Guidelines on the investigation and management of venous thrombosis at unusual sites

Abstract

Deep vein thrombosis (DVT) of the lower limb veins and pulmonary embolism (PE) are the most commonly encountered manifestations of venous thrombosis in routine clinical practice. Consequently, they have a strong evidence base supporting their optimal management. Venous thrombosis at other ‘unusual sites’ is well documented, but given the paucity of robust studies its management has often been extrapolated from experience of lower limb DVT and PE. The objective of this guideline is to provide healthcare professionals with guidance, based on contemporary evidence, on the appropriate investigation and treatment of venous thrombosis at these other sites. The writing group was selected to be representative of UK-based experts. MEDLINE and EMBASE were searched for publications from 1996 onwards using the key word relevant to the venous thrombosis site and limits clinical trial, humans, core clinical journals, and English language. Additional relevant papers were identified by screening reference lists and by the identification of publications known to the writing group. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology (BSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. Where evidence exists, the relevance of hereditary thrombophilia to the development and subsequent management of thrombosis at specific unusual sites is discussed. If unusual site thrombosis develops in the context of an antiphospholipid syndrome, the risk of recurrence is felt to be increased and long-term anticoagulation should be considered. The epidemiology, diagnosis and management of cerebral venous and sinus thrombosis (CVST) have been reviewed in consensus statements published in 2010 and 2011 (Einhaupl et al, 2010; Saposnik et al, 2011). CVST, responsible for less than 1% of all strokes, most often affects young adults and children with approximately 75% of patients being female (Stam, 2005). Reported annual incidence rates include 4 per million of the population, 7 per million children and about 12 per million deliveries. Obstruction of cerebral veins causes cerebral oedema and venous infarction, while occlusion of venous sinuses causes intracranial hypertension. Therefore, CVST should be considered in young and middle-aged patients with recent unusual headache, stroke-like symptoms in the absence of usual risk factors, intracranial hypertension or haemorrhagic cerebral infarcts. The most sensitive diagnostic test is magnetic resonance venography [magnetic resonance imaging (MRI) with venography]. If MRI is not available then high resolution computed tomography (CT) as an initial examination is useful but it can be normal initially. Recognized underlying causes include infection, particularly of the head and neck, systemic inflammatory disorders, leukaemia (especially with asparaginase treatment), head injury and dehydration. While myeloproliferative neoplasms (MPNs), such as polycythaemia vera and essential thrombocythaemia, are causes of CVST (De Stefano et al, 2008), in the absence of overt MPN the JAK2 mutation has not been associated with CVST (Koopman et al, 2009). Use of oestrogen-containing combined oral contraceptives (C-OCPs) is a precipitating factor (de Bruijn et al, 1998a; Martinelli et al, 1998a) with a higher risk associated with third generation pills (de Bruijn et al, 1998b). A systematic review of 17 studies found an increased risk of CVST in patients using C-OCPs [odds ratio (OR) 5·6; 95% confidence interval (CI) 4·0–7·9], in patients with F5 R506Q (factor V Leiden; OR 3·4; 95% CI 2·3–5·1), with F2 G20210A (prothrombin gene mutation; OR 9·3; 95% CI 5·9–14·7) and with high fasting levels of homocysteine (OR 4·1; 95% CI 2·5–6·5) (Dentali et al, 2006a). There were insufficient patients with deficiency of antithrombin, protein C or S to draw conclusions. Although the prognosis of CVST is generally good, death may occur within hours of presentation due to cerebral herniation. Coma at presentation, thrombosis of the deep cerebral venous system, CNS infection, cancer and intracranial haemorrhage (ICH) are associated with a worse prognosis (Ferro et al, 2004; Wasay et al, 2008). Mortality in the first month is 5·6% with 70% of deaths directly attributable to the CVST (Dentali et al, 2006b). Most subsequent deaths are due to cancer. Eighty percent of surviving patients recover completely or have only a mild functional or cognitive deficit (Dentali et al, 2006b). Recanalization usually occurs in the first 4 months irrespective of continued anticoagulation (Baumgartner et al, 2003; Dentali et al, 2006b). An updated systematic review of therapeutic dose unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and the use of thrombolysis was undertaken in 2010 (Einhaupl et al, 2010). Anticoagulant therapy was associated with a pooled relative risk of death of 0·33 (95% CI 0·08–1·21) and of death or dependency of 0·46 (95% CI 0·16–1·31), based on two small studies. No new symptomatic intracerebral haemorrhages were observed in patients treated with heparin. Given that early treatment is likely to be safe and potentially beneficial it is recommended that patients with CVST without contraindications to anticoagulant therapy should be treated with therapeutic dose heparin. ICH is not regarded as a contraindication to anticoagulant treatment. If patients deteriorate despite adequate heparin therapy and other causes of deterioration have been excluded, thrombolysis may be a therapeutic option in selected cases. However, a small non-randomized study of localized thrombolysis demonstrated that patients with large haemorrhagic infarcts and impending herniation did not benefit (Stam et al, 2008). An expert consensus concluded that thrombolytic therapy should be reserved for patients with extensive CVST that is likely to be fatal or not responding to anticoagulant therapy but is not indicated when deterioration is caused primarily by ICH (Ageno et al, 2010a). In patients with impending herniation surgical decompression should be considered. The optimal duration of anticoagulation is unknown. Indeed, observational studies are unclear as to whether anticoagulation reduces the risk of recurrent CVST (Kenet et al, 2007). Expert consensus recommended 7–14 d heparin treatment to ensure consistent therapeutic anticoagulation (Ageno et al, 2010a). This could be followed by a vitamin K antagonist for 3 months if CVST was secondary to a transient risk factor, for 6–12 months in patients with unprovoked CVST and in those with ‘mild’ thrombophilia, such as heterozygous F5 R506Q or F2 G20210A mutation (Einhaupl et al, 2010). Long term anticoagulation has been suggested for patients with recurrent episodes of CVST and in those with one episode of CVST and ‘severe’ thrombophilia, such as antithrombin, protein C or protein S deficiency, homozygous F5 R506Q or F2 G20210A mutation, antiphospholipid antibodies and combined abnormalities (Einhaupl et al, 2010). An alternative expert consensus suggested that indications for continued anticoagulation in patients with unprovoked CVST were incomplete clot resolution on repeat imaging, persisting risk factors or thrombophilia (Ageno et al, 2010a). A systematic review identified an overall CVST recurrence rate of only 2·8% (Dentali et al, 2006b). In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) the CVST recurrence rate was 1·5% per annum with a 3 year cumulative recurrence of 5·7% (Miranda et al, 2010). An increased risk of recurrence was associated with male sex [Hazard Ratio (HR) 6·2, 95% CI 2·1–18·6]. This was not completely explained by a lower risk of recurrence in women with a first episode of C-OCP-associated CVST. These observational studies also demonstrated subsequent DVT or PE in 3–4% of CVST patients, with male sex and MPN being prominent risk factors (Miranda et al, 2010). The risk of recurrent CVST in pregnancy appears to be low (Dentali et al, 2006b) but whether there is a need for thromboprophylaxis in pregnancy is unknown. In children with CVST, recurrence only occurred when CVST was diagnosed after 2 years of age and was more likely when there was persistent occlusion on repeat imaging and in association with F2 G20210A (Kenet et al, 2007). In populations over the age of 40 years the annual incidence of retinal vein occlusion (RVO) is 1·6/1000 of which 75% are branch retinal vein occlusion (BRVO) and 25% central retinal vein occlusion (CRVO) (Klein et al, 2000; Cugati et al, 2006). The incidence rises to approximately 5/1000/year over the age of 64 years (David et al, 1988). Typical presentation is with acute, painless visual loss in one eye. The diagnosis can usually be made by clinical examination alone. In a meta-analysis of 21 studies, hypertension was found in 64% of cases, hyperlipidaemia in 35% and diabetes in 15%. RVO is predominantly a disorder of the elderly but is not associated with direct measures of atherosclerosis, endothelial dysfunction, inflammation or coagulation activation. Open-angle glaucoma and raised intraocular pressure are local risk factors for CRVO. There is no strong association with hereditary thrombophilia: a meta-analysis of 26 studies found that only hyperhomocysteinaemia (OR 8·9 95% CI 5·7–13·7) and anticardiolipin antibodies (OR 3·9 95% CI 2·3–6·7) had significant associations with RVO (Hayreh et al, 1994). The association with F5 R506Q was of borderline significance (OR 1·5 95% CI 1·0–2·2) (Janssen et al, 2005). The visual prognosis is driven by the development of macular oedema and neovascularization rather than recurrence. Consequently, standard therapy has been laser photocoagulation. Intraocular steroids are licensed for macular oedema as are anti-angiogenic agents (ranibizumab, bevacuzimab), which have also produced improved visual outcomes [e.g. clinically significant improvement in 46% vs. 17% in control subjects (Brown et al, 2010)]. Ipsilateral recurrence rate is estimated at 1% per annum with a future 10–15% risk of contralateral RVO. The role of anticoagulant therapy in preventing recurrence is unknown and trial data limited. Trials of antiplatelet therapy have failed to show significant benefit (Houtsmuller et al, 1984). Moreover, a large cohort study of 686 patients with RVO showed that those taking antiplatelet agents or anticoagulation at the time of occlusion had more severe retinal haemorrhage and were more likely to show subsequent deterioration in vision (Hayreh et al, 2011). Two randomized trials of LMWH (6 months and 20 d) both resulted in improved visual outcome compared to aspirin. LMWH was not associated with an excess of bleeding but there were trends towards reduced neovascularization and reduced recurrence (Farahvash et al, 2008; Ageno et al, 2010b). However, because the visual benefit may arise from an anti-angiogenic effect of heparin and because comparison was with aspirin, which is not recommended, this should not be extrapolated to support anticoagulation in general. While aspirin is not recommended in treatment or secondary prevention of RVO, in patients with underlying cardiovascular disease an anti-platelet agent should be considered for secondary prophylaxis for atherosclerosis. Early trials of thrombolytic therapy were complicated by haemorrhage but a more recent randomized trial of low dose tissue plasminogen activator followed by 8 d of heparin showed benefit at 1 year, compared to haemodilution, for CRVO but not BRVO without any major haemorrhages (Hattenbach et al, 2009). None of these interventions, including haemodilution (Chen et al, 1998), have accumulated sufficient supporting evidence to become the standard of care. Ophthalmology guidelines (http://www.rcophth.ac.uk/page.asp?section=451&sectionTitle=Clinical+Guidelines) and expert opinion (Hayreh et al, 2002, 2011) do not recommend routine thrombophilia testing or antiplatelet or anticoagulation therapy. However, LMWH has received cautious support from the results of a meta-analysis (Lazo-Langner et al, 2010). Upper extremity deep vein thromboses (UEDVT) may involve the axillary, subclavian and brachial veins. These account for up to 10% of all DVTs (Flinterman et al, 2008), and occur with a rate of around 16 per 100 000 of the population per annum (Spencer et al, 2007). UEDVT are considered primary if they are idiopathic or associated with thoracic outlet syndrome (TOS) or effort (Paget-Schroetter syndrome) (Paget, 1875; Von-Schroetter, 1884) or secondary if they are associated with an underlying precipitant such as placement of a central venous catheter. Thoracic outlet syndrome comprises compression of the neurovascular bundle in the thoracic outlet. The compression may be due to either boney structures, such as the first rib and clavicle, or muscle bulk. Paget–Schroetter syndrome is considered a form of TOS in which thrombosis is induced by microtrauma to the vessel after vigorous effort. Central venous catheters (CVC), active malignancy, and inherited and acquired thrombophilia are considered risk factors for UEDVT. The most frequent risk factor is presence of a CVC (Spencer et al, 2007). Pacemakers are also a recognized risk factor for UEDVT. The incidence of UEDVT is highest for large diameter chest catheters (Grove & Pevec, 2000) and pacemakers with a higher number of leads (Rozmus et al, 2005; Korkeila et al, 2007). Upper limb surgery and plaster cast immobilization are associated with a 13-fold and sevenfold relative risk for UEDVT, respectively (Blom et al, 2005). Use of the C-OCP and HRT have not been shown convincingly to be risk factors. F5 R506Q and the F2 G20210A mutation may be risk factors for UEDVT but F5 R506Q was found much less commonly in patients with idiopathic UEDVT compared with idiopathic lower limb DVT (12% vs. 30%, P = 0·009) (Lechner et al, 2008). A systematic review of poor methodological quality studies concluded that compression ultrasound with a sensitivity of 97% (95% CI, 90–100%) may be an acceptable alternative to venography in the investigation of suspected UEDVT (Di Nisio et al, 2010). The use of clinical decision rules combined with D-dimer testing for the exclusion of UEDVT has not been adequately assessed (Merminod et al, 2006). The data on complication rates for UEDVT are derived from heterogeneous cohorts of patients. Pulmonary embolism (up to 30%), post-thrombotic syndrome (7–44%) (Hingorani et al, 1997; Prandoni et al, 2004; Kahn et al, 2005) and annual recurrence rates of 2–8% are reported (Prandoni et al, 1997, 2004; Baarslag et al, 2004; Martinelli et al, 2004). In a direct comparison of outcomes in patients with idiopathic UEDVT and lower extremity DVT, 5-year recurrence rates of 2% (95% CI 0–6) and 19% (16–22) respectively were described (Lechner et al, 2008). A Cochrane analysis showed no benefit for prophylactic dose heparin or low dose vitamin K antagonists (VKA) on the prevention of death or symptomatic DVT in patients with CVCs (Akl et al, 2011). Low dose VKA therapy resulted in a significant reduction in asymptomatic DVT [RR 0·42 (0·28–0·61)] (Akl et al, 2011). There are no randomized controlled trials on the optimal treatment of patients with UEDVT. The majority of patients are managed with a combination of brief heparin therapy followed by a vitamin K antagonist for between 3 and 6 months. A retrospective analysis of 110 episodes of first rib resection and scalanectomy performed for management of TOS demonstrated no benefit for pre-operative endovascular intervention (thrombolysis +/− venoplasty) compared with anticoagulation alone (Guzzo et al, 2010). Jugular vein thrombosis is most commonly seen in association with local sepsis, inflammation or trauma. It is most often recognized as part of Lemierre syndrome, which is characterized by a history of recent oropharyngeal infection, clinical or radiological evidence of internal jugular vein thrombosis, and isolation of anaerobic pathogens, mainly Fusobacterium necrophorum. There appears to be an excess of jugular vein thrombosis in patients with ovarian hyperstimulation syndrome et al, on imaging and treatment are limited. Obstruction of the can be caused by or is the of thrombosis for up to et al, 2006). causes are due to central venous or to et al, 2006). recognized causes include and et al, 2008). The most frequent and symptoms of thrombosis are or limb and chest vein et al, 2006). The rate is in the it is reported in of of central venous and of of pacemakers et al, et al, 2000; et al, 2006). is the first imaging usually performed and venography is performed if endovascular intervention is patients should anticoagulant therapy to the risk of pulmonary In patients with severe symptoms due to thrombosis, endovascular surgery with and is considered to be therapy et al, 2008). In of thrombosis associated with malignancy, with if may provide of by persisting risk factors, often be continued long-term in patients with The prognosis of thrombosis is much the causes of the In of thrombosis due to the prognosis is because most to appropriate therapy. The of thrombosis that of particularly and other to the may either direct of the or by risk factors include of the or compression that leads to venous and Most of with and symptoms of a lower limb DVT or pulmonary with lower limb DVTs should have their In the of venous patients, had and of these occurred in women and the age of years et al, 2008). The of the is in In the a anticoagulant was found in of patients but inherited abnormalities did not more in patients with than in with lower limb DVT et al, 2008). There is an increased risk of associated with the use of et al, 2008). There are no data that patients with should be managed from those with lower limb DVT, there may be a lower for use of thrombolysis in with a low risk of The optimal duration of anticoagulation is unclear the history of is not to and for to particularly in and anticoagulation may be considered et al, 2008). The use of and endovascular surgery is The vein is from the and veins. The most underlying of vein thrombosis is et al, causes are infection, inflammation or and or account for up to a of (De Stefano et al, and is a of MPN et 2011). all patients should be assessed for the JAK2 mutation et al, & 2008; et al, 2010). is an of thrombosis et al, 2007). are an factor et al, 2000; et al, 2000; Dentali et al, as may be antiphospholipid antibodies & 2007). can be with and or with symptoms of hypertension The diagnosis can be made by MRI or The is and has a et al, 2010). The risk of bleeding is high in patients with with or and anticoagulation is not usually In without anticoagulation with LMWH followed by is usually but should be made on a There is no evidence to duration of Although it has been suggested that anticoagulation should be given long-term in the presence of a thrombophilia or if there is a of this is not based on any strong evidence et al, 2005; et al, et al, et al, 2010). in patients with a recurrent thrombosis is et al, 2011) and there is evidence for long-term In this recurrence may be by a combination of both anti-platelet and oral anticoagulant agents et al, 2011). In without there are no trials as to the of It has been recommended that those without hypertension and with should be et al, with no vein thrombosis occurs in approximately per million per The usual presentation is with and have an underlying disorder and up to may have a MPN et al, with of patients JAK2 in this The diagnosis can be made with or Most patients are and is followed by systemic in one third of et al, 2009). If this then should be considered. Use of thrombolysis has been reported in small This appears to be more when rather than et al, 2004). vein thrombosis for 10% of & The most causes are inflammation or infection, and surgery et al, is to the the with and leads to and or MRI is the diagnostic investigation of for suspected cases. is in patients with but anticoagulation is the treatment of & 2010). for long-term anticoagulation has been for patients with thrombophilia but this is not based on any vein thrombosis is and disease is the most et al, It can with bleeding and but normal et al, 2004). is recommended for those with bleeding vein thrombosis is an with a clinical usually affects and in association with other and dehydration. children are as often as and the vein is as as the may to vein thrombosis with of the and In adults is more in than in Most of in adults with and et al, 2008), which can be severe in the of In of may in Although has in the of patients with et al, 2008), of patients had active syndrome, and were has been identified in of syndrome et al, and has been associated with primarily et al, et al, 2008). There are no associations between and is diagnosed by with of venography may be regarded as the The management of patients with should the underlying factors. with heparin and subsequently is but there is evidence to the duration of treatment. The prognosis of factors, with normal at presentation being associated with a In of the prognosis is poor with a of months et al, 2008). associated with syndrome is not associated with an increased risk of is vein thrombosis to et al, 2010). It usually within 4 of and most commonly in the first 4 are and include lower and It can be to from other or inflammatory et al, 2010). is with or MRI vein thrombosis may the veins and in of cases, with fatal et al, Most but have been described after infection, inflammatory disease and recent surgery complicated by is with In to the and of ovarian vein thrombosis, it is in patients have and with & In a of 50 patients this of surgery for all had which showed no thrombosis but on the routine performed months 40 had ovarian vein thrombosis of these ovarian vein thromboses were to the were treated with and of the patients symptoms of PE on & Venous thrombosis of the or is vein thrombosis of the It is a with and a thrombosis on the of the to the Although and thrombophilia have been as factors there are no studies to The diagnosis can be by ultrasound but is not is towards investigation is not indicated and anticoagulation is not because embolism not occur and resolution occurs within et al, venous thrombosis of the lower or veins or their is more than DVT of the et al, et al, 2005). Two of are seen in and occur in an vein et al, 2010a). factors for are the as for DVT (Di et al, 2005; Nisio et al, and (95% CI of the population attributable risk for first DVT or PE et al, is associated with an increased risk of to that of DVT, most commonly et al, & thrombophilia is an has been reported as the first of venous thrombosis in of patients with protein C or S deficiency and around of those with F5 R506Q et al, et al, Martinelli et al, et al, there are no data to that the presence of a thrombophilia should management or rates of recurrence or on the and history of have on to or for and are likely towards the more clinically severe of the it is that was regarded as a can to DVT and PE. In a study of of at in et demonstrated that had at diagnosis with symptomatic DVT and In only of was the DVT with the DVT is less likely with at the site of an but more likely if the the of a vein than its particularly the vein if to the or within of it et al, et al, et al, 2010a). may to In an ultrasound study of of had to DVT within d et al, with LMWH therapy dose and prophylactic duration d) in of et with venous thrombosis symptomatic 2·8% symptomatic DVT, and recurrent 3 months factors for recurrence or to DVT within of the male history of absence of veins and severe venous et al, 2003; et al, to 3 the has such a high risk of to DVT that such patients are no in trials in but rather given therapeutic anticoagulation as for DVT et al, et al, Prandoni et al, 2005; et al, Although often diagnosed there is a strong for ultrasound of to those with DVT or at the both of which therapeutic anticoagulation the being to surgical intervention anticoagulation was shown to be as and et al, Nisio et al, 2007). D-dimer has an sensitivity and for et al, and has not been assessed for sensitivity and for DVT in the presence of A Cochrane review (Di Nisio et al, of therapeutic trials in found that and did provide but there was no evidence of their in preventing recurrence or The Study reported compared to d of prophylactic or therapeutic LMWH or oral were all safe and reduced the risk of or recurrence by approximately a benefit which was 3 months Although to show in preventing to there was a to lower rates in the LMWH at the of the treatment not at 3 months month of prophylactic dose LMWH was as as therapeutic in of resolution and rates of recurrence and 3 months (Prandoni et al, 2005). the randomized trial in of assessed the and of prophylactic dose for d et al, 2010b). at or within 3 of the were not in this There was no excess bleeding and relative risk reduction for symptomatic DVT or PE at d) was (95% CI, in the treatment rate vs. While the and in these guidelines is to be and at the time of to the the British Society for Haematology the any for the of these to the for of and of the and all the None of the have a of