A 42-year-old male was admitted to the Department of Angiology, Arterial Hypertension, and Diabetes in Wroclaw in April 2010 with an internal jugular vein thrombosis documented on ultrasound. Pain and swelling to the left side of the neck developed several days prior to the admission. An ultrasound performed at the primary physician’s office revealed a thrombus in the left jugular vein. CT angiography performed during hospitalization at Department showed the presence of thrombotic material in brachiocephalic vein trunk and in the left subclavian vein, thickening of Waldeyer’s ring, inflammatory lesions of the right maxillary sinus, and isolated enlargement of mediastinal lymph nodes (fig. 1, 2). Pain and swelling in the representation of the sternocleidomastoid muscle and slightly increased circumference of the upper limb ipsilateral to the thrombotic site were documented during physical examination. The symptoms of thrombosis were accompanied by fever, up to 38°C. Laryngological examination revealed upper respiratory tract infection with inflammatory lesions of the pharyngeal mucosa, and compression of the palatine tonsils produced purulent discharge. A mucous content was obtained during maxillary sinus puncture.
The patient had no relevant medical history, apart from gastroesophageal reflux disease and cholecystectomy, performed several years earlier due to cholelithiasis. He had no family history of venous thromboembolic disease. Moreover, he had no history of exposure to transient risk factors for venous thromboembolism. Abnormalities in laboratory findings included slight leukocytosis with neutrophilia, and elevated concentrations of CRP and fibrinogen (tabl. 1). The remaining laboratory parameters, abdominal ultrasound, chest radiography, and Doppler ultrasound of lower extremity veins were normal. Gastroscopy and colonoscopy were formerly performed due to gastric problems, but neither revealed any significant abnormalities.
An INR-controlled treatment with low molecular weight heparin (LMWH) at a weight-adjusted dose and vitamin K antagonist (VKA) was initiated. Heparin was discontinued after INR values have reached the therapeutic range (2.0–3.0), and only VKA treatment was continued. In addition, cefuroxime was administered for 7 days in order to resolve the inflammatory lesions of the upper respiratory tract.
Due to the unprovoked character of venous thrombosis with atypical localization, the patient was tested for thrombophilia after 6 months of antithrombotic treatment. VKA was substituted with LMWH 7 days prior to the testing. The tests did not reveal a deficiency of C and S protein or antithrombin, nor the presence of Leiden factor, mutation of G20210A prothrombin gene, MTHFR gene polymorphism, anticardiolipin antibodies, anti-beta2-glikoprotein I antibodies, or lupus anticoagulant (tabl. 1). Due to enlarged mediastinal lymph nodes illustrated on the CT, the patient was referred to a hematological outpatient clinic. Initially, long-term antithrombotic treatment was recommended, due to the idiopathic character of venous thrombosis and as a result of the ongoing hematological observation. The mediastinal lesions regressed spontaneously during a two-year follow-up. Two years after the thrombotic episode, the patient was retested for antiphospholipid syndrome. The antithrombotic treatment was discontinued 7 days prior to the venipuncture. The testing yielded a weak-positive result for lupus anticoagulant, and did not show the presence of anticardiolipin and anti-β2-glikoprotein I antibodies. The antithrombotic treatment was reinstituted, with the testing repeated every 12 weeks in accordance with the IHI guidelines . The treatment was discontinued several days prior to each testing in order to avoid the modulatory effect of therapeutic agents on lupus anticoagulant expression. Ultrasound was performed because the patient reported pain and swelling of the right shoulder (fig. 3). A fresh thrombotic material occluding the right brachiocephalic vein, reaching up to the union of the internal jugular vein and subclavian vein, was discovered and interpreted as a recurrent venous thrombosis of the contralateral brachiocephalic vein. Antiphospholipid syndrome was diagnosed as well, based on the listed findings and fulfilled laboratory and clinical criteria, with a referral for long-term antithrombotic treatment.
Venous thrombosis in the upper extremities is a very rare and atypical localization for venous thromboembolism. Despite an existing anatomical continuity of the venous drainage from the upper half of the body, deep vein thrombosis involving the veins of the upper limbs (i.e. subclavian and axillary vein), internal jugular vein, and more proximal veins (brachiocephalic vein and superior vena cava), seems to bear some different clinical characteristics, and affects different groups of patients. Deep vein thrombosis of the upper limbs is frequently associated with increased physical activity involving abduction of the arm (Paget-Schroetter syndrome), thoracic outlet syndrome, pulmonary neoplasms, lymphoproliferative diseases, catheterization of central veins, or implantation of a cardiac pacemaker . While the internal jugular thrombophlebitis was previously associated mostly with nasopharyngeal infections (Lemierre’s syndrome) . The catheterization of central veins is currently the most common etiological factor of this condition . Thrombosis is usually septic in both cases. Other risk factors of developing internal jugular vein thrombosis include trauma, surgeries, massage of the neck, neoplasms of the head and neck, and intravenous drug abuse. In contrast, proximal veins of the thorax are a very rare primary location of venous thrombosis, which is usually associated with pulmonary neoplasms, chronic conditions, and catheterization of central veins [5, 6]. Moreover, each case of venous thrombosis with rare and atypical localization can be associated with either inborn or acquired hypercoagulability, for example thrombophilia (deficiency of antithrombin, protein S, protein C, presence of Leiden factor, mutation of prothrombin gene, elevated level of VIII, hyperhomocysteinemia, antiphospholipid syndrome). Data on the prevalence of symptomatic pulmonary embolism concomitant with venous thrombosis in the area described above are inconclusive; according to various authors, this complication occurs in 8.7–36% of presenting cases [5, 6].
Antiphospholipid syndrome (APS) is an autoimmune disorder accompanied by the synthesis of autoantibodies (aPI) against membrane phospholipids and phospholipid-binding proteins. The antiphospholipid antibodies (aPI) interfere with the coagulation system and increase the risk of arterial thrombosis (stroke, myocardial infarction), venous thrombosis (venous thromboembolic disease), microvascular thrombosis, and obstetrical failu-res resulting from changes in placental vessels. Apart from the abovementioned clinical diagnostic criteria of APS, the syndrome can be associated with an array of other abnormalities. Its clinical manifestation can also include cardiac involvement with heart valve damage and potential systemic embolic complications. Apart from ≥ 1 clinical criterion, at least one laboratory criterion has to be met in order to diagnose APS, namely the presence of lupus anticoagulant (LAC), IgG and/or IgM anticardiolipin antibodies (aCI; medium or high titer > 40 GPL, MPL, or > the 99th percentile), or IgG and/or IgM anti-beta2-glikoprotein I antibodies (anti-B2GPI; > the 99th percentile) . According to the guidelines of the International Society on Thrombosis and Haemostasis , the presence of antiphospholipid antibodies should be detected at least twice at a ≥ 12-week interval, no earlier than 12 weeks and no later than 5 years after a vascular episode.
In the case of our patient, the APS-specific laboratory abnormalities manifested many months after the initial episode of venous thrombosis. The tests for antiphospholipid antibodies quite often yield negative results in APS patients with thrombosis. This phenomenon is considered to be a result of a ‘depletion’ of aPI in the course of thrombotic process. As a result, aPI are present in the blood at a detectable level some time after a thrombotic episode. On the other hand, aPI can be detected transiently in some cases, which is clinically insignificant. Therefore, according to the ISTH guidelines, the tests for aPI should be conducted no earlier than 12 weeks following a thrombotic episode, and the positive result should be confirmed after at least 12 weeks. In the case of our patient, the laboratory indices of APS were observed no sooner than two years after the thrombotic episode. The unprovoked character of venous thrombosis in our patient and its atypical location (brachiocephalic vein) necessitated longer follow-up to explain an etiology of the condition; the thrombosis could be a result of either the proliferative process (mediastinal lesions), or thrombophilia. Contrary to the case of inborn thrombophilia, the results of testing for APS can change with time; this necessitates serial testing in clinically justified cases.
Notably, even a few days of discontinued antithrombotic treatment were sufficient to induce another episode of venous thrombosis in our patient. It should be stressed that the presence of lupus anticoagulant is associated with high risk of thromboembolic complications. Therefore, continuation of therapy with low molecular weight heparin during evaluation of antiphospholipid syndrome is acceptable. In the presented case, antithrombotic treatment should be maintained despite ongoing process of diagnosing coagulation disorders.
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5. Oymak FS, Buyukoglan H, Tokgoz B (2005) Prevalence of thromboembolic disease including superior vena cava and brachiocephalic veins. Clin Appl Thromb Hemost; 11, 2: 183–189.
6. Otten TR, Stein PD, Patel KC, Mustafa S, Silbergleit A (2003) Thromboembolic disease involving the superior vena cava and brachiocephalic veins. Chest; 3, 123: 809–812.
Adres do korespondencji:
dr med. Krzysztof Mastej
Katedra i Klinika Angiologii, Nadciśnienia Tętniczego i Diabetologii Uniwersytetu Medycznego im Piastów Śląskich we Wrocławiu
ul. Borowska 213, 50–556 Wrocław
tel.: +44 71 733 22 00
Acta Angiol Vol. 20, No. 1 pp. 39–45
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