Complications in oral and maxillofacial surgery: management of hemostasis and bleeding disorders in surgical procedures

Oral and maxillofacial surgeons perform a wide variety of surgical procedures. One of the major complications of these various surgical techniques is uncontrolled bleeding. The best management of perioperative hemorrhage is prevention. This includes proper preoperative patient evaluation, knowledge of the various bleeding disorders, and the characterization of the correct methods of management. This article evaluates various causes of bleeding, and identifies both local and systemic and pathways. Considerations of treatment for patients with these various disorders are discussed regarding the best management options for adequate hemostasis.     

Hemophilic arthropathy of the elbow

Hemophilia is a hereditary disease in which circulating levels of coagulation factors are lacking, resulting in a propensity toward bleeding. Intra-articular hemorrhages are a hallmark of hemophilia and may lead a cascade of cytokine elaboration and?inflammatory-mediated changes, which ultimately result in cartilage loss and arthropathy. Diarthrodial joints, such as the knee, elbow, and ankle, are most commonly affected. This article highlights issues surrounding hemophilic arthropathy of the elbow and focuses on preventive measures, management strategies of the hemophilic elbow, and treatment options for established arthropathy.     

Characterization of Factor VIII Inhibitors

Factor VIII (FVIII) inhibitors develop as either alloantibodies against exogenous FVIII in patients with congenital hemophilia A after FVIII-replacement therapy or as autoantibodies against endogenous FVIII in previously healthy, nonhemophilic individuals. The predominant immunoglobulin G (IgG) subclass of FVIII inhibitors is IgG(4). The main epitopic regions are known to be located, however, in the A2, A3, and C2 domains. The A2 and A3 epitopes have been identified between amino acid residues 484 and 509 and residues 558 and 565, respectively. Both of these regions are close to the binding sites for activated FIX (FIXa). Two regions have been identified in the C2 domain, one in the amino-terminal portion of the domain (residues 2181-2243) and the other in the carboxy-terminal portion of the domain (residues 2248-2312 and residues 2315-2330). In addition, a crystallographic analysis of a complex of the C2 domain and a human monoclonal IgG(4)(K) Fab revealed that this type of antibody is in direct contact with hydrophobic and basic residues of the membrane-binding surface. Inactivated FVIII is rapidly cleared from the circulation in the presence of inhibitors. The inhibitors also bind to essential FVIII ligand proteins, including von Willebrand factor, FIXa, FXa, and thrombin, and to surface membrane phospholipid. Some type 2 inhibitors interfere with binding to activated protein C.     

Functional disability in children with hemophilic arthropathy

Hemophilia is a coagulation disorder characterized by acute hemorrhages into the musculoskeletal system, leading eventually to arthropathy and disability. We investigated the functional loss, namely disability, in hemophiliacs. The clinical and radiological characteristics of joint involvement were also evaluated. There were 31 patients between the ages of 3 and 18 years and 65 involved joints. The knees were the most commonly affected joints followed by the elbows and ankles. There was a positive correlation between the radiological and clinical evaluation scores; however, the clinical evaluation score did not correlate with age. The radiological score increased in conjunction with increasing age of the patients. We observed a significant relationship between the disability score and the clinical evaluation and radiological scores. These observations suggest that hemophilia is a life-long condition, with a high potential for functional disability if not promptly and adequately controlled. The main principle in the treatment of hemophilic arthropathy is the restoration of the patient’s lifestyle and mobility with a comprehensive multidisciplinary approach.     

Tailored prophylaxis in children with severe hemophilia: A four-year Iranian study

BackgroundProphylaxis the current standard care for patients with severe hemophilia should be planned to optimize the replacement therapy and minimize bleeding. We report our single-center experience of tailored prophylaxis in children affected by hemophilia A (HA) and hemophilia B (HB).MethodsThis study was conducted on 55 patients, under 15 years, with HA (PWHA, n: 46) and HB (PWHB, n: 9) between 2015 and 2019. According to the phenotype, three prophylaxis regimens: 25−50 unit/kg once, twice, or three-times a week for PWHA, and two: 30−50 unit/kg once or twice a week for PWHB were administered. Following the occurrence of > 3 joint bleeding, or > 4 soft tissue bleeding, or one spontaneous major bleeding in the last 3 months, the prophylaxis regimen is changed. Annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), target joints development, inhibitor development, and hemophilia joint health score (HJHS) also were assessed.ResultsA mean ± SD of 2520 ± 1045 IU/kg/yr coagulation factor (F) VIII was used to reduce ABR and AJBR from 1.02 ± 1.11 and 0.8 ± 1.3 (in the first year of the study) to 0.27 ± 0.44 (P < 0.001) and 0.19 ± 0.38 (P = 0.004) (at the end of the study) in PWHA, respectively. Furthermore, in PWHB, in the first year of the study, with using 2168 ± 1216 IU/kg coagulation FIX, ABR and AJBR were 0.19 ± 0.39 and 0.06 ± 0.1. At the end of the study, ABR and AJBR were 0.02 ± 0.05 (p = 0.156) and 0.01 ± 0.03 (p = 0.361), respectively. During the study period, the mean number of the target joints and mean HJHS were 0.25 ± 0.57 and 7.6 ± 2.1 for PWHA and 0 and 6.3 ± 1.8 for PWHB, respectively.Finally, 5 PWHA (11 %) did not need dose-escalation in their prophylaxis regimen, whereas 31 (67 %) and 10 (21 %) PWHA needed two and three infusions a week, respectively. In PWHB, 7 (78 %) and 2 (22 %) were adjusted to receive a once and twice weekly regimen, respectively.ConclusionOur results suggest that tailored prophylaxis is an effective strategy to reduce the rate of bleeding and optimize the replacement therapy in children with hemophilia.     

血友病A患者FⅧ基因联合诊断及其DNA测序突变分析

目的探讨血友病A(HA)患者及携带者的基因诊断方法及诊断率。方法对20例HA患者及家系成员采用长距离PCR扩增(LD-PCR)技术、限制性内切酶酶切位点连锁分析(BclⅠPCR/RFLP)、可变串联重复序列多态性分析(St14 VNTR/PCR);并对FⅧ基因18号内含子的BclⅠ区段、19号内含子的HindⅢ相应区段进行DNA测序。结果检出22号内含子倒位携带者1例和倒位者6例;BclⅠPCR/RFLP酶切位点突变患者3例,携带者5例;St14 VNTR家系的连锁分析,发现携带者6例,患者5例;联合诊断家系总阳性率为90.0%;DNA测序两个区段突变位点分析,共发现5种突变。结论采用联合基因诊断方法,对FⅧ基因的3个位点进行联合基因诊断,可提高HA的诊断率及准确率;用PCR-DNA测序法可发现5种突变,并且这些突变位点在国内报道较少,22例患者突变检出率达50.0%。     

Additional factor XII (hageman factor) deficiency in hemophilia a and in von willebrand syndrome

Summary Factor XII plasma levels were investigated with several methods in patients with hemophilia A and B and von Willebrand syndrome. There seem to be some families with hemophilia A or von Willebrand syndrome, who have an additional, congenital, partial lack of factor XII (Hageman factor). The mode of inheritance is independent of the other coagulation disorder. Frequently, the first indication of an additional factor XII deficiency is the disproportionate prolongation of the activated partial thromboplastin time (PTT) as regards the factor VIII level. The average factor XII level in patients with hemophilia A and von Willebrand syndrome is significantly lower than in normal subjects or patients with hemophilia B. It cannot be excluded that the frequently low levels of factor XII in patients with severe hemophilia are acquired and probably due to liver cell damage.Dedicated to Professor F. Hartmann, MD     

MRI对儿童血友病性关节病病情严重程度的评估价值及影像特点分析

目的探讨MRI对儿童血友病性关节病(HA)病情严重程度的评估价值及影像特点。方法选取2013年05月-2014年05月来我院经临床确诊的HA患者30例为观察组,并选取同期入院检查的年龄相仿的正常健康儿童30例作为对照组,采用Denver评分法分别对软组织及骨软骨的影像征象进行评估和量化监测,评价受检关节改变的严重程度,并比较两组受检儿童关节功能Fugl-Meyer评定,并将Denver评分与Fugl-Meyer评定量表做相关分析。结果对照组软骨在常规序列上显示信号均匀一致,无明显异常信号,软骨表面光滑,每层软骨线条显示清晰,表面呈中高信号,中间为等低信号。观察组患儿常规序列显示软骨信号异常,呈明显高信号,软骨分层不清,部分软骨表面毛躁,软骨信号异常可伴有滑膜增生。根据Denver评分结果将关节分为0分组7个关节,1-6分组10个关节和7-10分组13个关节。对照组儿童Fugl-Meyer评分(99.84±0.12)显著高于观察组(70.25±6.81)(P0.05),观察组患儿中随着Denver评分越高,Fugl-Meyer评分逐渐降低,差异具有统计学意义(P0.05)。HA患儿Denver评分与Fugl-Meyer评分呈负相关(r=-0.741,P0.001)。结论 Denver评分能够将MRI图像异常征象量化,且能够从关节软组织及软骨方面评价关节受损严重程度并进行分级,Denver评分和Fugl-Meyer评分能够提示病变发展程度及关节预后情况。     

重型血友病A患儿低剂量预防治疗血浆凝血因子Ⅷ谷浓度的检测

目的对重型血友病A患儿低剂量预防治疗的血浆凝血因子Ⅷ(FⅧ)谷浓度进行测定,以探索血FⅧ的谷浓度水平与年化关节出血次数的相关性。方法对28例重型血友病患儿进行低剂量预防治疗(8~10 U/kg/次,2次/周,周二、周五的同一时间给药),前瞻性观察9个月(每3月为一期,共三期),分别检测各期用药后72 h及96 h(周二、周五给药前)血FⅧ的谷浓度,并将血FⅧ的谷浓度水平与年化关节出血总数、关节功能评分变化的相关性进行统计学分析。结果 1用药后96 h血FⅧ的谷浓度28例患儿(占100%)全部在1.0%以下,用药72 h血FⅧ浓度22例(占78.6%)已降到1.0%以下,有6例患儿(占21.4%)仍能维持在1.0%以上,其中有4例(占14.2%)能达到2%以上。但是,100%的病例FⅧ的谷浓度无法达到3%。2低剂量预防治疗条件下,28例患儿年化关节出血数波动于4~15次。血FⅧ的谷浓度与年化关节出血数的散点图显示:达到1%以上的患儿,与谷浓度在1%以下的比较,年关节出血次数并无明显的下降趋势(P0.05)。3用药72 h血FⅧ谷浓度1.0%组,与1.0%组相比,血友病患儿年化关节出血的次数(P0.05),及关节HJHS评分的变化(P0.05)均无显著性差异。结论 1低剂量预防治疗,血友病患儿血FⅧ的谷浓度偏低,仍有较高的年化关节出血,提示低剂量预防方案可能剂量不足,无法达到预防的目的。2血友病患儿血FⅧ的谷浓度存在个体异质性,21.4%的患儿用药后72 h可达到1%以上,但FⅧ谷浓度与年化关节出血次数可能无相关性,应当探索每个患儿个性化的最适的血FⅧ谷浓度。     

Synergistic inhibition of PARP‐1 and NF‐κB signaling downregulates immune response against recombinant AAV2 vectors during hepatic gene therapy

Host immune response remains a key obstacle to widespread application of adeno‐associated virus (AAV) based gene therapy. Thus, targeted inhibition of the signaling pathways that trigger such immune responses will be beneficial. Previous studies have reported that DNA damage response proteins such as poly(ADP‐ribose) polymerase‐1 (PARP‐1) negatively affect the integration of AAV in the host genome. However, the role of PARP‐1 in regulating AAV transduction and the immune response against these vectors has not been elucidated. In this study, we demonstrate that repression of PARP‐1 improves the transduction of single‐stranded AAV vectors both in vitro (～174%) and in vivo (two‐ to 3.4‐fold). Inhibition of PARP‐1, also significantly downregulated the expression of several proinflammatory and cytokine markers such as TLRs, ILs, NF‐κB subunit proteins associated with the host innate response against self‐complementary AAV2 vectors. The suppression of the inflammatory response targeted against these vectors was more effective upon combined inhibition of PARP‐1 and NF‐κB signaling. This strategy also effectively attenuated the AAV capsid‐specific cytotoxic T‐cell response, with minimal effect on vector transduction, as demonstrated in normal C57BL/6 and hemophilia B mice. These data suggest that targeting specific host cellular proteins could be useful to attenuate the immune barriers to AAV‐mediated gene therapy.