Chronic thrombotic scarring in patients with acute deep venous thrombosis of the lower limbs

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Original papers

2010, Vol. 12, no. 2, 114-119

Chronic thrombotic scarring in patients with acute deep venous thrombosis of the lower limbs

Sorin Crişan

¹

, Ştefan Vesa

¹

, Cătălin Pestrea

²

, Delia Herghea

³

, Daniela Vornicescu

⁴

, Monica Chirilă

¹

, Iulia Maria Crişan

⁵

1 5^th Medical Clinic, „Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania

2 Department of Cardiology, „Nicolae Stăncioiu” Heart Institute, Cluj-Napoca, Romania

3 Department of Epidemiology, „Prof. Dr. I. Chiricuţă” Oncologic Institute Cluj-Napoca, Romania

4 Dermatology Clinic, „Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania

5 Student, „Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania

Received 23.03.2010 Accepted 6.04.2010 Med Ultrason

2010, Vol. 12, No 2, 114-119

Address for correspondence: Assoc. Prof. Sorin Crişan

5^th Medical Clinic, „Iuliu Haţieganu”

University of Medicine and Pharmacy Cluj-Napoca, Romania

Str.Tăbăcarilor 11, Zip Code 400139 Fax: +40264437572

Phone: +40722550880, +40740234884 Email: [email protected] Abstract

Some patients with acute deep venous thrombosis of the lower limbs may present risk factors for recurrent disease. Aims: To analyze the most important conditions related to recurrent deep venous thrombosis of the lower limbs, other than thrombophilias. Patients and methods: We examined 88 consecutive patients (47 males-53.41%, average age 64.9±13.9 years) admitted to a Medical Clinic in 2007.

Duplex ultrasonography was performed to assess acute deep venous thrombosis and post-thrombotic syndrome. Anamnesis and physical examination were used to detect risk factors for recurrent disease. The 28 subjects with acute deep venous thrombosis and post-thrombotic syndrome were included in group A (31.82%). Group B comprised 60 patients (68.18%) with acute deep venous thrombosis without post- thrombotic syndrome. Results: Risk factors for recurrent disease in groups A and B were the following: personal history of deep venous thrombosis of the lower limbs (17 subjects versus 7, p<0.0001), varicose veins (14 vs 24, p=0.51), obesity (13 vs 18, p=0.21), malignancy (6 vs 8, p=0.25), chronic obstructive lung disease (5 vs 6, p=0.24), prolonged immobilization (1 vs 7, p=0.21), major surgery (1 vs 1, p=0.54), stroke (0 vs 3, p=0.62), family history of deep venous thrombosis, immobilizing plaster cast, and congestive heart failure (0 vs 1, p=0.54). Location of thrombi in patients in groups A and B was as follows: 18 patients in group A vs 25 subjects in group B on the left side and 13 patients in group A vs 20 patients in group B on the right side (p=0.02). Conclusion: Post-thrombotic syndrome correlated with personal history of deep venous thrombosis and previous deep venous thrombosis located in the left lower limb.

Keywords: deep venous thrombosis, post-thrombotic syndrome, recurrence, risk factors for thrombosis Rezumat

Unii pacienţi cu tromboză venoasă profundă acută a membrelor inferioare pot prezenta factori de risc pentru apariţia recurenţelor.

Obiectiv: Ne-am propus să studiem cele mai importante condiţii legate de recurenţa trombozei venoase profunde, altele decât trombofilia.

Pacienţi şi metodă de lucru: Am examinat 88 de pacienţi consecutivi (47 bărbaţi-53,41%, vârstă medie de 64,9±13,9 ani) internaţi într-o clinică medicală în anul 2007. Ultrasonografia duplex a fost folosită pentru stabilirea diagnosticului trombozei venoase profunde acute şi al sindromului posttrombotic. Anamneza şi examenul obiectiv au permis identificarea unor factori de risc pentru apariţia recurenţelor. Cei 28 de subiecţi cu tromboză venoasă profundă acută şi sindrom posttrombotic au format grupul A (31.82%), iar cei 60 de pacienţi cu tromboză venoasă profundă acută fără sindrom posttrombotic au format grupul B (68.18%). Rezultate: Factorii de risc pentru apariţia recurenţelor, la pacienţii din grupurile A şi B, au fost următorii: antecedentele personale de tromboză venoasă profundă (17 subiecţi versus 7, p<0,0001), boala varicoasă (14 vs 24 de pacienţi, p=0,51), obezitatea (13 vs 18, p=0,21), cancerul (6 vs 8, p=0,25), bronhopneumopatia obstructivă cronică (5 vs 6, p=0,24), imobilizarea prelungită la pat (1 vs 7, p=0,21), operaţiile majore (1 vs 1, p=0,54), accidentul vascular cerebral (0 vs 3, p=0,62), antecedentele trombotice familiale, imobilizarea gipsată şi insuficienţa cardiacă congestivă (0 vs 1, p=0,54). Localizarea trom- bilor a fost următoarea: la nivelul membrului inferior stâng, la 18 bolnavi din grupul A şi la 25 pacienţi din grupul B şi la nivelul membrului inferior drept, la 13 bolnavi din grupul A şi la 20 pacienţi din grupul B (p=0,02). Concluzie: Prezenţa sindromului posttrombotic s-a corelat cu antecedentele personale patologice trombotice şi cu localizarea trombozei venoase profunde acute la nivelul membrului inferior stâng.

Cuvinte cheie: tromboză venoasă profundă, sindrom posttrombotic, recurenţă, factori de risc pentru tromboză

Introduction

Venous thromboembolism is defined by the existence of deep venous thrombosis (DVT) and/or pulmonary embolism. There are many environmental or acquired risk factors (RF) associated with the development of DVT [1,2]. These factors are classified into three categories:

strong, moderate and weak. Fractures, hip or knee re- placements, major surgery and major trauma are strong

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than or equal to 2 and in those with score less than 2 associated with positive D-dimer test [10-12].

The main ultrasound criterion for detecting acute DVT was the lack of compressibility in at least one deep vein. Other acute DVT criteria were: increased cross- sectional diameter, absence of Doppler signal and collateralization. Thickened venous wall, decreased cross-sectional diameter, small echogenic thrombus and valvular insufficiency characterized the PTS [5,13].

We used two duplex ultrasound machines: General Electric Logiq 500 with a 7.5 MHz linear transducer and Aloka Prosound SSD 4000 equipped with a linear transducer with variable frequency between 7 and 10 MHz.

A total of 88 consecutive inpatients met the inclusion criteria for this study. Depending on the presence of PTS and DVT criteria patients were divided into two groups:

A (acute DVT patients with known or unknown PTS) and B (DVT subjects without PTS).

Following parameters were analyzed in all patients:

demographic data (gender, age), anamnestic data (personal history of DVT, laparoscopic or major general surgery, arthroscopic knee surgery, malignancy, chemotherapy, bed rest of more than three days, hormone replacement therapy, oral contraceptives, and pregnancy), physical exam data (obesity, varicose veins, stroke, respiratory insufficiency, congestive heart failure) hemato- logic tests (complete blood count, coagulation, D-dimer test), biochemical tests (fasting blood glucose and lipid profile, serum creatinine), morphological data (thrombus location, echogenicity and caliber, venous wall thickness and compressibility and collateralization) and functional data (spontaneous flow, Valsalva response, augmenta- tion, reflux).

Venous system of the lower limbs was analyzed bilaterally on segments: inferior vena cava and iliac veins, femoral veins (common, superficial and deep), popliteal vein and calf veins (posterior tibial, peroneal and anterior tibial veins, gastrocnemius and soleal veins).

We performed an observational transversal study.

Statistical analysis was done using Epi Info computer package, version 3.3.2. We performed univariate analysis (χ² test, ANOVA test with a p-value less than 0.05 as selected level of statistical significance) and logistic regression (to characterize parameters related to location of thrombi when p-value was less than 0.10 in univariate analysis)

Results

Eligible patients age was between 23 and 86 years (mean 64.9±13.9 years). Patients’ distribution by age was as follows: under 40 years (10 – 11.4%), 41-59 years (22 RF - odds ratio (OR) greater than 10. Moderate RF (OR

2-9) include personal history of thromboembolism, thrombophilia, cancer, chemotherapy, paralytic stroke, congestive heart failure, respiratory failure, arthroscopic knee surgery, oral contraceptives, hormone replacement therapy, and postpartum period. Some diseases and conditions are weak RF such as increasing age, immobility, obesity, laparoscopic surgery, varicose veins, and an- tepartum period [3].

Post-thrombotic syndrome (PTS), recurrence of thrombosis and pulmonary embolism are the main com- plications of DVT [4]. The following modifications of the deep veins characterize the PTS: thickened wall, decreased caliber, nonocclusive intraluminal material (thrombus), and reflux [5,6].

In many cases, older thrombi and deep-vein reflux are detected by ultrasonography in patients with clinical sus- picion of acute DVT. Recurrence depends on predisposing factors (e.g. personal history of thromboembolism, cancer and inherited blood clotting diseases as moderate RF) so re-thrombosis may occur in subjects with PTS [7-9].

Aims

We investigated the major diseases and conditions (location of thrombi and predisposing factors for venous thromboembolism other than thrombophilias) associated with recurrent thrombosis.

Patients and methods

This study was conducted at the Internal Medi- cine Department of the Municipal Hospital „Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania between January and Decem- ber 2007. The study protocol was approved by the local Ethics Commitee.

The algorithm for diagnosis of DVT was based on the determination of pre-test probability of DVT, D-dimer test and compression ultrasonography [10]. Predicting pre-test probability means the calculation of the Wells’

score by adding the points given to different clinical characteristics and by subtracting two points if there is an alternative diagnosis such as Baker’s cyst. The main clinical characteristics which are awarded one point are swelling of the whole leg, personal history of DVT, col- lateral non-varicose superficial veins, plaster immobilization, paralysis, bed rest more than three days, and active cancer. Possible score is between -2 and 9. Score of 2 or higher means that DVT is likely. Thrombosis is unlikely if the score is less than 2. Compression ultrasonography was performed in patients with score greater

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– 25%), 60 – 74 years (34 – 38.6%) and over 75 years (22 – 25%). There were 47 men (53.4%) and 41 women (46.6%).

Some RF were encountered in many patients: varicose veins (38 subjects – 43.1%), obesity (31 patients – 35.2%), personal history of DVT (24 – 27.2%), cancer (14 – 15.9%), respiratory failure (11 – 12.5%) and bed rest more than three days (8 – 9%).

We found 183 occluded venous segments in the 88 patients included in our study: tibioperoneal (49 – 55.6%), soleo-gemelar (47 – 53.4%), popliteal (39 – 44.3%), femoral (38 – 43.1%) and iliac (10 – 11.3%).

Thrombi location was in the left lower limb in 43 cases (48.8%) and in the right lower extremity in 33 subjects (37.5%). Only 12 patients (13.7%) had bilateral thrombosis.

Chronic thrombotic scarring and deep vein reflux were found in 28 patients (31.8%) with acute DVT criteria.

The figures 1-3 illustrate the acute DVT diagnosis while the figures 4-7 present the changes encountered in the PTS.

Fig 1. Short-axis view of the right common femoral vessels.

Heterogenous hypoechoic intraluminal material dilating the common femoral vein. vfc: common femoral vein; afc: common femoral artery. dr: right lower extremity

Fig 3. Short-axis view of the right calf. Increased cross-section- al diameter of a posterior tibial vein. VTP: posterior tibial vein;

ATP: posterior tibial artery.

Fig 2. Longitudinal and transverse images of the right popliteal vessels. Dilated popliteal vein with heterogenous intraluminal deposition of thrombotic material. vp: popliteal vein; ap: popliteal artery.

Fig 4. Transverse view of the left femoral vessels. Left side:

without compression. Right side: with compression. Common femoral vein with nonocclusive thrombus. 1 (AFS): superficial femoral artery; 2 (VFC): common femoral vein; 3 (AFP): deep femoral artery.

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Fig 5. Short-axis view of the left superficial femoral vessels.

Left side: without compression. Right side: with compression.

Decreased cross-sectional diameter of the superficial femoral vein, nonocclusive intraluminal material. 1 (AFS): superficial femoral artery; 2 (VFS): superficial femoral vein.

Fig 7. Short-axis view of the right popliteal vein. Distal com- pression maneuver detecting a long venous reflux. VP: popliteal vein.

Fig 6. Transverse view of the right popliteal vessels. Intralumi- nal echogenic material without shadowing. A POPL: popliteal artery; V POPL: popliteal artery.

Characteristics of patients included in our study are presented in Table I.

Some patient characteristics had a p-value less than 0.1: personal history of DVT (p<0.001), left side of le- sions - acute thrombus and chronic thrombotic scarring (p=0.08), iliac vein involvement (p=0.09), femoral location of thrombi (p=0.1) and male gender (p=0.1). We performed unconditional logistic regression with these five factors (Table II).

As can be seen in Table II, only two features showed a statistically significant correlation with the presence of chronic thrombotic scarring in patients with acute DVT:

personal history of DVT (p<0.0001) and thrombosis located in the left lower extremity (p=0.0244).

Discussion

The mean age of our patients was approximately 65 years. It is known that incidence and prevalence of DVT increases with increasing age [14]. For example, in people over 80 years, the incidence of DVT can reach a value of 10‰year [15,16]. Caprini [17] has developed a useful tool in determining thrombotic risk score (Total Risk Factor Score) according to which DVT prophylaxis should be performed. According to age, each patient receives one, two or three points, as follows: one point (age between 41 and 60 years), two points (age between 60 and 74 years) and three points (age over 75 years). For example, the three points characterize the DVT high risk so that patients require prophylaxis with heparin [17].

Of the 88 patients included in the study, 47 were men.

The male-to-female ratio in our sample was 1.14. Bauer- sachs et al [18] examined 1388 outpatients (658 men and 730 women) with confirmed DVT. They found that prevalence of DVT was higher in men and proximal DVT was more frequent in men than in women (59.6% vs 44.5%, p<0.001). Andreou et al [19] examined 1838 outpatients and found that the prevalence of DVT was higher in men compared to women (14.4% vs 9.4%, p=0.001).

The most common RF were varicosis and obesity (found in more than one third of patients), personal history of DVT (27.2%) and active cancer (15.9%). Caprini [17] gave one point for varicose vein and obesity, two points for cancer and three points for DVT personal history. In patients with cancer, thromboembolic disease is the second leading cause of death [20].

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PTS frequency in our patients was 31.8%. Labropou- los et al [23] followed 153 patients for 5 years after acute episode of DVT. Recurrence rate was 26.1% in these patients. Brandjes et al [7] found a frequency of 20%.

Percentage of Hennerici et al [5] is at least double - 40- 50%. A total of 50 of the 490 patients included in the PROLONG Study had recurrent DVT (12.2%) [24].

In our study PTS correlated with personal history of thromboembolism and previous thrombosis of the left extremity. According to The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II), the recurrence probability is twofold for those with a personal history of thromboembolism [9]. Labropoulos et al [23]

found that factors associated with DVT recurrence were Table I. Patient characteristics

Parameters Group A

N=28 Group B

N=60 OR 95% CI* p

Men 19 28 2.41 0.86-6.91 0.1

Age (mean ± standard deviation, median,

range) 65.5±13.3

65 (35-86) 64.6±14.3

69 (23-84) – – 0.78

41-59 years 7 15 – – –

60-74 years 9 25 0.77 0.2-2.93 0.89

≥75 years 9 13 1.48 0.36-6.13 0.75

Major general surgery 1 1 2.19 0.0-83.72 0.54

Personal history of DVT 17 7 11.7 3.49-41.12 <0.001

Malignancy 6 8 1.77 0.47-6.56 0.25

Respiratory diseases 5 6 1.96 0.46-8.28 0.24

Stroke 0 3 0.7 0.03-8.21 0.62

Chemotherapy 3 0 0.7 0.03-8.21 0.62

Arthroscopic knee surgery 0 1 2.19 0.0-83.72 0.54

Varicose veins 14 24 1.5 0.55-4.08 0.51

Obesity 13 18 2.02 0.73-5.66 0.21

Immobilization > three days 1 7 0.28 0.01-2.49 0.21

Tibioperoneal 18 31 1.68 0.61-4.71 0.38

Muscular (soleo-gemelar) 18 29 1.92 0.7-5.38 0.24

Popliteal 14 25 1.4 0.52-3.8 0.61

Femoral 16 22 2.33 0.84-6.37 0.12

Iliac 6 4 3.82 0.84-18.2 0.09

Left-sided DVT 18 25 2.52 0.91-7.09 0.08

Right-sided DVT 13 20 1.73 0.63-4.79 0.34

* 95% confidence interval

In our study, more than half of the thrombi were located in the calf. A total of 106 of the 239 patients examined by Pennell et al [21], representing 44.4%, had calf thrombosis. Calf thrombosis is important because it is known that calf vein thrombosis involves the proximal veins in 25% of patients [1].

The left side-to-right side ratio was 1.30. Virchow (1851), cited by Ludwig et al [22], found that DVT occurs five times more frequently in the left leg versus right leg.

Thrombi were located bilaterally in 13.7% of our patients. Bilateral thrombosis was encountered in 19.7% of symptomatic cases of Pennell et al [21]. Clinically silent contralateral thrombosis was diagnosed in 34% of their patients.

Table II. Unconditional logistic regression with five factors

Factors OR 95% CI p

Men 2.1081 0.6778-6.5571 0.1977

Personal history of DVT 20.3202 4.8501-85.1343 <0.0001

Femoral 0.9677 0.2759-3.3949 0.9591

Iliac 2.0399 0.3310-12.5696 0.4423

Left side DVT 5.0128 1.2313-20.4076 0.0244

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unprovoked DVT (relative risk 2.9) and age more than 65 years (relative risk 1.5).

Limitations

There were no patients with the following RF: pregnancy, oral contraceptives, hormone replacement therapy, polycythemia vera, total hip or knee replacement, arthroscopic procedures, laparoscopic surgery, spinal cord injuries and major trauma.

We could not evaluate thrombophilia.

Conclusion

In our study, PTS correlated with personal history of thromboembolism and previous left lower leg thrombosis.

Competing interest No conflict of interest.

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