Extensive deep vein thrombosis treatment using fondaparinux and edoxaban: a case report

A 63-year-old man was referred to our hospital because of pain, redness and swelling
in his left leg persisting for 1 month. At the onset of symptoms, he consulted the
neighboring dermatological clinic where he was diagnosed with cellulitis. Antibiotics
and nonsteroidal anti-inflammatory drug were administrated, but his symptoms did not
improve. After 1 month, he was referred to our VTE specialist department.

The patient had a history of hypertension, which was treated with a calcium channel
blocker and an angiotensin receptor blocker. At the initial examination, his body
mass index was 33 kg/m
²
, the vital signs showed a mildly elevated blood pressure (134/84 mmHg) and his peripheral
oxygen saturation was 98 % in ambient air. The physical examination revealed a tender
and swollen left leg. Laboratory test showed elevated levels of urinary acid (8.3 mg/dL)
and blood glucose (116 mg/dL). His HbA1c was 5.7 %. Prothrombin and partial thromboplastin
times were normal, although D-dimer concentrations were increased to 5.9 ?g/mL (normal,
1.00 ?g/mL). Plasma protein C, protein S, and antithrombin levels were within normal
limits, and creatinine clearance was 113.8 mL/min, as calculated using the Cockcroft–Gault
method. Chest X-rays showed no abnormalities. Echocardiography was significant for
mild concentric left ventricular hypertrophy with normal left ventricular function
and showed no signs of increased right ventricular pressure.

DVT was suspected because of the patient’s symptoms and elevated D-dimer concentrations.
Ultrasonography revealed a thrombus in the left but not in the right femoral vein
(Fig. 1), and computed tomographic angiography revealed clots in the right distal pulmonary
artery. The maximum circumference of the thighs showed a swelling in the left leg
(left calf: 47 cm, left ankle: 28.5 cm, right calf: 44 cm, right ankle: 27 cm).

Fig. 1. Ultrasonography showing the regression of deep venous thrombosis. a Ultrasonography (iU-22, Philips) images of the left lower extremity showing extensive
deep vein thrombosis at the initial examination (1 month after the first appearance
of symptoms); Additional file 1. b Ultrasonography (Noblus, Hitachi Aloka Medical) images of the left lower extremity
after 3 months of treatment; Additional file 2. Although some thrombi are still visible in the popliteal vein, no remaining thrombi
were observed in the left superficial femoral and soleus muscle veins. c Ultrasonography (Aplio XG, Toshiba) images of the left lower extremity after 6 months
of treatment; Additional file 3. No remaining thrombi were observed and only mural thrombi remained in the popliteal
vein

We instructed the patient to wear medical compression stockings and provided the anticoagulant
treatment with subcutaneous injections of fondaparinux (7.5 mg once daily for 5 consecutive
days on an outpatient basis), followed by oral administration of edoxaban (60 mg once
daily from day 6). Different from western countries, the self- injection of fondaparinux
is not allowed in Japan, so the patient was required to visit the hospital every day.
After 2 weeks, swelling of the left leg improved, although redness and pain persisted.
Subsequent ultrasound examination of the leg after 3 months of treatment with edoxaban
revealed no clots in the left superficial femoral vein and soleus muscle vein. Moreover,
D-dimer concentrations had dropped to normal levels, indicating decreased activation
of secondary fibrinolysis. However, because some clots were still observed in the
popliteal vein (Fig. 1), treatment with edoxaban was continued.

After 6 months, the swelling and redness in the lower leg had completely disappeared,
and D-dimer concentrations remained normal. Ultrasonography showed further regression
of the clots in the left popliteal vein, leaving only mural thrombi (Fig. 1). Throughout the treatment period, doses of fondaparinux and edoxaban were not changed,
and no bleeding complications occurred. The symptom of recurrence of pulmonary embolism
was not observed during the clinical course. We suggested to end the edoxaban therapy
after 6 month, but the patient hoped for a continuation of the anticoagulation therapy.

Discussion

Until recently in Japan, proper management of DVT required continuous antithrombotic
therapy using unfractionated heparin followed by VKA administration within the optimal
therapeutic range. In Japan, fondaparinux was approved in 2011. The approval of fondaparinux
injections for VTE has relieved patients and physicians of the need for complex dose
adjustments, 24-h infusion control, and blood tests every 6 h. Fondaparinux is associated
with recurrent VTE and major bleeding rates similar to those occurring with intravenous
unfractionated heparin (UFH) 7], 8]. The reasons for outpatient treatment in this case were that the patient was hemodynamically
stable and did not suffer from renal failure, cancer, massive pulmonary embolism,
heart failure, or bleeding. Furthermore, he had a good understanding about his illness.

Edoxaban was approved in Japan prior to the world as an oral factor Xa inhibitor,
and the ESC guidelines recommend the use of edoxaban following acute-phase parenteral
anticoagulation therapy. Dabigatran also gained approval as an oral VTE treatment
following acute-phase parenteral anticoagulation therapy by Europe and United States
besides Japan.

The RE-COVER and Hokusai-VTE trials mandated at least 5 days of heparin or low molecular
weight heparin (LMWH) treatment prior to initiation of dabigatran or edoxaban 9]–11]. Dabigatran and Edoxaban both showed a no inferiority to warfarin for the prevention
of recurrent VTE, and a significantly lower risk of major bleeding. Additionally,
a lower proportion of the administered dose of edoxaban is eliminated via the kidneys
(35 %) compared to dabigatran (85 %) 12], 13]. The pharmacokinetics of edoxaban were not affected by enoxaparin, whether administered
concomitantly or 12 h apart 14]. Edoxaban is a once daily tablet, which is easier to swallow than dabigatran. In
addition, dabigatran is not approved for VTE treatment in Japan. These reasons led
us to choose this regimen using fondaparinux and edoxaban in this case.

The ACCP guideline stated that in patients with acute DVT of the leg, the guideline
suggest early ambulation over initial bed rest (Grade 2C), and that in patients with
acute DVT of the leg and whose home circumstances are adequate, the guideline recommend
initial treatment at home over treatment in hospital (Grade 1B). Unfortunately this
patient couldn’t be hospitalized, so we started the anticoagulant therapy carefully.
According to the RIETE registry 15], home treatment of DVT is appropriate in younger men with adequate weight who have
no complications of heart failure, respiratory diseases, or cancer. Additionally,
we suggest that patients must also understand their condition of illness, visit the
hospital daily for fondaparinux administration at least 5 days, and put on and remove
medical stockings by themselves or with the help of a family member. Moreover, other
medical institutions, including specialist facilities that manage hemorrhagic events
or pulmonary embolism, and clinics that cooperate with appropriate specialist institutions
are appropriate alternatives to hospitals.

The objectives of DVT treatment include the prevention of recurrence and regression
of thrombotic clots, although echogenic masses tend to regress slowly 16]. The precise mechanism by which the factor Xa inhibitor edoxaban causes thrombus
regression remains unclear, and no fibrinolytic activity of this agent has been described.
Initiation of fibrinolysis occurs through a number of orchestrated interactions among
fibrin and plasminogen as well as its activator and results in the generation of plasmin
17]. Therefore, the efficacy of edoxaban may reflect the potency of the fibrinolytic
response relative to that of the coagulation response.

Edoxaban reportedly exerts a stable anticoagulant effect compared with conventional
drugs 18], 19] and serum D-dimer concentrations are widely used as a marker for secondary fibrinolysis
following clot formation. In the present case, D-dimer concentrations rapidly normalized
within 2 weeks and remained in the normal range at 6 months. However, clots continued
to regress after the normalization of D-dimer concentrations, warranting the development
of more sensitive markers of fibrinolysis during slow regression of thrombosis.

In the Hokusai-VTE Study 9], edoxaban was compared with VKA. A therapeutic range was achieved ?60 % of the treatment
period and the reoccurrence of thrombosis was effectively prevented. Factor Xa inhibitors
may provide more stable effects on the fibrinolytic system easily.

The ESC guidelines recommend that treatment for DVT be continued for at least 3 months,
and extensions of the treatment period should be considered depending on individual
patient conditions. Our patient’s VTE risk was idiopathic, which is why we treated
him with NOACs for more than 3 months.

In this case, symptoms improved after 3 months, and thrombotic clots remaining in
the popliteal vein subsequently regressed further while continuing treatment, indicating
the importance of thorough follow-up with ultrasonography and monitoring of subjective
symptoms and blood parameters.

Attention is described at the end. In this case, he was misdiagnosed with cellulitis
at the onset. The initial misdiagnosis leads to delay of treatment. Cellulitis is
an acute, spreading pyogenic inflammation of the dermis and subcutaneous tissue, usually
complicating a wound, ulcer, or dermatosis. The area, usually on the leg, is tender,
warm, erythematous, and swollen. The differential diagnosis of cellulitis is very
important to DVT 20].