scholarly journals Intravenous Bevacizumab Therapy in a Patient with Hereditary Hemorrhagic Telangiectasia, ENG E137K, Alcoholic Cirrhosis, and Portal Hypertension

2017 ◽  
Vol 11 (2) ◽  
pp. 293-304
Author(s):  
Luigi F. Bertoli ◽  
Pauline L. Lee ◽  
Lauren Lallone ◽  
James C. Barton
Keyword(s):  
Portal Hypertension ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Positive Association ◽  
Alcoholic Cirrhosis ◽  
Intravenous Iron ◽  
Platelet Counts ◽  
Bevacizumab Treatment ◽  
Severe Epistaxis ◽  
Multivariable Analyses ◽  
Mucosal Bleeding

Intravenous bevacizumab decreased mucosal bleeding in some patients with hereditary hemorrhagic telangiectasia (HHT). We treated a 47-year-old male who had HHT, severe epistaxis, and gastrointestinal bleeding, alcoholic cirrhosis, and portal hypertension with intravenous bevacizumab 2.5 mg/kg every 2 weeks. We tabulated these measures weekly during weeks 1–33 (no bevacizumab); 34–57 (bevacizumab); and 58–97 (no bevacizumab): hemoglobin (Hb) levels; platelet counts; units of transfused packed erythrocytes (PRBC units); and quantities of iron infused as iron dextran to support erythropoiesis. We performed univariate and multivariable analyses. We sequenced his ENG and ACVRL1 genes. Epistaxis and melena decreased markedly during bevacizumab treatment. He reported no adverse effects due to bevacizumab. Mean weekly Hb levels were significantly higher and mean weekly PRBC units and quantities of intravenous iron were significantly lower during bevacizumab treatment. We performed a multiple regression on weekly Hb levels using these independent variables: bevacizumab treatment (dichotomous); weekly platelet counts; weekly PRBC units; and weekly quantities of intravenous iron. There was 1 positive association: (bevacizumab treatment; p = 0.0046) and 1 negative association (PRBC units; p = 0.0004). This patient had the novel ENG mutation E137K (exon 4; c.409G→A). Intravenous bevacizumab treatment 2.5 mg/kg every 2 weeks for 24 weeks was well-tolerated by a patient with HHT due to ENG E137K and was associated with higher weekly Hb levels and fewer weekly PRBC units.

Altered Expressions of CXCR4 and CD26 On T-Helper Lymphocytes in Hereditary Hemorrhagic Telangiectasia

2021 ◽  
Author(s):  
Alexandre GUILHEM ◽  
Pierre Portalès ◽  
Sophie Dupuis-Girod ◽  
Sophie Rivière ◽  
Thierry Vincent
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Severe Infection ◽  
Intravenous Iron ◽  
Surface Expression ◽  
T Helper ◽  
Membrane Expression ◽  
Susceptibility To Infection ◽  
T Helper Lymphocytes ◽  
Infectious Risk ◽  
Healthy Control

Abstract Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (telangiectasia, arteriovenous malformations), patients exhibit a specific infectious risk and a deficit of T and natural killer (NK) lymphocytes. As the CXCR4/CXCL12 chemotactic axis is dysregulated in HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes.Results: Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating helper and cytotoxic T lymphocytes (including naive, memory and activated subsets) and NK cells.The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs 1026 cells/mm3, p<0.0001), correlated with age (r=-0.46, p=0.005), requirement of intravenous iron or blood transfusions (median: 291 vs 627 cells/mm3, p=0.03) and CXCR4 surface expression (r=0.353, p=0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs 5.74 for CXCR4 and 3.21 vs 4.33 for CD26, p=0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the naive T-helper lymphocytes (median: 2.34 vs 1.32, p=0.0002), also observed on the T and T-helper populations.Conclusions: Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection.

scholarly journals Topical Propranolol Improves Epistaxis Control in Hereditary Hemorrhagic Telangiectasia (HHT): A Randomized Double-Blind Placebo-Controlled Trial

2020 ◽  
Vol 9 (10) ◽  
pp. 3130
Author(s):  
Meir Mei-Zahav ◽  
Yulia Gendler ◽  
Elchanan Bruckheimer ◽  
Dario Prais ◽  
Einat Birk ◽  
...  
Keyword(s):  
Placebo Group ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Controlled Trial ◽  
Intravenous Iron ◽  
Common Adverse Event ◽  
Open Label ◽  
Two Phase ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Propranolol Group

Epistaxis is a common debilitating manifestation in hereditary hemorrhagic telangiectasia (HHT), due to mucocutaneous telangiectases. The epistaxis can be difficult to control despite available treatments. Dysregulated angiogenesis has been shown to be associated with telangiectases formation. Topical propranolol has demonstrated antiangiogenic properties. We performed a two-phase study, i.e., a double-blind placebo-controlled phase, followed by an open-label phase. The aim of the study was assessment of safety and efficacy of nasal propranolol gel in HHT-related epistaxis. Twenty participants with moderate-severe HHT-related epistaxis were randomized to eight weeks of propranolol gel 1.5%, or placebo 0.5 cc, applied to each nostril twice daily; and continued propranolol for eight weeks in an open-label study. For the propranolol group, the epistaxis severity score (ESS) improved significantly (−2.03 ± 1.7 as compared with −0.35 ± 0.68 for the placebo group, p = 0.009); hemoglobin levels improved significantly (10.5 ± 2.6 to 11.4 ± 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (−1.99 ± 1.41, p = 0.005). The most common adverse event was nasal mucosa burning sensation. No cardiovascular events were reported. Our results suggest that topical propranolol gel is safe and effective in HHT-related epistaxis.

Longitudinal assessment of progressive decrease in platelet counts as a surrogate marker of liver fibrosis and portal hypertension

2020 ◽  
Vol 73 ◽  
pp. S747
Author(s):  
Neta Gotlieb ◽  
Naama Schwartz ◽  
Shira Zelber-Sagi ◽  
Gabriel Chodik ◽  
Varda Shalev ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Surrogate Marker ◽  
Longitudinal Assessment ◽  
Progressive Decrease ◽  
Platelet Counts

scholarly journals Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis

1980 ◽  
Vol 79 (6) ◽  
pp. 1139-1144 ◽  
Author(s):  
Didier Lebrec ◽  
Patrice De Fleury ◽  
Bernard Rueff ◽  
Henri Nahum ◽  
Jean-Pierre Benhamou
Keyword(s):  
Portal Hypertension ◽  
Gastrointestinal Bleeding ◽  
Esophageal Varices ◽  
Alcoholic Cirrhosis

Profiles of Antibodies Specific to Platelet Glycoproteins in ITP Differ in Remission, Relapse and Stable Phases; and Anti-GpIIb/IIIa, -GpIb/IX Were Associated with Bleeding Manifestations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1250-1250
Author(s):  
Carlos J. Bidot ◽  
Wenche Jy ◽  
Lawrence L. Horstman ◽  
Eugene Ahn ◽  
Vincenzo Fontana ◽  
...  
Keyword(s):  
Platelet Dysfunction ◽  
Platelet Surface ◽  
Platelet Counts ◽  
Acute Relapse ◽  
Significant Difference ◽  
Three Stages ◽  
Mucosal Bleeding ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Common Target

Abstract BACKGROUND: In immune thrombocytopenic purpura (ITP), antiplatelet antibodies (APtAb) bind to antigens exposed on the platelet surface to mediate platelet clearance from circulation. GpIIb/IIIa, GpIb/IX and GpIV, common target antigens in ITP, are receptors for fibrinogen, von Willebrand factor and collagen, respectively, and are involved in platelet aggregation and adhesion, playing critical roles in hemostasis and thrombosis. It has been suggested that APtAb binding to these molecules interfere with their function, inducing platelet dysfunction and enhancing bleeding in ITP. In the present study, we investigated profiles of antibodies against these antigens in different stages of ITP, and in relation to bleeding manifestations. METHODS: We measured IgG and IgM APtAb against the three most prevalent glycoprotein target antigens, GpIIb/IIIa, GpIV and GpIb/IX, by PAICA [Macchi, et al; 1996, Thromb Haemost76:1820]. We studied 130 patients with ITP. There were 87 women (66.9%) and 43 men (33.1%). ITP was classified into three stages, (i) acute/relapse, 28 pts (21.5%); (ii) chronic/stable (platelet counts &lt;150,000 for at least 6 mo’s), 69 pts (53.0%); (iii) remission, 33 pts (25.3%). The chronic/stable patients were further divided into bleeders (n=27) and non-bleeders (n=19). Those patients with visible multiple petechias or echymosis at more than three sites, or mucosal bleeding were defined as bleeders; non-bleeders had none of these signs. RESULTS: (1) IgG APtAb against GpIIb/IIIa, GpIV and GpIb/IX were all significantly more frequent in acute/relapse (77%, 70%, and 67%, respectively) than in chronic/stable ITP (52%,55%, and 44%), at p=0.005, p=0.003, p=0.04, respectively. (2) All IgG APtAb were significantly more frequent in acute/relapse and chronic/stable ITP compared to remission, p&lt;0.0001. (3) IgM APtAb were detected in approximately 50% of patients in relapse and stable stages for all 3 antigens; there was no significant difference in frequency between acute/relapse and chronic/stable, but both were significantly higher than in remission. (4) Multiple antibodies (≥ 2 antigens positive) were observed in 50–70% of patients in both relapse and stable stages. (5) When we compared frequencies of APtAb between bleeders and non-bleeders, both IgG and IgM APtAb were significantly more frequent in bleeders, for all antigens except IgM GpIb/IX. Interestingly, 96.7% of bleeders had at least one APtAb of IgG or IgM class, while only 58% were positive in non-bleeders (p&lt;0.0002). This difference persisted when reanalyzed to ensure equal mean platelet counts between bleeders and non-bleeders. It was also found that positivity for APtAb of IgG (but not IgM) class against the pair, GpIIb/IIIa and GpIb/IX (but not GpIV) was predictive of bleeding. CONCLUSIONS. Distinctive profiles of APtAb to GpIIb/IIIa, GpIb/IX, and GpIV were observed in different stages of ITP. IgG APtAb were frequently seen in acute/relapse and chronic/stable, both clases (IgG-IgM) were rarely seen in remission. Patients with signs of bleeding more frequently had IgG APtAb to the pair, GpIIb/IIIa and GpIb/IX, suggesting this pair of APtAb interferes with platelet hemostatic functions, enhancing the bleeding manifestations of ITP.

Cell-Derived Microparticles in ITP Patients with vs. without Bleeding Tendency.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2092-2092
Author(s):  
Vincenzo Fontana ◽  
Wenche Jy ◽  
Pamela Dudkiewicz ◽  
Eugene Ahn ◽  
Lawrence Horstman ◽  
...  
Keyword(s):  
Coagulation Factors ◽  
P Value ◽  
Hemorrhagic Diathesis ◽  
Bleeding Tendency ◽  
Platelet Counts ◽  
Activated Platelets ◽  
Pertinent Data ◽  
Significant Difference ◽  
History Of ◽  
Mucosal Bleeding

Abstract INTRODUCTION: In immune thrombocytopenic purpura (ITP), autoantobodies mediate platelet destruction, leading to thrombocytopenia and a hemorrhagic diathesis. Although platelet counts are used to assess risk of bleeding in ITP, this is not dependable since some seldom bleed while others bleed excessively at the same level of thrombocytopenia. Cell-derived microparticles (C-MP) are microvesicles released upon activation or apoptosis from blood cells such as platelets (PMP), leucocytes (LMP) and red cells (RMP) as well as endothelial cells (EMP). Their roles in hemostasis, thrombosis and inflammation are increasingly appreciated. We investigated C-MP in ITP in patients with bleeding tendency vs. those without. METHODS: Thirty-seven patients (24 F/13M, mean age 53.8 yr) with chronic ITP (platelet counts <50,000/μL for at least 3 mo’s) were studied. Patients with bleeding tendency (BL) were defined as those who met any of the following criteria: history of spontaneous frequent mucosal bleeding (nose, gum etc), episodes of organ bleeding such as GI, GU, CNS bleeding, menorrhagia with recurring anemia, cutaneous bleeding characterized by gross petechiae on >2 sites (leg, arm, trunk etc) or multiple (>5) ecchymosis >3cm sizes or wet purpuras. Patients with similar platelet counts but not meeting any of these criteria were defined as non-bleeders (NBL). The BL group consisted of 17 pt (7M/10F, mean age 53.6 yr) while the NBL group comprised 20 pt (6M/14F, mean age 54.0 yr). The BL group contained 12 with skin bleeding and 5 with mucosal /organ bleeding. Pertinent data are summarized in Table. Coulter XL flowcytometer was employed to identify LMP by anti-CD45, PMP by anti-CD41, RMP by anti-glycophorin, and EMP by the combination CD31+/CD41-. Platelet counts and aPTT were also compared between the groups. RESULTS: Mean platelet count was similar in both groups (27,000/μL). When C-MP were compared between BL vs NBL, there was no significant difference in mean levels of EMP (203 vs 169, p > 0.05) or LMP (1342 vs 1422, p > 0.05). However, RMP were significantly higher in the NBL group (2878 vs 1310, p = 0.01). See Table. PMP were also higher in NBL (3498 vs 1771) but did not reach significance. The aPTT was shorter in the NBL (24.4s vs 26.5s) but not significantly. CONCLUSION / DISCUSSION: These data support the unexpected conclusion that RMP are significantly associated with hemostasis in ITP. PMP were also elevated in NBL compared to BL but did not reach significance in this study. Our previous study documenting elevated PMP in NBL vs BL [Jy et al, JLCM119:334, 1992] employed a different assay system [Coulter EPICS V (2 watt laser) and detection by light scatter with CD42 not CD41]. Other factors implicated in hemostasis in ITP include increased number of larger young platelets and activated platelets. Our data suggest that elevated RMP may be a significant hemostatic factor in thrombocytopenic states. However, we also note a trend of increased PMP, as well as shortened aPTT in NBL. Since RMP are known to express phosphatidylserine (binding sites for coagulation factors), they can promote coagulation to facilitate blood clotting, and thus may aid in prevention of bleeding in thrombocytopenic patients. Table 1. BLEEDERS NON-BLEEDERS p value No Patients 17 20 Age 53.6 54.0 Sex (M/F) 7/10 6/14 Plt (count/uL) 27,000 27,000 n. s. aPTT (sec) 26.5 24.4 n. s. C-MP (count/uL): EMP 203 169 n. s. LMP 1,342 1,422 n. s. PMP 1,771 3,498 n. s. RMP 1,310 2,878 0.01

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