Spontaneous Venous Thrombosis Research Articles

Otogenic Sinus Thrombosis and Hemophilia: A Clinical Case

Background. Patients with hemophilia are protected from thrombosis by a deficiency of one of coagulation factors, therefore thrombotic complications are rare in them. Currently, few descriptions of spontaneous venous thrombosis in adult hemophiliacs can be found in the literature. Even fewer data of thromboembolic complications are reported in pediatric practice. At present, no clear recommendations are given for the management of thrombotic complications in children with hemophilia, which requires further study of this issue to develop prevention and treatment regimens, including otogenic sinus thrombosis in this category of patients.Case description. A 7-year-old boy was transferred from the Somatic Hospital to the Intensive Care Unit of Regional Clinical Hospital No. 2 in Tyumen (Russia) with an Otorhinolaryngology Unit. He was diagnosed with non-perforative form of acute right-sided suppurative otitis media, acute right-sided mastoiditis, thrombosis of the right sigmoid sinus. The anamnesis shows that the child is diagnosed with hemophilia A, of moderate severity (factor VIII level — 5%), for which he has been receiving factor VIII replacement therapy for the last year. Upon admission, a general blood test revealed no abnormalities, with a slight increase in acute-phase parameters: C-reactive protein, fibrinogen, signs of hypocoagulation. Due to negative dynamics, the child underwent anthromastoidotomy against the background of intensive replacement therapy. Surgery revealed the presence of granulation tissue with hemorrhagic thrombi in the antrum and aditus. In the postoperative period, replacement therapy was accompanied with antibacterial and anticoagulant therapy.Conclusion. The management of patients with otogenic sinus thrombosis against the background of hereditary factor VIII deficiency is a difficult task. On the one hand, it requires surgical intervention and anticoagulant therapy in order to prevent further thrombosis, on the other hand — intensive replacement therapy in order to reduce the risks of hemorrhagic complications. The described case demonstrates the need for an interdisciplinary approach to the diagnosis and treatment of a patient with otogenic thrombosis of lateral sinus against the background of hemophilia A. The approach is to minimize the risks of intraoperative complications and insure a favorable outcome.

ORBITAL VENOUS LYMPHATIC MALFORMATION : REVIEWING THE CLINICORADIOLOGICAL ASPECT OF A LESS KNOWN ENTITY.

Hemangiomas and venous lymphatic malformations are the two most common orbital vascular lesions seen in pediatric patients. Orbital venouslymphatic malformations (OVLMs) (previously referred to as ′lymphangiomas′) are relatively less common, benign cystic type I vascular malformations. OVLMs may remain clinically unapparent or might manifest in late childhood with slowly progressive proptosis, periorbital swelling and displacement of globe. These malformations usually enlarge gradually. Sudden proptosis may be seen with spontaneous intraorbital hemorrhage or venous thrombosis. Acute presentation includes severe pain, compressive optic neuropathy or loss of vision, when intervention is indicated. Imaging plays critical role in diagnosis. The imaging mainstay is based on USG with high resolution probes and MRI with contrast.

Genome Editing of Factor IX Paralogs in Zebrafish Demonstrates Subfunctionalization of Procoagulant Function

Hemophilia is an inherited monogenic bleeding disorder affecting ~400,000 individuals worldwide, with 20% of cases due to deficiency of factor IX (FIX, hemophilia B), affecting 1 in 30,000 male births. Although there are many exciting new treatments for this disorder, there are still unknown features of FIX. This includes potential distribution from plasma to tissue, which may affect some therapies. The zebrafish is a unique model to study coagulation disorders due to its high fecundity, external development, and optical transparency, as well as a high degree of genetic and functional conservation with the mammalian hemostatic system. Due to an ancestral gene duplication event in zebrafish, 30-40% of the zebrafish genome is duplicated, including the FIX gene (f9), resulting in the paralogs f9a and f9b. Such paralogs may arise due to subfunctionalization of the ancestral gene, raising the possibility that this could identify roles for mammalian FIX that have not previously been discovered. Here we utilize CRISPR/Cas9 genome editing to produce large deletions in f9a and f9b using guide RNAs that delete the intervening regions between exons 2 and 8, uncovering evidence for subfunctionalization. Assessment of hemostasis in 3 day post fertilization (dpf) mutant larvae using laser-mediated endothelial injury unexpectedly revealed that single and double f9a and f9b homozygous mutants exhibited normal thrombus formation. Upon crossing these mutants into an antithrombin (at3) deficient background (which exhibits spontaneous venous thrombosis), loss of F9b (f9b-/-;at3-/- mutants) prevented intravascular thrombosis development. f9a-/-;at3-/- double mutants were indistinguishable from f9a+/+;at3-/- siblings, both showing spontaneous thrombosis. These results demonstrated subfunctionalization of F9 activities, which could be due to differential functions or tissue-specific expression. The latter was investigated using whole mount in situ hybridization in wild-type larvae, revealing that f9a and f9b are both expressed in the liver. To evaluate function, microinjection of zebrafish f9a and f9b cDNAs regulated by a ubiquitous promoter was performed in one-cell stage f9b-/-;at3-/- zebrafish embryos. Analysis at 3 dpf found that only F9b could restore spontaneous thrombosis, confirming functional differences between F9a and F9b. Alignment of human FIX to F9a and F9b indicated conservation of functional domain sequences (signal sequence, propeptide, Gla, Egf1, Egf2, activation peptide, and protease). These domains were individually swapped between the f9a and f9b plasmids. Except for Egf1, all individual domains of F9a exchanged into F9b were able to restore thrombus formation in f9b-/-;at3-/- mutants. Replacement of F9b Egf1 with a F9aQ59G modified Egf1 domain (F9b has a glycine at this orthologous position), resulted in normal function. In summary, these data show clear evidence for subfunctionalization of F9 in zebrafish larvae, with F9b retaining procoagulant function. F9a possesses an active protease domain, but variation in Egf1 prevents it from contributing to canonical circulating FIX activity. We hypothesize that the alternative role for F9a might represent a previously unknown activity or tissue localization of human FIX. This putative role would also be deficient in hemophilia B patients and/or may be lacking in current therapies. An additional possibility is that this represents another means for regulation of FIX. In both cases, further study could lead to novel therapeutic ideas for patients with hemophilia B.

WORK HARD OR SMART? A CASE OF EFFORT-RELATED SUBCLAVIAN THROMBOSIS

WORK HARD OR SMART? A CASE OF EFFORT-RELATED SUBCLAVIAN THROMBOSIS

EPIPLOIC APPENDAGITIS: AN UNCOMMON CASE OF ACUTE ABDOMINAL PAIN WITH CHARACTERISTIC IMAGING FINDINGS.

Introduction: th th Epiploic appendagitis is an uncommon cause of abdominal pain and is frequently undiagnosed. Obese men in their 4 and 5 decade of life are most affected. It generally mimics other serious causes of acute abdomen and thus the denitive diagnosis relies on cross-sectional imaging primarily computed tomography ndings. Most often the condition is caused due to torsion of an epiploic appendage or spontaneous venous thrombosis of a draining appendageal vein. Appendices epiploicae are small (0.5-5 cm long), fat lled pouches of peritoneum projecting from the external surface of colon and are supplied by blood vessels that protrude through the bowel wall. They are present commonly over distal colon particularly numerous at the rectosigmoid junction. Case: We are reporting a case of 42 years old male patient, who presented to the surgical OPD at Dr. RPGMC Tanda with chief complaint of acute abdominal pain localized in the left iliac fossa with tenderness in the region. The ultrasonography report was inconclusive and the patient was further evaluated using biochemical investigations and contrast enhanced CT of the abdominopelvic region. The CECT revealed fat dense ovoid shaped lesion in the left iliac fossa with surrounding fat stranding and hyperdense rim suggestive of intraperitoneal focal fat infarction. The condition was managed conservatively with empirical antibiotics and analgesics. Conclusion: Epiploic appendagitis is a self-limiting disease but persistence of symptoms or recurrence requires surgical management with laparoscopic appendage excision. The anatomical and surgical knowledge of epiploic appendagitis is very important to raise awareness about this clinical condition and to manage it appropriately.

Neutrophils, Cancer and Thrombosis: The New Bermuda Triangle in Cancer Research.

Spontaneous venous thrombosis is often the first clinical sign of cancer, and it is linked to a worsened survival rate. Traditionally, tumor-cell induced platelet activation has been the main actor studied in cancer-associated-thrombosis. However, platelet involvement alone does not seem to be sufficient to explain this heightened pro-thrombotic state. Neutrophils are emerging as key players in both thrombus generation and cancer progression. Neutrophils can impact thrombosis through the release of pro-inflammatory cytokines and expression of molecules like P-selectin and Tissue Factor (TF) on their membrane and on neutrophil-derived microvesicles. Their role in cancer progression is evidenced by the fact that patients with high blood-neutrophil counts have a worsened prognosis. Tumors can attract neutrophils to the cancer site via pro-inflammatory cytokine secretions and induce a switch to pro-tumoral (or N2) neutrophils, which support metastatic spread and have an immunosuppressive role. They can also expel their nuclear contents to entrap pathogens forming Neutrophil Extracellular Traps (NETs) and can also capture coagulation factors, enhancing the thrombus formation. These NETs are also known to have pro-tumoral effects by supporting the metastatic process. Here, we strived to do a comprehensive literature review of the role of neutrophils as drivers of both cancer-associated thrombosis (CAT) and cancer progression.

Spontaneous Outflow Venous Thrombosis of an Unruptured Arteriovenous Malformation in the Setting of COVID-19 Infection

A 63-year-old man with a known left frontal AVM presented with a recent increase in seizure activity. Approximately two weeks prior to admission the patient was found seizing and febrile with a temperature of 38.2 ℃. At that time the patient had reported a one-week history of dry cough, shortness of breath and dyspnea on exertion. Nasopharyngeal swab testing with polymerase chain reaction (PCR) was positive for SARS-CoV-2.

1511 Epiploic Appendagitis After Rigorous Exercise in a Woman: An Easily Misdiagnosed Cause of Acute Abdomen

INTRODUCTION: Acute abdominal pain can be a surgical emergency. However, benign etiologies, such as epiploic appendagitis (EA), can present with similar symptoms. We report a case of an otherwise healthy woman, on oral contraceptives (OCP), presenting with severe abdominal pain related to epiploic appendagitis. Timely recognition of this condition is important to avoid misdiagnosis and unnecessary surgical interventions. CASE DESCRIPTION/METHODS: A 44-year-old woman with a past medical history of ovarian cyst and BMI 25 presented to the Emergency Department with a three-day history of sharp left lower quadrant (LLQ) pain. Patient reported that she started a vigorous aerobic exercise regimen 6 weeks before. Only medication was norgestimate-ethinyl estradiol for contraception. Vital signs normal. Physical exam showed tender LLQ without rebound tenderness or rigidity. Initial testing including complete blood count, basic metabolic panel, pregnancy test, urinalysis, and vaginitis panel were unremarkable. Given worsening pain, CT scan of abdomen and pelvis with contrast was obtained showing an encapsulated oval, pericolonic fatty nodule adjacent to the sigmoid colon, with surrounding fat stranding consistent with EA. Patient was discharged home with conservative pain management. Her OCP was discontinued. She had no symptom recurrence within a 3-year period. DISCUSSION: EA is an uncommon cause of acute abdominal pain that mimics serious medical or surgical emergencies such as acute diverticulitis, appendicitis, or, gynecological emergencies such as ruptured ectopic pregnancy. It is, generally, a self-limited ischemic infarction involving the epiploic appendices, which are normal outpouching fat of the lower colon and rectum. EA can be divided into primary versus secondary. The primary form is caused by either torsion or spontaneous venous thrombosis of an epiploic appendage central draining vein. It commonly occurs in men aged 20–50. Risk factors include obesity, hernia, and rigorous exercise. Secondary form is related to inflammation of adjacent organs. Although our patient does not match the typical profile for EA, rigorous exercise and probably OCP usage, a risk factor for thromboembolic phenomena, may have triggered this episode. Diagnosis of EA is by imaging via ultrasound or CT scan, and complete resolution typically occurs within two weeks with conservative management. Prompt identification of EA is essential in patients at risk, to avoid unnecessary surgical procedures.

Epiploik Apendiks Enflamasyonu: Primer Epiploik Apandajit

Epiploic appendices are extensions of omentum which covers most of the colon. Most of the pathologic changes are related with spontaneous torsion or venous thrombosis culminating with inflammation and is referred as primary epiploic appendagitis (PEA). There is no pathognomonic symptom, finding or laboratory test for this relatively rare intra-abdominal inflammation. A non-toxic patient with acute onset localized abdominal pain in the right or left lower quadrant is the typical presentation. Imaging studies such as ultrasound and tomography with the awareness of PEA in differential diagnoses of intra-abdominal pathologies are the key to correct diagnosis. Since the conservative treatment is sufficient in most of cases, accurate and timely diagnosis can ensure the appropriate patient management and can prevent unnecessary hospitalizations and interventions.

Heestermans M, Salloum-Asfar S, Salvatori D, Laghmani EH, Luken BM, Zeerleder SS, Spronk HMH, Korporaal SJ, Wagenaar GTM, Reitsma PH, van Vlijmen BJM. Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice. Blood. 2016;127(21):2630-2637.

The Editors of Blood retract the 26 May 2016 paper cited above. In this paper, the authors reported on the role of platelets, neutrophils, and coagulation factor XII (FXII) in spontaneous venous thrombosis in mice. After performing additional studies using F12-deficient mice, a new F12 small interfering RNA (siRNA), and a mismatch control siRNA, the authors found that the aggravating effect of low FXII on spontaneous venous thrombosis reported in the above-cited paper was specific to the F12 siRNA used in the original study. This particular F12 siRNA has an additional prothrombotic off-target effect on coagulation that is unrelated to FXII. Upon discovering this error, the authors contacted the journal to correct the scientific record.

Cerebellar cortical vein thrombosis mimicking a vermian tumor: case report

Cortical vein thrombosis is an uncommon cause of stroke and generally occurs in the supratentorial compartment. Spontaneous venous thrombosis with infarction in the posterior fossa usually occurs in association with either dural sinus thrombosis and/or thrombosis of the petrosal vein, usually with venous infarction of the cerebellar hemisphere. Our goal is to present the case of a patient with thrombosis of cerebellar cortical veins, without sinus involvement, which mimicked a vermian cerebellar tumor.

Spontaneous central venous thrombosis and shunt occlusion following peritoneovenous shunt placement for intractable ascites

A 43-year-old man had a peritoneovenous shunt inserted for the treatment of chylous ascites secondary to myelofibrosis. Despite being on anticoagulation for superior mesenteric vein thrombosis, he developed shunt dysfunction within two weeks of insertion. Superior venacavography showed multiple filling defects in the right axillary vein, no filling of the right brachiocephalic and right subclavian vein, and thrombotic occlusion of the internal jugular veins bilaterally. The shunt was removed 11 days after insertion, and there was extensive thrombosis of the venous end of the shunt and the compressible pump chamber. Shunt thrombosis is known to occur but remains a rare complication, with 87% of such obstructions being due to a thrombus at the tip of the venous end of the shunt. Extensive thrombosis of the shunt (as in the present case) is very rare.

Recurrent Upper Extremity Thrombosis Associated with Overactivity: A Case of Delayed Diagnosis of Paget-Schroetter Syndrome

Paget-Schroetter syndrome is thrombosis of the axillary-subclavian vein that is associated with strenuous and repetitive activity of the upper extremities. Overuse of the arm coupled with external compression results in microtrauma in the intima of the subclavian vein, resulting in the activation of the coagulation cascade. Diagnosis is usually made by Doppler ultrasound and the treatment involves thrombolysis, while routine surgical decompression of the thoracic outlet is controversial. In this report, we present a case of a patient who presented with a second episode of spontaneous right upper extremity deep venous thrombosis. The first episode was inadequately treated with oral anticoagulation alone. During the second episode, Paget-Schroetter syndrome was diagnosed, after careful review of his occupational history. He subsequently underwent angioplasty and decompression of thoracic outlet with no recurrence of thrombosis in a 12-month follow-up period.

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

AbstractRecently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNA-mediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology.

Mouse models of venous thrombosis are not equal

Publisher9s Note (31 May 2018): The article that is the focus of this commentary, Heestermans et al, has been retracted. In this issue of Blood, Heestermans et al1 evaluated the roles of platelets, neutrophils, and factor XII (FXII) in a new mouse model of spontaneous venous thrombosis.

Bisalbuminaemia due to novel mutation at a critical residue involved in recycling; Albumin Lyon (510His → Arg)

ObjectivesTo define the underlying cause of bisalbuminaemia in an individual presenting with spontaneous venous thrombosis. MethodPlasma was examined by electrospray time-of-flight mass spectrometry (TOF MS) to assess albumin mutations and to quantify variant expression level. Tryptic peptide mapping and DNA sequencing were used to precisely define the mutation. ResultsWhole protein MS indicated a 19Da increase in the mass of 50% of the albumin molecules suggesting a His→Arg substitution. A novel heterozygous 510His→Arg mutation was identified by peptide mass mapping and confirmed by DNA sequencing of exon 12 of the albumin gene. ConclusionThe nature and location of the mutation suggest it would have no direct influence on haemostasis through altered warfarin binding or increased fibrinogen attachment and it appears to be incidental to the thrombotic phenotype. However the highly conserved His510 residue is recognised as being of critical importance in albumin recycling through interaction with its savaging neonatal Fc receptor. The normal albumin level of 41.1g/l and the coequal expression of albumin Lyon demonstrate that the conservative 510His→Arg substitution does not interfere with the pH dependant capture and release of albumin by the receptor.

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

AbstractPathologic blood clotting is a leading cause of morbidity and mortality in the developed world, underlying deep vein thrombosis, myocardial infarction, and stroke. Genetic predisposition to thrombosis is still poorly understood, and we hypothesize that there are many additional risk alleles and modifying factors remaining to be discovered. Mammalian models have contributed to our understanding of thrombosis, but are low throughput and costly. We have turned to the zebrafish, a tool for high-throughput genetic analysis. Using zinc finger nucleases, we show that disruption of the zebrafish antithrombin III (at3) locus results in spontaneous venous thrombosis in larvae. Although homozygous mutants survive into early adulthood, they eventually succumb to massive intracardiac thrombosis. Characterization of null fish revealed disseminated intravascular coagulation in larvae secondary to unopposed thrombin activity and fibrinogen consumption, which could be rescued by both human and zebrafish at3 complementary DNAs. Mutation of the human AT3-reactive center loop abolished the ability to rescue, but the heparin-binding site was dispensable. These results demonstrate overall conservation of AT3 function in zebrafish, but reveal developmental variances in the ability to tolerate excessive clot formation. The accessibility of early zebrafish development will provide unique methods for dissection of the underlying mechanisms of thrombosis.

Thrombosis in the uremic milieu--emerging role of "thrombolome".

Chronic kidney disease (CKD) is characterized by retention of a number of toxins, which unleash cellular damage. CKD environment with these toxins and a host of metabolic abnormalities (collectively termed as uremic milieu) is highly thrombogenic. CKD represents a strong and independent risk factor for both spontaneous venous and arterial (postvascular injury) thrombosis. Emerging evidence points to a previously unrecognized role of some of the prothrombotic uremic toxins. Here, we provide an overview of thrombosis in CKD and an update on indolic uremic toxins, which robustly increase tissue factor, a potent procoagulant, in several vascular cell types enhancing thrombosis. This panel of uremic toxins, which we term "thrombolome" (thrombosis and metabolome), represents a novel risk factor for thrombosis and can be further explored as biomarker for postvascular interventional thrombosis in patients with CKD.

Contrast-enhanced ultrasound appearance of primary epiploic appendagitis

Primary epiploic appendagitis (PEA) is a rare, benign self-limiting condition more often secondary to torsion or spontaneous venous thrombosis of a draining vein of the epiploic appendages; symptoms can mimic an acute abdomen [1]. The diagnosis is based on abdominal computed tomography or ultrasound [2–5]. More recently, a fairly characteristic contrast-enhanced ultrasound (CEUS) feature was described as a central area of no enhancement [6]. A 38-year-old man with a body mass index of 27 and without any significant clinical history was admitted to our hospital for the abrupt onset of acute localised pain in the left lower quadrant of the abdomen. The patient was afebrile and had no intestinal symptoms. The blood tests showed no abnormalities. Grey-scale ultrasound examination focused on the point of maximal tenderness revealed a well-delineated, oval, and homogeneously hyperechoic intra-abdominal mass, with a maximum diameter of 30 mm. The mass was adjacent to the abdominal wall and located anteromedial and adherent to the left colon. It was uncompressible and no thickening of the left colon wall was identified (Fig. 1). Fig. 1 Grey-scale ultrasound focused on the point of maximal tenderness. An oval hyperechoic mass is adherent to the left colon wall (arrow). Arrowheads mark the boundary of the mass The mass was evaluated with CEUS: a blood pool second-generation contrast agent (SonoVue®, Bracco, Milan, Italy) and a Philips iU22 ultrasound machine (Philips Healthcare, Best, The Netherlands) with a contrast harmonic imaging technology and a 3–9 MHz linear probe were used. The real-time images were displayed on a split screen: the left side displayed the contrast harmonic imaging, allowing the visualisation of the microvascularisation without the fundamental grey-scale echoes; the right side of the screen displayed the grey-scale images. The contrast harmonic imaging revealed a thick rim of arterial enhancement and a wide hypoechoic central area (Fig. 2). The CEUS appearance of the mass was unvaried in the venous phase; in particular, the wide central area remained hypoechoic. A computed tomography scan revealed the typical features of PEA (Fig. 3) [7]. Fig. 2 Contrast-enhanced ultrasound (arterial phase). The left image shows a thick rim of enhancement and a hypoechoic central area of the mass. On the right side is displayed the grey-scale image. Arrowheads mark the boundary of the mass Fig. 3 Computed tomography. An oval lesion (arrow), 2 cm in diameter, with attenuation similar to that of fat and with surrounding inflammatory changes, is localised next to the anterior left colon wall The patient was managed conservatively and the symptoms were completely resolved after 6 days. The follow-up grey-scale ultrasound, 4 and 19 days from the first examination, revealed progressive shrinkage of the mass. The patient gave informed written consent for the grey-scale sonography, the CEUS, and the computed tomography. Specific clinical features and grey-scale sonography findings of PEA are lacking; furthermore, there is the absence of flow in colour Doppler imaging [8, 9]. In this single patient, CEUS has confirmed that a thick rim of enhancement and a hypoechoic central area of the mass are characteristic features of PEA, as was previously reported by Gorg [6]. Therefore, in the adequate clinical context, the use of CEUS can give an immediate answer, thus allowing the diagnosis of PEA at the bedside.

Spontaneous Deep Venous Thrombosis: An Unrecognised Entity with Sorafenib

Hepatocellular carcinoma is the most common, malignant tumor of liver. Most cases of hepatocellular carcinoma are associated with either viral hepatitis or cirrhosis. But major risk factor for hepatocellular carcinoma in developing countries is mainly chronic hepatitis B. Sorafenib is one of the first line drug which has been extensively used in metastatic and inoperable hepatocellular carcinoma. We report a rare case of spontaneous deep venous thrombosis of bilateral lower limbs as an important unrecognized side effect of sorafenib.