Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and ...bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA.
A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated.
Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group).
Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.
•Caplacizumab reduces exacerbation and refractoriness in iTTP.•As initial therapy, caplacizumab accelerates response and reduces the need for PEX and hospital stay.
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Immune thrombotic ...thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX.
Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare disease characterized by a severe deficiency of the enzymatic activity of ADAMTS13 caused by autoantibodies, with an ...incidence of 3-4 x106inhabitants per year according to the few published data available. Accurate estimates of the incidence of aTTP are important to assess the resources required for current treatments and to anticipate the need to develop new treatments. The aim of this study was to determine the actualincidence of aTTP in Spain, as well as its diagnosis, management, and associated complications.
Material and methods:A cross-sectional surveywascarried out among hematologists working in Spanish hospitals by means of an email that was sent to all members of the three main hematological scientificsocieties of Spain. All participants were asked to report the number of patients over the age of 16 years with a de novodiagnosis and relapses examined between Jan 2015 and Dec 2017. They were also asked about the number of patients that were known and alive in each hospital without having experienced any episode during such period. The population area of each participating hospital was consideredto calculate the incidence and prevalence of the disease. We also estimated the hospitalization service, mean hospital stay, percentage of ADAMTS13 activity at diagnosis and during follow-up, initial management, refractory cases and exacerbations (as defined by Scully et al.), treatment-related complications, and sequelae of aTTP. The median, interquartile ranges, and percentages were used for the descriptive analysis. Given that no personal data were treated, this study did not require the approval of a Research Ethics Committee.
Results:A response was received from 42 centers (Figure 1). All hospitals except a private one belonged to the Spanish public health system, which provides health coverage to the entire Spanish population.A total of 203 episodes were reported (138 new episodes). The calculated population of the participating centers was nearly 21 x 106inhabitants. The incidence was 2.25 x106inhabitants per year, and the prevalence 19 x106inhabitants. Six patients died before they could start treatment (all but one in first episodes) and five were sent to other hospitals; thus, a total of 192 episodes were eventually treated. Table 1 and 2 show the data of the enzymatic activity of ADAMTS13 and the ADAMTS13 inhibitor at diagnosis, as well asthe complications.
Plasma exchange (PEX) was performed by the Hematology and Nephrology Departments of 29 (70.7%) and 12 (29.3%) hospitals, respectively. The median hospital stay was 14 days (IQR: 10-20). Seventy-five episodes (39.1%) required admission to the intensive care unit with a median stay of 4 days (IQR: 3-7). During first-time episodes, a median of 12 PEX procedures (IQR: 8-19) were performed per patient, whereas in the case of relapses, a median of 9 (7-10) PEX procedures were carried out per patient. One plasma volume (PV) was used in the PEX procedures performed in 34% of the episodes, while 1.5 PVs were used in 56% of the episodes, and other PVs were used in the remaining 9.8%. The median duration of the PEX procedures was 121 minutes (IQR: 118-180).
PEX and corticosteroids were the initial treatments administered in 98.4% of the episodes. Rituximab was used as a first-line treatment for new episodes in 18 of the 127 patients (14.1%), as a second-line treatment in 34 patients (26.6%), and as a prophylactic treatment (followingremission) in 4 patients (3.5%).
In addition to the 6 early deaths, 9 patients died despite receiving the treatment (15 of 203 episodes, accounting for a mortality rate of 7.3%). Refractoriness to the PEX + corticoids was observed in 31 episodes of the 192 ones treated (16.1%), and at least one exacerbation (26.5%) took place in 51 episodes.
Conclusion.Wecalculated the incidence ofclinically diagnosed aTTP associated with a severe ADAMTS13 deficiency inalmost half of the Spanish population which provided a high accuracy to our findings. These data are concordant with those published previously in other countries. Despite the currently available therapies, considerable rates of refractoriness and mortality still persist.Our data will be very useful for estimating the budget invested in this pathology and proposing standards for the diagnosis and treatment of this disease in our region.
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Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. De La Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Mingot-Castellano:Novartis: Consultancy; Novonordisk: Consultancy; Roche: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Amgen: Consultancy; CSL Behring: Consultancy; Sobi: Consultancy.
Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a ...reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.
Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.
We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12™ (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).
We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval CI -1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).
Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.
NCT01896557.
Progressive multifocal leukoencephalopathy (PML) is a feared entity that occurs most frequently in conditions of extreme immunodeficiency. The diagnosis is often made long after the onset of symptoms ...due to the physicians' unfamiliarity, and the unavailability of diagnostic tests in some medical centers. Although the incidence of PML is decreasing among HIV patients with the advent of highly active antiretroviral therapy (HAART), in Brazil this entity is the fourth highest neurological complication among these patients. The authors present the case of a middle-aged man who tested positive for HIV concomitantly with the presentation of hyposensitivity in the face and the right side of the body, accompanied by mild weakness in the left upper limb. The clinical features worsened rapidly within a couple of weeks. The diagnostic work-up pointed to the working diagnosis of PML after brain magnetic resonance imaging; however, the detection of the John Cunningham virus (JCV) in the cerebral spinal fluid was negative. HAART was started but the patient died after 7 weeks of hospitalization. The autopsy revealed extensive multifocal patchy areas of demyelination in the white matter where the microscopy depicted demyelination, oligodendrocytes alterations, bizarre atypical astrocytes, and perivascular lymphocytic infiltration. The immunohistochemistry was positive for anti-SV40, and the polymerase chain reaction of the brain paraffin-embedded tissue was positive for JCV. The authors highlight the challenges for diagnosing PML, as well as the devastating outcome of PML among HIV patients.
•There is no delay in ADAMTS13 recovery after PEX start in caplacizumab–treated patients with iTTP from the Spanish registry.•Caplacizumab allows suspending PEX earlier, thus creating the impression ...that there is a delay in ADAMTS13 recovery after PEX end.
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Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median interquartile range, 14.5 7.7-27.2 vs 13.0 8.0-29.0 days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 12.0-43.0 vs 11.0 3.5-20.0 days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 4.0-9.0 vs 15.0 11.0-21.5 days, P < .001) or non-caplacizumab-treated episodes (11.0 6.0-26.0 days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 17.2-47.5, 27.0 19.0-37.5 and 29.5 15.2-45.0 days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.
Caplacizumab is approved as an addition to plasma exchange (PEX) and immunosuppression for the treatment of acute autoimmune thrombotic thrombocytopenic purpura; however, it is controversial whether caplacizumab use delays recovery of ADAMTS13. Mingot-Castellano and colleagues, on behalf of the Spanish Apheresis Group and the Spanish Registry of Thrombotic Thrombocytopenic Purpura, present a retrospective study demonstrating that recovery of ADAMTS13 levels to ≥20% is similar whether caplacizumab is used or not. The early addition of caplacizumab enables earlier discontinuation of PEX.
Neem tree (Azadirachta indica A. Juss. fam. Meliaceae) has been extensively employed to combat diverse pathologies. Moreover, it has been described that its leaf extract present anticarcinogenic ...action. Thus, the neem extract (NE) chemical and antioxidant properties was evaluated, and also, the capacity of two dermatological formulations incorporated with neem extract (F1 and F2) to avoid oxidative UVB-induced skin injury in hairless mice. NE constituents were investigated and free radical scavenging ability were determined by different methods in vitro. Skin from mice treated with F1 and F2 and submitted to UVB radiation were tested for different parameters of inflammation and oxidative injury. Results show that the NE polyphenol and flavonoid content were 135.30 and 37.12mg/g, respectively. High performance liquid chromatography (HPLC) results demonstrated the existence of azarachtin, rutin, ursolic acid and tannic acid. NE presented scavenging ability by ABTS radical, ferric-reducing antioxidant power (FRAP), inhibition of lipid peroxidation and iron chelation. In vivo, it was observed that mice treated with F1 and F2 showed amelioration of the inflammation by reducing UVB induced skin edema. However, only samples from animals treated with F1 had lower neutrophil recruitment (measured by myeloperoxidase activity), and returning the oxidative status to baseline levels in parameters such as reduced glutathione level, ferric reducing ability (FRAP), and scavenging of free radical (ABTS). Concluding, NE demonstrated a good antioxidant property in vitro, and the data suggest the use of NE added F1 to prevent skin damage caused by UVB irradiation.
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