De novo arteriovenous malformations in post-thrombotic limbs

Abstract

A 50-year-old woman presented with progressive, painful and disabling swelling of the left lower limb following a left ovarian cyst excision 2 years ago. She had gross oedema of the left lower limb with multiple pubic varices. Contrast-enhanced CT and digital subtraction imaging revealed diffuse arteriovenous malformation (AVM) with feeders from the left internal iliac artery and a short segment significant stenosis of the proximal left common iliac vein. She underwent angioplasty and stenting of the left iliac vein. Her symptoms dramatically improved following the procedure and her limb swelling regressed within 6 months. The occurrence of post-thrombotic AVMs has been long established in the dural and portal systems. This report deals with an analogous phenomenon following iatrogenic deep venous thrombosis of the left lower limb, its pathogenesis, natural history and a review of treatment options.

Background

The presence of de novo arteriovenous malformations (AVMs) due to a thrombotic event has been described in the dural and portal systems.

Similar high-flow lesions in the peripheral venous system are uncommon. Any patient with aggravated symptomatology and months to years after deep venous thrombosis (DVT) should be evaluated for this particular entity. Based on our own experience and review of existing literature, we maintain that the AVM is not a principal contender for treatment; rather, the venous pathology is. Further clinical studies are essential to comprehend the natural history and how these AVMs contribute to clinical expression in post-thrombotic limbs.

Case presentation

A 50-year-old woman presented with debilitating and painful left lower limb oedema and difficulty in walking for 6 months. She had no systemic symptoms. There was a history of elective laparotomy and left ovarian cyst excision, at an outside hospital, 2 years ago. The baseline contrast-enhanced CT of the abdomen and pelvis was reported as only a left ovarian cyst, which was later found to be dermoid on histopathology. There was no AVM reported in the prior imaging. In the postoperative period, she developed swelling of the left lower limb. A duplex scan revealed a left iliac vein DVT, which was managed conservatively with anticoagulation.

When she presented to us, the left lower limb was swollen and tense, compared with the right lower limb (figure 1A).

Figure 1.

(A) Massive left lower limb swelling associated with pubic varices at presentation. (B) Pubic varices secondary to proximal venous hypertension (blue arrows). (C) Regressed limb swelling, on 1 year of follow-up, after iliac vein recanalisation.

She also had dilated suprapubic varices. No pulsations were appreciated on palpation over the varices (figure 1B).

There were no skin changes or ulceration. Abdominal examination revealed a midline scar of the prior surgery. The abdomen was soft and non-tender, with no palpable mass.

Investigations

A contrast-enhanced CT scan revealed early opacification of the left internal iliac vein (LIV) suggestive of an abnormal communication between the left internal iliac artery(IIA) and LIV (figure 2A, B). Other findings included a short-segment tight stenosis of the left common iliac vein (CIV) as well as multiple torturous venous collaterals in the pubic region, perineum, groin, thigh and gluteal region. Digital subtraction angiography showed a diffuse nidus in the left side of the pelvis, predominantly supplied by the branches of the proximal left IIA and steno-occlusive lesion of the left CIV where it was crossed by the AVM nidus (figure 3A–C).

Figure 2.

(A) CT angiogram showing early contrast filling (blue arrow) of the pubic varices. (B) CT angiogram, coronal sections, showing nidus at the level of left internal iliac artery and vein and enlarged limb girth on the left side (blue arrows).

Figure 3.

(A) Diagnostic angiogram demonstrating an acquired arteriovenous malformation with a diffuse nidus around the left internal iliac vessels (blue arrow). (B) Delayed images during diagnostic angiogram showing rapid venous filling. (C) Diagnostic venogram revealing proximal common iliac vein compression with the diffuse disease along the length (blue arrow).

Differential diagnosis

The differentials that were considered include trauma during surgery leading to either isolated venous stenosis or an AV fistula, malignant venolymphatic obstruction, post-thrombotic syndrome or de novo AVM contributing to left CIV compression.

Treatment

As her symptoms were attributable mainly to venous hypertension with a clinically silent AVM, it was decided to address only the venous obstruction. The occluded segment was crossed, dilated by serial balloon angioplasty and deployment of a wall stent (Boston Scientific) measuring 18 mm×9 cm (figure 4A–C). Poststenting venogram showed a good antegrade flow through the stent, with no collaterals. She was placed on therapeutic anticoagulation and compression therapy postprocedure.

Figure 4.

(A) Left CIV balloon plasty. (B) Sgnificant waisting along with the inflation site. (C) Poststenting venogram demonstrating uniform and brisk flow across the CIV. CIV, common iliac vein.

Outcome and follow-up

She has been on follow-up with us for the past 2 years and remains asymptomatic. At the last review, she was relieved of all her symptoms and can ambulate without difficulty. Her limb swelling significantly decreased (figure 1C).

Discussion

AVMs have been traditionally believed to be of congenital aetiology.¹ Historically, there have been a few reports in cerebral and portal circulation of spontaneous novel AVMs, hypothesised to be secondary to venous thrombosis.^{2 3}

In 1991, Fournier et al reported four cases of acquired dural AVMs as sequelae of cerebral venous thrombosis.²

Terada et al demonstrated the development of new AVMs in an animal model by inducing venous hypertension.⁴ The process of neovascularisation following DVT is well established, though awareness and consequent contribution to the pathology are disputable, especially in peripheral vein thromboses.

To contribute to a refined understanding, a literature search was conducted on PubMed using keywords Lower limb, Arteriovenous malformation, Arteriovenous fistula, May Thurner syndrome and Deep venous thrombosis, restricted to English literature, up to December 2020, which has yielded 9 other case reports, elaborating 21 cases (tables 1 and 2). Our review and analysis indicate that spontaneous AVMs after lower limb DVT may be a less known and thereby overlooked entity. The arterialisation of a post-thrombotic limb can be suspected if the patient develops intractable painful oedema, progression of skin changes with ulceration and lesser encountered symptoms such as pulsatile/bleeding varices or congestive cardiac failure.

Table 1.

Literature review concerning acquired peripheral AVMs following DVT

Author	Age/sex	Side	DVT	Time since DVT (months)	Symptoms	Location of AVM	Treatment	Follow-up
Chikamatsu et al8	67/M	Left	+ve	36	Painful swelling and ulcer	External iliac, common femoral and deep femoral arteries	Palma procedure, surgical ligation of arterial feeders followed by embolisation	Asymptomatic
Elias et al13	18/M	B/L	+ve	6	Painful limb swelling	Common femoral artery (right), common femoral, superficial femoral and profundafemoris (left)	Four treated medically, one by endovascular stent graft, one by embolisation and one by surgical ligation (the rest not mentioned)	Improvement in clinical status
	82/F	Right	+ve	1	Painful limb swelling	Common femoral artery
	82/M	Left	+ve	17	Painful limb swelling and lipodermatosclerosis	Common femoral artery
	75/M	Right	+ve	36	Limb swelling	Superficial femoral artery
	89/M	Left	+ve	17	Painful limb swelling	Common femoral artery
	64/M	Left	+ve	120	Painful oedema, bleeding varices, Right heart failure	Internal iliac, common femoral, profundafemoris, popliteal
	73/F	Right	+ve	120	Painful oedema	Common femoral artery
	71/M	Right	+ve	24	Painful oedema, lipodermatosclerosis, right heart failure	Common femoral, superficial femoral and profundafemoris
	48/M	Left	+ve	24	Debilitating oedema	Common femoral and superficial femoral
	71/M	Left	+ve	20	Debilitating oedema	Common femoral and superficial femoral
Link et al7	80/F	Left	+ve	72	Swelling, hyperpigmentation, pulsatile mass over the inguinal ligament	Medial circumflex femoral artery	Embolisation+sclerotherapy (3 years later)+compression therapy	Recurrent ulcer requiring sclerotherapy
	55/F	Left	+ve	60	Painful swelling of the involved limb	Inferior epigastric artery	Embolisation+compression therapy	Well controlled
Link and Granchi14	86/M	Left	+ve	84	Swelling and painful ulcers	IIA	Embolisation+foam sclerotherapy+laser+compression	Asymptomatic
Yuan et al12	78/M	Left	+ve	24	Painful swelling of the limb, suprapubic varices	IIA	CIV stenting	Asymptomatic
Huynh et al15	91/F	Left	+ve	12	Painful limb swelling+ulceration	IIA	Embolisation+venous stenting	Asymptomatic
Coelho et al16	77/F	Left	+ve	?	Painful swelling	IIA	Embolisation followed by exclusion of fistula by stent grafting followed by iliac vein stenting	Asymptomatic
Che et al17	82/F	Left	+ve	?	Swelling and pain	IIA	Embolisation and stenting of left CIV	Asymptomatic
	71/F	Left	+ve	?	Swelling and pain	IIA	Embolisation and stenting of left CIV	Asymptomatic
	79 /F	Left	+ve	?	Limb swelling and ulcer	IIA	Embolisation and left CIV	Asymptomatic
Gao et al10	56/F	Left	+ve	24	Painful swelling, hyperpigmentation, ulcer and varices	Lumbar artery, iliac artery and CFA	Embolisation followed by femoral–femoral vein bypass by Gore-Tex graft followed by CIV stenting	Asymptomatic

AVM, arteriovenous malformation; B/L, Bilateral; CFA, Common femoral artery; CIV, common iliac vein; DVT, deep venous thrombosis; F, female; IIA, internal iliac artery; M, male; +ve, Positive.

Table 2.

Analysis of the literature review

Variable	Results
Age (years)	18–91 years (median of 71.2 years)
Sex	Male	11 (52.4%)
	Female	10 (47.6%)
Side	Left	16 (76.2%)
	Right	4 (19%)
	Bilateral	1 (4.8%)
Time to DVT (months)	1–120 months (median of 33.2 months)
Symptoms	Painful swelling	21
	Lipodermatosclerosis	4
	Ulcers	4
	Varices	4
	Bleeding	1
	Right heart failure	2
Location	Internal iliac artery	8
	Common femoral artery	11
	Superficial femoral artery	5
	Profundafemoris artery	4
	External iliac artery	2
	Popliteal artery	1
	Medial circumflex femoral artery	1
	Inferior epigastric artery	1
	Lumbar artery	1
Procedure	Embolisation	11
	Venous stenting	7
	Exclusion stent grafting	2
	Surgical ligation of arterial feeders	2
	Vein–vein bypass	2
	Sclerotherapy of varices	2
	Medical management	4

DVT, deep venous thrombosis.

De novo AVM formation is possibly governed by epigenetic factors such as prolonged venous hypertension and hypoxia-induced paracrine effects. There have been various theories put forward to understand the evolution of a novel AVM, triggering us to ponder on the basics of angiogenesis versus recanalisation. The fibrin clot has been proven to support angiogenesis by acting as a scaffold as well as being abundant in proangiogenic growth factors.⁵ In addition, shear stress caused by venous hypertension and hypoxia induced by thrombus load have been shown to result in the upregulation of hypoxia-inducible factor-1 and growth factors such as vascular endothelial growth factor, platelet-derived growth factor, angiopoietins and chemokines from the endothelium as well as the platelet-rich thrombus.⁶ These chemokines act in a paracrine fashion by recruiting the endothelial progenitor cells which are induced to differentiate in the favourable fibrin milieu, leading to neovasculogenesis. The elevated venous pressures may later lead to thickening and arterialisation of the new vessels, leading to the development of a spontaneous AVM. The other hypotheses include remodelling of the vasa vasorum in response to lofty venous pressures or the modification of innate microscopic arteriovenous (AV) communications into clinically and radiologically significant AV shunts following an insult. There have also been studies that propose prothrombotic phenomena like factor V Leiden mutation, which may predispose to spontaneous AVMs, not only because of recurrent thrombotic events but also because of impaired recanalisation.⁷ All the patients in the review, except one,⁸ have received only therapeutic anticoagulation for DVT.

Although the definitive sequence of events is unproven, the existence of novel AVMs can be seen as a late sequela of venous thrombosis that can be effectively treated, when recognised. It may be a tribute to the human body’s attempt at intrinsic repair, especially when we draw an analogy to the practised surgical tradition of creating an AV fistula in patients undergoing a deep vein bypass to improve patencies.⁹

Because natural history remains to be a puzzle, the management presents a conundrum. Though most of the papers in the review addressed the AVM by embolising or excluding it, the recent report by Gao et al effectively questions this line of treatment.¹⁰ Their patient underwent multiple episodes of embolisation followed by exclusion stenting of the AVF only to get symptomatic relief much later by successful venous stenting. This uncertainty is also prompted by patients who underwent a sole embolisation procedure, considering it the primary pathology, obtaining incomplete relief or requiring subsequent sclerotherapy for venous ulcer development. This indicates that in most cases, the AVM may not be a principal dilemma; rather, the contributing venous occlusion is. This is in contrary to,

Koshy et al, who reported successful outcomes by managing both inflow and outflow components in an iliac AV fistula, where the arterial element had a significant phenotypical translation.¹¹ Yuan et al, who approached their patient by isolated venous stenting, have noted that at 3 months, the AVM had disappeared on imaging evaluation.¹² We propose that, in post-thrombotic novel vascular malformations, the AVM needs addressing, only if it is clinically noteworthy.

Patient’s perspective.

Following the rapid development of my left leg swelling, I was apprehensive there may be underlying cancer. However, after my investigations, my doctors have convinced me that it is something less morbid and treatable. Following the vein intervention, my leg has come back to its normal size over 6 months and remains the same to this day.

Learning points.

• Spontaneous de novo arteriovenous malformations are extremely uncommon sequelae of post-thrombotic limbs.

• Epigenetic factors like venous hypertension and hypoxia, secondary to thrombus load, induce chemokines that act in a paracrine manner, promoting angiogenesis.

• Deep venous recanalisation is an effective treatment option to relieve outflow obstruction.

Ethics statements

Patient consent for publication

Obtained.