,relatives with certain protein defiency,familial history of venous thrombosis,certain blood tests results like prolonged APTT.These tests are relatively expensive and should be performed when a high suspicion of relation to DVT.
They include Factor V Leiden, Factor II G20210A, Natural inhibitor deficiency, High factor VIII, factor IX, or factor XI, lupus anticoagulant High thrombin activatable fibrinolysis inhibitor, Hyperhomocysteinaemia, Dysfibrinogenemia or hyperfibrinogenemia, Plasminogen deficiency and many others.
IMAGING TECHNIQUES
DOPPLER ULTRASOUND
A compression doppler ultrasound should be the initial test in patients with an intermediate to a high pretest probability score. It has a high sensitivity up to 96% and a high specificity up to 99% too in symptomatic patients presenting with lower limb DVT.If results come out as negative in intermediate to high pretest probability patients, it is insufficient alone to rule out DVT in such cases.
As all the other techniques it has some limitations as well. It has a low specificity and sensitivity in DVT associated with calf and upper limbs. It does not reliably differentiate between old and new clots formed in the process. The technique is simple, readily available, quick and repeatable, all this adding up to the low cost of the procedure
Figure 15: An illustrated normal Doppler ultrasound of the Left Posterior Tibial vein from the radiology department of the second Medical Clinic Sf.Spridon
The most common findings include incompressibility of the veins which suggests the presence of a thrombus. Care should be taken when compressing the veins as a part of the clot can dislodge and travel resulting in a thromboembolic event.
The thrombus can also be seen as finding on its own, it is usually hypoechogenic and quite challenging to visualize on a B-mode, and as it is ages it becomes even more echogenic. A filling defect can also be seen by the Doppler ultrasound.
Figure 16: Doppler ultrasound of the CFV illustrating the presence of a thrombus in the second Medical Clinic Sf.Spiridon.
Flux abnormality is another finding associated with the Doppler ultrasound and the last but not the least, collateral circulation is also appreciated by this technique.
Figure 17: A Doppler ultrasound illustrating the presence of thrombus and flux abnormality in a case of complete thrombosis of the Femoral Vein in the second medical clinic Sf.Spridon.
CONTRAST VENOGRAPHY
It has been long regarded as the GOLD STANDARD in diagnosis of DVT. However it is not recommended in the initial evaluation, it is indicated in situations where it is impossible to realize rapidly a Doppler ultrasound and in cases with insufficient Doppler ultrasound diagnosis. It is required in only 10% of cases. As specific and sensitive it may be, it has its own limitations. It requires a skilled performer and a cooperative patient, large volumes of contrast substances are introduced. The procedure itself has some associated adverse effects; they include pain, skin reaction and thrombophlebitis. Severe adverse effects result into skin necrosis due to an allergic reaction, impaired renal function and post injection DVT may also develop. It is therefore contraindicated in patients with renal injury and severe reactions to contrast agents.
The four common findings described by Rabinov and Paulin include constant filling defects, abrupt termination of the dye column, non-filling of the entire deep venous system and diversion of flow .
Figure 18: A venogram demonstrating extensive DVT of the profound veins. Various filling defects are present throughout the venous system which are interpreted as thrombi.
OTHER IMAGING TECHNIQUES
CT
Computerized Tomography is an uncommon investigation used in the detection of a thrombus. It has a specificity and sensitivity of 96% and 95% respectively.The finding commonly appreciated is an intraluminal filling defect due to the presence of a thrombus.CTV(spiral multidetector-row CT venography) is useful for differentiating DVT and other causes of leg swelling in patients with equivocal or insufficient Doppler findings and furthermore for obtaining additional information in patients with known DVT before endovascular treatment. The procedure itself is cumbersome, exposes patients to high radiation doses, costly and time consuming. Keeping this into mind, most hospitals have prohibited usage of this para-clinical tool in the evaluation of DVT alone. Other frequent limitations could be renal failure due to the high dose usage of contrast substance; some patients might present an allergy to the contrast agent.
Figure 19: CT Venography illustrating bilateral DVT,arrows indicate the exact location of the thrombus.
MRI
It has a sensitivity and specificity of 96% and 93% respectively. It can be performed without the injection of a contrast medium. It helps us visualize pelvic veins and defines the upper limit of the extension of the thrombus into the VCI and iliac veins. However as other para-clinical tools, it has its own challenges as well. These include limited availability to all hospital centers and required technical expertise
Figure 20: MRI in a patient with a recurrent popliteal DVT,arrow indicates the presence of Thrombus.
DIAGNOSTIC ALGORITHM IN CLINICAL PRACTICE
Patients with signs and symptoms of a suspected DVT should be further assesed by a clinical pretest score(Wells Score) which was described in the earlier part of my thesis.Patients are grouped into low probablity if their Wells score is less than or equal to 2 and high probablility if its more than or equal to 3.
LOW PRETEST PROBABLITY
Patients in this group have low possibilty of a DVT,in this case a D-Dimer assay should be performed.A normal value of D-dimer assay effecitevely rules out DVT without the need of any other imaging techniques.If D-dimer values are raised then a compression doppler ultrasound is mandatory to perform.
HIGH PRETEST PROBABILITY
Patients in this criteria have an added probability of DVT presence.A compression doppler ultrasound is followed up in this case.DVT is confirmed in case of presence of documented ultrasound findings.However an unsatisfactory ultraound test doesn’t rule out DVT and further D-Dimer assay should be performed. If the D-dimer is elevated, imaging should be repeated within 1 week (or earlier if symptoms are worsening) as an isolated distal DVT could be missed initially on ultrasound might extend into the proximal veins and could possibly be detected on the second time.
In patients with unexplained swelling of the whole leg without satisfactory ultrasound findings,the possibility of pelvic vein thrombosis should be considered, in this case CT, MRI or venography may be indicated.
Figure 21: Diagnostic algorithm using D-dimer testing and ultrasound imaging in patients with suspected DVT.
CHAPTER 2
PERSONAL PART
AIMS AND OBJECTIVES OF THE STUDY
We intend to study exisisting cases of DVT associated patients in our clinic.The primary objectives of the study include the following:-
To assess the demographic characteristics of the patients with DVT hospitalized in the Internal Medicine Clinic.
To observe the frequency of variable locations of DVT.
To detect the risk factors for DVT in our hospital-based practice
To determine the reliability of the Wells score as a clinical tool to assess the risk of DVT.
To evaluate the diagnostic accuracy of the D-dimer assay for DVT diagnosis.
To study the correlation of the inflammatory markers in the pathogenesis of DVT
MATERIALS AND METHODS
This review was based on a retrospective observational study that included 62 patients diagnosed with DVT from January 2015 to June 2016. This information was obtained from the hospital archives. The cases were selected on basis of the patient’s diagnosis on discharge via thorough analysis of the patient’s medical files available at the Internal Medicine Clinic. The data was abstracted from the medical records. Data included patients demographics (age, gender, occupation and residence), social history (smoking, drugs history), past medical history (active cancer or undergoing any chemotherapy, any recent surgical history, previous DVT), Doppler ultrasound findings, Echocardiographic findings and results from hematological samples. When any information was not available, it was classified as not available or missing.
The data were analyzed using SPSS for windows 19.0.For nominal variables, the Chi-Square test and Phi and Cramer’s V test were used for comparing variables for significant differences and the contingency coefficient was used as a measure of association. For numeric variables, means were compared using one-way ANOVA, followed by Bonferroni post hoc test. Differences were considered statistically significant for p values under 0.05.
RESULTS AND DISCUSSION
All the statistical data collected was represented using graphical methods including tables, pies and charts.The significant statistical data were further evaluated in the discussion part.
EPIDEMIOLOGICAL AND DESCRIPTIVE PARAMETERS
Gender
Male gender is known to be more prone to DVT.Certain clinical criteria for DVT pre-test probability also include male gender as one of the variables that has an increased risk of developing DVT.The obvious reasons for this issue of the gender effect on the history of VTE is not well known and still needs various explanations from studies .Women are prone to DVT during their child bearing age, however after the age of 50 men are more commonly affected. Contrary to this, in our study of 62 patients, male gender constituted of 29 patients while female gender constituted of 33 patients. This represented 46.8% and 53.2% respectively for male and female gender as per the pie chart illustrated below.
Age
Advanced age is a known risk factor in the prognosis of DVT. Administrative databases such as Medicare includes large number of patients but limited information and validation, thus much remains to be learned about the epidemiology of VTE in the elderly. In our study the patients were categorized into various age groups. This included 18 to 35 years represented by 2 patients corresponding to 3.2%, 35 to 50 years represented by 9 patients and 14.5%,50 to 75 years included 18 patients and 29% and finally>65 years represented by the highest 33 patients and a 53.2%.This data is represented in the pie chart below. Various explanations have been given as per why elderly are more prone to DVT by previous studies. A study in Netherlands suggested that various co morbidities which are associated with old age increase the risk of thrombosis.CHF was found to increase the VTE risk by 2.5 to 3.5 fold while COPD was found to increase the risk 1.2 to 1.3 times. The same study suggested that age related risk factors like muscle strength also contributed to the occurrence of DVT.The exact mechanisms were not very clear but diminished function or efficacy of the calf muscle pump could lead to reflux and stasis of blood. This would subsequently lead to thrombosis. The pie chart below represents the statistical data.
Profession
In our study patients were grouped into the following categories, working class had a total of 19 patients and a 30.6%, retired included 41 patients and the highest percentage of 66.1% and only 2 patients were unemployed representing a mere 3.2%. The explanation to this could be the fact elderly who are retired are mostly at home and therefore having a sedentary lifestyle. This short term immobility could cause stasis of blood and thus resulting in the thrombosis. Certain studies have even shown that certain occupations that require prolonged sitting in cramped positions and kneeling are also at a high risk of developing DVT..The data discussed above is presented statistically below.
Orthostatism
Orthostatism is a known risk factor in the pathogenesis of DVT.Standing or seated immobility causes short term immobility which increases the risk of thrombus formation by slowing down the blood circulation, increasing its likelihood to pool. This stasis of blood also leads to hypercoagulability and inflammation. This descriptive parameter was based on whether the patient had long hours of immobility due to certain working requirements or not.
Patients were grouped into a simple yes or no criterion, these included 19 patients corresponding to 30.6% and 43 patients corresponding to 69.4% respectively. The statistical representation is illustrated below.
Figure 25: A pie chart illustrating the distribution of patients with orthostatism
Settlement
Patients were grouped into either Rural or Urban. The urban group included 29 patients represented by a 46.8% while the rural included 33 patients and a 53.2%.This is summed up in the table and pie chart below. Patients from the rural area were more prone to DVT contributing to the fact that they had comparative limited access to medical facilities.
Fig: A pie chart representing the settlement of patients in our Study
Drug History
Certain drugs are associated with a high causal risk for DVT. Oral contraceptive pills contain hormones like progesterone and estrogen which increase the risk of thrombus formation by 2 to 8 fold. These oral contraceptive pills contain desogestrel which is known to have a higher activated protein C resistance and higher levels of sex hormone binding globulin than those containing gestodene which indicate a higher thrombosis risk..Immunosuppressive drugs also contain hormones which causes increased risk for thrombosis. This parameter had three groups of variables, firstly with a positive drug history which was reported in 11 patients which is represented by 17.7%,secondly a negative drug history which includes 50 cases and a 80.6% and thirdly one patient had such details missing, represented by a mere 1.6%.This is represented statistically below.
Pregnancy
Normal pregnancy induces pro-coagulant changes causing an increased risk of a thrombotic event. Studies show that the risk for VTE increases 5 to 10 fold compared to non-pregnant women. The postpartum period posses an even higher risk which is reported to be 15 to 35 times more than the non-pregnant woman at the same age.
Female patients with current pregnancy included three (3) patients representing 4.8% while the non-pregnant patients represented 59 (95.2%).This is represented below. Our results didn’t have any statistical significance.
Smoking
Smoking is a well known independent risk factor for pathogenesis of DVT.It increases the risk of DVT by multiple mechanisms,it increases the levels of fibrinogen and certain clotting factors.This in turn increases platelet activation and aggregation.Smoking is also implicated in alteration of fibrinolysis mechanism,ensuring the increasing tendency of clot formation.The risk of DVT is increased several folds when smoking and increased levels of BMI are correlated
A meta analysis in China supported that the association of VTE and smoking is mediated by an acute mechanism supported by a dose reponse relationship for the amount of current smoking and the higher risk in current compared to past smokers.Smoking is known to be associated with a higher fibrinogen level. It has been shown that the fibrinogen concentration decreased rapidly after cessation of smoking and the fibrinogen concentration was nearly equal in past smokers and non-smokers.
According to our studies, some patients were found to be current smokers while some had previously been smokers.Our results didn’t have any conclusive statistical significance.In this criteria, patients with a positive smoking response included 17, with a 27.4%.Patients who denied included 43, with a 63.4%.Data was found missing in 2 patients, that represents 3.2%.This is represented in the pie chart below.
BMI
The total number of patients who had available BMI values included 37. The least value noted was 18.42 and the highest was 42.The mean value of BMI was 29.73.The frequency and the precise values of BMI are appreciated in the histogram below.
Days Of Hospitalization
A total number of 62 patients were included in this criterion. The least days of hospitalization included 2 and the highest was 18.
The mean number was approximately 7 days. The histogram below illustrates the precise frequency and the number of days hospitalized for all the patients.
Figure 31:A histogram illustrating the distribution of the number of hospitalized days against the frequency
Echocardiographic Findings
For Right Atrial dilatation (RAD) a total of 35 patients had available ultrasound results.13 patients had normal dimensions, representing 37.1% while 22 patients had an increased size of RA that evaluated for a 62.9%.35 patients had invalid ultrasound findings which were disregarded in the representation below.
.
For Right Ventricular hypertrophy (RVH) a total of 34 patients had available results. This included 23 patients with a normal RV size, contributing to a valid 67.7% while 11 patients had increased RV dimensions, a valid 32.35%.However 28 patients had unavailable ultrasound results. They were however disregarded in the pie chart below.
For tricuspid regurgitation, valid 69.7% had no(0) regurgitation reported.27.27% had grade 1 regurgitation present while only a mere 3.03% had grade 2 regurgitation reported. This is represented graphically below.
Doppler Ultrasound Findings
A criterion was established to find out whether one location, two locations or multiple locations were involved in DVT.55 patients in general had the data readily available.19 patients were reported having one location involved, presenting 34.5%, 18 patients had two locations involved with a 32.7% and lastly 18 patients had multiple locations involved resulting in the remainder 32.7%. This is represented efficiently in the pie chart below.
A criterion was established to appreciate the precise limb involved. A total of 55 patients had appreciable findings. They were further categorized as follows, 27 patients had left leg involvement, a 49.1%,24 patients had right leg involved equaling a 43.6% while only 2 patients had both legs involved equally representing a mere 3.64%, 2 patients had the left arm involved represented by 3.64% .The remaining number of 7 patients were invalid and thus weren’t represented in the pie chart below.
Individual deep veins of the upper and lower limb were then studied and the results represented in tables and pie charts.
Firstly, data concerning the internal jugular vein involvement was reviewed.55 patients had valuable ultrasound findings. Out of these only one patient had IJV as the location for thrombosis; this represented a mere valid 1.8% while the other 54 patients had no IJV involvement, accounting for a valid 98.2%.The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
Data regarding the involvement of the brachial vein was collected. A total of 55 patients had the ultrasound performed. Out of these only two patients had brachial vein involvement as the location for thrombosis, this represented a mere 3.6% valid while the other 53 patients had no brachial vein involvement, accounting for a valid 96.4% The invalid cases were 7 resulting in the remaining total 11.3%,which were eventually excluded from the pie chart presentation below.
The involvement of Subclavian vein was then studied. A total of 55 patients had the ultrasound performed. Out of these only one patient had involvement present, accounting for a mere 1.8% valid while the other 55 patients had no brachial vein involvement, accounting for a valid 98.2% The invalid cases were 7 resulting in the remaining total 11.3%,which were eventually excluded from the pie chart presentation below.
The last profound vein of the upper limb, the axillary vein was then evaluated. A total of 55 patients had the ultrasound performed. Out of these only two patients had axillary vein involvement as the location for thrombosis, this represented a mere 3.6% valid while the other 53 patients had no involvement, accounting for a valid 96.4% The invalid cases were 7 resulting in the remaining total 11.3%,which were eventually excluded from the pie chart presentation below.
Regarding the deep veins of the lower limbs, starting with the common femoral vein 55 patients had the ultrasound performed. Out of these 19 patients had this vein involvement as the location for thrombosis, which represented a valid 34.5% while the other 36 patients had no CFV involvement, accounting for a valid 65.5%.The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
Secondly the femoral vein or also referred to as the superficial femoral vein was then statistically reviewed. A total of 55 patients had ultrasound performed. Out of these, 17 patients had this vein involvement as the location for thrombosis, which represented a valid 30.9% while the other 38 patients had no involvement, accounting for a valid 69.1%.The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
Thirdly the profound femoral vein was reviewed statistically. A total of 55 patients had the ultrasound performed. Out of these 8 patients had this vein involvement as the location for thrombosis, which represented a valid 14.5% while the other 47 patients had no involvement, accounting for a valid 85.5%.The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
Fourthly, the popliteal vein was reviewed statistically. A total of 55 patients underwent an ultrasound. Out of these 31 patients had the vein involved as the location for thrombosis, which represented a valid 50.0% while the other 14 patients had no involvement, accounting for a valid 38.7 %.The invalid cases were 7 resulting in the remaining total 11.3%, which were included in the pie chart presentation below.
For the peroneal vein, a total of 55 patients had the ultrasound performed. Out of these only one patient had involvement present, accounting for a mere 1.8% valid while the other 55 patients had no peroneal vein involvement, accounting for a valid 98.2%. The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
For the anterior tibial vein, a total of 55 patients had the ultrasound performed. Out of these only two patients had anterior tibial vein involvement as the location for thrombosis; this represented a mere valid 3.6% while the other 53 patients had no involvement, accounting for a valid 96.4%. The invalid cases were 7 resulting in the remaining total 11.3%, which were eventually excluded from the pie chart presentation below.
Finally, the posterior tibial vein was statistically reviewed. A total of 56 patients had the ultrasound performed. Out of these 11 patients had posterior tibial vein involvement as the location for thrombosis, this represented a valid 19.6% while the other 45 patients had no involvement, accounting for a valid 80.4%. The invalid cases were 6 resulting in the remaining 9.7% which were eventually excluded from the pie chart presentation below.
The documented ultrasound findings were then statistically presented individually.
Firstly the presence of thrombus was reviewed. A total of 57 patients had the ultrasound performed. Out of these 52 patients had the presence of thrombus reported, this represented a valid 91.2% while the other 5 patients had the thrombus absent, accounting for a valid 8.8%. The invalid cases were 5 resulting in the remaining total 8.1% which were eventually excluded from the pie chart presentation below.
Secondly the presence of collateral circulation was statistically reviewed. A total of 57 patients had the ultrasound performed. Out of these 30 patients had the presence of collateral circulation reported, this represented a valid 52.6% while the other 11 patients were reported with absent, accounting for a valid 19.3%.16 patients had this parameter missing in their ultrasound findings, accounting for a valid 28.1%. The invalid cases were 5 resulting in the remaining total 8.1% which were eventually excluded from the pie chart presentation below.
Lastly, the presence of flux abnormality was observed. A total of 56 patients had the ultrasound performed. Out of these 54 patients had the presence of the abnormality reported, this represented a valid 96.4%% while the other 2 patients were reported with absent flux abnormality, accounting for a valid 3.6%.The invalid cases were 6 resulting in the remaining total 9.7% which were eventually excluded from the pie chart presentation below, however included in the table below.
Blood analysis
DD is a known end product of fibrin degradation which could be detected in blood using various readily available immunological tests. Various studies have emphasized that it can be either a reliable or an unreliable tool in DVT diagnosis. In our study 60 patients had the assay performed, out of these 56 patients had an increased value of DD, this represented a valid 93.3% while the other 4 patients were reported with a normal value of DD, accounting for a valid 6.7%.The invalid cases were 2 resulting in the remaining total 3.2% which were eventually excluded from the pie chart presentation below.
FDP is a well known biomarker for diagnosis of DVT.Studies have shown that these clot degradation products have a role in ruling out thromboembolic events.In a study patients with DVT had significantly elevated levels of FDP compared to control subjects. The technique of evaluating FDP was however into question, thus needing more studies to improve the techniques of FDP detection. Contrary to this, in our study we failed to find any significant results corresponding to previous studies.
Our study assessed 46 patients in general, out of these 15 patients had FDP present, this represented a valid 32.6% while the other 31 patients reported with an absent FDP, accounting for a valid 67.4%.The invalid cases were 16 resulting in the remaining total 25.8% which were eventually excluded from the pie chart presentation below.
.
Various studies have showed that leukocytes, especially PMN have a role in the formation of the early thrombus. The exact mechanisms are understood to be complex. In our statistical study; out of 59 patients only 15 had an increased value of WBC count representing a valid 25.4%.44 patients had a normal count of WBC resulting in a valid 74.6%.The invalid cases reported were 3, constituting for the remainder of the total 4.6%.They were excluded in the pie chart below. In the contrary, our study didn’t show any significance related to previous studies.
For Hb levels, out of the total 59 patients 17 had an increased value of Hb count representing a valid 28.8%.7 patients had a normal count of Hb resulting in a valid 11.9%, while 35 patients had a decreased count accounting for valid 59.3% .The invalid cases reported were 3, constituting for the remainder of the total 4.8%.They were excluded in the pie chart below.
Figure 54: A pie chart illustrating the Hb levels
Regarding RDW-SD, out of the total 62 patients, 22 had an increased value representing a valid 38.6%.34 patients had normal values resulting in a valid 59.6%, while 1 patient had a decreased count accounting for a valid 1.8%. The invalid cases reported were 5, constituting for the remainder of the total 8.1%.They were included in the table below.
Table 3: A table representing the statistical data regarding RDW-SD
The pie chart below illustrates the statistical data presented in the table above.The invalid cases are disregarded
Figure 55: A pie chart illustrating RDW-SD analysis
For INR, the following data was analyzed. Out of the total 62 patients 15 had an increased value representing a valid 25.9%.43 patients had normal values resulting in a valid 74.1%.The invalid cases reported were 4, constituting for the remainder of the total 6.5%.They were excluded in the pie chart below.
Out of the total 62 patients for NT-Pro BNP reviewed, 17 had an increased value representing a valid 60.7%.11 patients had normal values resulting in a valid 39.3%.The invalid cases reported were 34, constituting for the remainder of the total 54.8%.They were included in the table.
Table 4: A table representing statistical data regarding NT-PRO BNP
The pie chart below illustrates the statistical data represented in the table above. The invalid patients have been disregarded.
Figure 57: A pie chart illustrating the analysis of NT-PRO BNP in blood
Out of the total 62 patients for PLT (Platelets) reviewed, only one patient had an increased value representing a valid 1.7%.49 patients had normal values resulting in a valid 83.1%.9 patients had a decreased value of PLT, represented by a valid 15.3%.The invalid cases reported were 3, constituting for the remainder of the total 4.8%.They were excluded in the pie chart below.
Out of the total 62 patients for CRP reviewed, 31 patients had an increased value representing a valid 68.9%.14 patients had normal values resulting in a valid 31.1%.The invalid cases reported were 17, constituting for the remainder of the total 27.4 %.They were included in the table below.
Table 5: A Table representing the statistical data for CRP
The pie chart below illustrates the statistical data represented in the table above. The invalid cases are disregarded.
ESR is known to have a role in pathogenesis of DVT.Various studies have supported this notion. Out of the total 62 patients for ESR/1 HR reviewed, 18 patients had an increased value representing a valid 60%.12 patients had normal values resulting in a valid 40%.The invalid cases reported were 32, constituting for the remainder of the total 51.6 %.They were included in the table below.
Table 6: A table representing the statistical data regarding ESR
The pie chart below illustrates the statistical data reperesented in the table above.The invalid cases were disregarded.
Figure 60: A pie chart illustrating the ESR analysis
According to various studies fibrinogen is involved in the pathogenesis of DVT.There are various mechanisms in which its contribution is understood.Out of the total 62 patients for fibrinogen reviewed, 15 patients had an increased value representing a valid 55.6%.12 patients had normal values resulting in a valid 44.4%.The invalid cases reported were 35, constituting for the remainder of the total 56.5 %.They were included in the table. Our study found similar results to the previously described.
Table 7: A table representing the statistical data for Fibrinogen
The pie chart below illustrates the statistical data represented in the table above.The invalid cases have been disregarded.
Figure 61: A pie chart illustrating the analysis for Fibrinogen
Wells score
Wells score is described in various literatures as a good clinical tool to assess the risk for DVT. In the study, a total of 61 patients had the data available.9 patients had a Score of 3 representing a 14.75%, 25 patients had a Score of 4 representing a 40.98%, 19 patients had a Score of 5 representing a 31.15% and finally 8 patients had a Score of 6 equaling to 13.11%.This is represented graphically below.
CORRELATIVE PARAMETERS
For mean days hospitalization and gender,out of the total of 62 patients male gender was found to have a higher number of days of hospitalization compared to female gender.This was represented graphically below.The precise values of mean days of hospitalization for each gender is appreciated from the graph below.
Figure 63: A graph representing the gender against the mean days of hospitalization
For mean days hospitalization and age groups,out of the total 62 patients it was observed that the oldest age group >65 years had the highest days of hospitalization,equalling to approximately 8 days.This is further represented graphically below.The exact values of the mean days of hospitalization for the other age groups are represented in the same graph below.
The mean days of hospitalization and the clinical wells score was then reviewed.Out of the 62 patients.Wells Score of 3 and 5 had the highest mean days of hospitalization,while Score 6 had the lowest mean days of hospitalization.The precise values of the mean days of hospitalization is graphically presented below.
Figure 65: A graph representing the Wells scores against the mean days of hospitalization
For mean days of hospitalization and the number of locations involved,out of the availabale 62 patients it was noted that patients who had multiple locations involved had the highest mean number of days of hospitalization.Patients with just one location involved had the lowest mean days of hospitalization.This is also illustrated graphically below.
For orthostatism and mean number of days hospitalized,out of the 62 patients studied patients with no ortostatism reported had a higher number of mean days hospitalized compared to those who had orthostatism reported.This is represented graphically below
For correlational studies of gender and the number of locations involved,out of the 29 Male patients reviewed,the highest valid 35.7% included the patients who had multiple locations involved.The values of a single location and two locations are included the table below.
Table 8: A statistical table representing the Male gender and the frequency of variable locations
The pie chart below represents the statistical data represented in the table above.The invalid case was also included.
Figure 68: A pie chart illustrating the percentage of variable locations involved for Male gender
For correlational studies of the Female patients out of the total 33 patients,the highest valid 37% involved one location,the precise values for other number of locations involved were mentioned in the table below.
Table 9: A table representing the statistical data for Female gender and the frequency of variable locations involved
The pie chart below illustrates the statistical data represented in the table above.The invalid cases are also included.
Figure 69: A pie chart illustrating the percentage of variable locations involved for Female gender
The precise location for the occurance of DVT was then studied for both genders.For Male out of a total of 29 patients the highest frequency with 15 patients and a valid 53.6% was the Left Leg.The exact frequencies and valid percentage for other limbs involved are summarised in the table below.
Table 10: A table representing the statistical data regarding the limb involvement in Male gender
The pie chart below illustrates the statistical data represented in the table above.The invalid case was included.
Figure 70: A pie chart illustrating the percentage of precise limb involved in Male
For females, out of a total 33 patients,Right Leg was the most location accounting for 14 patients with a valid 51.9%.The exact frequencies and valid percentage for other limbs involved are summarised in the table below. Invalid cases are also presented in the table below.
Table 11: A table representing the statistical data regarding the limb involvement in Female gender
The pie chart below illustrates the statistical data represented in the table above.The invalid patients were included.
Figure 71: A pie chart illustrating the percentage of precise limb involved in Female
The association between age groups and the frequency of location was reviewed.
For age group 18-35,out of the two patients both had multiple locations involved resulting in a 100% validity.
For age group 35-50,with a frequency of 5 patients and a valid 55.6% two locations were most involved.A single location constituted 33.3% and multiple locations presented 11.1%.This data was presented in the pie chart below.
Figure 73: A pie chart illustrating the age group 35-50 and the frequency of locations involved
For age group 50-65,one location and two locations involved had an equal 35.3%.Multiple locations presented with 27.8% while invalid cases constituted of the remaining 5.6%.This data is illustrated in the pie chart below
For the age group >65 one location and multiple locations constituted of 30.3% equally,two locations involved presented a 21.2%.The invalid cases were represented by 18.18%.This is illustrated below.
An association between orthostatism and gender was then established.Out of the total 62 patients for both genders,male patients had a 14.52% positive affirmation to orthostatism while the rest 32.26 %denied to being orthostatic.For female patients 16.13% had a positive response to orthostatism while 37.1% denied such affirmations. This data is represented in the graph below.
For the correlational studies of orthostatism and age groups the following results were obtained.For age group 18-35 they all presented with a postive response to orthostatism,accounting for the total 3.23% of them.Age group 35-50 also had an increased postive response to orthostatism of 11.29% to the negative response which accounted for a valid 3.23%.For age groups 50-65 the positive response was higher compared to the negative response,16.13% and 12.9% respectively.Age group >65 had only a negative response to orthostatism accounting for 53.23%.Generally all the working groups had a higher comparative percent of postive response of orthostatism.This explains why the elder population had a negative response as they are mostly retired.These results were illustrated in the graph below.
For comparative studies of Wells score and gender involvement,the following data was collected.Male patients had a higher frequency than female patients for Score 4 and 6 while female patients had comparative higher frequencies for Score 3 and 5.The precise values of each one of them are illustrated in the bar chart below.
Figure 78: A graph illustrating the correlational studies between the gender and the wells score against the frequency
For comparative studies of age groups and wells score the following data was obtained.For Score 3 the age group with the highest frequency of cases was >65 years subgroup,for Score 4 also the subgroup >65 had the highest number of cases reported.For Score 5 the subgroup with the highest frequency of cases was >65.Subgroup 50-65 had the highest cases reported for Score 6.
The exact frequency for each score and group is represented statstically below.
Figure 79: A graph illustrating the correlational studies between age groups and wells score against the frequency
For correlational studies of BMI and Wells score the following information was obtained.For each Score independently,the frequency of cases with an increased BMI were reported more frequently than cases with a normal or decreased BMI.The precise frequency for the BMI levels and Wells score are illustated below.
For comparative studies of Wells score and presence of the thrombus the following results were obtained. For each Score individually,the frequency of patients with a presence of thrombus were relatively higher compared to the patients with an absence of thrombus.Wells Score 4 had the highest frequency of patients with the presence of thrombus.The precise data regarding each parameter is illustrated below.
Table 12: A table representing the correlational statistical data regarding the presence of thrombus and the wells score
The bar chart below illustrates the statistical data described above.
Figure 81: A bar graph illustrating the correlational study between the wells score and the presence of thrombus against the frequency
For comparative studies of Wells score and the value of DD assay, the following results were attained.For each Score individually,the frequency of patients with an increased DD were relatively higher compared to the patients with a normal DD value.Wells Score 4 had the highest frequency of patients with the increased DD. The precise data regarding each parameter is illustrated below. The chi-square test represented below was used to correlate the nominals.There was no correlation obtained.
Table 13: A table representing comparative statistics between the Wells score and DD analysis
Table 14: Chi square test comparing the nominals.
Figure 82: A bar chart illustrating the correlational studies between DD and Wells score
The association of DD and NT-PRO BNP was reviewed..This is illustrated below,for increased DD levels,61.54% of the patients had also elevated NT-PRO BNP levels while the minority of 38.46% had normal values.The invalid cases were disregarded in the table below.Nothing significant was obtained in correlation to previous studies.
Table 15: A table representing the statistical data for DD and NT-PRO BNP
The bar chart below illustrates the statistical data presented in the table below.The invalid cases were disregarded.
Figure 83: A bar chart illustrating the correlation between DD and NT-PRO BNP against the frequency
Various studies have shown a correlation between DD and RDW-SD in diagnosis of DVT.The exact mechanisms involved are understood to be complex.Comparative studies of DD and RDW-SD was reviewed and presented statistically in various methods as described below.Our study failed to obtain the same results as described previously.The table below represents the statistical data collected .
Table 16: A table representing the statistical collected for DD and RDW-SD
Table 17: A table representing the correlational Phi and Cramer’s V test performed for the nominals,V value of 0.232 and P value of 0.223 were found be inconclusive
The bar chart below illustrates the correlational data between these two blood analysis.
Inflammatory markers are known to influence the pathogenesis of DVT.In our study we tried to correlate the various parameters and we found a strong correlation between ESR to CRP and CRP to Fibrinogen.
CRP and ESR were correlated as per the general statistical data and comparative data represented below.
Table 18: A table representing general comparative statistical data between ESR and CRP
The table below shows the correlative tests performed on these two nominals.
Table 19: A table representing the correlational test of Phi and Cramer’s V test for the nominals.V values ≈1,in our study 0.555 and P values <0.05,in our study 0.008 are significant
The comparative data between CRP and Fibrinogen was then analyzed.There was a strong correlation between these two inflammatory markers.The general statistical and correlative data was presented below.
Table 20: A table representing the general statistical data for CRP and Fibrinogen
The table below shows the correlative tests performed on these two nominals
Table 21: A table representing the correlational test of Phi and Cramer’s V test for the nominals.V values ≈1,in our study 0.756 and P values <0.05,in our study 0.000 are significant
Figure 86:A bar chart illustrating the correlational data between CRP and Fibrinogen
DISCUSSIONS
In this study several significant results and interpretations are analyzed individually and comparatively below.
The gender that was more commonly affected according to the results was Female,which had a slightly higher frequency compared to the Male.DVT is known to have a preference to Male gender according to previous studies performed but this is still debatable and more studies are required to elaborate this..
Patients more than 65 years old were the most affected according to the study.This is further supported by previous studies supporting DVT to be a disease of the elderly.The answer to this could be the process of aging itself,which causes abnormalities in the coagulation cascade and also attributes to the loss of the vein structural intergrity.The elderly are in a constant prothrombotic state.Studies have shown that certain coagulation factors,Fibrinogen and DD are significantly higher in this population either acquired or inherited are a direct link to occurance of thrombosis.Chronic heart failure is a common pathology in elderly patients.This is associated with hypercoagulability and finally this leads to venous stasis which is postulated by Virchow as one of the theory of understanding DVT.
Retired patients were of increased risk of DVT according to our study.This could be explained by the fact that most of them were more than 65 years of age and had a sedentary lifestyle which could have led to the occurance of DVT.Sedentary lifestyle avoidance among many other factors is well known to be a preventive method for DVT.
Past medical drug history is a known factor as an etiology for DVT.These drugs include immunosurpressive and anti -conceptional drugs containing hormones.According to our study only limited patients had a positive drug history which accounted for the insignificance in statistical analysis.
Pregnant women are known to be at a high risk of a thrombotic event.This is explained by the fact that pregnancy is a hypercoagulable state.During pregnancy plasma levels of many clotting factors increase significantly to prevent postpartum hemorrhage.Our study illustrated minimum cases of pregnant women who had DVT,thus the statistical irrelevance.
Smoking is a well known independent risk factor for pathogenesis of DVT.It increases the risk of DVT by multiple mechanisms,including the increase in levels of fibrinogen and certain clotting factors.This in turn increases platelet activation and aggregation.Smoking is also implicated in alteration of fibrinolysis mechanism,this ensures the increase in tendency to clot.The risk of DVT is increased several folds when smoking and increased levels of BMI are correlatedAccording to our studies some patients were found to be current smokers while some had previously been smokers.Our results didn’t have any conclusive statistical significance.
BMI and DVT has a strong correlation.In our studies the mean value of BMI was 29 which was classified as being Overweight.Clinical trials suggest that TF(tissue factor) pathway is upregulated in obesity.Thus obese patients have higher levels of coagulations factors like F8,Thrombin and TAT complexes.This emaphises the point that obesity could also be classified into a hypercoagulable state.Obesity is also related with a higher platelet activation rate thus implicating on an overal increased risk of thrombus formation.
Doppler ultrasound as one of the paraclinical investigation had significant results.Majority of the patients had one specific location involved,furthemore the Left leg was the most frequent location of DVT in our study.Regarding the deep veins of the upper limb,Brachial vein and Axillary vein were the most common locations.For the deep veins of the lower limb,Popliteal vein followed by Common Femoral vein were mostly involved.The documented findings in a doppler ultrasound were significantly present in our study.Thrombus presence,Collateral circulation and Flux abnormality were all present in majority of the patients with an available ultrasound.
Blood tests with significant importance to our study are discussed below.DD is a known marker for DVT diagnosis though various studies have shown its negative predictive factor in DVT diagnosis due to its false positive and false negative comparisions.In our study majority of patients had an increased vale of DD assay and were confirmed later by positive ultrasound findings.FDP is also a marker frequently associated with DVT diagnosis.However in our study minimum patients had presence of FDP,thus of very little statistical significance.WBC count was predicted normal in majority of the patients.Majority of patients had a decreased HB count in our case study.The INR levels of majority of the patients in our study were well regulated.Thrombocytes were also reported to be normal in our case study.
Acute phase reactants including ESR/1HR,CRP and Fibrinogen had expected increased levels in majority of the patients in our study.According to various studies these acute phase reactants have a relation to the pathogenesis of DVT.These inflammatory cytokines influence the expression of TF which is the initiator of the extrinsic pathway of coagulation.This thus enhances a trigger for future thrombotic events.Moreover to the inflammataory role of Fibrinogen,other explanations to the increased level of fibrinogen as an individual factor are considered.In recent studies,Koenig came up with the idea that high levels of fibrinogen may lead to an increase size of thrombus thus forming a compact network dimension.This compact structure impaires fibrinolysis by interfering the binding of plasminogen to its receptor.This hypothesis is highly debatable and more studies are required for a better understanding.
The Modified Wells Score is a frequently used clinical pretest in various clinics.In our study all patients had either an Intermediate Score or a High score,varying from values of 3 to 6.
Male patients had a higher mean days of hospitalization compared to the Female gender.Age group >65 had the highest mean of number of days hospitalized.
According to our study patients with multiple locations involved had the highest mean of number of days hospitalized.The more the number of locations involved the more severe the outcome of DVT which required further reassement in the clinic.
Female patients had a higher reported percentage of orthostatism compared to Male.Various studies have shown that orthostatism is one of the most frequent cause of DVT in Women.Other more frequent causes include anti-contraceptive pills and immobility.
Age group 18-35 all patients were orthostatic,for age group 35-50 the comparative percentage of positive response to orthostatism was higher.Age group 50-65 also had a higher comparative percentage of presence of orthostatism,while age group >65 had all with a negative response.According to our study patients from the three working class groups had a history of orthostatism,while the age group >65 had patients who were mostly retired.Orthostatism and DVT had a well known correlation.Decreased mobility of the feet for long hours under certain working conditions causes stasis of blood as explained by Virchow,which inturn causes a higher risk of blood clots formation.
The comparative studies of Wells Score and BMI suggested that for each score individually majority of patients had an increased BMI.This further emphesises the discussion about obesity being a risk factor for DVT which was explained earlier in the discussion.
Our studies showed us that for each Wells score majority of the patients had a presence of Thrombus.This shows us that our study emphasises on the Wells Criteria as being quite useful in our clinic.Our study emphesises the importance of the Wells score as described by previous studies.
The correlation studies between Wells Score and DD showed us the following.For each Wells score majority of the patients had an increased value of DD.This show us the importance of using both these investigations in diagnosis of DVT cases.Various studies performed by medical residents have shown to support the correlation of DD and Wells score to identify and rule out DVT successfully.
According to our study we obtained no correlation between DD, NT-PRO BNP and RDW.Increased levels of NT-PRO BNP is associated with a hypercoagulable state which means a higher risk of thrombus formation.Further studies are required to establish the correlation of these parameters. Studies show that RBC are a major components of blood clots,they are also active in random cell trapping during cloting.They therefore participate actively in thrombus formation.RBC contribute to blood viscosity by releasing pro-coagulatory factors thereby activating the coagulation cascade.However whether this functions indipendently or with the aid of the inflammatory cytokines is yet to be distinguished.This hypothesis needs more clarification from scholars.
A strong correlation was obtained for several inflammatory markers including ESR,CRP and Fibrinogen from our study.Several previous studies have obtained significant results of great value.This correlation is attributed to the fact that the process of thrombus formation and venous wall damage induces a system inflammatory response thus resulting in the elevated inflammatory markers independently.
LIMITATIONS OF THE STUDY
A retrospective study is known to have a large number of cases for an influential statistical significance.Contrary to this, our study evaluated only 62 patients thus resulting in the insignificance of certain parameters which are of high interest to various scholars.Our study also had essential data regarding blood parameters and paraclinical imaging missing for certain patients.The study was biased on only the inpatients admitted to our clinic.Long term follow up of the patients was disregarded due to lack to adequate time and limited resources.Certan criteria were based on the objective signs and symptomns reported by the patients which could have been false or misinterprated by the doctors in our practice.
CONCLUSIONS
Obesity, orthostatism, age more than 65 are high risk factors in pathogenesis of DVT.
In the majority of the patients more than two locations of the thrombus formation was observed, just one third of the DVT cases involved one location.
DVT was more frequent present in the left leg and veins in the calf or thigh were most commonly affected.
Wells score was confirmed as a reliable clinical tool to assess risk of DVT in our clinic. It is known to have a high sensitivity, high specificity and a high positive predictive value with high accuracy. There is a significant correlation between the Wells score reflected in DVT probablity and Doppler Ultrasound findings.
Doppler ultrasound is a good, available, non invasive and reliable method to confirm DVT in clinical practice.
D-dimer testing were positive in the majority of cases and shoud be used to exclude thromboembolic disease, as recommended by guidelines, especially in patients with low predicted risk of deep vein thrombosis.D-Dimer testing is incorporated into a diagnostic strategy with clinical estimation of pretest probability and ultrasound imaging technique.
We failed to find some correlations between the following laboratory parameters;NT pro BNP, D Dimer and RDW-SD.
In patients with DVT thrombus formations induces a systemic inflammatory reaction which is reflected by increasing level of acute phase reactants, as confirmed in our study too.
Increased level of red blood cell distribution width, a easily measurable laboratory variable, could be considered part of the diagnostic stratergy, a significant association between RDW and DVT is demonstrated by some previous studies but the mechanism of association requires further evaluation from researchers.
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