Use of Rivaroxaban for Prophylaxis of Superficial Venous Thrombosis in Klippel-Trenaunay-Weber Syndrome: Case Report and Systematic Review
Hina Quamar and Cynthia Wu
Klippel-Trenaunay-Weber syndrome (KTWS) is a congenital malformation syndrome involving blood and lymph vessels and disturbed bone and soft tissue growth. Complications of KTWS include deep-vein thrombosis, pulmonary embolism, gastrointestinal bleeding, and vascular (usually lymphatic) blebs within capillary malformations. We present a case of a young male patient with KTWS who presented with superficial venous thrombosis and microangiopathic hemolytic anemia in a presentation similar to disseminated intravascular coagulation. He was ultimately maintained on prophylactic rivaroxaban to prevent recurrent thrombotic events. We performed a literature search to identify similar cases and to summarize common presenting features and treatment modalities that were offered.
Le syndrome de Klippel-Trenaunay-Weber (KTWS) est un syndrome de malformation congénitale impliquant le sang et les vaisseaux lymphatiques et les os perturbés et la croissance des tissus mous. Les complications de la KTWS comprennent la thrombose veineuse profonde, l'embolie pulmonaire, les saignements gastro-intestinaux et les bulles vasculaires (habituellement lymphatiques) dans les malformations capillaires. Nous présentons un cas d'un jeune patient mâle avec KTWS qui a présenté une thrombose veineuse superficielle et une anémie hémolytique microangiopathique dans une présentation semblable à la coagulation intravasculaire disséminée. Il a finalement été maintenu sur des rivaroxaban prophylactiques pour prévenir les épisodes récurrents de purpura. Nous avons effectué une recherche documentaire pour identifier des cas similaires et pour résumer les caractéristiques communes de présentation et les modalités de traitement qui ont été offerts.
An 18-year-old man from Edmonton with known Klippel-Trenaunay-Weber syndrome (KTWS) had a history of a slowly increasing vascular mass on his left chest and left arm. He began tetradecyl (sclerosant) injection in December 2009. His fifth dose was on 20 May 2010. The goal of these injections was to reduce the size of these malformations and decrease symptoms. After his fifth injection, he experienced flu like symptoms accompanied by worsening pain in his left arm over the site of venous malformation with swelling and ecchymosis. His fatigue and pain had progressed such that he was largely bed bound at home for three days before presenting to the emergency room.
Examination revealed: BP 128/73, temperature 39.5 degrees Celsius, O2 saturation 100% on 6L non-rebreather mask. He was profoundly icteric. A large vascular malformation was present on his left posterior thorax and there was a significant swelling of his left arm extending from the shoulder down to his hand and fingers. Smaller hemangiomata were noted on his left arm and hand. The venous malformation and left arm were extremely tender with significant bruising and provoked by even minimal movement.
When investigated, his hemoglobin was 24g/L, white blood cell count was 21.4 with a neutrophil count of 19, platelets 98. Electrolytes and creatinine were normal. Markers of hemolysis were positive with a total bilirubin 588, unconjugated bilirubin 212 and LDH 1597. Direct antiglobulin test was negative. D-dimer greater than 20. Computed tomography angiogram ruled out any obvious sources of bleeding. Blood cultures were negative for any source of infection.
The patient was diagnosed with Kasabach-Merritt syndrome - coagulopathy resulting from coagulation factor consumption within vascular malformations. It was felt that the precipitating factor was his preceding tetradecyl injection. He was treated with aggressive supportive care/blood product transfusion. After bleeding was ruled out as a cause for the anemia, he was commenced on routine deep-vein thrombosis (DVT) prophylaxis with low dose low-molecular-weight heparin (LMWH). Interestingly, he noted that the painful symptoms immediately started to improve after anticoagulation was started. An ultrasound of his left arm over the venous malformation revealed old superficial venous thrombosis with recanalization. His coagulopathy eventually settled and his complete blood count and biochemical parameters started to normalize. He was discharged in stable condition. Table 1 summarizes the laboratory parameter trends from initial disseminated intravascular coagulation presentation to recovery.
Table 1. Laboratory Parameter Trends from Initial Disseminated Intravascular Coagulation Presentation to Recovery
He was referred to outpatient Hematology for evaluation of preventative measures prior to undergoing further sclerosing therapy for his KTWS. He had a few minor attacks largely characterized by significant arm pain requiring time off work. These occurred even in the absence of sclerosing therapy. Subsequent magnetic resonance imaging of the arm in December 2010 confirmed evidence of thrombosis in the areas of malformation including the left hemithorax, axilla, arm, 4th and 5th fingers. It was suggested that he commence long term low dose LMWH to try and prevent further symptomatic superficial thromboses.
Figure 1. Magnetic resonance imaging of patient showing hemangioma within venous malformation.
Due to expense and inconvenience of injections, other options were explored. After discussion regarding off-label use of rivaroxaban in this situation, he was commenced on low dose rivaroxaban 10 mg daily. He tolerated this well. He has been on treatment since 2013, aside from one episode of pain recurrence during anticoagulation interruption for dental surgery and one episode of recurrent arm pain/swelling (ultrasound negative for DVT) after heavy manual labour and upper extremity exertion. His acute thrombotic event was managed on low-molecular-weight heparin.
To review how thrombotic manifestations of KTWS are managed, we performed a comprehensive literature search on PubMed using MESH terms: KWS, thrombosis, DIC and Kasabach-Merritt coagulopathy. Of the 97 publications found, 81 were excluded as they were focused on non-thrombotic complications of KTWS. Two randomized control trials were excluded as they examined assessment and recurrence of thrombosis but not treatment and 2 cases reports were excluded as they were not in English. One case report was excluded as description of thrombosis was not reported. Results of the remaining 11 case reports are summarized in Table 2.
Table 2. Review of KTWS cases with Thrombotic Complications
This case describes a young man with KTWS and complex coagulopathy. KTWS is a congenital malformation syndrome involving blood and lymph vessels and disturbed bone and soft tissue growth.1
The main characteristics of coagulopathy in KTWS are moderate reduction in platelets, reduction in fibrinogen and other plasma coagulation factors, evidence of fibrinolysis, and the presence of fibrin split products. In studying this phenomenon, Gilon et al demonstrated a relative decrease in the peripheral blood platelet count as opposed to an increase in platelets within the haemangioma in patients with this disorder.23 Gilon et al theorized that the tortuosity of the vessels within the haemangioma resulted in the trapping and subsequent destruction of platelets which, in turn led to the activation of the coagulation mechanism and a localized intravascular coagulopathy.23 Localized intravascular coagulation rarely progresses to disseminated intravascular coagulation, especially under acute conditions (e.g., sclerotherapy of the venous malformation, surgery, bone fracture, or menstruation).2
Treatment of KTWS includes: sclerotherapy, embolization, compression stockings (to reduce lymphedema) and anticoagulation to prevent venous thromboembolism in vascular anomalies.7 When coagulopathy – local or more disseminated – results, treatment is supportive in nature. This include fresh frozen plasma, platelets, human activated protein C. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low-molecular-weight heparin is recommended.8
Our patient was considered for use of anticoagulation for secondary prevention of thrombotic events as his recurrent debilitating pain syndromes were assumed secondary to microthrombotic events within his venous malformation. There is data to support the use of short term low dose anticoagulation in the treatment of acute superficial vein thrombosis (SVT).9 Randomized controlled studies have demonstrated the efficacy and safety of systemic anticoagulation with therapeutic/intermediate doses of LMWH or prophylactic doses of fondaparinux administered for 4–6 weeks.9 Fondaparinux 2.5 mg/day is currently the only anticoagulant with a license for the treatment of SVT.23 With a large permanent venous malformation and previous recurrent thrombotic events within this vascular system, we elected to extend anticoagulation to indefinite duration. We chose to use rivaroxaban 10 mg daily due to inconvenience of daily subcutaneous heparin injections. Secondly, therapeutic rivaroxaban has been shown to be as safe and as effective compared to standard warfarin therapy in the treatment of DVT and PE.10 Thirdly, prophylactic rivaroxaban (10 mg daily) has been shown to be effective and safe as a DVT prophylactic regimen in the those undergoing major orthopedic surgery.11 Finally, prophylactic dose anticoagulation has been shown to be effective in the treatment of SVT.9
In conclusion, KTWS is a rare condition that can be complicated by a variety of thrombotic manifestations. Recurrent overt thrombotic events may be successfully treated with anticoagulation. Our patient despite symptomatic and frequent recurrent events of SVT have remained stable for over five years on, though still off label, low dose newer anticoagulant.
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Informed consent was obtained from all patients for being included in the study.