influence of compression in reducing inflammation in pts · 2019. 12. 2. · compression therapy...

Tomasz Urbanek Dep. of General Surgery, Vascular Surgery

Angiology and Phlebology

Medical University of Silesia, Katowice, Poland

Influence of compression in reducing inflammation in PTS

Disclosure

- flight and accomodation during the CIRC meeting in Bologna supported by the Center of Interdisciplinary Research on Compression

- no other conflict of interest

Post-Thrombotic Syndrome (PTS)

„....chronic venous symptoms and/or signssecondary to deep vein thrombosis.....”

Eklof B, Perrin M, Delis K, Rutherford R, Gloviczki P.

The VEIN TERM transatlantic interdisciplinary consensus document. J Vasc Surg 2009; 49: 498–501

Secondary Chronic Venous Disease

PTS

Valve damage

Vein obstruction

POST-THROMBTOTIC SYNDROME

PTS - reflux vs. obturation

US Doppler - 6 months after DVT

/180 pts. with PTS/

24% - no abnormalities in US

48% - „residual thrombosis”

37,5% - reflux

54% - reflux + „residual thrombosis”

Prandoni P. et al.: Vein abnormalities and the posthrombotic syndrome.

J Thromb Haemost. 2005; 3: 401-402

PTS severity assessment (Villalta scale)

Symptoms

Pain

Cramps

Heaviness

Pruritus

Paresthesia

/patient self reported/

Signs

- Oedema

- Skin induration

- Hyperpigmentation

- Venous ectasia

- Redness

- Pain during calf compression

-/clinician assesment/

0 - 4: no PTS

5 – 14: mild (5-9) /moderate (10-14) PTS

15 or more, or presence of ulcer: severe PTS

O - absent, 1 – mild, 2 - moderate, 3 - severe

Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thromboticsyndrome (abstract). Haemostasis 1994;24:158a.

Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C; Subcommittee on Control of Anticoagulation of the Standardisation

Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of

the leg for use in clinical investigations: a recommendation for standardisation. J Thromb Haemost 2009; 7: 879–83.

NEJM; 355, 2006

Local Vein pathology

Thrombus presence - response of the vein wall to the thrombus

Vein wall remodeling /thickening, fibrosis/

Inflammation related to the thrombus presence, recanalisation, intra -and/or perivenous inflammatory reaction

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Lower leg pathology:

Venous hypertension /obstruction, reflux/

Microcirculation injury

Tissue level inflammation

Skin and soft tissue changes/Varicose veins, Swelling, Trophic changes, Ulcer occurrence/

Post-thrombotic vein&syndrome/Inflammation[secondary chronic venous disease]

RABINOVICH A et al. Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

J Thromb Haemost. 2015; 13: 398–408 BioSOX

PTS laboratory predictors /at baseline, 1 month and 6 months/ after a first proximal DVT

C reactive protein (CRP)

ICAM-1

interleukin (IL)-6

IL-10

/follow up -24 months/

Conclusion: ICAM – 1 over time was most consistently associated with the risk of PTS.

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INFLAMMATORY MARKERS FOR PTS DEVELOPMENT

Rabinovich A, Cohen JM, Cushman M, Kahn S; BioSOX Investigators: Association between inflammation biomarkers, anatomic extent of deep venous

thrombosis, and venous symptoms after deep venous thrombosis. JVS Venous Lymphatic Disorders 2015; 3: 347-353

PTS laboratory predictors /at baseline and @ 1 month/: C-reactive protein (CRP)Intercellular adhesion molecule – 1Interleukin -6Interleukin -10 + Villalta score evaluation

Conclusion: Levels of CRP and IL-6 at DVT diagnosis were associated with thrombotic disease burden,

as measured by DVT extent, and severity of DVT symptoms and signs.

PTS - Secondary Chronic Venous Disease

Inflammation ??

Inflammation ??

PTS - Secondary Chronic Venous Disease

182 women with pregnancy - related DVT

Blood sample taken in late follow up period + Villalta assessment /

41% of cases were diagnosed with PTS 3-16 years after index pregnancy.

OR for PTS

CRP 2.3 (95% CI; 1.2-4.2, p=0.008)

IL-6 1.9 (95% CI; 1.0-3.5, p=0.04)

IL-10 10.8 (95%CI; 1.3-89.8, p=0.01)

AN INFLAMMATION POST ACUTE DVT EPISODECORRELATES WITH THE HIGHER PTS RATE

Wik HS. et al.: The role of inflammation in post-thrombotic syndrome after pregnancy-related deep

vein thrombosis: A population-based, cross-sectional study. Thromb Res. 2016;138:16-21

Villalta score category at 1 month after DVT and PTS occurrence @ 24 months

score 5-9 HR 2.74 [95% CI 1.62, 4.64]

score 10-14 HR 5.81[95% CI 2.99, 11.29]

score >14 HR 7.59 [95% CI 3.31, 17.44]

SOX trial secondary analysis

Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep

venous thrombosis. Ann Intern Med. 2008; 149: 698-707

Residual DVT symptoms presence 1 month after the diagnosis of DVT

– higher risk of PTS occurrence

Markers of venous obstruction or persistant inflammation ?

Susan R. Kahn et al. Predictors Of The Post-Thrombotic Syndrome In a Large Cohort Of Patients With Proximal

DVT: Secondary Analysis Of The Sox Trial. Blood 2013 122:460;

A. C. BOUMAN, J. J. M. SMITS, H. TEN CATE , A. J. TEN CATE-HOEK

Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome.

Journal of Thrombosis and Haemostasis. 2012; 10: 1532–1538

228 consecutive patients 12 months after DVT index

Signifficant association with PTS in multivariance analysis for:

Varicosities (odds ratio [OR] 13.4 95% confidence interval [CI] 3.0–59.1 P = 0.001)

Previous ipsilateral DVT (OR 6.3 95% CI 1.5–26.9 P = 0.012)

CRP > 5 mg at 12 months after DVT (OR 8.0 95% CI 2.4–26.4 P = 0.001)

.

Conclusion: Persistent inflammation rather than hypercoagulability might be the most important etiological factor in PTS, and may be a target for future therapy.

INFLAMMATION AND PTS DEVELOPMENT

Roumen-Klappe EM, Janssen MCH, van Rossum J, Holewijn S, van Bokhoven MMJA, Kaasjager K, Wollersheim H, den Heijer M. Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study. J Thromb Haemost 2009; 7: 582–7

110 patients with a first DVT:

Plasma concentrations of IL-6 and CRP on the day of admission

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Thrombus clearence

Venous outflow obstruction after 1 year

Conclusion: The results of this study suggest that inflammation might play a role in incomplete thrombus clearance, venous outflow obstruction and the development of PTS after 1 year.

INFLAMMATION AND PTS DEVELOPMENT

• PTS PREVENTION

• PTS TREATMENT

COMPRESSION AND PTS:

WHY COMPRESSION IN POST DVT PATIENTS ?

ACUTE DVT

Consensus Statement for compression stockings in venous & lymphatic disordersInternational Consensus Group: E. Rabe, H. Partsch, J. Hafner, Ch. Lattimer, G. Mosti, M. Neumann, T.Urbanek,

M. Hüebner, S. Gaillard, P. Carpentier Phlebology 2017

Recommendation 15Use of immediate compression to reduce pain and swelling, thereby

allowing instant mobilisation in acute DVT /1B/

/Compression should be used immediately after the DVT event/

Recomendation 16Use early compression and mobilization in addition to

anticoagulation to avoid thrombus propagation in acute DVT

/Compression should be used immediately after the DVT event/

Partsch H. et al. Immediate mobilisation in acute vein thrombosisreduces post thrombotic syndrome. Int Angiol 2004; 23: 206 -12

• Immobilisation (9 days) without compression stocking - 17

• Unna boots + early mobilisation - 18

• Elastic compression + early mobilisation - 18

Follow up 28,9 (+/- 4,9) months

DVT treatment – early mobilisation and ambulation decrease the Postthrombotic Syndrome occurence

0

1

2

3

4

5

6

7

8

9

Villalta/

Prandoni

scale

early mobilisaton immobilisation

Assessement of PTS severity

Villata scale: < 5 points (no PTS)

- Walking patients - 46%

- Immoblisation - 18%

No compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg).

Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosisBlood 2018; 132: 2298–2304.

592 patients /Ideal DVT study subanalysis/

Residual Venous Obstruction (RVO):

No immediate compression group - 66.7%

Immediate compression group - 46.3%

/Risk Reduction 20.4% (OR, 0.46; 95% CI, 0.27-0.80; P = 0.005)/

Postthrombotic syndrome rate (after 24 months)

No Residual Venous Obstruction 46.0%

Residual venous obstruction 54.0%

(OR, 0.65; 95% confidence interval, 0.46-0.92; P =0.013).

Compression use after DVT episode for post-thrombotic syndrome avoidance ?

Prandoni P. et al.: Below – knee elastic compression stocking to prevent the post-thrombotic syndrome. Ann Int Med. 2004; 141: 4: 249-256

Proximal DVT

Knee-lengh elastic CS /30 – 40mmHg/ - 2 yrs.

Follow up - 5 yrs

0

10

20

30

40

50

6 12 24 60

% of PTS

no CS

CS

PTS after 49 months (mean): CS - 26% vs Control - 49% NNT 5 (3-11)

months

Class II ECS vs „Placebo stockings”Post-thrombotic syndrome /Ginsberg Criteria/

SOX TRIAL

Kahn S. et al. Compression stokings to prevent post-thrombotic syndrome: a randomised placebo controlled trial. Lancet 2014; 383:880-88

Most proximal extent of DVTActive ECS Placebo

ECS

Iliac 10.8% 12.4%

Common femoral 26.7% 27.2%

Femoral 31.3% 31.2%

Popliteal 31.3% 29.2%

Primary outcome - the cumulative incidence of PTS from 6 to 24 months follow-up

Randomization:

ECS - 410 pts vs Placebo ECS

Active ECS: Knee – length

30-40 mm Hg compression.

Cumulative incidence of PTS

14.2% /active ECS/ vs. 12.7% /placebo ECS/ (HR 1. 13; 95% CI 0.73-1.76; p=0.58)

„In patients with acute DVT of the leg, we

suggest not using compression stockings

routinely to prevent PTS (Grade 2B)”

Remarks: This recommendation focuses on

prevention of the chronic complication of PTS

and not on the treatment of symptoms. For

patients with acute or chronic symptoms, a trial

of graduated compression stockings is often

justified.

DVT patient

compression or no compression in PTS prevention?

Be carefull with final conclusions!

Appelen D, van Loo E, Prins MH, Neumann MHAM, Kolbach DN.

Compression therapy for prevention of post-thrombotic syndrome (Review)

Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD004174.

10 RCTs - 2361 participants /Five trials with main outcome (PTS) assessment -1393 pts/*

Patients with DVT who wear elastic compression stockings are less likely to develop PTS

RR 0.62 (95% CI 0.38-1.01) /follow up 2-6.3 yrs/ /level of evidence – low/

The compression did not lead to reduced incidence of severe PTS

RR 0.76 (95% CI 0.53-15)

Thigh-length stockings did not provide better protection against development of PTSthan knee-length stockings.

Aschwanden (2008)*, Brandjes (1997)*, Kahn (2014) *, Prandoni (2004)*, Partsch (2004)*,

Ginsberg (2001) , Jayaraj (2015), Mol (2016), Prandoni (2012), Roumen-Klappe (2009)



Recommendation 18

Use of medical compression stocking as early as

possible after diagnosis of DVT in order to prevent PTS

/1B*/

*downgraded from 1A in the 2008 consensus document

• How long ?

• Which class ?

• Knee lenght or higher ?

PTS prevention by compression

IDEAL STUDY RESULTSAll patients wore ESC for 6 months after prox DVT - if free from PTS at 6 months, randomized to continue for more 18 months or tailor coninued use according to Villata score

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Individualized duration of ECS is non–inferior to standard 2 years duration

66% in intervention group able to stop wearing ESC before 2 years Individualized duration of compression

PTS: Individalized 29% vs. Standard duration of compression: 28%

ten Cate–Hoek A, Lacet Hematology 2017

PTS Treatement Secondary venous disease

reflux/obstruction

- Compression

- Risk factors elimination (modification?)

- Pharmocological treatment

- Invasive obstruction treatment /PTA, stent pacement/

- Local wound treatment /if needed/

/often combined treatment needed/



VENOUS LEG ULCER GUIDELINES

Recommendation 8

Use of ulcer MCS (‘ulcer kits’) to improve VLU healing

/1A/

Recommendation 9

Use of ulcer MCS (‘ulcer kits’) to reduce pain in patients with VLU

/1A/

Recommendation 7

Use of MCS to reduce recurrence of VLU

/1A/

MCS – Medical Compression Stocking

Beidler SK, Douillet CD, Berndt DF, Keagy BA, Rich PB, Marston WA. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy. J Vasc Surg. 2009; 49: 1013–1020

Conclusion: Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

/TGF-β1 was up-regulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1α, IL-1β, IFN-γ, IL-12p40 and GM-CSF before compression therapy, and

IL-1 Ra after therapy. IFN-γ levels significantly decreased following therapy in the rapidly healing patients/

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Gohel MS, Windhaber RAJ, Tarlton JF, Whyman MR, Poskitt KR.The relationship between cytokine concentrations

and wound healing in chronic venous ulceration. J Vasc Surg 2008; 48: 1272-7

Conclusion: Wound fluid collection volume correlates with ulcer size. Ulcer healing correlated with increased concentrations of TGF1, possibly reflecting increased fibrogenesis in the proliferating wound. Aside from this, there was a large variation in wound and serum cytokine levels that largely limits their usefulness as markers of healing.

COMPRESSION >>>> INFLAMMATORY CYTOKINES↘↘

ULCER HEALING ↑↑



Recommendation 19

Use the Medical Compression Stocking for treatment

of symptomatic PTS /1B/

A systematic literature review determined there is moderate-quality

evidence supporting compression. An RCT reported significant

improvement in haemodynamic parameters in PTS (Lattimer 2013)

Which compression?

• Class ?

• Duration?

• Below or above knee?

Compression results in the significant improvement in haemodynamicparameters in post-thrombotic syndrome patients

Lattimer Ch. et al. Compression stocking signifficantly improve hemodynamic performance in post-thrombotic syndrome irrespective of class or lenght JVS 2013; 58: 158-65

Conclusion: Compression signifficantly improved all hemodynamic parameters on air pletysmograhy. However, the hemodynamic benefit did

not signifficantly change with the class or lenght of stocking.

Class 1 (18-21mm)

Class 2 (23-32mm)

Below knee

Above knee

[Air pletysmography]

Compression use in

Secondary Chronic Venous Disease

• PTS Prevention ++/-

• Venous symptom decrease ++

• Progression avoidance ? (++/-)

• Venous leg ulcer treatment +++

• Venous recurrence prevention +++

/all above venous hypertension and inflammation process related/

influence of compression in reducing inflammation in pts · 2019. 12. 2. · compression therapy...

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