Servier – Phlebolymphology

Sandeep Raj Pandey,
MS, FVES, FIDF, FIUA
Annapurna Hospital,
Kathmandu, Nepa

ABSTRACT

Propagation of a thrombus from a superficial vein into a deeper vein post endovenous thermal ablation is called endothermal heat-induced thrombosis (EHIT). It is generally considered clinically insignificant if the thrombus does not propagate to the deep venous system. Diagnosis of EHIT is based mainly on 4 classification categories for both saphenofemoral junction and saphenopopliteal junction. The condition can be treated with antiplatelet or anticoagulation therapy, although monitoring may be sufficient, especially in less-severe cases. Rivaroxaban may be a promising alternative for treatment of severe EHIT because the dosage regimen is simplified without compromising efficacy or safety and is easily available as an oral anticoagulant and is more cost-effective than perenteral enoxaparin. Prospective, randomized, controlled studies are needed to better understand EHIT and to develop more definitive recommendations on prevention and treatment options for this condition. Therefore, the true clinical significance of EHIT is still being determined.

Introduction

There is evidence that the population is significantly impacted by chronic venous insufficiency (CVI). Often asymptomatic, CVI may also present as varicose veins (in 20% to 30% of the population), edema, skin changes (up to 6%), and ulceration (active venous ulcerations in up to 0.5%).^1,2 Related issues such as cosmetic concerns, debilitating symptoms, and complications that may be limb threatening (eg, postthrombotic syndrome) or even life threatening (eg, venous thromboembolism, sepsis) may also affect quality of life.^2,3

A common cause of CVI is superficial venous reflux disease, treatment of which has seen revolutionary change with the advent of endovenous thermal ablation technologies. Of these, the most robustly investigated—endovenous laser ablation (EVLA) and radiofrequency ablation (RFA)— have been determined to be safe, effective, and durable as conservative varicose therapies.^2,4 Furthermore, both these therapies (carried out under tumescent anesthesia application) allow transition of care to the ambulatory setting. Periprocedural outcomes are improved and the return to work is speedier than with surgical stripping.^2,5 These days, RFA and laser have replaced surgical stripping almost everywhere.

However, with use of these heat-inducing techniques (endovenous thermal ablations), reports began to emerge of an association with deep venous thrombosis (DVT). For example, in 2004, Hingorani et al, in a study based on postprocedure surveillance ultrasound findings, showed its association with DVT of the common femoral vein (CFV).^2,6 An increased risk of DVT (from 0% to 8%) was also reported in other publications from the early 2000s.^2,7 Later reports, believing these postoperative thrombi to be distinct from DVT, called them thrombus extension.^2,8 And although not considered abnormal to find on ultrasound imaging a superficial thrombus in a vein segment that’s been treated, the propagation of such a thrombus could be a risk for development of symptomatic DVT and pulmonary embolism (PE). Figure 1 shows DVT after endovenous heat-induced thrombosis (EHIT).⁹

Figure 1. Diagram of endothermal heat-induced thrombosis (EHIT) extending into a deep vein.
After reference 9: Thoracic Key. https://thoracickey.com/ complications-of-the-treatment-of-venous-insufficiency/

EHIT and classic DVT are considered diagnostically and clinically to be separate entities. The ultrasonographic appearance of EHIT is distinct, showing up as a hyperechogenic, noncompressible area that has an abnormal venous flow and augmentation involving the saphenofemoral junction (SFJ) or saphenopopliteal junction (SPJ) after ablation of the great saphenous vein (GSV) or small saphenous vein (SSV), respectively.^2,11 DVT on the other hand shows up as a hypoechogenic area. EHIT behaves like a stable thrombus, and spontaneous regression often occurs within a few weeks of observation or after a short anticoagulation treatment.² Figure 2 shows thrombus echogenicity of DVT and EHIT on duplex ultrasound.

Reported rates of EHIT after endovenous ablation range from 0% to 3%.² It is usually on routine follow-up with duplex ultrasound that it’s diagnosed, as most are asymptomatic, and that can be anywhere from 24 hours up to 2 weeks after the procedure (local ultrasound protocols vary),² In our practice, we usually have high-risk patients come in for ultrasound follow-up, aiming to prevent EHIT. Whereas most EHIT are asymptomatic (ie, silent), a history of recent endothermal venous ablation or a thrombus at the junction has been associated with PE (rare cases).²

Anatomically, EHIT (which, as the term evokes, is provoked) is considered to be a form of DVT; however, with regard to clinical course, EHIT is more benign than DVT that is unprovoked or that occurs in a remote vein segment.² Exactly how the mechanism of excessive thrombus formation differs between the heat-inducing procedures EVLA and RFA is not known.²

For thrombotic complications after venous ablation, reports should take into consideration all postprocedure ultrasound findings. For example, EHIT reports most often describe thrombi that protrude into the CFV or the popliteal vein, but a deep calf thrombus can also be considered EHIT when it extends into a calf vein from a treated perforator, a treated SSV that drains directly into a gastrocnemius vein, or a treated below-knee GSV through a perforator.² DVTs that would not be considered EHIT (ie, non-EHIT DVT) include a deep vein thrombus nonadjacent to the SFJ after GSV ablation, a thrombus remote from the SPJ after SSV ablation, a remote calf vein thrombus after GSV ablation, and a DVT in the contralateral limb.² It’s possible to find both EHIT and non-EHIT DVT in the same patient.^2,12 Proper clinical history and ultrasonography findings may be helpful in differentiating them.

Figure 2. Thrombus echogenicityin ultrasonography. Deep venous thrombosis (DVT) is hyperechoic (left, white arrow), and endovenous heat-induced thrombosis (EHIT) is hyperechoic (right, white arrow).
Image courtesy of S.R. Pandey.

Although considered the gold standard, ultrasonography for DVT diagnosis does have a wide variation in sensitivity, particularly when duplex ultrasound is used for below knee scans. For that reason, the incidence of calf DVT after endovenous ablation could be higher than reported, possibly accounting for some cases of PE of unknown source.² Anatomic location should clearly distinguish between EHIT and non-EHIT DVT, but whether pathologic differentiation can be made on the basis of ultrasound appearance of the thrombus—mainly echogenicity, hypo or hyper—is unclear.²

Preclinical studies in animals have shown significantly greater hypercellular response, fibroblastic reaction, and edema in histologic specimens of EHIT after RFA than for classic DVT, with thrombi from the EHIT specimens appearing more echogenic than those of DVT.² A greater echogenicity of EHIT on ultrasound examination has been shown as well in preliminary human studies, with EHIT’s mildly echoreflective thrombus distinguishing it from a classic acute DVT’s echolucency.^2,14

The time frame for development of EHIT is not completely clear: whereas EHIT usually develops within 72 hours, it has also been identified 1 to 4 weeks after endovenous ablation on occasion via postprocedure surveillance ultrasound examination.² This lack of clarity with regard to timing makes it uncertain whether an EHIT that develops more than 1 week after ablation should be considered EHIT and treated as such or as a classic DVT.²

Indeed, evidence suggesting that thrombi occurring at the site of endovenous ablation within 30 days of the procedure is potentially related to the procedure itself (directly or indirectly) was shown in a prospective study by Lurie and Kistner.¹² In their investigation in patients undergoing RFA of the GSV, levels of both C-reactive protein and D-dimer— markers of inflammation and hemostatic activation— significantly increased at 24 to 36 hours after treatment and returned to baseline levels at 1 month, indicating that these processes are present for a prolonged period of time after venous surgical trauma.²

Rather than EHIT, another broader term “postablation superficial thrombus extension” has been used by some for a thrombus extension from the superficial to the deep system after endovenous ablation via any kind of chemical or thermal technique.¹⁵ They note that such extension differs from a classic DVT in that it typically occurs within 1 week, there is no progression, and within 2 weeks it has usually resolved.

Definitions of the terms EHIT, non-EHIT DVT, and postablation superficial thrombosis are recommended by Kabnick et al² below to help provide clinical guidelines for the management of thromboembolic events that follow endovenous thermal ablation, events that can lead to serious consequences (eg, PE):

• EHIT: any thrombus detected by ultrasound within 4 weeks of endovenous thermal ablation originating from the treated vein and protruding into a deep vein.
• Non-EHIT DVT: a DVT occurring in a venous segment not contiguous with the thermally ablated vein.
• Postablation superficial venous thrombosis: presence of thrombus in a superficial vein other than the treated vein. This vein may or may not be contiguous with the ablated vein.

In order to validate or revise proposed definitions, Kabnick et al recommend that future reporting for thromboembolic events after endovenous thermal ablation include detailed information on anatomic location, clinical presentation, and time of occurrence of these events.² If possible, reports should include detailed sonographic features and progression of all these thrombi at follow-up ultrasound examination.²

It’s important that other—non-EHIT—thrombotic events are also recognized and reported because non-EHIT thrombotic events occurring during thermal ablation are probably triggered by systemic factors more related to an acquired prothrombotic state than to the thermal energy itself.2

Pathophysiology

As mentioned above, with the advent of endothermal ablation technologies, including EVLA and RFA, for treatment of superficial venous reflux, thrombus propagation associated with these procedures emerged, and though incidence was low, it was recognized early. Over time, the concept of EHIT was differentiated from DVT as a separate entity, with EHIT’s pathophysiology believed directly related to the heat-induced injury during treatment.¹⁶ Classification systems for EHIT were developed, supporting its recognition as a distinct process¹⁶ (4 of these that have gained prominence in the literature are outlined in the section on Diagnosis below).

The rarity of EHIT made it difficult to identify its risk factors. These include a vein diameter >10 mm, operative time >40 minutes, a Caprini score >6, multiple phlebectomies, old age, etc. Notable, there has been a progressive reduction in the incidence of EHIT, possibly related to practitioner experience or changes in technique (eg, increasing the ablation distance from the SFJ).¹⁶

Treatment of EHIT is chosen on the basis of the extent of thrombus propagation. A fully occlusive EHIT appears to be exceedingly rare, and as most EHIT resolve spontaneously or with a limited course of antiplatelet or anticoagulation therapy, their true clinical and pathological significance is unclear.¹⁶

Diagnosis

The causes behind pain and swelling after a therapeutic procedure can be difficult to differentiate; without duplex ultrasound imaging, it is also difficult to clinically distinguish EHIT from DVT.⁹ With significant differences in the natural course of EHIT and DVT and in their treatment, the etiology of postoperative complications should be determined in all patients with pain and swelling.⁹

Duplex ultrasound
Postprocedure duplex ultrasound is not necessary for all patients to evaluate them for EHIT or DVT.⁹ However, in those that have significant postoperative pain or swelling and those at high risk for DVT and EHIT, duplex ultrasound imaging should be used to assess the site of ablation for hematoma or superficial branch or truncal vein thrombus, with both B mode and color flow, using 2–10 MHz transducers (Figure 3),⁹ in both the supine and standing position.⁹ The transducer wavelength should be chosen in accordance with the patient’s body habitus and the depth of the superficial and deep venous system at the site under evaluation.⁹ Measurements (via electronic cursor) taken in transverse, axial, and orthogonal positions can be used to determine the distance and relationship between any thrombus identified and the vein wall, as well as the presence, absence, and extent of protrusion into the deep system.⁹

Figure 3. Ultrasound appearance of endothermal heat-induced thrombosis (EHIT), when thrombus has extended into the deep vein from the saphenous vein.
Abbreviations: CFV, common femoral vein; GSV, great saphenous vein.
After reference 9: Thoracic Key. https://thoracickey.com/
complications-of-the-treatment-of-venous-insufficiency/

Figure 4. Kabnick’s endothermal heat-induced thrombosis (EHIT) classification. A) Class I EHIT; B) class II EHIT; C1) class III EHIT; C2) class III EHIT. We also follow Kabnick’s EHIT classification, and usually encounter EHIT I-II, rarely EHIT III-IV.
Abbreviations: RT CFV, right common femoral vein.
Images courtesy of S.R. Pandey.

Classification systems by Kabnick, Lawrence, Harlander-Locke, and the American Venous Forum, are outlined here²:
1. The Kabnick EHIT classification (Class I-IV) is defined as follows: Class I) Extension of thrombus up to and including the deep vein junction (Figure 4A); Class II) Propagation of thrombus into the adjacent deep vein but comprising <50% of the deep vein lumen (Figure 4B); Class III).
Propagation of thrombus into the adjacent deep vein but comprising >50% of the deep vein lumen (Figure 4C1,C2); and Class IV) Deep vein occlusive thrombus contiguous with the treated superficial vein (Figure 1).

2. The Lawrence EHIT classification¹⁷ (Level 1-6) is defined as follows: Level 1) Thrombus extension that remains peripheral to the epigastric vein; Level 2) Thrombus extension that is flush with the orifice of the epigastric vein; Level 3) Thrombus extension that is flush with the saphenofemoral junction (SFJ); Level 4) Thrombus bulging into the CFV; Level 5) Thrombus bulging into the CFV and adherent to the wall of the CFV past the SFJ; and Level 6) Thrombus extension into the CFV consistent with a DVT.

Figure 5. Saphenopopliteal junction (SPJ)—small saphenous vein (SSV) EHIT levels. A) Schematic showing levels A-D; B) imaging for EHIT level C.
Panel A is from reference 19: Harlander-Locke et al. J Vasc Surg. 2013;58:427-431. ©2013, Society for Vascular Surgery. Published by Elsevier, Inc. All rights reserved. Panel B image courtesy of S.R. Pandey.

4. The American Venous Forum (AVF) classification for EHIT (Class I-IV) is defined as follows: Class I) Thrombus without propagation into the deep vein; a, Peripheral to superficial epigastric vein; b, Central to superficial epigastric vein, up to and including the deep vein junction; Class II) Thrombus propagation into the adjacent deep vein but comprising <50% of the deep vein lumen; Class III) Thrombus propagation into the adjacent deep vein but comprising >50% of the deep vein lumen; and Class IV) Occlusive deep vein thrombus contiguous with the treated superficial vein.

Treatment

As the natural history of EHIT is considered more benign than that of classic DVT, its management remains controversial. Indeed, EHIT is often asymptomatic, progression to PE is rarely reported, and there is no conclusive evidence that treating it reduces the incidence of PE. Additionally, much more conservative treatment methods are in use now than those employed for early case series when EHIT was recognized as a complication of thermal ablation (those used inferior vena cava filter placement and saphenofemoral thrombectomy with ligation).¹⁸ Notable, most of the EHIT treatment reports were made before widespread use of direct oral anticoagulants, an evolution in treatment that should be taken into account.

Conducting a prospective randomized trial on EHIT is challenging because of its low incidence. Because of this, treatment recommendations are based primarily on retrospective institutional case series, though also influenced by surgeon preference and anecdotal experience. Of the EHIT classifications in the literature, the main ones are the above-mentioned Kabnick classification and the Lawrence classification for GSV ablations¹⁹; there is also a proposed modification for the SSV by the Harlander-Locke classification. The AVF EHIT classification combines these different systems.

With an eye to reduce the number of EHITs from the outset, Sadek et al²⁰ demonstrated that increasing the ablation distance to >2.5 cm from the deep venous junction could be helpful.

Rivaroxaban may be a promising alternative for treatment of severe EHIT because the dosage regimen is simplified without compromising efficacy or safety and is easily available as an oral anticoagulant and is more cost-effective than perenteral enoxaparin.

Treatment based on EHIT classification
With the suggestion that treatment should be based on an accepted EHIT classification system, recommendations for antiplatelet and anticoagulant therapies for EHIT have lessened.2 Treatment based on the combined AVF-EHIT classification is described below:

Treatment of EHIT after ablation of the GSV
EHIT I: No treatment is suggested for EHIT I; surveillance only.

EHIT II: No treatment is suggested for EHIT II; weekly surveillance until thrombus resolution. In high-risk patients, consideration may be given to antiplatelet therapy versus prophylactic or therapeutic anticoagulation with weekly surveillance. Treatment would cease after thrombus retraction or resolution to the SFJ (GSV) or SPJ (SSV).

EHIT III Treatment with therapeutic anticoagulation is suggested for EHIT III, with weekly surveillance, and cessation of treatment after thrombus retraction or resolution to the SFJ (GSV) or SPJ (SSV).

EHIT IV: Treatment for EHIT IV should be individualized, taking into account the risks and benefits to the patient. A DVT line of treatment should be followed: anticoagulation, thrombolysis, or thrombectomy.

Delayed presentation of EHIT have been treated by thrombolysis and open thrombectomy (Figures 6 and 7).²¹

Figure 6. A) Venography showing femoral and iliac vein filling defect caused by thrombotic occlusion. B) Follow-up venography after aspiration thrombectomy and catheterdirected thrombolysis.
After reference 21: Kwak et al. Vasc Specialist Int. 2016;32(2):72-76. ©2016, The Korean Society of Vascular Surgery

Figure 7. Open thrombectomy of the left saphenofemoral junction. Thrombus (that nearly obliterated the vein) removed via a small longitundinal venotomy. The thrombus extended from the great saphenous vein that was obliterated by the previous endovenous laser ablation.
After reference 21: Kwak et al. Vasc Specialist Int. 2016;32(2):72-76. ©2016, The Korean Society of Vascular Surgery.

Conclusion

EHIT behaves differently than a spontaneous DVT, displaying ultrasonography chronicity at a much earlier time. Close duplex ultrasound observation of EHIT I without pharmacologic prescription is suggested. Treatment of EHIT II with low-molecular-weight heparin or non–vitamin K antagonist oral anticoagulants (NOACs) until the EHIT can be reclassified to EHIT I by duplex ultrasonography is suggested. EHIT III or IV should be treated according to the suggested guidelines for DVT.

CORRESPONDING AUTHOR
Athanasios D. Giannoukas, MS, FVES, FIDF,
FIUA
Annapurna Hospital, Kathmandu, Nepal
EMAIL: sandeeprajpandey@gmail.com


References
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