Hemophilia Patients Research Articles

Exploring the application of doggybone DNA to facilitate non-viral gene therapy delivery to hemophilia patients

Exploring the application of doggybone DNA to facilitate non-viral gene therapy delivery to hemophilia patients

Sensitive Measurement of Clinically Relevant Factor VIII Levels in Thrombin Generation Assays Requires Presence of Factor XIa.

Hemophilia A (HA) is characterized by decreased or absent factor VIII (FVIII) activity. Current FVIII assays are based on clotting time and thus only provide information about the initiation of coagulation. In contrast, thrombin generation assays (TGAs) can be used to measure the full coagulation spectrum of initiation, propagation, and termination that provide information on the whole course of thrombin generation and inhibition. However, the commercially available TG kits lack sensitivity for measurements of hemophilia plasma within lower FVIII ranges, which is essential for explaining differences in bleeding phenotypes in hemophiliacs at clinically low levels of FVIII. Optimization of the TGA for measurements of low FVIII levels in severe HA patients. TGA measurements were performed in severe HA pooled plasma (n = 10). Investigations of several preanalytical and analytical variables of the assay were performed in a stepwise process and adjusted based on sensitivity toward intrinsic coagulation activation. TGA initiated by tissue factor (TF) alone at varying concentrations was unable to significantly differentiate between FVIII levels below 20%. In contrast, TGA activation with low concentrations of TF in presence of FXIa appeared to be highly sensitive for FVIII changes both in high and low ranges. In addition, a representative TGA curve at trough levels could only be produced using the dual TF/FXIa TGA. We propose a critical optimization for the setup of the TGA for measurements in severe HA plasma. The dual TF/FXIa TGA shows increased sensitivity, especially in lower FVIII ranges, which allows for better individual characterization at baseline, prediction of interventions, and follow-up.

Clinicopathological Parameters of Haemophilia Patients at a Tertiary Care Centre in Northern India.

Haemophilia affects a large number of people all over the world, yet very little is known about the clinical manifestations and diagnostic protocols of the condition in areas with limited access to resources in developing countries. Understanding the clinical spectrum and diagnostic approach will help with the design of measures to address the situation in these places. The primary objective of this study was to examine the clinicopathological parameters of haemophiliacpatients. From the departmental archive, a thorough history of each patient was retrieved, including values of bleeding time, prothrombin time, activated partial prothrombin time, and percentage of specific factor activity. Out of a total of 385 cases over the period of six years, 86.75% were classified as haemophilia Aand 13.25% of cases were diagnosed as haemophilia B. In terms of the severity of the disease, 44.93% were classified as severe, 42.08% as moderate, and 12.99% as mild. Joint bleeding was the first and most typical clinical manifestation of the disease, accounting for 34.80% of cases, followed by ecchymosis (23.12%), post-traumatic bleeding (12.73%), epistaxis (12.20%), and gum bleeding (8.05%). 1.56% of patients had a positive screening test for the hepatitis C virus, followed by 1.30% for HIV and 0.78% for hepatitis B surface antigen. In the presence of joint bleeding, ecchymosis, and post-traumatic bleeding in an otherwise healthy individual, a clinician should be alerted to the possibility that the patient has haemophilia and should request a work-up for the bleeding disorder.

Augmented Degradation of Factors VIII and IX in the Intermittent Movement State

The most common clinical presentation of hemophilia A and hemophilia B is bleeding in large joints and striated muscles. It is unclear why bleeding has a predilection to affect joints and muscles. As muscles and joints are involved in intermittent movement, we explored whether this phenomenon could be associated with an impact on factor VIII and IX levels. Purified proteins and a mouse model were assessed using coagulation assays, Western blot analysis and immuno-staining. Movement caused an increase in thrombin activity and a decrease in factor VIII and factor IX activity. The decrease in factor VIII activity was more significant in the presence of thrombin and during movement. Under movement condition, sodium ions appeared to enhance the activity of thrombin that resulted in decreased factor VIII activity. Unlike factor VIII, the reduction in factor IX levels in the movement condition was thrombin-independent. High factor VIII levels were found to protect factor IX from degradation and vice versa. In mice that were in movement, factor VIII and IX levels decreased in the microcirculation of the muscle tissue compared with other tissues and to the muscle tissue at rest. Movement had no effect on von Willebrand factor levels. Movement induces reduction in factor VIII and IX levels. It enables an increase in the binding of sodium ions to thrombin leading to enhanced thrombin activity and augmented degradation of factor VIII. These data suggest a potential mechanism underlying the tendency of hemophilia patients to bleed in muscles and joints.

Longitudinal observations of TFPI levels in paediatric Haemophilia A patients.

Inhibition of tissue factor pathway inhibitor (TFPI) is a potential new mode of action to achieve haemostasis in haemophilia A and B patients. Knowledge about potential developmental changes of TFPI levels during childhood are a prerequisite to translate adult doses of TFPI inhibitors to doses in paediatric patients. In this study we present longitudinal data for total TFPI concentrations (TFPI-T) and TFPI activity (TFPI-A) from 48 paediatric Haemophilia A patients in the age range from 3 to 18 years (2-12 observations per patient). TFPI-T and TFPI-A tend to decrease over age during childhood. Lowest values were observed between 12 and<18 years. On average, TFPI-T and TFPI-A were lower in adolescent haemophilia patients than in adult haemophilia patients. In summary, the presented information on TFPI levels in children adds to the current knowledge of developmental haemostasis and it can be helpful in evaluating how children respond to haemophilia treatment including the new class of anti-TFPI compounds.

Magnetic resonance imaging evaluation of the disc morphology of temporomandibular joint in patients with severe hemophilia.

This study aimed to assess the morphological differences in the articular disc (AD) between hemophilic patients and healthy individuals of the control group for further association with signs and symptoms. Fourteen severe hemophilic patients had their AD evaluated by magnetic resonance imaging (MRI). The morphological findings were compared to those of a control group consisting of 14 healthy individuals. MRI was used to evaluate all the components of the temporomandibular (TMJ), including the AD, resulting in sequential T1-weighted parasagittal images. All the images were acquired with teeth in maximum intercuspation position. Morphological alterations showed significant statistical differences (P-value = 0.0068), whereas no statistical differences were found in the other variables, including TMJ pain, headache, bruxism and mouth opening limitation. In the group of non-hemophilic individuals, only two (14.29%) presented AD with non-biconcave features, whereas in the group of hemophilic patients, nine (64.29%) presented AD with a morphology other than biconcave. In patients with severe hemophilia, there seems to be a pattern of morphological alterations in the articular disc over time. The standard biconcave morphology of AD tends to change into other ones, particularly biplanar, hemiconvex and folded.

RNA sequencing suggests that non-coding RNAs play a role in the development of acquired haemophilia.

Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.

Analysis of Macrophage Migration Inhibitory Factor Genotype in Hemophilia a Patients.

Hemophilia A, an X-linked bleeding disorder, is caused by a complete or partial deficiency in factor VIII. Multiple factors engage in the development and progression of bleeding episodes in hemophilia patients, especially arthropathy. Detection of macrophage migration inhibitory factor (MIF)-173 G/C polymorphism in people with hemophilia A (PWH) and the possible associations between the type of MIF gene polymorphism and selected disease-related variables. This case-control study included 95 male patients with hemophilia A and 95 non-hemophiliac subjects, all aged from 2 months to 63 years. An allele-specific polymerase chain reaction (AS-PCR) with a multiplex technique was used to detect MIF polymorphisms. A significantly higher frequency of GG polymorphism was reported in the control group (81, 85.3%) compared to PWH (64, 67.4%), while a significantly higher frequency of GC polymorphism was found in PWH (21, 22.1%) than that in healthy subjects (10, 10.5%), P < 0.05. The G allele polymorphism was detected in 90.0% of the control group compared to 78.4% of PWH (149 subjects), while the C allele frequency was higher in PWH (41, 21.6%) compared to that in healthy individuals (18, 10.0%), P < 0.05. The frequencies of varied MIF-173 polymorphisms did not show significant differences among patients with different clinical presentations or in relation to presence of inhibitors, P > 0.05. MIF-173 GC polymorphism is seen in PWH more than that in healthy individuals. Further studies are required to detect additional SNPs through sequencing of the MIF gene and to detect MIF serum levels during bleeding episodes.

Effect of Radiosynovectomy with Rhenium-188 in the Treatment of Knee Joint Inflammation in Patients with Hemophilia

Background: One of the effective methods to control chronic hemophilic synovitis is radiosynovectomy. Rhenium-188 is a new radionuclide, and its half-life is 0.7 day. This study aimed to investigate the effect of radiosynovectomy with Rhenium-188 on the knee joint of hemophilic patients.&#x0D; Methods: Thirty patients with hemophilic synovitis of the knee visited in the orthopedic clinic in 2019 and 2020, entered the study. They all had at least two bleeding per month; in the supine position with slight knee flexion, after local sterilization, 550 to 750 MBq Rhenium-188 was injected into the knee. A splint was installed for five days. The demographic characteristics, radiography, articular line tenderness, joint line tenderness, flexion and extension restrictions, and joint volume characteristics were evaluated before and six months after injection.&#x0D; Results: The amount of monthly injected factors (VIII and IX) 6 months after injection was decreased from 5260.2±1836 units to 3870.83±1106 units (p&lt;0.001). The radiographic classification has not changed within six months. The average knee pain score decreased from 7.3±1.2 to 2.3±1.1, after six months (p&lt;0.001), and knee flexion increased from 84.6±26.22 to 114±21.58 degrees (p&lt;0.001). None of the patients have experienced complications such as skin necrosis or joint infection. All patients have reported that the pain increases 24 hr after the injection were manageable.&#x0D; Conclusion: The use of Rhenium-188 radiopharmaceutical in radiosynovectomy of 30 hemophilic patients’ knees is effective in reducing pain, tenderness of the joint line, and the number of bleeding episodes, and it improved knee range of motion in the short term (6 months).

Managing Relevant Clinical Conditions of Hemophilia A/B Patients.

The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.

Orthopedic surgical procedures in people with hemophilia.

People with hemophilia tend to develop joint lesions secondary to the recurrent hemarthroses typical of their condition. These usually include chronic synovitis and arthropathy chiefly affecting their ankles, knees, and elbows. In addition, muscular hematomas, albeit less frequently, may also result in complications such as acute compartment syndrome, pseudotumors, bone cysts and peripheral nerve compression. Joint lesions may require some of the following surgical interventions: arthroscopic synovectomy (in cases of synovitis), arthroscopic joint debridement, radial head resection, opening-wedge tibial osteotomy, arthrodesis, arthrodiastasis (of the ankle), tendon lengthening (hamstrings, Achilles tendon), progressive extension of the knee by placing an external fixator in cases of flexion contracture of the knee, supracondylar femoral extension osteotomy in cases of knee flexion contracture and, eventually, a total joint arthroplasty when the affected joint has been destroyed and the patient experiences severe joint pain. Total knee arthroplasty in hemophilic patients is associated with a high infection risk (7% on average). As regards the complications following muscle hematomas, acute compartment syndrome requires urgent performance of a fasciotomy when hematological treatment is incapable of resolving the problem. Surgical resection of hemophilic pseudotumors is the best solution, with those affecting the pelvis (secondary to iliopsoas hematomas) being particularly difficult to resolve. Peripheral nerve lesions can often be effectively addressed with hematological treatment, although a surgical neurolysis of the ulnar nerve is indicated if nonoperative treatment fails.

Individualizing primary prophylaxis in patients with hemophilia A and B, adherence and new products.

The purpose of prophylaxis in hemophilic patients is to prevent bleeding. The latest guidelines of the World Hemophilia Federation recommend that all patients with a severe hemorrhagic phenotype should receive prophylactic treatment, defined as the regular administration of therapeutic products (either factor concentrates or nonfactor replacement treatments). These products are aimed at preserving hemostasis and preventing bleeding, especially into joints. The guidelines also stipulate that prophylaxis should allow patients with hemophilia to lead healthy and active lives, participating in most physical and social activities, similar to the nonhemophilic population.

Towards achieving a haemophilia-free mind.

Towards achieving a haemophilia-free mind.

Haemophilic arthropathy: basic protocols for clinical examination and imaging.

In haemophilia, screening protocols in the prevention and treatment of common lesions still require unification of criteria. Patients with haemophilia seek medical consultation exclusively for two reasons: because they have requested an appointment for a routine check-up (1-2 times a year in case of severe haemophilia) or because they have developed acute bleeding that requires treatment. The purpose of this paper is to emphasize the importance of an early differential diagnosis of joint damage and to review the techniques that allow an effective evaluation. The World Federation of Haemophilia recommends the 'Primary Prophylaxis' treatment modality, and today, severe haemophilia patients adhering to that factor VIII/IX therapy have significantly reduced common injuries: haematomas, haemarthrosis, synovitis, and haemophilic arthropathy. The basic protocols and minimum data for the control of musculoskeletal health are described. In summary, the primary goal of the haematologist-led multidisciplinary care team treating patients with haemophilia is likely to restore and/or preserve joint and musculoskeletal health, which is essential to promoting quality of life. Appropriate factor replacement regimens are required to prevent bleeding, these should be combined with physical activity and a physiotherapy program, in accordance with the recommendations of the World Health Organization for the general population.

Local Anesthesia Onset and Pain Perception in Hemophilic and Thalassemic Conditions.

The study aims to evaluate and compare the onset of local anesthesia (LA) and pain perception during endodontic treatment in hemophilic and thalassemic patients. Methods: The study included 90 patients with symptomatic irreversible pulpitis of the mandibular molars. Three groups (n = 30 in each group) were included. Group 1: hemophilic patients; group 2: thalassemic patients; and group 3: individuals without any systemic diseases. Onset of LA and visual analogue scale (VAS) scores was recorded immediately after the administration of local anesthesia, during the pulp exposure procedure, and during canal instrumentation, and were compared between the three groups. Frequency distribution, ANOVA, and linear regression analysis (p < 0.05) were applied. Results: The mean onset time was 46 ± 34 s in the hemophilic group, 42 ± 23 s in the thalassemic group, and 38 ± 12 s in controls, but the differences were statistically insignificant. After LA administration (LA-VAS), all three groups experienced a statistically significant reduction in pain (p = 0.048). On pulp exposure (PE-VAS) (p = 0.82) and during canal instrumentation (CI-VAS) (p = 0.55), there was no statistically significant difference in pain perception between the groups. The coefficients indicate a positive correlation between the VAS and onset time, indicating a positive reduction in the VAS following the administration of LA. Conclusions: Hemophilic patients exhibited a clinically longer average onset time for LA. However, the difference among the three groups with regard to the overall pain perception after LA administration, during and after pulp exposure, and during canal instrumentation was statistically insignificant.

Activation of the Acute-Phase Response in Hemophilia.

To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) ≥30. Subgroup analysis of the remaining nonobese hemophilia patients (BMI: 18-29.9) revealed a significant spike of IL-6, CRP, and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients who did not experience recent bleeding had IL-6, CRP, and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a fourfold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia.

Depression and anxiety among hemophilia patients enrolled in clinical trials: a multi-center cohort study.

Hemophilia patients enrolled in clinical trials often exhibit various physical and psychological symptoms. However, little is known about anxiety and depression among them. This study assessed the effects of depression and anxiety on hemophilia patients enrolled in clinical trials and identified risk factors for these disorders. A multi-center, cohort study was conducted from January to December 2022. Sixty-nine hemophilia patients who enrolled in clinical trials participated at baseline (T1, prior to treatment initiation) and completed the informed consent. Risk factors were measured at baseline to predict depression and anxiety at 3 months (T2). Sixty-four hemophilia patients were included in the final analysis. More hemophilia patients had moderate-severe depression (28 [43.75%]) and anxiety (16 [25.00%]) at T2 than at T1 (12 [18.75]), (5 [7.81%]). Depression was aggravated in 23 (35.94%) patients and anxiety was aggravated in 12 (18.75%) patients. Frequently acquired medical information (OR 11.378, CI 1.319-98.114, P = 0.027), baseline GAD-7 (OR 1.341, CI 1.015-1.772, P = 0. 039) and PHQ-9 (OR 1.465, CI 1.039-2.065, P = 0.029) are important factors predicting depression and anxiety in hemophilia patients. Hemophilia patients enrolled in a clinical trial have significant anxiety and depression. The frequency of acquiring medical information and the baseline PHQ-9 and GAD-7 scores were risk factors for anxiety and depression. Thus, hemophilia patients should receive education regarding clinical trials and undergo evaluations of their anxiety and depression; these changes will enable prompt detection of their psychological burden and identify potential psychological intervention strategies.

State of Dental Health and Management Needs of Young Hemophilic Patients: A Case-control Study.

In particular, when it comes to systemic diseases like hemophilia, good dental health is crucial to a person's overall health and wellness. Through the means of this study, we aim to assess the prevalence of various dental anomalies in children suffering from hemophilia in comparison to healthy children and assess their treatment needs. This was a descriptive, case-control study with 400 subjects, 200 each in the study (hemophilic) and control (nonhemophilic) groups. The subjects' ages ranged from 5 to 15 years. Utilizing the oral hygiene index-simplified (OHI-S), the state of oral hygiene was documented (OHI-S). Using decaying extracted filled tooth (DEFT) and decayed, missing, and filled tooth (DMFT) for the primary and permanent dentition, respectively, teeth afflicted by dental caries and teeth restored/extracted as a result of dental caries were assessed. Statistical Package for the Social Sciences (SPSS) software (version 27.0) was used for statistical analysis. Hemophilic people had a considerably greater incidence of dental caries. Furthermore, even though their DMFT/DEFT and OHI-S scores were barely poorer than those of healthy people, children with hemophilia had a significantly larger percentage of dental treatment needs across all age categories than the other group. The percentage of hemophilic children who needed dental treatment across different age groups was significantly higher than the other group, which supports our observations that the dental health status of hemophilic children was poor and treatment requirement was high among them as well. This is true even though the DMFT/DEFT scores and OHI-S scores in hemophilic children were only slightly worse than in healthy individuals. Sharma S, Shahi AK, Chandra S, et al. State of Dental Health and Management needs of Young Hemophilic Patients: A Case-control Study. Int J Clin Pediatr Dent 2023;16(2):380-387.

A Retrospective, Long-term Follow-up of the Clinical Outcomes and Cost-effectiveness of Single-anesthetic Multiple Total Joint Procedures in Hemophilic Arthropathy.

Although total joint replacement (TJR) procedures are efficacious, perioperative high-dose factors replacement therapy (FRT) to avoid catastrophic bleeding represents a significant hurdle, particularly for patients with multiple joint affection. Double simultaneous bilateral TJRs were reported as safe and cost-effective. However, little is known about multiple TJRs. The feasibility and effects remain debatable. Surgeons need to weigh the high cost of FRT against safety. Accordingly, we aimed to evaluate the clinical outcomes and cost-effectiveness of single-anesthetic multiple-joint procedures of lower limbs in end-stage hemophilic arthropathy. Our retrospective cohort study retrieved data from an inpatient database of patients with hemophilia who underwent total knee arthroplasty (TKA), total hip arthroplasty (THA), and/or ankle arthrodesis from January 2000 to April 2016. Complications, hospital stays, transfusion, doses of clotting factor, medical costs, range of motion (ROM), Harris hip scores (HHSs) and Hospital for special surgery knee scores (HSSs) were recorded. A P value < 0.05 was considered significant. A total number of 81 patients were included in this study, among which 89 TKAs and 52 THAs were performed. Compared to the single TJR group, the simultaneous multiple TJR group showed a significantly higher rate of blood transfusions (P < 0.05). But no significant differences were found in the length of hospital stays, factor consumption, hospitalization costs excluding prosthesis expenses, and total complication rates. Finally, similar postoperative ROM, HHS, and HSS were witnessed in two groups (P value > 0.05). Our data indicated that simultaneous multiple TJRs are a safe and cost-effective choice for treating hemophilic patients with multiple HA-affected lower limb joints.

Effect of low-level laser therapy on post-extraction hemostasis in patients with hemophilia — A prospective cohort study

Dental extraction in hemophiliacs can be complicated by perilous bleeding. Although developments in local hemostatics and factor replacement have made outpatient extraction feasible, there is no standard protocol for preventing hemorrhagic exigency. Low-level laser therapy (LLLT) has firmly established role in hemostasis due to its ability to seal vessels, but this function has not been conclusively established in hemophiliac patients. The objective of our study was to evaluate the effectiveness of LLLT as compared with the standard protocol alone in achieving post-extraction hemostasis.A prospective interventional cohort study was designed and consisted of 60 patients with hemophilia A or B, who reported to the Maulana Azad Institute of Dental Sciences, New Delhi between October 2021 and March 2022. These were divided equally into test and control groups, both following the standard protocol. In the test group, extraction sockets were exposed to LLLT. The study assessed time required, instance of rebleeding, and additional methods employed for hemostasis in each group.The results showed a 22.42% reduction in average time taken to achieve hemostasis in the test group as compared with the control group. The tranexamic acid pack was replaced in two cases in both groups after 60 min of procedure. Three cases in the control group required suturing, and one case required cauterization. Rebleeding occurred in four cases in the test group and in 13 cases among the controls. Postoperative factor was infused in three and 12 cases in the test and control groups, respectively.The authors believe that perioperative use of LLLT should be encouraged because it demonstrated a significantly reduced time for hemostasis among hemophilia patients.