Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras.

The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans' health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20-5.75 and HR 2.49, 95% CI 2.20-2.82, both p < .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77-2.21, p < .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status.

The Pitfalls of Global Hemostasis Assays in Myeloproliferative Neoplasms and Future Challenges.

Venous and arterial thromboembolism are major complications of myeloproliferative neoplasms (MPNs), comprising polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Global hemostasis assays, including thrombin generation assay (TGA), rotational thromboelastometry (ROTEM), and thromboelastography (TEG), have been proposed as biomarkers to assess the hypercoagulability and thrombotic risk stratification in MPNs. We performed a systematic literature review on the parameters of TGA, ROTEM, and TEG and their association with thrombotic events and treatment strategies in MPNs. Thirty-two studies (all cross-sectional) were included, which collectively enrolled 1,062 controls and 1,608 MPN patients. Among the 13 studies that reported arterial or venous thrombosis, the overall thrombosis rate was 13.8% with 6 splanchnic thromboses reported. Out of the 27 TGA studies, there was substantial heterogeneity in plasma preparation and trigger reagents employed in laboratory assays. There was a trend toward increased peak height among all MPN cohorts versus controls and higher endogenous thrombin potential (ETP) between ET patients versus controls. There was an overall trend toward lower ETP between PV and PMF patients versus. controls. There were no substantial differences in ETP between JAK2-positive versus JAK2-negative MPNs, prior history versus negative history of thrombotic events, and among different treatment strategies. Of the three ROTEM studies, there was a trend toward higher maximum clot firmness and shorter clot formation times for all MPNs versus controls. The three TEG studies had mixed results. We conclude that the ability of parameters from global hemostasis assays to predict for hypercoagulability events in MPN patients is inconsistent and inconclusive. Further prospective longitudinal studies are needed to validate these biomarker tools so that thrombotic potential could be utilized as a primary endpoint of such studies.

A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting.

INTRODUCTION: Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice. AIM: Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. METHODS: Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. RESULTS: Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. CONCLUSION: PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.

A new strategy for uncontrollable bleeding after treatment with rivaroxaban or apixaban.

Anticoagulants are used in several settings to reduce the risk of thromboembolic events, but they can be associated with severe complications, such as potentially fatal bleeding. Two of the most widely used direct oral anticoagulants (DOACs), rivaroxaban and apixaban, are factor Xa inhibitors. If a patient receiving treatment with a factor Xa inhibitor presents with a major bleeding event, the physician must determine whether reversal of anticoagulation is needed. Rivaroxaban and apixaban have relatively short half-lives. In some cases, it may be sufficient to provide supportive care while the agent is metabolized. The administration of a specific agent to reverse factor Xa inhibition may be clinically indicated in certain settings, such as when rivaroxaban and apixaban were given less than 12 hours earlier (assuming normal renal function), when the timing of the previous dose is unknown, or in the event of a catastrophic bleed. The US Food and Drug Administration (FDA) recently granted accelerated approval to andexanet alfa, a recombinant protein analogue of factor Xa, for patients treated with rivaroxaban or apixaban who require reversal of anticoagulation owing to life-threatening or uncontrolled bleeding. Off-label treatments used in this setting include prothrombin complex concentrates.

A cross-sectional analysis of cardiovascular disease in the hemophilia population.

Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.

Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry.

The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals.

D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study.

BACKGROUND: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. OBJECTIVE: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. DESIGN: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). SETTING: 13 university-affiliated clinical centers. PATIENTS: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. INTERVENTION: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. MEASUREMENTS: Recurrent VTE during an average follow-up of 2.2 years. RESULTS: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). LIMITATIONS: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. CONCLUSION: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial.

The myeloproliferative neoplasm, myelofibrosis, is a morbid and frequently fatal illness encompassing primary myelofibrosis, and end-stage essential thrombocythemia and polycythemia. Bevacizumab (15 mg/kg intravenous (i.v.) every 21 days) was tested in a phase II international trial conducted by the Myeloproliferative Disorders Research Consortium. Thirteen patients were enrolled in the first stage of this 2-stage trial. Among the 11 patients who received therapy, only 3 received more than 4 cycles of therapy; none of the patients achieved an objective response. Furthermore, significant toxicity, not directly related to the vascular or gastrointestinal events typically associated with the anti-VEGF monoclonal antibody preparation in other disease states, was observed. Lack of objective responses coupled with toxicity led to the decision to terminate the study early. If future studies incorporate bevacizumab in combination therapy for myelofibrosis, more modest doses should be considered. (clinicaltrials.gov Identifier 00667277).

Dosing, efficacy, and safety of recombinant factor VIIa (rFVIIa) in pediatric versus adult patients: the experience of the Hemostasis and Thrombosis Research Society (HTRS) Registry (2004-2008).

BACKGROUND: The longitudinal registry of the Hemostasis and Thrombosis Research Society (HTRS) provided data on treatment of bleeding episodes for pediatric and adult patients with congenital hemophilia complicated by inhibitors to factor VIII or IX. PROCEDURE: Data from 2,041 recombinant factor VIIa (rFVIIa)-treated episodes were recorded in the HTRS Registry between January 2004 and November 2008 and included in this retrospective analysis. The authors compared dosing, efficacy, and safety in 1,712 episodes in 284 children (age ≤18 years) and 329 episodes in 145 adults (>18 years). RESULTS: Patients were predominantly non-Hispanic white (52% of children, 68% of adults) with hemophilia A (91%). The majority of bleeds were spontaneous (55% pediatric, 69% adult) and occurred in the joint (55% pediatric, 65% adult). rFVIIa was used first line in most episodes (90% pediatric, 93% adult); 27% of episodes in both age groups were treated with a single dose. Children and adults received comparable median number of doses (three) and duration of therapy (1 day); adults had lower median [range] initial doses (90 [46-400] µg/kg vs. 120 [37-400] µg/kg) and median [range] total doses (270 [46-21,392] µg/kg vs. 480 [50-43,200] µg/kg) than children. Effectiveness was comparable between the groups. No thromboembolic complications were reported. CONCLUSIONS: Dosing of rFVIIa was somewhat higher in pediatric than adult patients in the HTRS registry population, with similar effectiveness. Safety assessment, demonstrating lack of thromboembolic events associated with treatment of bleeding episodes, was similar between the children and adults in this retrospective registry.

Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study).

Elevated levels of circulating tissue factor-bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (N = 23) was 5·6% while the higher TFMP group observation arm (N = 11) was 27·3% (Gray test P = 0·06). The cumulative incidence of VTE in the low TFMP was 7·2% (N = 32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin (P = 0·58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group.

Difficult clinical challenges in haemophilia: international experiential perspectives.

Haemostasis management in people with haemophilia can present a range of challenges to physicians. Specific challenges that may be encountered relate to regimens for immune tolerance induction, use of central venous access devices, optimizing care of paediatric patients with inhibitors and improving outcomes in acquired haemophilia. There are also challenges related to performing surgery, and the establishment of specialist centres is valuable with regard to this. These challenges are considered in the light of available data, and with perspectives gained from the experience of experts treating patients around the world. Sharing this knowledge may help to improve patient management.

Low molecular weight heparins differ substantially: impact on developing biosimilar drugs.

Generic drugs are an important component for meaningful health-care reform currently being debated in the United States. Aside from defining the period of drug exclusivity, however, there is a critical need to ensure that generics of biologic medicines (biosimilars) are safe and effective. For low molecular weight heparins (LMWHs), the standard of care for management of venous thromboembolism, their complex structure and polypharmacological actions make producing a generic LMWH more challenging than a generic small molecule medicine. Because biosimilar LMWHs will be used interchangeably with their branded product, inherent variability between products could lead to important differences in potency, safety, or effectiveness, including unanticipated immune responses. Awareness of the specific problems associated with biosimilar LMWH development led to new recommendations from several expert bodies. This article discusses the implications of these differences for the production of biosimilar LMWHs and provides recommendations to address the limitations in the pending U.S. Congress legislation, a well-intentioned undertaking but one that must preserve the health and welfare of citizens who require these critical care medications.

Microvascular free flap failure caused by unrecognized hypercoagulability.

BACKGROUND: Microvascular free flap techniques have improved over the past two decades such that flap failure rates have dropped to under 3 percent in most large series of high-volume centers. However, despite technical and patient-selection advances, some components of free flap failure might be attributable to undiagnosed patient factors. METHODS: In this clinicopathologic conference article, the authors present four patients with major free flap microvascular complications who were later diagnosed with multiple risk factors for hypercoagulability and biochemical abnormalities, and present the characteristic associated findings. RESULTS: Previously undiagnosed hypercoagulability was present in four patients with major free flap microvascular complications. Hematologic consultation and laboratory investigation revealed the biochemical abnormalities. CONCLUSIONS: In certain patients undergoing microvascular free flap reconstruction, undiagnosed hypercoagulability risk factors can be a source of free flap failure that is independent of patient selection or technical factors. Diagnosis, management, patient counseling, and initiation of deep venous thromboembolism prophylaxis measures are critical clinical components of care of these patients.