Hepatic and Renal Histotripsy in an Anticoagulated Porcine Model.

PURPOSE: To determine the risk of mechanical vessel wall damage resulting in hemorrhage during and after hepatic and renal histotripsy in an anticoagulated in vivo porcine model. MATERIALS AND METHODS: Non-tumor-bearing pigs (n = 8; mean weight, 52.5 kg) were anticoagulated with warfarin (initial dose, 0.08 mg/kg) to a target prothrombin time (PT) of 30%-50% above baseline. A total of 15 histotripsy procedures were performed (kidney: n = 8, 2.0-cm sphere; liver: n = 7, 2.5-cm sphere). Treatments were immediately followed by computed tomography (CT) imaging. Animals were observed for 7 days while continuing anticoagulation, followed by repeat CT and necropsy. RESULTS: All animals survived to complete the entire protocol with no signs of disability or distress. Three animals had hematuria (pink urine without clots). Baseline PT values (mean, 16.0 seconds) were elevated to 22.0 seconds (37.5% above baseline, P = .003) on the day of treatment and to 28.8 seconds (77.8% above baseline, P < .001) on the day of necropsy. At the time of treatment, 5 of 8 (63%) animals were at a therapeutic anticoagulation level, and all 8 animals (100%) reached therapeutic levels by the time of necropsy. There were no cases of intraparenchymal, peritoneal, or retroperitoneal hemorrhage associated with any treatments despite 5 of 7 (71%) liver and all 8 (100%) kidney treatments extending to the organ surface. CONCLUSIONS: Liver and kidney histotripsy seems safe with no elevated bleeding risk in this anticoagulated animal model, supporting the possibility of histotripsy treatments in patients on anticoagulation.

Unexplained Hematocrit Increase after Therapeutic Phlebotomy in a Patient with Marked Erythrocytosis.

We report a patient with hereditary erythrocytosis who underwent a therapeutic phlebotomy and had a post-phlebotomy hematocrit that was higher than the pre-phlebotomy hematocrit. We could not discern a reason for this hematocrit increase after phlebotomy. Instead of performing another phlebotomy, we performed an automated red cell depletion via an apheresis instrument. This procedure is essentially a red cell exchange, but 5% albumin is used as the replacement fluid instead of red blood cells. The patient's hematocrit decreased from 80% to 39% after three consecutive daily red cell depletion procedures. We share our experience to report the unusual finding of a patient's hematocrit that increased with phlebotomy and to raise awareness of the red cell depletion procedure.

Emergent Reversal of Antithrombotics and Treatment of Life-Threatening Bleeding from Coagulopathies: A Clinical Review.

BACKGROUND: Reversal of antithrombotic agents and treatment of life-threatening bleeding episodes from coagulopathies can be a stressful scenario for clinicians, especially when the selection of treatment options should occur quickly. Understanding the options available for these agents requires emergency physicians to be familiar with the current data surrounding new therapies and dosing strategies for the treatment of bleeding from reversible and nonreversible antithrombotics and coagulopathic conditions. OBJECTIVE: To provide quick resource guides for the reversal of major or life-threatening bleeding caused by antithrombotic agents or in the setting of coagulopathies. METHODS: A literature search for articles published through September 2021 related to antithrombotic reversal and treatment of acute bleeding from coagulopathies was conducted using the PubMed clinical database. Selected articles were used to generate 5 guidance tables in this clinical review. DISCUSSION: Four guidance tables for how to treat major or life-threatening bleeding from antithrombotic agents and 1 table for how to manage life-threatening bleeding for coagulopathies are presented as a quick reference tool for the emergency physician. Additional information on upcoming reversal agents and possible treatment options are provided herein. CONCLUSIONS: In this clinical review, a series of 5 tables were created to provide quick and comprehensive guidance for the emergency physician when treating major or life-threatening bleeding caused by antithrombotic agents or coagulopathies. © 2022 Elsevier Inc.

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/µL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

The emergent reversal of coagulopathies encountered in neurosurgery and neurology: a technical note.

It is imperative for neurologists, neurosurgeons, and neurointensivists to know how to stop life-threatening hemorrhage in both surgical and non-surgical patients. However, knowing how to medically correct a coagulopathy has become increasingly challenging as more contemporary and sophisticated anticoagulation agents are developed and prescribed. In a time-sensitive and life-threatening situation, where there is little margin for error, the neurosurgeon may not have ready access to information about the drug or condition that caused the coagulopathy or the information on how to treat it. This thorough review of the literature provides a comprehensive overview of the medications and conditions that can lead to persistent and/or life-threatening intracranial hemorrhage.

Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network.

PURPOSE: Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-L-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. METHODS: Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. RESULTS: Seventy-six percent of subjects were refractory to previous treatment, 39% refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53% and did not differ between groups. Incidence of ≥3 PN was 32% in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. CONCLUSIONS: Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

Cerebellar hemorrhage as a first presentation of acquired Hemophilia A.

BACKGROUND: Acquired hemophilia A (AHA) is an uncommon coagulation disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). While intracranial hemorrhage is a known complication of AHA, intracranial hemorrhage as the presenting manifestation of AHA has only been described in three previous case reports. METHOD: We report a case of an 86-year-old woman with no previously reported history of coagulopathy presenting with an acute intraparenchymal cerebellar hemorrhage and laboratory studies demonstrating an isolated prolonged activated partial thromboplastin time (aPTT). We discuss an approach to the prolonged aPTT, and review the literature concerning the diagnosis and treatment of AHA. RESULTS: Occipital decompressive craniectomy with evacuation of the hemorrhage was performed. Eight hours following the procedure, the patient's status acutely declined with demonstration of a reoccurrence of the cerebellar hemorrhage and new right frontal lobe hemorrhage. After discussion with the patient's family, life-sustaining support measures were withdrawn. Postmortem analysis revealed a low FVIII activity level and the presence of FVIII inhibitor. CONCLUSION: The presentation of intracranial hemorrhage with an isolated prolonged aPTT is concerning for an acquired hemophilia with FVIII deficiency. Other causes of isolated prolonged aPTT such as a lupus anticoagulant must also be considered. Preoperative identification and work-up of the coagulation abnormality is essential to guide initial treatment.

Coagulation concepts update.

OBJECTIVE: Since the previous comprehensive radiology review on coagulation concepts that was done in 1990, many studies have been published in the medical and surgical literature that can guide the approach of a radiology practice. The purpose of this article is to provide an analysis of these works, updating the radiologist on proper use and interpretation of coagulation assessment tools, medications that modify the hemostatic system, and the use of transfusions prior to interventions. CONCLUSION: The basic tools for coagulation assessment have not changed; however, results from subspecialty research have suggested ways in which the use of these tools can be modified and streamlined to safely reduce time and expense for the patient and the health care system.

Augmented and standard Berlin-Frankfurt-Munster chemotherapy for treatment of adult acute lymphoblastic leukemia.

The augmented Berlin-Frankfurt-Munster (aBFM) regimen has demonstrated improved outcomes in children with acute lymphomblastic leukemia (ALL), but efficacy in adults is unknown. In this retrospective study, we evaluated clinical outcomes in 29 adult ALL patients (aged 19-70) treated with standard BFM (sBFM) or dose-intensive aBFM. Patients were stratified into risk groups based on age, cytogenetic abnormalities, peripheral leukocytosis and response to induction chemotherapy. Inter-mediate risk patients less than 50 years old and all high-risk patients were assigned to aBFM. Complete remission after induction therapy was achieved in 93% of patients. Fifteen patients completed a full course of BFM chemotherapy, with seven discontinuing because of relapse, three because of toxicity, two because of transplantation and two toxic deaths. Five-year event-free survival (EFS) was 45% (95% CI 30-67%), with 39% and 50% rates of EFS observed in the aBFM and sBFM subgroups at 5 years, respectively. Overall survival at 5 years was 62% (95% CI 46-82%), with 61% and 62% in the aBFM and sBFM subgroups alive at 5 years, respectively. Two toxic deaths were observed, and infections and neuropathy were the most common toxicities. sBFM and aBFM have efficacy and toxicity comparable with other adult ALL regimens.

Fulminant EBV-driven CD8 T-cell lymphoproliferative disorder following primary acute EBV infection: a unique spectrum of T-cell malignancy.

Fulminant Epstein-Barr virus (EBV)-driven clonal T-cell lymphoproliferative disorder (T-LPD) is rare and most patients are of Asian origin. The disease usually develops shortly after primary acute EBV infection and the mechanism remains poorly understood. Here we report such a rare case in a 28-year-old Caucasian female with systemic lupus erythematosus (SLE). Immunophenotypic and molecular studies revealed that the proliferating lymphoid cells displayed a CD8(+) T-cell phenotype with clonal rearrangement of the T-cell receptor gamma gene. Epstein-Barr virus-encoded RNA was also observed in the clonal lymphoid cells by in situ hybridization. The patient subsequently developed fatal virus-associated hemophagocytic syndrome one month after the primary acute EBV infection. The case represents the first report of fulminant EBV-driven CD8(+) T-LPD occurring in an immunocompromised Caucasian SLE patient. This study, along with studies of similar Asian cases reported in the literature, suggests that dysregulated immunity due to either acquired or genetically determined susceptibility may result in an abnormal response to primary EBV infection and contribute to the pathogenesis of EBV-mediated fatal T-LPD.

A 5-drug regimen maximizing the dose of cyclophosphamide is effective therapy for adult Burkitt or Burkitt-like lymphomas.

Burkitt lymphoma (BL) and Burkitt-like lymphomas (BLL) are clinically and biologically aggressive B-cell malignancies. Brief-duration, high intensity multidrug regimens with central nervous system (CNS) prophylaxis have proven to be effective, with published series of adult patients documenting complete response (CR) rates of 80 to 100 percent and 2-year event-free survival (EFS) rates ranging from 60 to 90 percent. Based upon the known sensitivity of BL to cyclophosphamide and favorable results reported from the Dana Farber Cancer Center using high-dose CHOP in diffuse aggressive lymphomas, we tested a regimen designed to maximize the administered dose of cyclophosphamide while eliminating other agents commonly used in BL protocols. Eleven patients with Burkitt or Burkitt-like lymphoma were treated with 4 cycles of a 5-drug regimen, called high-dose CHOP, which contains a cyclophosphamide dose of 4 gm/m2 with each cycle. Intrathecal methotrexate and midcycle high-dose methotrexate were added as CNS prophylaxis. Ten patients achieved a complete response (91 percent) and with a median follow up of 38 months, the 3-year EFS is 64 percent and the 3-year overall survival (OS) is 72 percent. Three patients recurred after the achievement of a CR. Treatment-related toxicities included myelosuppression, neutropenic fevers/infections, and tumor lysis syndrome requiring hemodialysis in 2 patients. There were no treatment-related deaths and none of the patients had to discontinue therapy secondary to toxicity. In conclusion, the high-dose CHOP with midcycle methotrexate regimen produces response rates and EFS rates comparable to other regimens, with an acceptable toxicity profile. Utilization of high dose cyclophosphamide may eliminate the need for several other agents in Burkitt lymphoma regimens.

Phase II study of weekly low-dose paclitaxel for relapsed and refractory non-Hodgkin's lymphoma: a Wisconsin Oncology Network Study.

This study was performed to determine the clinical activity and safety of weekly low-dose paclitaxel (90 mg/m2) given as a 1-hour infusion in patients with relapsed and refractory non-Hodgkin's lymphoma (NHL). Thirty patients were treated on a phase II protocol conducted at the University of Wisconsin Comprehensive Cancer Center and within the Wisconsin Oncology Network (WON). A cycle of therapy was defined as paclitaxel at 90 mg/m2 weekly for 6 consecutive weeks followed by a 2-week rest period. Cycles were repeated as long as there was no disease progression or unacceptable toxicity. In general, the patients were heavily pretreated with a median of 4 prior therapies (range 2-11), and 73% were refractory to the most recent systemic therapy. The median age was 70 (range 44-97). All NHL histological subtypes were eligible. Of the 30 eligible patients enrolled, 26 were evaluable for response and 28 for toxicity. The overall response rate was 23% (95% confidence interval (CI) 9.0-43.7%). One patient had a complete response, and 5 patients had partial responses. The median response duration was 3.2 months (range 1.4-11.8 months). The median event-free survival was 1.9 months. The major toxicity was neuropathy. Despite the limited marrow reserve in this patient population, myelosuppression was minimal. Paclitaxel given in this dose and schedule has modest activity in previously treated non-Hodgkin's lymphoma. The response rate appears similar to other reports using different doses and schedules. Myelosuppression appears less with this schedule than with other schedules.

FXIII polymorphisms, fibrin clot structure and thrombotic risk.

Fibrin clot structure is highly dependent on factor XIII activity. Activated FXIII catalyzes the formation of the peptide bonds between the gamma and alpha chains in noncovalently bound fibrin polymers and incorporates various adhesive and antifibrinolytic proteins into the final fibrin clot. In the absence of activated FXIII, clots are unstable and susceptible to fibrinolysis. Several studies have examined the effects of FXIII polymorphisms on final fibrin clot structure and clinical thrombotic risk. The Val34Leu FXIII polymorphism is associated with increased activation by thrombin. In the presence of saturating thrombin concentrations, however, FXIIIa specific enzyme activity is not affected by genetic polymorphisms. Fibrin clots formed in the presence of the FXIII 34Leu polymorphisms do tend to be thinner and less porous, however. The effects of prothrombin concentrations on clot structure have suggested that thinner clots are more resistant to fibrinolysis and associated with increased thrombotic risk. Most clinical studies of 34Leu FXIII carriers, however, have demonstrated a lower incidence of both venous and arterial thrombosis in carriers of the mutant allele compared to Val/Val carriers. One recent study has suggested that the interactions between FXIII phenotype and plasma fibrinogen concentrations significantly influence clinical thrombotic risk.

Heparan sulphate proteoglycan in scleromyxedema promotes FGF-2 activity.

The cause of progressive dermal sclerosis, proliferation of fibroblasts, and collagen deposition in scleromyxedema is unknown. We analyzed the heparan sulphate proteoglycans (HSPG) in cutaneous nodules from a patient with scleromyxedema in order to ascertain their role in the binding of fibroblast growth factor (FGF) and promoting signaling complex assembly. Total heparan sulphate (HS) was detected with a monoclonal antibody to HSPG on paraffin sections. Binding of FGF to HS was assessed using FGF-2 followed by anti-FGF-2 antibody. The formation of HS-mediated signaling complex was studied using soluble FR1-AP, which contains the extracellular domain of FGF receptor-1 linked to alkaline phosphatase (AP) and monoclonal anti-AP-antibody. Anti FGF-2 and anti-AP antibodies were visualized using the DAKO Envision Plus system. The dermal nodule of scleromyxedema contained ample HS and these bound FGF-2 and FR1-AP. Specificity was confirmed by prior incubation with heparitinase (no staining) and omission of FGF-2 (no staining). Increased amounts of HSPG were present in the dermal nodules of scleromyxedema compared to adjacent normal dermis and these bound FGF-2, immobilized the soluble receptor protein FGFR-1 and, therefore, formed a ternary complex composed of HSPG, FGF-2 and FGFR-1 in vitro. Since this complex resembles the signaling complex formed on live cells, HSPG in the nodules of scleromyxedema are in a configuration that promotes FGF activity.