How to Deal with Patients with Hypercoagulable States and Severe Superficial Valvular Incompetence

by Suman Rathbun, MD and Federico Silva, MD

In the United States, an estimated 23% of adults have varicose veins, and 6% have more advanced chronic venous disease (CVD), including skin changes and healed or active venous ulcers.(1) Varicose veins have long been considered a cosmetic problem that only affects emotional well-being, but are not the source of disability. Varicose veins,however, are frequently the cause of discomfort, pain, loss of working days, and deterioration of health-related quality of life (QOL). Severe CVD may also lead to loss of limb or loss of life. ^[^1]

Varicose veins of the lower limbs are dilated subcutaneous veins that are more than 3 mm in diameter and measured in the upright position.^[^2] Synonyms include varix, varices, and varicosities—all a result of superficial vein incompetence. Active venous ulcers are present in up to 0.5%, and between 0.6% and 1.4% have healed ulcers. On the basis of estimates of the San Diego epidemiologic study, more than 11 million men and 22 million women between the ages of 40 and 80 years in the United States have varicose veins, and more than 2 million adults have advanced CVD with skin changes or ulcers.^[^1]

Demographics for venous disease

The National Venous Screening Program screened 2,234 Americans for venous disease. The participants’ mean age was 60 years— 77% were women and 80% were white. The CEAP (clinical, etiologic, anatomic, pathologic) classification was C0: 29%, C1: 29%,C2: 23%, C3: 10%, C4: 9%, C5: 1.5%, and C6: 0.5%. This highlighted that most disease was mild. Deep and superficial venous reflux was documented in 37% of participants and obstruction was found in 5% of participants.^[^3]

The biological cause of superficial venous incompetence is likely an intrinsic, morphologic or biochemical abnormality in the vein wall, although the etiology can be multifactorial. One theory is that the origin of venous reflux in patients with primary varicose veins can be local or multifocal structural weakness of the vein wall, and that this can occur together or independently of proximal saphenous vein valvular incompetence.^[^4] Varicosities can also develop as a result of secondary causes, such as previous deep vein thrombosis (DVT), deep venous obstruction, superficial thrombophlebitis, or arteriovenous fistula. Varicose veins may also be congenital and present as a venous malformation.

Varicose veins can progress to a more advanced form of chronic venous dysfunction, chronic venous insufficiency (CVI) that may heighten the risk of thrombosis.^[^5] In CVI, increased ambulatory venous hypertension initiates a series of changes in the subcutaneous tissue and the skin: activation of the endothelial cells, extravasation of macromolecules and red blood cells, diapedesis of leukocytes, tissue edema, and chronic inflammatory changes most frequently noted at and above the ankles.^[^6] Limb swelling, pigmentation, lipodermatosclerosis, eczema, or venous ulcerations associated with inflammation can develop in these patients—all which may increase their risk of thrombosis.

Thrombotic risk

There is an increased risk for thrombosis due to the mere presence of VV, but the cause is not completely understood and is a matter of debate. It has been postulated that a reason for increased thrombotic risk might be a reduction in fibrinolytic activity related to deep vein thrombosis (DVT), superficial vein thrombosis (SVT), chronic venous insufficiency (CVI), and varicose veins. A small study investigated whether D-dimer levels were increased in the varicose veins of patients in comparison to their own arm samples.^[^8]Twenty-four patients (C2-6) awaiting saphenous laser ablation were compared to an equal number matched controls. Concurrent venous blood samples were taken from the arm and a lower calf/ankle (varicose) vein. The median (interquartile range) D-dimer (ng/mL) level was significantly greater in the ankle than in the arm blood of the same patient but did not occur in the controls. Based on this, the authors stated that increased thrombotic activity or dissolution of formed sub-clinical fibrin thrombus may explain the association of varicose veins with superficial vein thrombosis.

The link between varicose veins and thromboembolism risk

In another study evaluating the differences between varicose veins and ulnar veins, the investigators demonstrated that in 40 patients with primary VV increased levels of high sensitive C-reactive protein (hsCRP), von Willebr and factor and D-Dimer were present when compared to ulnar blood samples. This finding suggested that inflammatory markers and indicators of endothelial dysfunction are increased in VV blood samples. This is most probably the consequence of deteriorated blood flow in dilated and tortuous superficial veins with increased venous pressure. Damage to the venous wall, which causes a chronic inflammatory response, together with the pro-coagulant properties of local blood, may promote further progression of the disease and thrombotic complication.^[^9]

The incidence of venous thrombosis in patients with varicose veins has been evaluated. A recent study of a large primary care registry in Germany showed 132 out of 2,357 (5.6%) DVT episodes among patients with VV, compared to 728 out of 80,588 (0.9%) in the patient cohort without VV (p < 0.0001).^[^7] A study looking at the incidence of SVT in VV aimed to address the role of the programmed cell death in the vein wall by comparing patients with VV with history of SVT to uncomplicated VV. Vein segments from the proximal part of the great saphenous vein (GSV), the distal part of the vein, and from a varicose tributary in 16 patients with varicose vein disease and one patient with SVT, were evaluated for the immunohistochemical expression of pro-apoptotic (Bax, p53, Caspase 3, BCL-6, BCL-xs), anti-apoptotic (BCL-xl and BCL-2) and proliferation (Ki-67) markers. The vein wall in SVT showed increased pro-apoptotic activity compared to uncomplicated disease and normal veins. These results, albeit from a small sample, question whether increased vein wall cell apoptosis is a causative factor for SVT in varicose veins or a repairing mechanism of the thrombosis itself.^[^10]Therefore, patients with varicose veins may in fact have a hypercoagulable state due to their underlying

inflammatory disease.

The incidence of hypercoagulable states in patients with varicose veins has been evaluated in small studies. A prospective study of 230 patients with VV evaluated the incidence of inherited thrombophilia. A total of 128 patients had an acute episode or a previous history of SVT, while 102 patients did not. Coagulation profile investigation included serum levels of protein C (PC), protein S (PS), anti-thrombin III (AT III),plasminogen (Plg), A2 antiplasmin (A2Apl), and activated protein C resistance (APCR).This was performed at least three months after the SVT episode to ensure that the results were not altered. Obesity, age, and PS deficiency were found as factors associated with SVT in patients with VVs. ^[^11] Another study prospectively followed 97 patients with SVTs and VVs for 55 months, and 13 patients had SVT recurrence— all of which had thrombophilia, most commonly FII mutation. ^[^12]In patients with VV, an increased risk of DVT was also associated with acquired hypercoagulable states, including previous DVT (adjusted odds ratio (OR): 9.07, 95% confidence interval (CI): 7.78 -10.91), VV (OR 7.33 [CI 6.14 - 8.74]), hospitalization during the last 6 months (OR 1.69 [CI 1.29 - 2.22]), malignancy (OR 1.55 [CI 1.19 - 2.02]), and age (OR 1.02 [CI 1.01 -1.03]. Special attention is required for patients with VV, a history of previous venous thromboembolism, comorbid malignancy, and recent hospital discharge—particularly those with a combination of these factors.^[^7]

After-evaluation findings for post-treatment thrombotic risk

Despite the increased risk of venous thromboembolism in patients with varicose veins, the overall incidence of venous thrombosis after varicose vein treatment is low. A large national British code-based study retrospectively identified 35,374 patients with VV that underwent endovenous vein treatment over two years. The overall incidence of VTE was 0.51%. A total of 126 patients presented with post-operative DVT (0.36%) and 53 with aPE (0.15%). The median time to re-presentation with DVT and PE was 11 days (IQR: 0–77 days) and 18 days (IQR: 8–48 days), respectively. The incidence of VTE was comparable in those undergoing open surgery (0.54%), sclerotherapy (0.19%), and endovenous laser therapy (0.47%). The incidence of VTE appeared to be highest in those undergoing bilateral redo or short saphenous vein surgery, as well as those undergoing a combination of endovenous laser ablation (EVLT) and phlebectomy.

Based on these findings, the authors recommended DVT prophylaxis in this population.^[^13]A study from Denmark of 500 consecutive patients (580 legs) with GSV reflux randomized to endovenous laser ablation, radio frequency ablation, foam sclerotherapy, and surgical stripping for great saphenous varicose veins, reported one patient that developed a pulmonary embolus after foam sclerotherapy and one deep vein thrombosis after surgical stripping. No other major complications were recorded.^[^14)]VTE appears to be rare after vein treatment. Another randomized trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom compared foam, laser, and surgical varicose vein therapy. The frequency of any procedural complications was lower in the laser group (1.0%) than in the foam group (6.2%) or the surgery group (7.1%) (P<0.001 for both comparisons).

The reported serious adverse events at six months were three DVTs (n= 286 patients, 1.02%) in the foam group, and no thrombosis reported in the other groups.^[15]Based on the above reported low risk of VTE after varicose vein treatment, whether to test for thrombophilia in patients with or without history of VTE remains controversial. The American College of Chest Physicians guidelines recommend against the use of prophylaxis in patients with asymptomatic thrombophilia.^[^16] Since is not likely to change the peri-procedural management, it is likely not warranted to test patients for thrombophilia, regardless of their presentation. The national treatment guidelines vary in their approach to treatment of VV in the setting of hypercoagulable states. The American College of Phlebology clinical practice guidelines on superficial venous disease do not mention hypercoagulable states in their recommendations.^[^17] The American Venous Forum recommends selective evaluation for hypercoagulable states for those with recurrent DVT, thrombosis at a young age, or thrombosis in an unusual site. They also recommend laboratory examinations in patients with long-standing venous stasis ulcers and in selected patients who undergo general anesthesia for the treatment of chronic venous disease. ^[^18]

Other opinions

The UIP (Union Internationale du Phlebologie) guidelines on chronic venous disorders make a similar statement that the role of thrombophilia in chronic venous disease needs to be determined.^[19] So, how should we approach patients with superficial venous incompetence and hypercoagulable states? Patients with severe valvular incompetence that otherwise would be candidates for intervention and have an acquired thrombophilia as described above can be managed conservatively and have acquired hypercoagulable states addressed, ideally by waiting three months after an infection, hospital admission, or surgery. If there is known malignancy, deferring treatment should be discussed with the patient. In patient swith severe valvular insufficiency with inherited thrombophilia and a history of VTE, a discussion of the estimated risks and benefits with the patient should be paramount in deciding when and if to proceed.

If the decision is made to proceed with VV treatment, prophylactic therapy for VTE prevention may be considered. Options include aspirin, low molecular weight heparin(LMWH), warfarin and direct oral anticoagulant medications (DOACS). There is no data to support prophylactic use of ASA after venous procedures in thrombophilic patients, but data from ASPIRE and WARFASA trials evaluating the recurrence of VTE in patients with a history of unprovoked VTE prescribed 100 mg of aspirin showed a statistical significant risk reduction compared to placebo.^[^20] Prophylactic LMWH has been studied as a preventative measure after procedures in few studies.

A Spanish trial randomly assigned 262 VV patients undergoing treatment who had at least two risk factors (patient, medical, surgical, and hypercoagulable states) to 10 days of prophylactic LMWH—both groups had compression and early ambulation. The patients had visits at 30 days and at three months, and underwent surveillance DVT screening ultrasound at each visit, whether they had symptoms or not. Two patients in the LMWH had known thrombophilia, two in each group had history of VTE, 14 had family history of VTE, and 10 were taking oral contraceptives. No DVTs were found in any group.

Final thoughts

SVT developed in both groups, although it was not statistically different (9.2% in LMWH group vs. 3% in no LMWH group, p=0.18).^[21] The use of DOACs has not been studied for VTE prevention after varicose vein treatment but may be considered given the ease of use and low bleeding risk in patients with a history of VTE. Despite the lack of evidence, endothermal heat-induced thrombosis (EHIT) very proximal to the GSV junction may be treated with a short course of anticoagulation due to the concern of progression to DVT. In conclusion, the incidence of hypercoagulable states in patients with varicose veins is low. Although, varicose veins themselves confer a biological increased risk of hypercoagulability likely due to inflammation, the incidence of VTE post varicose vein treatment is also low. If it is determined that the patient has an elevated risk of VTE, in the absence of definitive studies and national guidelines, the risks and benefits of prescription of anticoagulation for prevention of VTE post-varicose vein treatment should be carefully reviewed with the patient.

References:

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