Turoctocog alfa pegol provides effective management for major and minor surgical procedures in patients across all age groups with severe haemophilia A: Full data set from the pathfinder 3 and 5 phase III trials.

INTRODUCTION: Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. AIM: Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. METHODS: Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII <1%) received perioperative turoctocog alfa pegol treatment planned to achieve FVIII activity levels >80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0-11 years) undergoing minor surgeries received 20-75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). RESULTS: pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1-6. No safety concerns or inhibitors were identified. Forty-five minor surgeries in 23 children were performed without complications. CONCLUSION: Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

Patient-reported outcomes and joint status across subgroups of US adults with hemophilia with varying characteristics: Results from the Pain, Functional Impairment, and Quality of Life (P-FiQ) study.

INTRODUCTION: Pain and functional impairment associated with joint disease are major problems for people with hemophilia, and impact on health-related quality of life (HRQoL) may vary across groups defined by demographic and treatment-related characteristics. OBJECTIVE: To evaluate differences in overall HRQoL, pain, function, and joint status between P-FiQ study subgroups. METHODS: Adult males with hemophilia and a history of joint pain/bleeding completed a pain history and the patient-reported outcome instruments EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), and Hemophilia Activities List (HAL); optionally, joint status was assessed (Hemophilia Joint Health Score v2.1 [HJHS]). Scores were analyzed between subgroups across sets of participant characteristics. RESULTS: A total of 381 adult males with hemophilia were enrolled, with median age of 34 years. Worse scores on EQ-5D-5L index, BPI pain severity/interference, HAL overall score, and HJHS were generally associated with being college educated, unemployment, self-reporting both acute and chronic pain, and self-reporting anxiety/depression. CONCLUSIONS: Measures of joint status and HRQoL were consistently lower in participants who had higher educational levels, were unemployed, self-reported having both acute and chronic pain, and self-reported having anxiety/depression. A greater understanding of the association of these factors with disease outcomes may improve individualized patient management.

Internal consistency and item-total correlation of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adult people with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

BACKGROUND: The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH) of any severity in the USA who experience joint pain and/or bleeding. OBJECTIVE: To assess internal consistency (IC) and item-total correlation (ITC) of assessment tools used in the Pain, Functional Impairment, and Quality of Life study. METHODS: Participants completed 5 patient-reported outcome instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) and underwent an optional physiotherapist-administered musculoskeletal exam (Hemophilia Joint Health Score v2.1) during routine visits. Reliability assessment included IC and ITC of each instrument. RESULTS: A total of 381 adult PWH (median age, 34 years) were enrolled. Participants were predominantly white/non-Hispanic (69.2%); 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). IC was generally high across the instruments employed (Cronbach's alpha 0.79-0.98) with the exception of HAL use of transportation (0.58) and IPAQ total physical activity (0.51). ITC was high (Pearson's product-moment correlation coefficient >0.20) for all items except the "vigorous intensity activities" item of IPAQ, which was applicable to less than one-third of participants. The ITCs were generally highest in domains/scores that measured the functional consequences of hemophilic arthropathy on mobility and pain. CONCLUSION: The demonstrated reliability (IC/ITC) of the patient-reported outcome instruments and Hemophilia Joint Health Score v2.1 support a role for these instruments in evaluating adult PWH in US clinical and research settings.

Reliability of patient-reported outcome instruments in US adults with hemophilia: the Pain, Functional Impairment and Quality of life (P-FiQ) study.

BACKGROUND: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment. OBJECTIVE: This study aimed to assess the reliability of five patient-reported outcome (PRO) instruments in people with hemophilia (PWH) in a non-bleeding state. METHODS: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC). RESULTS: Participants completing the retest (n=164) had a median age of 33.9 years. Median time for completion of the initial survey with PRO instruments was 36.0 minutes and for the five PRO instruments, median retest time was 21.0 minutes. The majority of participants had hemophilia A (74.4%), were white and non-Hispanic (72.6%), and self-reported arthritis/bone/joint problems (61%). Median/mean test-retest concordance was EQ-5D-5L 80.0%/79.1%, BPI 54.5%/58.9%, IPAQ 100%/100%, SF-36v2 77.8%/76.4%, and HAL 77.4%/75.9%. ICCs for test-retest reliability were EQ-5D-5L index 0.890; BPI - severity 0.950; BPI - interference 0.920; IPAQ total activity 0.940; SF-36v2 overall health 0.910; HAL total score 0.970. CONCLUSION: All five PRO scales showed acceptable test-retest reliability in adult PWH. Therefore, the choice of instrument to be used for research or clinical care should be driven by instrument characteristics other than reliability.

Feasibility of the Von Willebrand disease PREVENT trial.

BACKGROUND: Despite treatment, women with von Willebrand disease (VWD) have lower von Willebrand factor (VWF) levels and greater blood loss at delivery than controls. Current weight-based dosing does not account for the ~1.5-fold increase in blood volume in pregnancy. METHODS: To evaluate the feasibility of a trial to prevent postpartum hemorrhage (PPH), we reviewed pre-pregnancy and 8th month VWF levels in women with VWD with and without PPH following vaginal delivery, assessed VWF concentrate use at delivery by U.S. hemophilia treatment center physician survey, and reviewed thrombosis risk with VWF concentrate by literature review. We determined trial interest and acceptability by structured interviews of physicians and patients. Analysis was by Student's t-test for continuous data, and chi-square or Fisher's exact test for discrete data. RESULTS: PPH was associated with lower pre-pregnancy VWF:RCo, p<0.005; higher pre-pregnancy, 8th and 9th-month weight, each p<0.001; a family bleeding history, p=0.036; and VWF concentrate treatment, p=0.005. Surveyed physicians reported first-line therapy at delivery was VWF concentrate, at a mean dose 50IU/kg. A trial of a 1.5-fold volume-based dose increase was acceptable to physicians and patients, if it is safe and if costs and visits are minimized. A literature review determined thrombosis risk with VWF concentrate is low, 0.4%. CONCLUSIONS: This study suggests pre-pregnancy VWF:RCo may predict PPH, but 50-80IU/kg VWF concentrate dosing may not prevent PPH. If pharmacokinetic modeling confirms volume-based dosing achieves VWF levels comparable to pregnant controls, it may be possible to determine if volume-modified VWF concentrate dosing will reduce PPH in VWD.

Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.

PURPOSE: Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. RESULTS: The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. CONCLUSIONS: This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient with Hermansky-Pudlak syndrome subtype 6.

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.

Current controversies in the diagnosis and management of von Willebrand disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the world. The spectrum of VWD spans quantitative and qualitative deficiencies of von Willebrand factor (VWF), a platelet adhesive protein. It manifests primarily as mucocutaneous bleeding, but severely affected patients may suffer soft tissue bleeding and hemarthroses. There is disagreement in the multiple guidelines published regarding diagnosis, especially of type 1 VWD, which also remains the most opaque with respect to molecular characterization. Treatment with desmopressin (DDAVP) is most effective in type 1 VWD, but regimens are not standardized. It is not clear which type 2 VWD patients with qualitative deficiencies can be treated with DDAVP and which ones should receive VWF concentrates. No guidelines stipulate which patients might benefit from prophylactic VWF infusions and how they should be dosed. These are some current controversies in VWD that are discussed in this review.

Management of VWD.

VWD is the most common inherited bleeding disorder known. It is caused by a deficiency or dysfunction of the VWF molecule. Bleeding risk varies between modest increases in bleeding seen only with procedures to major risk of spontaneous hemorrhage depending upon the type of VWD. The treatment approach to VWD has changed little in the past 2 decades, but there are numerous subtleties in optimal management. Management includes the prevention or treatment of bleeding by raising endogenous VWF levels with medications such as desmopressin or providing exogenous VWF concentrates. Fibrinolytic inhibitors and topical hemostatic agents are also effective adjunctive measures. Bleeding specific to women presents a special challenge because of heavy menstrual bleeding and pregnancy. Successful management of pregnancy in patients with VWD involves coordination with obstetrics, anesthesia, and the coagulation laboratory monitoring VWF:RCo and FVIII:C levels. Prophylactic treatment with VWF concentrates is emerging as an effective preventive therapy in patients with severe disease. Antibodies to VWF present a special challenge in the management of rare patients with type 3 disease. New therapies on the horizon include recombinant VWF, anti-VWF aptamers, and medications such as IL-11 to raise VWF levels. The key to effective treatment of VWD is an accurate diagnosis of the specific type and selection of hemostatic products appropriate for the clinical situation.

Venous thromboembolic disease.

Venous thromboembolism (VTE) remains a common and life-threatening complication among patients with cancer. Thromboprophylaxis can be used to prevent the occurrence of VTE in patients with cancer who are considered at high risk for developing this complication. Therefore, it is critical to recognize the various risk factors for VTE in patients with cancer. Risk assessment tools are available to help identify patients for whom discussions regarding the potential benefits and risks of thromboprophylaxis would be appropriate. The NCCN Clinical Practice Guidelines in Oncology for VTE provide recommendations on risk evaluation, diagnosis, prevention, and treatment of VTE in patients with cancer.

Thrombotic microangiopathy during docetaxel, trastuzumab, and carboplatin chemotherapy for early-stage HER2+ breast cancer: a case report.

Chemotherapy-induced thrombotic microangiopathy is a severe illness that has occurred in a small number of patients treated with carboplatin and combination of docetaxel and trastuzumab chemotherapy. We describe herein the case of a patient with stage IIB breast cancer who developed thrombotic microangiopathy after five cycles of carboplatin, docetaxel, and trastuzumab.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura.

BACKGROUND: Photochemical treatment of fresh-frozen plasma (FFP) with amotosalen and ultraviolet (UV) A light (PCT FFP) results in inactivation of a broad spectrum of pathogens while retaining coagulation factor activity, antithrombotic proteins, and von Willebrand factor-cleaving protease (VWF-CP) activity. STUDY DESIGN AND METHODS: A randomized, controlled, double-blind Phase III trial was conducted with PCT FFP or control FFP for therapeutic plasma exchange (TPE) in patients with thrombotic thrombocytopenic purpura (TTP). Owing to the rarity of this diagnosis, the trial was not powered to demonstrate small differences between treatment groups. Patients were treated with study FFP for a maximum of 35 days until remission was achieved (for a maximum of 30 daily study TPEs with no remission) plus an additional 5 days after remission. RESULTS: Among the 35 patients treated, the primary endpoint, remission within 30 days, was achieved by 14 of 17 (82%) PCT patients and 16 of 18 (89%) control patients (p = 0.658) The 90 percent confidence interval for treatment difference in remission rate for test - control was (-0.291 to 0.163). Time to remission, relapse rates, time to relapse, total volume and number of FFP units exchanged, and number of study TPEs were not significantly different between groups. Improvement in VWF-CP and inhibitors was similar for both groups. The overall safety profile of PCT FFP was similar to control FFP. No antibodies to amotosalen neoantigens were detected. CONCLUSION: The comparable results between treatment groups observed from this small trial suggest that TPE with PCT FFP was safe and effective for treatment of TTP.

Use of short tandem repeats for DNA fingerprinting to rapidly diagnose graft-versus-host disease in solid organ transplant patients.

BACKGROUND: Graft-versus-host disease (GVHD) is a rare complication following liver transplantation and carries a poor prognosis with mortality approaching 90-95%. Diagnosis of GVHD is often delayed due to early symptoms mimicking more common, entities such as drug reactions and viral syndromes. To date, definitive diagnosis has been difficult and has relied on a constellation of clinical and histopathologic variables. We present the use of short tandem repeat DNA "fingerprinting" technology as a method of early, definitive diagnosis of GVHD in patients after liver transplantation. METHODS: A patient status-postorthotopic cadaveric-liver transplant, with an uncomplicated immediate posttransplant course, presented 4 weeks after transplant with fever, diarrhea, and maculopapular rash on her palms, soles, and back. The patient's condition worsened despite empiric treatment for an infectious etiology. Skin and rectal biopsies were suspicious for GVHD. RESULTS: DNA was isolated from the skin and rectal biopsies as well as from a donor lymph node. PCR amplification was done for nine highly polymorphic short tandem repeats for each specimen and a unique DNA "fingerprint" was obtained from each. DNA from skin and rectum demonstrated mixed chimerism with both donor and recipient alleles detected. Thorough analysis confirmed GVHD. CONCLUSION: Short tandem repeats for DNA fingerprinting represents an efficient and reproducible method for the definitive diagnosis of GVHD after liver transplantation. Rapid detection of GVHD using this technology, coupled with early initiation of therapy, may lead to improved survival for patients with GVHD after solid organ transplant.