Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

A lower fibrinogen threshold does not lead to increased bleeding risk in patients receiving therapeutic plasma exchange: A prospective single-center analysis.

BACKGROUND: Plasma exchange (PLEX) therapy is indicated for several disorders. The 5% albumin is often used as a sole replacement fluid during most PLEX. However, each 1.0 plasma volume exchange depletes coagulation factors by ~65%. Although most coagulation factors recover to hemostatic levels within 24 h post-PLEX, fibrinogen requires 48-72 h to recover. Fibrinogen is the key coagulation protein for hemostasis. Therefore, fibrinogen is often monitored during the acute course of PLEX, and plasma is supplemented to prevent bleeding if fibrinogen is <100 mg/dL. STUDY DESIGN AND METHODS: We conducted a prospective, single-center, observational study to evaluate bleeding risk in adults who received an acute course of PLEX with a fibrinogen level of 80-100 mg/dL without plasma supplementation during the procedure or before central venous catheter removal. The study group was compared to patients with plasma fibrinogen >100 mg/dL. RESULTS: Among the 275 patients who received 1406 PLEXes, 62 patients (23%) who underwent 323 PLEXes met the inclusion criteria, and only 2 (3%) patients had bleeding while on oral anticoagulants. In contrast, out of 275 patients, 143 (52%) with fibrinogen levels >100 mg/dL received 751 PLEX treatments, and bleeding occurred in 2 (1%) while on low-molecular-weight heparin. CONCLUSIONS: Our findings suggest that a pre-procedure fibrinogen threshold of 80-100 mg/dL without plasma supplementation does not increase bleeding risk unless patients were on anticoagulation.

Redefining outcomes in immune TTP: an international working group consensus report.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.

Clinical Relevance of Preclinical and Clinical Studies of Four-Factor Prothrombin Complex Concentrate for Treatment of Bleeding Related to Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) are widely used for the prevention and treatment of venous thromboembolism and stroke. When emergency reversal of DOAC-related anticoagulation is required, specific DOAC reversal agents are recommended, including idarucizumab for dabigatran reversal and andexanet alfa for apixaban and rivaroxaban reversal. However, specific reversal agents are not always available, andexanet alfa has not been approved for urgent surgery, and clinicians need to know the patient's anticoagulant medication before administering these treatments. Four-factor prothrombin complex concentrates (4F-PCCs) are recognized as nonspecific, alternative hemostatic agents for treatment of DOAC-related bleeding. Evidence from preclinical and clinical studies shows that they may reduce the anticoagulant effects of DOACs and may help control DOAC-related bleeding. However, randomized controlled trials are lacking, and most data are from retrospective or single-arm prospective studies in bleeding associated with activated factor X inhibitors. There are no clinical data showing the efficacy of 4F-PCC for the treatment of bleeding in dabigatran-treated patients. This review focuses on the current evidence of 4F-PCC use in controlling bleeding associated with DOACs and provides an expert opinion on the relevance of these data for clinical practice. The current treatment landscape, unmet needs, and future directions are also discussed.

Thrombotic thrombocytopenic purpura in caplacizumab era - An individualized approach.

Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by a severe deficiency (< 10 % activity) of ADAMTS13 enzyme due to an autoantibody (aTTP) or genetic defect leading to congenital TTP (cTTP). The management of aTTP has evolved over the last 30 years, beginning with plasma exchange (PLEX) being the standard of care, leading to gradual aggressive immunosuppression therapies to manage exacerbations and relapses. Although PLEX had reversed the mortality from > 90 % to < 10-20 %, early deaths do occur in severe aTTP, especially when there is a delay in diagnosis and/or PLEX initiation. There is growing evidence that aTTP is often associated with the long-term neuropsychiatric sequela, probably associated with brain damage caused by microthromboses. Recently, a disease-modifying agent, caplacizumab, a potent nanobody that inhibits the interaction between the A1 domain of von Willebrand factor with GPIb on platelets, was approved by various agencies for the treatment of aTTP. Two clinical trials showed its efficacy in rapidly correcting platelet counts and preventing exacerbations because caplacizumab was continued for 30 days post-PLEX, irrespective of ADAMTS13 recovery. However, caplacizumab was associated with higher and unusual bleeding side effects compared to the placebo due to a severe acquired von Willebrand syndrome that persisted for the duration of therapy. Because of its longer half-life coupled with early aggressive rituximab therapy, it is prudent to use caplacizumab judiciously to avoid serious bleeds and to reduce costs. This manuscript provides a rational approach for using caplacizumab, an important disease-modifying agent.

A case of hyperhemolysis syndrome in sickle cell disease and concomitant COVID-19.

BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon transfusion reaction described in several hematologic disorders, including sickle cell disease (SCD). HHS is characterized by a decline in hemoglobin (Hb) values below pre-transfusion levels following transfusion of red blood cells (RBCs), coupled with laboratory markers consistent with hemolysis. The proposed pathophysiologic mechanisms underlying HHS include increased phosphatidylserine expression, macrophage activation, and complement dysregulation. Many pathophysiologic mechanisms thought to contribute to HHS have been similarly described in cases of severe COVID-19. CASE REPORT: A 28-year-old male with a history of HbSS presented with shortness of breath, right-sided chest pain, and a two-day history of fever. Polymerase chain reaction (PCR) detected SARS-CoV-2 infection with the omicron variant. The patient required an RBC transfusion (pre-transfusion hemoglobin [Hb]5.8 g/dL) with an immediate post-transfusion Hb of 6.3 g/dL. However, Hb rapidly declined to 1.7 g/dL, and lactate dehydrogenase (LDH) rose to 8701 u/L. The absolute reticulocyte count of 538 × 109/L correspondingly fell to 29 × 109/L. Despite additional RBC transfusions and initiation of immunosuppressive therapy, he expired on Day 9(D9). CONCLUSION: Given the similarities in their proposed pathophysiology, patients with SCD and concomitant SARS-CoV-2 infection may be predisposed to developing HHS.

Hemoglobin S target of <50% as compared to 30% in chronic red cell exchange for secondary stroke prevention in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. STUDY DESIGN: This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10-year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). RESULTS: Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83-99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. CONCLUSION: The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.

Multiplex Fragment Analysis for Flexible Detection of All SARS-CoV-2 Variants of Concern.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge, and effective tracking requires rapid return of results. Surveillance of variants is typically performed by whole genome sequencing (WGS), which can be financially prohibitive and requires specialized equipment and bioinformatic expertise. Genotyping approaches are rapid methods for monitoring SARS-CoV-2 variants but require continuous adaptation. Fragment analysis may represent an approach for improved SARS-CoV-2 variant detection. METHODS: A multiplex fragment analysis approach (CoVarScan) was validated using PCR targeting variants by size and fluorescent color. Eight SARS-CoV-2 mutational hot spots in variants of concern (VOCs) were targeted. Three primer pairs (recurrently deleted region [RDR] 1, RDR2, and RDR3-4) flank RDRs in the S-gene. Three allele-specific primers target recurrent spike receptor binding domain mutants. Lastly, 2 primer pairs target recurrent deletions or insertions in ORF1A and ORF8. Fragments were resolved and analyzed by capillary electrophoresis (ABI 3730XL), and mutational signatures were compared to WGS results. RESULTS: We validated CoVarScan using 3544 clinical respiratory specimens. The assay exhibited 96% sensitivity and 99% specificity compared to WGS. The limit of detection for the core targets (RDR1, RDR2, and ORF1A) was 5 copies/reaction. Variants were identified in 95% of samples with cycle threshold (CT) <30 and 75% of samples with a CT 34 to 35. Assay design was frozen April 2021, but all subsequent VOCs have been detected including Delta (n = 2820), Mu, (n = 6), Lambda (n = 6), and Omicron (n = 309). Genotyping results are available in as little as 4 h. CONCLUSIONS: Multiplex fragment analysis is adaptable and rapid and has similar accuracy to WGS to classify SARS-CoV-2 variants.

Successful use of lenalidomide to treat refractory acquired von Willebrand disease associated with monoclonal gammopathy.

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage.

BACKGROUND: Four-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH). STUDY DESIGN AND METHODS: We completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging. RESULTS: There was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC. CONCLUSION: There was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.

Utilization of emicizumab in acquired hemophilia A: A case report.

BACKGROUND: Acquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context. CASE REPORT: We report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.

Efficacy of prothrombin complex concentrate in the management of oral factor Xa inhibitors associated major bleed assessed by ISTH and ANNEXA-4 criteria.

Direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in atrial fibrillation and treatment and prevention of venous thromboembolism. They are also associated with bleeding risk. Existing literature suggests that prothrombin complex concentrate (PCC) administration may help control bleeding due to factor Xa inhibitors (FXaI). To determine the hemostatic efficacy of PCC in patients with major bleeding due to FXaI, we performed a retrospective chart review of 50 patients who presented with FXaI associated major bleeding that required urgent hemostatic management. Hemostatic assessment was performed using ISTH and ANNEXA-4 criteria. Twenty patients presented with intracranial hemorrhage (ICH), 20 had gastrointestinal bleeding, 3 had visceral bleeding, 3 had genitourinary bleeding, and 4 had miscellaneous types of bleeding. Fifty-six percent (28/50) had effective hemostasis using ISTH criteria and 84% (42/50) achieved effective hemostasis by ANNEXA-4 criteria. Hemostatic efficacy was similar by both tools for ICH (75% each). However, there was a major difference between ISTH and ANNEXA-4 hemostatic efficacy assessments for GI bleeding (45% and 95%, respectively). When comparing rivaroxaban and apixaban, there was no significant difference in effective hemostasis using either criteria, time to hemostasis, thromboembolic events, or patient mortality. Five (10%) patients had thromboembolic events within seven days of PCC administration, and the 30-day mortality rate was 14% (7/50). Our study shows similar efficacy, thromboembolic events, and mortality associated with PCC compared to andexanet alfa using ANNEXA-4 criteria, suggesting that PCC may be a viable alternative.

Clinical Evaluation of the Abbott Alinity SARS-CoV-2 Spike-Specific Quantitative IgG and IgM Assays among Infected, Recovered, and Vaccinated Groups.

The coronavirus disease 19 (COVID-19) pandemic continues to impose a significant burden on global health infrastructure. While identification and containment of new cases remain important, laboratories must now pivot and consider an assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity in the setting of the recent availability of multiple COVID-19 vaccines. Here, we have utilized the latest Abbott Alinity semiquantitative IgM and quantitative IgG spike protein (SP) serology assays (IgMSP and IgGSP) in combination with Abbott Alinity IgG nucleocapsid (NC) antibody test (IgGNC) to assess antibody responses in a cohort of 1,236 unique participants comprised of naive, SARS-CoV-2-infected, and vaccinated (including both naive and recovered) individuals. The IgMSP and IgGSP assays were highly specific (100%) with no cross-reactivity to archived samples collected prior to the emergence of SARS-CoV-2, including those from individuals with seasonal coronavirus infections. Clinical sensitivity was 96% after 15 days for both IgMSP and IgGSP assays individually. When considered together, the sensitivity was 100%. A combination of NC- and SP-specific serologic assays clearly differentiated naive, SARS-CoV-2-infected, and vaccine-related immune responses. Vaccination resulted in a significant increase in IgGSP and IgMSP values, with a major rise in IgGSP following the booster (second) dose in the naive group. In contrast, SARS-CoV-2-recovered individuals had several-fold higher IgGSP responses than naive following the primary dose, with a comparatively dampened response following the booster. This work illustrates the strong clinical performance of these new serological assays and their utility in evaluating and distinguishing serological responses to infection and vaccination.

Complete ADAMTS13 remission in a patient with refractory autoimmune-mediated thrombotic thrombocytopenic purpura after infliximab.

Autoimmune thrombotic thrombocytopenic purpura (aTTP) is caused by autoantibodies to the von Willebrand Factor cleaving enzyme, ADAMTS13. Despite recent advances in the treatment of acute aTTP, relapse rates remain high. Guidance for the treatment of patients in clinical remission but with persistent severe ADAMTS13 deficiency who fail to respond to rituximab remains unclear. We report a case of a 29-year-old man diagnosed with aTTP at the age of 11. Over a period of 18 years, he had five clinical relapses with persistent severe ADAMTS13 deficiency (<10%) and presence of autoantibodies during clinical remissions despite immunosuppressive therapy with rituximab, bortezomib and azathioprine. While in a clinical remission, he was diagnosed with Crohn's disease and initially treated with adalimumab. When he subsequently developed antibodies to adalimumab, he was transitioned to infliximab. ADAMTS13 activity increased to 24% by 2 months of infliximab induction, and four months later the ADAMTS13 activity improved to 42%. This case demonstrates the importance of managing concurrent inflammatory disorders and suggests that TNF may play a role in autoantibody development and ADAMTS13 depletion.

Retrospective analysis of bleeding events after central venous catheter placement in thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic disorder caused by severe deficiency of ADAMTS13. Platelets are transfused prophylactically in non-TTP patients for central venous catheter (CVC) with a count <20 × 109/L to prevent bleeding. However, transfusing platelets in TTP prior to CVC placement remains controversial due to concern for arterial thrombosis and mortality. At our center, platelet transfusion is contraindicated in TTP, therefore, we analyzed data for bleeding complications following CVC placement. STUDY DESIGN AND METHODS: 95 acute episodes of TTP were identified. Twenty-six episodes were excluded for insufficient documentation or no CVC placement. The charts of 69 remaining episodes were reviewed. RESULTS: Of 69 TTP episodes, nine (13 %) had bleeding after a CVC placement. Of these, seven bleeds were minor, and the two were major related to the technical issues during femoral venous access causing arterial bleeds. Median platelet count before the CVC placement among those experiencing bleeding complications was 12 × 109/L (range 3-44) as compared to median count of 15 × 109/L (range 4-257) in those who did not bleed (p = 0.258). Among 44 episodes with a platelet count <20 × 109/L, seven (16 %) had bleeds. CONCLUSION: Major bleeding complications following CVC placement in TTP is uncommon and most likely related to technical challenges. Median platelet count was similar in patients who bled versus those who did not, suggesting that platelet transfusion is unnecessary to correct platelet count prior to a CVC placement in TTP.

Immune checkpoint inhibitor toxicity: A new indication for therapeutic plasma exchange?

Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.

Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort.

Heavy menstrual bleeding is common in adolescents. The frequency and predictors of bleeding disorders in adolescents, especially with anovulatory bleeding, are unknown. Adolescents referred for heavy menstrual bleeding underwent an evaluation of menstrual bleeding patterns, and bleeding disorders determined a priori The primary outcome was the diagnosis of a bleeding disorder. Two groups were compared: anovulatory and ovulatory bleeding. Multivariable logistic regression analysis of baseline characteristics and predictors was performed. Kaplan Meier curves were constructed for the time from the first bleed to bleeding disorder diagnosis. In 200 adolescents, a bleeding disorder was diagnosed in 33% (n=67): low von Willebrand factor levels in 16%, von Willebrand disease in 11%, and qualitative platelet dysfunction in 4.5%. The prevalence of bleeding disorder was similar between ovulatory and anovulatory groups (31% vs 36%; P=0.45). Predictors of bleeding disorder included: younger age at first bleed (OR: 0.83; 95%CI: 0.73, 0.96), Hispanic ethnicity (OR: 2.48; 95%CI: 1.13, 5.05), non-presentation to emergency department for heavy bleeding (OR: 0.14; 95%CI: 0.05, 0.38), and International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool score ≥4 (OR: 8.27; 95%CI: 2.60, 26.44). Time from onset of the first bleed to diagnosis was two years in the anovulatory, and six years in the ovulatory cohort (log-rank test, P<0.001). There is a high prevalence of bleeding disorders in adolescents with heavy periods, irrespective of the bleeding pattern. Among bleeding disorders, the prevalence of qualitative platelet dysfunction is lower than previously reported.

Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel.

Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.

Thrombin Generation in a patient with Triple Positive Antiphospholipid Syndrome Treated with Three Different Anticoagulants.

INTRODUCTION: Venous and arterial thrombosis is one of the hallmarks of Antiphospholipid Antibody Syndrome (APS). The traditional treatment for individuals with APS and venous thrombosis has been vitamin K antagonists. However, with the widespread use of direct oral anticoagulants (DOACs) there has been conflicting evidence regarding their safety and failure rate as alternatives to warfarin. Reasons for this failure remain elusive. We utilized the thrombin generation assay (TGA) to investigate the anticoagulation efficacy of three different agents in a patient with triple-positive APS to acquire a better understanding of the pathophysiology of APS. METHODS: Blood samples were obtained from a single patient with APS at five distinct time points while on three different anticoagulants: rivaroxaban, warfarin, and enoxaparin. The effects of these anticoagulants on TG potential were evaluated using the TGA. RESULTS: In the presence of thrombomodulin, rivaroxaban had the highest endogenous thrombin potential, thrombin peak, velocity index, and thrombin inactivation velocity (821.9 nMmin, 121.5 nM, 36.44 nM/min, 7.19 nM/min) when compared to warfarin (121-367 nMmin, 13.85-121.5 nM, 3.02-3.85 nM/min, 0.64-4.55 nM/min) and enoxaparin (242-378.8 nM min, 21.33-23.78 nM, 2.87-3.85 nM/min, 0.747-0.784 nM/min). This trend was also observed in the absence of thrombomodulin. CONCLUSIONS: These results suggest that patients with APS treated with rivaroxaban may be at greater risk for thrombosis compared to warfarin or enoxaparin. The findings may provide insight into the recent studies in patients with triple positive APS randomized to different anticoagulants demonstrating high rates of thrombosis with rivaroxaban. Further studies are necessary to elucidate the clinical significance.

Comparison of low fixed dose versus standard-dose rituximab to treat thrombotic thrombocytopenic purpura in the acute phase and preemptively during remission.

The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m2 weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100-200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity <50 % during remission (6 patients, 10 courses of 4 infusions) achieved a median peak ADAMTS13 activity of 99 %, in a median of 1 month, with no clinical relapses. Our results provide additional evidence for the efficacy of low-dose rituximab, with the benefit of much lower cost, less infusion time, and theoretically lower risk of toxicity.