How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

T4-mediated rescue of aortic malformations in hypothyroid rats indicates maternal thyroid status can affect great vessel development.

Pexacerfont is a corticotrophin-releasing factor subtype 1 receptor (CRF-1) antagonist developed for potential treatment of anxiety and stress-related disorders. In male rats, pexacerfont caused hepatic enzyme induction leading to increased thyroxine (T4) clearance. When administered to pregnant rats on gestation day 6 to 15, pexacerfont at 300 mg/kg/day (30× mean AUC in humans at 100 mg/day) produced similar effects on thyroid homeostasis with serum T4 and thyroid-stimulating hormone levels that were 0.3-0.5× and 3.3-3.7× of controls, respectively. At this dose, fetuses of pexacerfont-treated dams presented findings associated with maternal hypothyroidism including growth retardation and increased skeletal alterations. Additionally, there were unexpected great vessel malformations that were mostly derived from the 4th pharyngeal arch artery in 5 (4.3%) fetuses from 3 (15.8%) litters. The etiology was unclear whether the vascular malformations were related to insufficient thyroid hormones or another mechanism. To better understand this relationship, pregnant rats were implanted with a subcutaneous L-thyroxine pellet designed to provide a sustained release of T4 throughout organogenesis in rat embryos (GD 6 to 15; the dosing period of pexacerfont). T4 supplementation produced a near euthyroid state in pexacerfont-treated dams and completely prevented the fetal vascular malformations. These results suggest maternal T4 levels during organogenesis may have a role in great vessel morphogenesis associated with patterning and/or regression of pharyngeal arch arteries. Although previous clinical reports have speculated a potential relationship between thyroid hormone homeostasis and early cardiovascular development, this is the first report to experimentally demonstrate this relationship in great vessel morphogenesis.

Impact of the superior cavopulmonary anastomosis on cerebral oxygenation.

BACKGROUND: Patients with univentricular heart disease may undergo a superior cavopulmonary anastomosis, an operative intervention that raises cerebral venous pressure and impedance to cerebral venous return. The ability of infantile cerebral autoregulation to compensate for this is not well understood. MATERIALS AND METHODS: We identified all patients undergoing a superior cavopulmonary anastomosis (cases) and compared metrics of cerebral oxygenation upon admission to the ICU with patients following repair of tetralogy of Fallot or arterial switch operation (controls). The primary endpoint was cerebral venous oxyhaemoglobin saturation measured from an internal jugular venous catheter. Other predictor variables included case-control assignment, age, weight, sex, ischemic times, arterial oxyhaemoglobin saturation, mean arterial blood pressure, and superior caval pressure. RESULTS: A total of 151 cases and 350 controls were identified. The first post-operative cerebral venous oxyhaemoglobin saturation was significantly lower following superior cavopulmonary anastomosis than in controls (44 ± 12 versus 59 ± 15%, p < 0.001), as was arterial oxyhaemoglobin saturation (81 ± 9 versus 98 ± 5%, p < 0.001). Cerebral venous oxyhaemoglobin saturation correlated poorly with superior caval pressure in both groups. When estimated by linear mixed effects model, arterial oxyhaemoglobin saturation was the primary determinant of central venous oxyhaemoglobin saturation in both groups (ß = 0.79, p = 3 × 10-14); for every 1% point increase in arterial oxyhaemoglobin saturation, there was a 0.79% point increase in venous oxyhaemoglobin saturation. In this model, no other predictors were significant, including superior caval pressure and case-control assignment. CONCLUSION: Cerebral autoregulation appears to remain intact despite acute imposition of cerebral venous hypertension following superior cavopulmonary anastomosis. Following superior cavopulmonary anastomosis, cerebral venous oxyhaemoglobin saturation is primarily determined by arterial oxyhaemoglobin saturation.

Effect of sirolimus on coagulopathy of slow-flow vascular malformations.

BACKGROUND/OBJECTIVES: Stagnant blood flow present in slow-flow vascular malformations can lead to localized intravascular coagulopathy (LIC), measured by elevated D-dimer levels, low fibrinogen, and/or thrombocytopenia. LIC can lead to localized thrombosis and/or bleeding, resulting in pain, swelling, and functional limitations. Patients with complex vascular malformations treated with sirolimus show clinical improvement in these symptoms. We hypothesized that the clinical benefits of sirolimus may correlate with improvements in coexisting LIC. DESIGN/METHODS: A retrospective chart review was performed, including D-dimer, fibrinogen, and platelet count, in patients with slow-flow vascular malformations treated with sirolimus. Laboratory values were assessed at three time points (presirolimus, 1-3 months postsirolimus, and last clinic visit). Clinical response, as defined by decreased pain and swelling, was extracted from the record. RESULTS: Thirty-five patients at our vascular anomalies center had been prescribed sirolimus between 2014 and 2017. Fifteen patients (12 combined slow-flow vascular malformations and three pure venous malformations) remained after excluding patients that did not have adequate records or a venous component to their vascular malformation. Patients who did not adhere to the treatment were also excluded. All 15 had elevated D-dimer levels prior to treatment and there was a statistically significant decrease in D-dimer levels following treatment with sirolimus. Symptomatic improvement of pain and swelling was reported after 3 months of starting sirolimus in 13/15 patients. CONCLUSION: This study suggests that sirolimus improves coagulopathy in slow-flow vascular malformations, as evidenced by reduced D-dimer levels. Improvement in LIC symptoms also correlates with sirolimus-corrected coagulopathy.

Role of VEGF165b/VEGFTOTAL ratio in gestational diabetes mellitus.

Proper vascular function is important for well-being of mother and growing fetus. VEGFTOTAL, and VEGF165b levels and its vascular endothelial complications in gestational diabetes mellitus (GDM) together with the association of inflammation and advanced glycation end products (AGEs) are less studied. VEGF165b/VEGFTOTAL (VEGF RATIO) in GDM pregnant women was investigated in this study. Plasma VEGFTOTAL was lower in GDM (17.68 ± 1.30 pg/mL) compared to non-GDM (25.69 ± 1.40 pg/mL). VEGF165b, ICAM-1, and AGEs were higher in GDM (9.9 ± 1.4 pg/mL, 201.04 ± 7.85 µg/mL, and 10.40 ± 0.98 µg/mL, respectively) and lower in non-GDM (6.47 ± 0.70 pg/mL, 174.1 ± 7.11 µg/mL, and 4.71 ± 0.39 µg/mL, respectively). Compared to non GDM (0.25 ± 0.02), VEGF RATIO was higher in GDM (0.45 ± 0.04) and correlated with -ICAM-1 (r = 0.375, p < .001) and AGEs (r = 0.199, p < .05). Tertile stratification of VEGF RATIO implied that frequency of GDM increases with increasing tertiles of VEGF RATIO (p for trend <.001). Association of VEGF RATIO with GDM was significant even after adjusting for AGEs (OR = 1.279, CI = 1.118-1.462, p < .0010) but it lost its significance when adjusted for ICAM-1 (OR = 1.006, CI = 0.995-1.017, p = .308). VEGF RATIO plays an important role in GDM in association with vascular inflammation.

Vascular Malformation Enlargement During Menopause.

Vascular malformations enlarge overtime, particularly during adolescence when follicle-stimulating hormone (FSH) rises. Lesions contain the receptor for follicle-stimulating hormone. FSH also becomes elevated during menopause. We present a patient with a venous malformation of the lip that presented for the first time after she entered menopause which was temporally related to a significant increase in her serum FSH levels that were measured. This observation supports the hypothesis that FSH might influence the pathophysiology of vascular malformations.

Successful living donor liver transplantation for giant extensive venous malformation.

We report our success in employing LDLT as a course of treatment for extensive hepatic VM. A 14-yr-old pediatric patient presented at our hospital with nosebleed, fatigability, orthopnea, and abdominal distension. He had a history of right hemicolectomy with primary anastomosis due to VM of the transverse colon at age seven. Coagulation abnormalities were apparent, characterized by high international normalized ratio of prothrombin time, decreased fibrinogen level, increased FDPs, and D-dimer. T2-weighted magnetic resonance imaging revealed numerous, variable-sized high signal intensity nodules. Abdominal ultrasonography and CT scan showed hepatomegaly with multiple hypo-echogenic lesions and arteriovenous shunting in the liver. Doppler ultrasound showed hypokinetic flow in the hypo-echogenic lesions of liver. Immediate LDLT was performed to avoid spontaneous rupture and DIC. The right lobe of the liver was implanted with temporary portocaval shunt to prevent intestinal congestion and bleeding. Pathologic examination of the explanted liver confirmed the presence of an extensive hepatic VM. The postoperative course was uneventful, and the patient remained symptom-free with normal liver function throughout the 12-month follow-up period.

Rivaroxaban for the treatment of consumptive coagulopathy associated with a vascular malformation.

The localized activation of coagulation in vascular malformations can lead to a consumptive coagulopathy characterized by elevated D-dimers and a consumption of fibrinogen and platelets, eventually giving rise to a bleeding tendency. By reducing coagulation activation, anticoagulant treatment with heparin is able to limit this haemostatic dysregulation and the associated bleeding diathesis. Here, we present a case of a consumptive coagulopathy due to a large venous malformation with a sustained correction of the fibrinogen depletion and associated bleeding tendency both with subcutaneous enoxaparin and with the oral factor Xa inhibitor rivaroxaban.

[Selected biological markers in various vascular lesions of the head and neck]. / Wybrane markery biologiczne w niektórych zmianach naczyniowych glowy i szyi.

Vascular anomalies are divided according to the contemporary system of classification into two groups: tumors and malformations. However, there is no consensus on juvenile angiofibroma's place in that system. The general characteristics of selected markers of angiogenesis and tissue remodeling are presented in the series in the context of current knowledge in the field of pathophysiology of vascular lesions. The mentioned markers are currently the subjects of multidirectional studies in oncology, as they take part in the process of neoangiogenesis and proliferation of tumors. Nevertheless, they have not been widely examined in vascular lesions. The indirect goal of that series is to indicate the possible research direction on vascular lesions to determine their molecular profile, to create a more specific system of classification, and above all to develop new diagnostic and treatment methods.

Treatment of a non-typical hepatic pseudolesion complicated by greatly elevated alpha fetoprotein: case report and literature review.

BACKGROUND: Hepatic pseudolesions detected by helical computed tomography (CT) are not rare, but it is difficult to make a final diagnosis when the hepatic lesion is complicated by the presence of greatly elevated alpha fetoprotein (AFP). Clinical treatment of non-typical hepatic pseudolesions complicated by greatly elevated AFP should confirm the diagnosis and minimize trauma. CASE PRESENTATION: Non-invasive procedures including ultrasonography, CT, and micro-invasive digital subtraction angiography could not safely differentiate this lesion from a malignant focus when it was complicated by greatly elevated AFP. Laparoscopic hepatectomy was performed, and pathological analysis showed chronic hepatitis, nodular regenerative hyperplasia, focal nodular hyperplasia of the liver, and mild vascular malformation. The tissue was HbsAg(-), HbcAg(-), and AFP(+). CONCLUSION: Heightened awareness of hepatic pseudolesion complicated by primarily elevated AFP will help physicians avoid unnecessary invasive procedures. Hepatic biopsy is inevitable because of greatly elevated AFP. For suspected hepatic pseudolesion with elevated AFP, needle-core biopsy and follow-up surveillance instead of hepatectomy are recommended to find the source of AFP and make a final diagnosis of pseudolesion.

Are there any similarities in the hepatic vascular anatomy among blood relatives?

BACKGROUND/AIMS: The existence of similarities in the hepatic vascular anatomy among blood relatives (BR) have never been studied before. Since in living donor liver transplantation (LDLT), the donor may be a BR, an opportunity is available to assess whether there are similarities in the hepatic vascular anatomy among BR. METHODOLOGY: We conducted an analysis of 61 LDLT during the period from January 2004 to August 2008. Based on preoperative multi-detector computed tomography data, the hepatic arteries (HA) were classified into 4 groups, the portal vein (PV) was classified into 2 groups and the right hepatic vein (RHV) was classified into 2 groups. The data of each group were then compared between BR (n=47) and NBR (n=14). RESULTS: With regard to the HA anatomy, 30 cases (68%) of the BR donor matched that of the recipient and 9 cases (69%) in the NBR donor. The PV anatomy was matched in 41 cases (87%) of BR donor and 11 cases (79%) in the NBR donor. The anatomy of the RHV was matched in 25 cases (53%) in the BR donor and 9 cases (64%) in NBR donor. There was no significant difference in all contexts. CONCLUSIONS: No similarities were therefore observed in the hepatic vascular anatomy among BR.

[Congenital galactosemia in newborn infant with vascular malformation of the internal organs].

The paper describes a case of hereditary thesaurismosis - galactosemia in neonate infant with mutation of GALT-gene (Q188R/N) and vascular malformation of the internal organs.

Angiogenic and prothrombotic markers in extensive slow-flow vascular malformations: implications for antiangiogenic/antithrombotic strategies.

BACKGROUND: Venous and combined malformations are slow-flow haemodynamically inactive lesions that are present at birth and worsen slowly with advancing age, showing no tendency towards involution. The pathogenesis of vascular anomalies has not been fully elucidated, but their formation and progression are closely related to angiogenesis. Localized intravascular coagulation associated with venous or combined malformations is characterized by low fibrinogen, high D-dimers, and normal platelet count. OBJECTIVES: To assess the relationship of angiogenic factors with prothrombotic and endothelial damage/dysfunction markers in patients with extensive slow-flow vascular malformations. METHODS: A 2-year study (2005-2007) included 31 consecutive patients with extensive slow-flow vascular malformations from one centre. RESULTS: Serum levels of the endothelial receptor tyrosine kinase TIE-2, matrix metalloproteinase (MMP)-9 and angiopoietin (Ang)-2 and plasma levels of D-dimer, plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator and von Willebrand factor (vWf) were significantly increased in patients compared with healthy controls, whereas serum levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, MMP-2, Ang-1, platelet-derived growth factor (PDGF)-AB and PDGF-BB were significantly decreased in patients compared with controls. A strong positive correlation was present between Ang-1 and PDGF-AB levels (r = 0.63, P < 0.001), between PDGF-AB and PDGF-BB levels (r = 0.67, P < 0.001), and between fibrinogen and PAI-1 levels (r = 0.41, P = 0.031). A strong negative correlation was present between Ang-1 and vWf levels (r = -0.48, P = 0.006), between D-dimer and fibrinogen levels (r = -0.71, P < 0.001), and between PDGF-AB and vWf levels (r = -0.42, P = 0.017). CONCLUSIONS: These findings suggest that angiogenic, coagulation and endothelial damage/dysfunction markers are possibly linked in pathogenesis of extensive slow-flow vascular malformations, and might have therapeutic implications.

Changes in cerebral blood oxygenation and hemodynamics after endovascular treatment of vascular malformation measured by time-resolved spectroscopy.

Although endovascular treatment has a high success rate, it is not clear how endovascular treatment affects cerebral perfusion and hemodynamics during the perioperative period. We evaluated changes in cerebral blood oxygenation (CBO) repeatedly after endovascular treatment employing time-resolved spectroscopy (TRS). We investigated a patient (10 months old, female) who suffered cerebral arteriovenous fistula. Cerebral angiography demonstrated a pial arteriovenous fistula with three feeders (left PICA, SCA, and AICA). TRS demonstrated a decrease of oxyhemoglobin, total hemoglobin, and oxygen saturation associated with an increase of deoxyhemoglobin in all of the regions measured just after embolization, indicating that embolization improved hyperemia caused by the AV shunt. Interestingly, progressive improvement of hyperemia was observed 3 and 8 days after embolization of the feeders. The present study demonstrated that embolization of the feeders caused progressive changes in CBO and hemodynamics during the perioperative period. TRS may be a useful tool for monitoring cerebral blood perfusion changes after endovascular surgery.

[Minimal bright red rectal bleeding: what should be considered?]. / Blut auf dem Stuhl. Woran ist bei der Differenzialdiagnose zu denken?

Blood in faeces or stains of blood on the surface or toilet paper are common problems among all age groups. Too few patients seek medical consultation because of these symptoms. The differential diagnosis is quite large. Most cases are caused by benign anorectal diseases like hemorrhoids. On the other hand neoplasias of the anus and intestine or inflammatory bowel disease are important diagnoses to be considered. We emphasize that every patient should be seen by a doctor and endoscopic investigation should be discussed.

Serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in children with hemangiomas and vascular malformations--preliminary report.

Impaired balance between proangiogenic and antiangiogenic factors has been implicated in the development of hemangiomas. Elevated vascular endothelial growth factor serum levels and basic fibroblastic growth factor urine levels in patients with proliferating hemangiomas were reported. However, whether these growth factors can be used for the differential diagnosis of vascular anomalies or assessment of the clinical course of hemangiomas has yet to be determined. We report here our preliminary results of serum vascular endothelial growth factor and basic fibroblastic growth factor levels as an aid in the diagnosis of hemangiomas and in the follow up of patients with this lesion. Twenty two children with infantile hemangioma (13 with proliferating hemangiomas, nine with involuting lesions), five children with vascular malformations, and 25 healthy children study group. Vascular endothelial growth factor and basic fibroblastic growth factor serum levels were analyzed by an ELISA assay. The serum vascular endothelial growth factor concentrations in children with proliferating hemangiomas were significantly higher than in patients with involuting hemangiomas, vascular malformations and healthy patients. The serum basic fibroblastic growth factor concentrations were low and similar in all patients with no statistical correlation between study groups. We concluded that (i) ELISA can easily determine vascular endothelial growth factor concentrations in different phases of hemangioma growth and help distinguishing them from vascular malformations. (ii) A potential role for vascular endothelial growth factor in the pathophysiology of hemangiomas is probable.

Chronic localized intravascular coagulation complicating multifocal venous malformations.

We present two female children aged 7 years with extensive multifocal venous malformations complicated by chronic localized intravascular coagulation. In both cases ultrasonography and magnetic resonance imaging revealed extensive venous malformations involving the skin, mucous membranes and pharynx, which were not apparent on clinical examination. Haematological investigations demonstrated persistent elevation of the D-dimer, consistent with chronic localized intravascular coagulation. The course of one patient was complicated by the development of multiple painful thromboses at distant sites following percutaneous sclerotherapy. Persistent elevation of the D-dimer occurring in association with large venous and veno-lymphatic malformations has been termed chronic localized intravascular coagulation, and is thought to occur due to thrombosis at sites of stagnant blood flow within venous malformations. It is of clinical concern due to the potential for transformation into serious thrombohaemorrhagic coagulation disorders, including disseminated intravascular coagulation. While previously described in association with large segmental venous malformations, these cases demonstrate the occurrence of chronic localized intravascular coagulation as a complication of disseminated multifocal venous malformations.

Effect of storage on microcytosis observed in dogs with portosystemic vascular anomalies.

Microcytosis is a common laboratory finding in dogs with iron deficiency and congenital portosystemic vascular anomalies (PSVA), however artefactual changes due to blood storage may occur which could mask this feature. This study evaluated the effects of storage on microcytosis in dogs with congenital PSVA. Full haematological parameters were measured on the day of sampling and following 24h storage at room temperature, in unaffected dogs (n=13) and in dogs affected with PSVA (n=24). Storage for 24h resulted in significantly higher MCV values in both groups of dogs (P<0.01). The percentage increase in MCV was greater in the control dogs (median 8.07%, range 5.64-9.31%) compared to affected dogs (median 6.05%, range 3.12-15.21%) (P<0.02). Storage of 1ml EDTA blood samples at ambient temperature for 24h prior to analysis, as occurs when samples are posted to external laboratories, will have significant effects on MCV and may mask microcytosis in dogs with PSVA.

Circulating Levels of Vascular Endothelial Growth Factor and Basic Fibroblastic Growth Factor in Infantile Hemangioma Versus Vascular Malformations.

Few preliminary reports studied the utility of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) for differentiation between infantile hemangiomas (IHs) and vascular malformations. The aim of this study was to investigate the role of serum VEGF and bFGF levels in differentiating IHs from vascular malformations and identifying the stage and clinical course of IHs. Serum levels of VEGF and bFGF were assessed in 60 infants and children with various cutaneous vascular anomalies defined in 3 groups: proliferating IHs (n = 25), involuting IHs (n = 23), and vascular malformations (n = 12), in comparison with their levels in 40 healthy matched control. Serum levels of VEGF and bFGF were significantly elevated in all groups as compared to control ( P < .001, respectively). Both proliferating and involuting IHs had comparable levels of both markers ( P > .05, respectively) that were significantly higher in comparison with vascular malformations ( P < .05, respectively). Significantly lower VEGF levels were found in IHs that had regressed spontaneously (n = 11) compared to those regressed by treatment (n = 37), ( P < .05); meanwhile, bFGF showed no significant difference between both groups ( P > .05). Using receiver operating characteristic curves, a combined use of VGEF and bFGF yielded a sensitivity of 85.42% and a specificity of 100% for differentiating IHs from vascular malformations. Serum VEGF and/or bFGF levels are increased in cutaneous vascular anomalies and can differentiate IHs from vascular malformations. None of these markers could help in identifying the stage of IHs. Low VEGF is associated with spontaneous regression of IHs.