RESUMO
A State of the Art lecture titled "Anticoagulation and Vascular Anomalies" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2023. Vascular anomalies have been classified by the International Society for the Study of Vascular Anomalies into vascular tumors and vascular malformations. Although some vascular tumors, such as tufted angioma and kaposiform hemangioendothelioma, and other vascular malformations can present with coagulation aberrancies, these are not generally managed with anticoagulation. A subclassification of vascular malformations includes slow-flow vascular malformations. It is this subgroup specifically that has a high risk of venous thromboembolism (VTE) and morbidity associated with coagulopathy that may be present. In these select cases, anticoagulation may be indicated to reduce the risk of VTE, treat VTE, or manage localized thrombosis in the malformation that causes significant pain and reduced quality of life. There are established risk factors for VTE in these patients that will be reviewed. Finally, we summarize relevant new data on this topic presented during the 2023 ISTH Congress.
RESUMO
Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.
Assuntos
Hiperplasia do Linfonodo Gigante , Hemofilia A , Humanos , Criança , Fator VIII , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/diagnóstico , Hemorragia/etiologia , AutoanticorposRESUMO
BACKGROUND: There are very few large population-based studies studying mental health in persons with von Willebrand disease (PwVWD). OBJECTIVES: We aim to assess prevalence of depression and anxiety in PwVWD over a period of 20 years and identify bleeding symptoms that may be more likely associated with depression and anxiety in PwVWD. METHODS: This is a retrospective cohort study using a deidentified national dataset from 1118 hospitals with 176 million patients. Cases were defined as patients aged 0-110 years, both male and female, with von Willebrand disease (VWD), without hemophilia. Controls were defined as patients aged 0-110 years, both male and female, without VWD or hemophilia. We compared rates of depression and anxiety in cases and controls and by type of bleeding symptoms. RESULTS: We identified 66 367 PwVWD and 183 890 766 controls. The prevalence of depression (23.12% vs 8.62%; p ≤ .00093; relative risk = 2.68) and anxiety (32.90% vs 12.29%; p ≤ .00093; relative risk = 2.68) was higher in PwVWD. Most of the bleeding symptoms were associated with higher rates of depression and anxiety in PwVWD with the highest rates with abnormal uterine bleeding, hematemesis, hemoptysis, hematuria, and melena. CONCLUSION: Our study shows that mental health disorders in PwVWD are a significant health burden, and that burden is increased with documented bleeding symptoms. It is important that primary care physicians and hematologists caring for this population recognize this increased risk and appropriately screen and refer to mental health professionals.
Assuntos
Ansiedade , Bases de Dados Factuais , Depressão , Saúde Mental , Doenças de von Willebrand , Humanos , Feminino , Masculino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Adulto , Prevalência , Estudos Retrospectivos , Doenças de von Willebrand/epidemiologia , Doenças de von Willebrand/complicações , Adolescente , Idoso , Depressão/epidemiologia , Adulto Jovem , Criança , Pré-Escolar , Ansiedade/epidemiologia , Idoso de 80 Anos ou mais , Lactente , Recém-Nascido , Hemorragia/epidemiologia , Fatores de RiscoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is most commonly treated with etoposide and dexamethasone. This standard of care therapy has improved survival, but â¼15% of patients still die in the first months after diagnosis, and poor responses prompting salvage therapy are frequent. Thus, identifying patients at risk promptly is likely to improve outcomes. We conducted a multi-institutional, retrospective study of pediatric and young adults treated per HLH-94 or HLH-2004 from 2010 to 2019 to identify patients at risk for early mortality. Biweekly data during the first 100 days of treatment were analyzed using receiver operating curves to define optimal prognostic indicators and their thresholds. The primary end point was survival to bone marrow transplant (BMT) or â¼1 year if no BMT was pursued. Eighty-nine patients met the study inclusion criteria. Pre-BMT mortality was 13% (n = 12), and overall mortality was 27% (n = 24). Laboratory markers measured on day 7 of therapy more efficiently predicted outcomes than did either pretreatment or later assessments. The most potent day 7 unfavorable marker was improvement in soluble CD25 (sCD25) of less than 25% from pretherapy levels. Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen were also discriminatory markers (area under the curve ≥ 0.7). The presence of ≥3 of these unfavorable markers was strongly associated with pre-BMT mortality (accuracy, 0.93). Thus, serial monitoring of sCD25 and assessment of other early (day 7) response markers optimally predicts prognosis with etoposide-based therapy and may indicate the need for earlier use of alternative, response-adapted therapeutic strategies for HLH.
Assuntos
Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Etoposídeo/uso terapêutico , Estudos Retrospectivos , Transplante de Medula Óssea , PrognósticoRESUMO
Pupil size and reactivity have been studied to objectively measure pain utilizing pupillometry measurements. Given the challenges associated with treating vaso-occlusive pain in pediatric patients with sickle cell disease, better assessment tools are needed. The objective of this study is to establish normative values for pupil size and reactivity in pediatric patients with sickle cell disease with the hope that pupillometry can be used as a tool to objectively measure pain and response to treatment with analgesic medications. Readings were performed using a NeurOptics PLR-2000 pupillometer. Forty-four males and 38 females, all black, were studied. Their median age was 11 years (range: 2 to 21). When comparing our participants with white participants in a previously published pediatric study, there was a significant difference in maximum constriction velocity ( t =3.45, P =0.009), maximum pupil size ( t =-5.57 mm, P <0.0001), and minimum pupil size ( t =-3.24, P =0.002). There was no significant difference in pupil size and reactivity between patients with sickle cell disease and black patients without the disease when compared with the previously published study. Therefore, further investigation of pupillometry within the black population during vaso-occlusive crisis and in the "well state" is warranted in pediatric patients with sickle cell disease.
Assuntos
Anemia Falciforme , Pupila , Criança , Feminino , Humanos , Masculino , Analgésicos/uso terapêutico , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Dor/etiologia , Dor/tratamento farmacológico , Medição da Dor , Pupila/fisiologia , Pré-Escolar , Adolescente , Adulto JovemRESUMO
Some vascular anomalies can present with challenging hematologic aberrations. Kaposiform hemangioendothelioma (KHE) may be complicated with Kasabach-Merritt phenomenon (KMP) and stagnant blood flow in slow-flow malformations can promote activation and consumption of coagulation factors, which results in bleeding and clotting known as localized intravascular coagulopathy (LIC). These patients can experience significant morbidity secondary to pain due to thrombosis and are at higher risk of hematologic complications during surgical procedures. No standard of care has been established to prevent or manage these complications. This review focuses on the management of coagulopathy in children and adults with vascular anomalies.
Assuntos
Transtornos da Coagulação Sanguínea , Hemangioendotelioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Malformações Vasculares , Adulto , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/terapia , Criança , Hemangioendotelioma/complicações , Hemangioendotelioma/terapia , Humanos , Malformações Vasculares/complicações , Malformações Vasculares/terapiaRESUMO
BACKGROUND: Vascular anomalies affect up to 5% of children with the majority affecting the head and neck. They present at different ages as a wide variety of lesions. A careful evaluation with history, physical examination, and imaging assists in the proper diagnosis. Depending upon the condition treatment options for vascular anomalies include topical therapy, selective photothermolysis, sclerotherapy, embolization, surgical excision, and targeted systemic therapy. CONCLUSION: Staged multimodal therapeutic regimens have proven to best control disease and allow for the preservation of function and aesthetics. The timing, sequence, and combination of therapies are best determined by a multidisciplinary vascular anomalies team. Patients and families need to be counseled on anticipated positive outcomes following a protracted course of treatment for the majority of vascular anomalies.
Assuntos
Malformações Arteriovenosas , Malformações Vasculares , Criança , Humanos , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/cirurgia , Estética Dentária , Pescoço/diagnóstico por imagem , Pescoço/patologia , Cabeça/diagnóstico por imagem , Cabeça/irrigação sanguínea , Cabeça/patologia , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapiaRESUMO
Bleomycin, a chemotherapy agent that inhibits synthesis of DNA, has been increasingly utilized in sclerotherapy for patients with vascular malformations. A serious long-term risk of intravenous bleomycin is dose-dependent interstitial pneumonitis. Little is known about absorption and circulating levels of bleomycin when used in sclerotherapy for patients with vascular malformations. This is an Institutional Review Board (IRB)-approved prospective study on patients receiving bleomycin sclerotherapy in the management of vascular malformations. Depending on the type of vascular malformation, bleomycin was administered either in the lumen or interstitial space of the involved lesion. A bleomycin assay measured serum bleomycin plasma concentrations versus time at seven intervals following treatment. Pharmacokinetic parameters were obtained for each participant and included peak plasma concentration (Cmax ), time to reach peak plasma concentration (Tmax ), volume of distribution (Vd ), elimination half-life (t1/2 ), the volume of plasma cleared of the drug per unit time (CL), and total systemic exposure area under the curve (AUC). Fifteen patients were enrolled (5: lymphatic, 4: venous, 6: arteriovenous malformations). Bleomycin was administered interstitially (IS) in 11 patients and intraluminal (IL) in four; median age of 13 years (range: 2-67). Pharmacokinetic analysis revealed terminal elimination half-life (t1/2λz ) of 88.51 (±23.09) and 111.61 (±37.75) minutes for the IS and IL groups, respectively. Vd was 4.86 L (±6.74) and 1.55 L (±0.54) for the IS and IL groups, respectively. AUC was 53.9 (±23.45) and 129.17 (±93.57) mg min/L for the IS and IL groups, respectively. There were no statistically significant differences in t1/2λz , Vd , or AUC parameters between groups. Bleomycin is absorbed systemically when used as a sclerosant for vascular malformations when injected either IS or IL.
Assuntos
Escleroterapia , Malformações Vasculares , Adolescente , Adulto , Idoso , Bleomicina , Criança , Pré-Escolar , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Soluções Esclerosantes/uso terapêutico , Resultado do Tratamento , Malformações Vasculares/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Slow-flow vascular malformations are abnormal vessels that can lead to activation and consumption of coagulation factors and thrombosis, known as localized intravascular coagulopathy (LIC). Most clinical and research evidence of vascular malformation hemostasis relies on conventional coagulation studies, which may not provide a complete picture. Thromboelastograpy (TEG) is a tool that can provide real-time assessment of a patient's coagulation dynamics, and may allow for a more individualized treatment approach. We hypothesized that patients with slow-flow vascular malformations will have changes in TEG parameters peri-procedure that will help predict blood product or medication administration. DESIGN/METHODS: Institutional Review Board approved prospective study of patients with slow-flow vascular malformations undergoing a sedated, minor procedure. TEG and conventional coagulation studies were obtained preprocedure, 15 min, and when possible, at 30 min after the start of the procedure. RESULTS: Twenty-five patients were enrolled. Median age was 15 years (range 3-47 years). Procedures included laser and/or sclerotherapy. There were no changes in TEG parameters from baseline to 15 min or 30 min. The following decreased from baseline to 15 min: fibrinogen 313 to 287 mg/dL (P = .001), D-dimer 1.3 to 1.1 mg/L (P = .02), hemoglobin 12.8 to 11.8 g/dL (P = .001), and platelet count 272 000 to 256 000 (P = .006). No patient had a bleeding/thrombotic complication during or within 1 week postprocedure. CONCLUSION: We saw no change in TEG parameters or bleeding or clotting complications despite significant numerical changes in conventional coagulation profiles, suggesting that conventional studies may not be as useful in determining risks of bleeding or thrombotic complications peri-procedure for minor procedures.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Hemostasia/fisiologia , Escleroterapia/métodos , Tromboelastografia/métodos , Malformações Vasculares/terapia , Adolescente , Adulto , Coagulação Sanguínea/fisiologia , Testes de Coagulação Sanguínea , Velocidade do Fluxo Sanguíneo/fisiologia , Criança , Pré-Escolar , Feminino , Hemorragia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
Assuntos
Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Sirolimo/uso terapêutico , Malformações Vasculares/sangue , Adolescente , Adulto , Transtornos da Coagulação Sanguínea/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Malformações Vasculares/complicações , Adulto JovemRESUMO
Griscelli syndrome type 2 (GS2) is an autosomal recessive condition associated with the development of hemophagocytic lymphohistiocytosis. GS2 is caused by a gene mutation involving RAB27A, which affects a melanosome anchoring complex in melanocytes and releases cytolytic granules from T cells and natural killer cells. GS2 is known to have immunologic compromise and oculocutaneous albinism. We present the case of 2 sisters who had vastly different phenotypic presentations despite having the same genetic frameshift mutation in the RAB27A gene. Patient 1 presented with seizures and neurological compromise, whereas patient 2 presented with pancytopenia and diarrhea. Both patients developed hemophagocytic lymphohistiocytosis.
Assuntos
Diarreia/patologia , Mutação da Fase de Leitura , Linfo-Histiocitose Hemofagocítica/patologia , Pancitopenia/patologia , Piebaldismo/patologia , Doenças da Imunodeficiência Primária/patologia , Convulsões/patologia , Proteínas rab27 de Ligação ao GTP/genética , Pré-Escolar , Diarreia/complicações , Diarreia/genética , Feminino , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Pancitopenia/complicações , Pancitopenia/genética , Piebaldismo/complicações , Piebaldismo/genética , Doenças da Imunodeficiência Primária/complicações , Doenças da Imunodeficiência Primária/genética , Prognóstico , Convulsões/complicações , Convulsões/genética , IrmãosRESUMO
BACKGROUND: Slow-flow vascular malformations (VM) can be associated with localized intravascular coagulopathy (LIC) that is characterized by elevated D-Dimer levels and low fibrinogen and platelets. This can lead to bleeding and clotting tendencies, which can give rise to functional limitations such as pain and swelling and even progress to disseminated intravascular coagulopathy. METHODS AND RESULTS: We conducted a chart review of four patients with evidence of LIC who were started on rivaroxaban. We found an improvement of D-Dimer and/or fibrinogen levels in all four patients. They also had an improvement of pain and functionality. CONCLUSIONS: We report on four patients in whom anticoagulation with a direct oral anticoagulant, rivaroxaban, was effective in controlling signs and symptoms of consumptive coagulopathy with no evidence of bleeding from the use of rivaroxaban.
Assuntos
Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Rivaroxabana/uso terapêutico , Malformações Vasculares/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Anticoagulantes/administração & dosagem , Transtornos da Coagulação Sanguínea/fisiopatologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/uso terapêutico , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Humanos , Masculino , Dor/fisiopatologia , Dor/prevenção & controle , Rivaroxabana/administração & dosagem , Resultado do Tratamento , Malformações Vasculares/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Vascular malformations (VM) are congenital lesions that can be debilitating and cause significant aesthetic and functional limitations. The chemotherapeutic agent bleomycin has been utilized as a sclerosant, directly injected percutaneously into the VM. Unfortunately, little is known about the benefits and short-term side effects of bleomycin with intralesional injections. PROCEDURE: An IRB approved, retrospective chart review was performed on patients with VM who had been treated with intralesional bleomycin. Data included type of VM, number of treatments, total bleomycin dose per m², and adverse effects. A questionnaire was administered to available patients to assess subjective outcomes and side effects. RESULTS: Forty-six patients were treated with 141 procedures of bleomycin sclerotherapy for VM. Patient ages ranged from 1 to 20 years (median age 10 years). The median cumulative bleomycin dose was 16.3 units/m²/person (range of 1.7-97.0 units/m²/person). Sixty-three percent of patients were reached for a questionnaire to assess short-term side effects. Ninety percent of patients surveyed were satisfied to very satisfied with the results from the procedure. About 24% of patients experienced transient nausea, vomiting and/or local hyperpigmentation. CONCLUSION: Bleomycin sclerotherapy can be an effective treatment of VM with repeat exposure with minor risk of short-term side effects, however, long-term risks are of great concern. Further studies are required to assess systemic absorption and long-term risks.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medidas de Resultados Relatados pelo Paciente , Escleroterapia , Malformações Vasculares/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. CONCLUSIONS: Children naïve to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide.