Acquired Coagulation Factor Deficiency Research Articles

Fatal acquired coagulation factor V deficiency after hepatectomy for advanced hepatocellular carcinoma as a possible immune checkpoint inhibitor-related adverse event: a case report

BackgroundAtezolizumab plus bevacizumab therapy was recently introduced as the first line for unresectable advanced hepatocellular carcinoma (HCC), but immune-related adverse events (IrAEs) due to atezolizumab are a great concern. Here, we report the case of a patient who developed fatal acquired coagulation factor deficiency after hepatectomy for HCC, treated with atezolizumab and bevacizumab before surgery.Case presentationA 70-year-old man received right trisegmentectomy of the liver with hepaticojejunostomy for advanced HCC with bile duct invasion, after atezolizumab and bevacizumab therapy. The patient suffered the sudden onset of severe multiple coagulation factor deficiency (II, V, VII, VIII, IX, X, XI and XII) immediately following reoperation for anastomotic leakage of hepaticojejunostomy, 7 days after hepatectomy. The coagulation factor deficiency did not reverse even with intensive treatment, and the patient died of uncontrollable bleeding 32 days after hepatectomy. An IrAE due to atezolizumab was suspected because the patient had developed the possible IrAE of enthesitis of the right gastrocnemius muscle before surgery, and specific inhibitors against factor V and anti-factor V autoantibodies were detected, leading to an ultimate diagnosis of autoimmune FV/5 deficiency (AiF5D).ConclusionSevere acquired coagulopathy should be recognized as a possible life-threatening IrAE when using atezolizumab and bevacizumab for HCC.

Diagnosis and treatment of autoimmune acquired coagulation factor deficiency

Autoimmune coagulation factor deficiency (AiCFD) is an acquired bleeding disorder caused by immunoglobulins (autoantibodies) that target a single coagulation factor. Most of these autoantibodies are polyclones and primarily neutralizing antibodies (inhibitors) that inhibit the function of coagulation factors; however, non-neutralizing autoantibodies that enhance clearance are also present. AiCFD has been reported in nearly all coagulation factors and von Willebrand factor, and its representative disease is acquired hemophilia A, which is caused by autoantibodies against coagulation factor VIII. The treatment for AiCFD consists of hemostatic therapy according to the bleeding symptoms and immunosuppressive therapy to eradicate autoantibodies. Hemostatic treatment varies depending on the deficient coagulation factor, and coagulation factor replacement therapy, platelet or fresh frozen plasma transfusions, and bypassing agents are provided. Although AiCFD is a rare disease, raising awareness of this disease is necessary because general physicians may also encounter it.

344: THIRTY YEARS OF SOLVENT/DETERGENT-TREATED PLASMA FOR TRANSFUSION IN CRITICALLY ILL PATIENTS

Introduction: OctaplasLG (Octapharma AG, Switzerland) is a solvent/detergent (S/D)-treated plasma preparation made from pooled fresh frozen plasma (FFP). First used in 1989 as an FFP alternative, S/D plasma was developed to increase pathogen safety in treating acquired coagulation factor deficiencies during active bleeding, bleeding prevention, and therapeutic plasma exchange (TPE). Here, we review published literature on the efficacy, safety, and cost effectiveness of S/D plasma. Methods: Medline (PubMed) and Google Scholar were searched for articles reporting “octaplas” or “octaplasLG” efficacy and/or safety in clinical settings. Results: Efficacy/safety was shown for multiple indications in different patient groups, such as cardiac surgery (n=125/117 adult/pediatric patients receiving S/D plasma), liver disease (n=30/20), liver transplantation (n=269/5), hemodilution/blood loss (n=47 adults), obstetrics/gynecology (n=38 adults), and TPE (n=167/41), as well as in 162 critically ill neonates/pediatric patients. Studies demonstrated S/D plasma could improve standard coagulation markers comparable with FFP and was also associated with greater endothelial protection. S/D plasma had lower incidences of allergic and febrile non-hemolytic transfusion reactions, and transfusion-associated circulatory overload compared with FFP, and almost no confirmed cases of transfusion-related acute lung injury reported after >13 million units transfused. Studies suggested S/D plasma was more cost-effective than FFP due to lower risk of transfusion-related complications. Literature results showed some countries have replaced FFP with S/D plasma to improve plasma safety. A new freeze-dried form has been recently developed with similar biochemical quality to S/D plasma, and is of particular interest for pre-hospital settings, e.g., trauma, where rapid reconstitution/flexible storage improves logistics/utilization. Conclusions: Available evidence from 30 years of global use indicates that S/D plasma is an efficacious alternative to FFP in adult/pediatric patients for multiple indications, with a favorable safety profile. The clinical utility of S/D plasma is also expanding, with the freeze-dried form having the potential to further improve patient outcomes and reduce costs.

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME: A VICIOUS CIRCLE OF CLOTTING AND BLEEDING

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME: A VICIOUS CIRCLE OF CLOTTING AND BLEEDING

Laboratory work-up/diagnostics of acquired factor XI inhibitor

Acquired coagulation factor deficiencies are caused by inhibitory autoantibodies which are usually directed against clotting factor VIII (FVIII), causing acquired hemophilia A (AHA). Clotting factor inhibitors usually cause abnormalities in screening coagulation tests (activated partial thromboplastin time [aPTT] and/or prothrombin time [PT]). Other coagulation factor inhibitors are much rarer, particularly inhibitors to factor XI (FXI). We present the case of an 82-year-old woman referred to a hematological center for isolated aPTT prolongation in pre-surgery screening tests. No bleeding symptoms were reported either at admission or in the patient’s medical history. One stage coagulation factor assays revealed lower factor VIII, IX, XI, XII levels. The Nijmegen modification of the Bethesda assay showed the presence of an inhibitor to factor XI (22.1 BU/mL). No autoantibodies to coagulation factors VIII, IX and XII were found: inhibitor titers were all below 0.6 BU/mL. Acquired hemophilia C was diagnosed (the presence of autoantibodies to clotting factor XI).

Congenital and acquired disorders of secondary hemostasis

: Hemostasis depends on a large number of interdependent processes to prevent spontaneous bleeding and to stop hemorrhage when vascular injury occurs. Although it is commonly divided into primary and secondary for the purpose of simplification and patient evaluation, both processes occur almost simultaneously in vivo. The goal of secondary hemostasis is to produce a firm, cross-linked fibrin clot to stabilize the platelet plug. Fibrin is generated from a series of enzymatic reactions that comprise the coagulation cascade. In this review, we describe the background, physiology, diagnosis, and treatment of congenital and acquired coagulation factor deficiencies. For each condition, we discuss the appropriate laboratory assays as well as the most current treatment modalities. In addition, we describe in detail the oral and parenteral anticoagulants currently available in the United States, their mechanism of action, laboratory monitoring (if appropriate), and how to reverse their effect in case of hemorrhage or need for an emergent procedure. Finally, we review the effect of systemic conditions such as liver disease and disseminated intravascular coagulation (DIC) on the coagulation cascade.

Examination of the effect of immunosuppressive therapy on acquired hemophilia A in elderly patients with bloodstream infections

Acquired hemophilia A (AHA) is an acquired autoantibody (inhibitor) against blood coagulation factor VIII (FVIII) that significantly reduces FVIII activity and causes a bleeding tendency. Immune acquired coagulation factor deficiency. The peak age of onset is in the 70s. In Japan, which has an aging society, the number of reports has recently been increasing, and it should be noted that AHA is a bleeding disease that can occur in the elderly. Examined 5 cases of AHA that were experienced in our hospital. The FVIII inhibitor level, APTT, underlying disease, treatment history, and outcome were retrospectively examined using medical records. The age of onset was 76-93 years. At the time of diagnosis, the Hb (mg/dL) value was 6.1-10.3, the APTT was 75.6-203.2 seconds, the FVIII inhibitor value (BU/mL) was 18-686, and the platelet count was within the normal range in all cases. Bleeding control was possible using a bypass hemostatic agent in 4 patients. All patients underwent immunosuppressive therapy. Two patients were discharged alive and 3 patients died. The cause of death was infectious disease in all cases. The total prednisolone-equivalent dose of the deceased patients was 1,240-3,206 mg; one patient was treated with cyclophosphamide and was treated with dexamethasone. Long-term immunosuppressive therapy is expected to increase the risk of infection in elderly patients. The risk assessment of AHA treatment-related bloodstream infections is insufficient, and it will be necessary to accumulate data and consider appropriate assessments and countermeasures.

Increased Incidence of Autoimmune and Infectious Diseases Among a Large Group of Diffuse Large B-Cell Lymphoma (DLBCL) Survivors: A Population-Based Study

▪Introduction: Treatments for lymphoma have improved significantly over the last three decades, particularly since the advent of rituximab for non-Hodgkin lymphoma. Improved survival rates have led to an increasing number of lymphoma survivors. Many of the treatments for lymphoma as well as lymphoma itself are known to affect the immune system; yet, despite the range of immune perturbations lymphoma survivors may have experienced, very little is known about their mid- and long-term immune health. Therefore, we investigated whether survivors of diffuse large B-cell lymphoma (DLBCL) have altered risk of developing autoimmune and infectious diseases compared to other cancer survivors.Methods: All 21,690 Californians aged ≥18 years when newly diagnosed with DLBCL during 1991-2012, surviving a minimum of 1 year from diagnosis and without evidence of HIV/AIDS were identified in the California Cancer Registry and followed in California hospital, emergency department and ambulatory surgery discharge databases through 2014. We categorized discharge diagnoses to classify autoimmune and infectious diseases. To avoid possible relationships to DLBCL pathogenesis, we excluded conditions identified prior to or within 1 year of cancer diagnosis from our incidence analyses. We calculated incidence rate ratios (IRRs) and associated p-values comparing the incidence of autoimmune and infectious diseases among female and male DLBCL survivors to that among breast and prostate cancer survivors >1-10 years after cancer diagnosis using multivariable Poisson regression models adjusting for age, race/ethnicity and year of cancer diagnosis. We estimated the cumulative incidence of developing new autoimmune and infectious disease conditions >1-10 years after diagnosis, accounting for death as a competing risk.Results: Most DLBCL patients had at least one hospitalization prior to or within 1 year of diagnosis (67.9%) and >1-10 years of diagnosis (78.6%). Median follow-up time was somewhat longer for female breast (8.2 years) and male prostate (8.3 years) cancer survivors than for DLBCL survivors (female, 6.3 years; male, 5.9 years). In DLBCL survivors, we identified a higher cumulative incidence of any autoimmune or any infectious disease diagnosis than in breast or prostate cancer survivors (Figure 1). After adjustment for age, race/ethnicity and year of diagnosis, we found DLBCL survivors to have a more than two-fold higher incidence of fungal pneumonia (IRR 6.2 versus breast; IRR 8.2 versus prostate), viral pneumonia (IRR 3.4 versus breast; IRR 4.5 versus prostate), bacteremia (IRR 2.6 versus breast; IRR 3.1 versus prostate), and CNS infections (IRR 2.6 versus breast; IRR 3.2 versus prostate) (all p<0.0001). Compared to prostate cancer survivors, male DLBCL survivors had higher incidence of liver abscesses (IRR 3.0), empyema (IRR 2.4), bacterial pneumonias (IRR 2.1), and infections of implanted devices (IRR 2.1). For autoimmune diagnoses, we found DLBCL survivors to have a higher incidence of autoimmune hemolytic anemia (IRR 10.1 versus breast; IRR 8.7 versus prostate), immune thrombocytopenia (IRR 3.1 versus breast; IRR 4.7 versus prostate), and diffuse connective tissue diseases (IRR 2.1 versus breast; IRR 2.5 versus prostate) (all p<0.0001). In comparing male DLBCL survivors to prostate cancer survivors, we additionally found an increase in acquired coagulation factor deficiencies (IRR 2.1), caused by autoimmunity against clotting factors. Finally, we found that DLBCL survivors had a markedly increased incidence of being diagnosed with impaired humoral immunity (IRR 16.0 versus breast; IRR 14.0 versus prostate), perhaps a reflection of persistent hypogammaglobulinemia.Conclusion: These findings in a large, population-based study suggest that compared to survivors of other common cancers, DLBCL survivors experience excess immune-related conditions, some expected (such as autoimmune hemolytic anemia and thrombocytopenia) and others unexpected (such as fungal and viral pneumonias and diffuse connective tissue diseases). This information suggests possible lasting effects of lymphoma and its treatments on the immune system and motivates further examination of immune function in DLBCL survivors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Splenectomy in a Severe Case of Acquired Factor X Deficiency Secondary to Amyloidosis: Case Discussion and Review of the Literature

Amyloidosis is a protein deposition disorder wherein amyloid fibrils affect soft tissues and visceral organs. One subtype is light-chain (AL) amyloidosis, which is characterized by amyloidogenic immunoglobulins produced generally by clonal plasma cells. Kidney and heart are the most commonly involved organs by AL amyloidosis while liver and sensory/autonomic nervous system can be clinically prominent. In a minority, acquired Factor X (FX) deficiency (related to amyloid binding this factor) can provoke a profound bleeding diathesis.We present a 62-year-old black male who was referred to our institution in May 2016 by a community hematologist after diagnoses of FX deficiency and monoclonal gammopathy. The patient initially presented with ecchymosis, hemearthroses, and blood per rectum. Workup revealed a hemoglobin 7.7g/dL, platelets 62x10³/µL and prolonged PT (35.4s) and aPTT (53.9s). Echocardiogram revealed concentric LV ‘hypertrophy’ and grade 2 diastolic dysfunction. Abdominal ultrasound identified an enlarged spleen of 18 cm. Fibrinogen level was 295mg/dL, PT and PTT mixing studies normalized, and FX activity was measured at 0.02U/mL (normal 0.2-0.4U/mL). Bone marrow biopsy showed plasma cell myeloma involving 50% of the marrow. He was started on therapy with cyclophosphamide, bortezomib, and dexamethasone.Unfortunately, the patient had no measurable response after 3 cycles of therapy at which time he presented with severe and progressive hemarthrosis, mucocutaneous bleeding, symptomatic anemia, thrombocytopenia, and elevations in PT/PTT. He received transfusions with fresh frozen plasma (FFP) around the clock, aminocaproic acid, and supportive transfusion of packed RBC and platelets. Due to active mucosal bleeding, the patient was administered vitamin K and transfused FFP every 4 hours. His coagulation parameters did not improve. Interestingly, despite his mixing studies correcting “in vitro,” he failed to demonstrate any “in vivo” correction despite FFP transfusion and three plasmapheresis treatments. Given his refractory bleeding, the surgical service was consulted regarding the prospect of a splenectomy. In an effort to optimize the patient for surgery, he received prothrombin complex concentrate (PCC) without significant improvement (Table 1). Ultimately, the patient underwent splenectomy (estimated blood loss 200cc) and was managed intra-operatively with FFP and aminocaproic acid infusion. His coagulation studies and platelet count improved immediately post-operatively (Table 1), and repeat FX level the following day demonstrated a normal value of 0.48 U/mL. Surgical pathology of the spleen was consistent with extensive deposition of amyloid (lambda subtype). To date, the patient has had a complete normalization of coagulation studies and FX levels and is clinically responding to daratumumab therapy.The incidence of coagulopathy in AL amyloidosis has been estimated to approach one third of all patients, largely due to acquired coagulation factor deficiency, and most commonly FX. Splenomegaly is present in fewer than 15% of patients with AL amyloidosis, however it is much more frequent in patients with acquired FX deficiency. Amyloid deposition in the spleen is thought to bind FX as well as sequesters platelets leading to potentially life threatening bleeding. Our review of the literature identified five previously reported cases of acquired FX deficiency secondary to AL amyloidosis which completely reversed after splenectomy (Kapoor et. al. American Journal of Hematology 2006), but our patient's presentation was particularly severe. Previous reports have also described the improvement of acquired FX deficiency in AL amyloidosis patients with high-dose melphalan (Choufani et. al. Blood 2001), although it is unclear what degree of clinically significant bleeding these patients were experiencing. Splenectomy is frequently reserved as last-line management in these patients, when more conservative measures such as FFP and plasmapheresis are not effective. This is due to the short half-life of the infused FX (Furie et. al. NEJM 1977), as well as its expedited clearance in the spleen, where it is bound to amyloid. While some cases using recombinant Factor VIIa and PCC have worked, they are more often ineffective. In patients with severe bleeding, splenectomy can produce rapid improvement as evidenced here. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Economic burden of major bleeding events in commercially insured patients with von Willebrand disease based on claims data from the United States.

BACKGROUND: von Willebrand disease (VWD) can lead to serious, life-threatening bleeding events associated with substantial clinical and economic burden. OBJECTIVE: To estimate the prevalence, health care resource utilization (HCRU), and costs associated with major bleeding events in patients with VWD. METHODS: This was a retrospective analysis of the IBM MarketScan database (2008-2016). Selected patients had ≥ 2 VWD diagnoses, no diagnosis of acquired coagulation factor deficiency, and continuous health care plan enrollment for ≥ 12 months from eligibility start date. Prevalence was calculated as the proportion of eligible patients with ≥ 1 major bleeding event during the observation period (start to end of continuous eligibility). HCRU and costs in the 12-month continuous enrollment period following the first major bleeding event were compared with those from a comparable 12-month period for patients without major bleeding events. RESULTS: Of the 19,785 patients with VWD, 15% experienced ≥ 1 major bleeding event during a median follow-up of 4 years; 89% of these events were gastrointestinal bleeds. For the economic analysis, 773 patients with ≥ 1 major bleeding event and 4,285 patients without major bleeding events met the selection criteria. Controlling for baseline covariates, patients with major bleeding events had significantly (P < 0.0001) more inpatient admissions (incidence rate ratio [IRR] = 3.2; 95% CI = 2.78-3.77), longer inpatient stays (IRR = 3.9; 95% CI = 3.12-4.93), and more emergency department visits (IRR = 2.0; 95% CI = 1.77-2.27) and outpatient visits (IRR = 1.3; 95% CI = 1.19-1.34) than patients without major bleeding events. Annual health care costs were significantly higher (P < 0.01) for patients with major bleeding events than those without them (predicted mean cost differences: total = $20,890, pharmacy = $2,593, and medical = $18,293). CONCLUSIONS: Major bleeding events were associated with increased HCRU and costs, mostly inpatient costs. Therefore, optimizing therapy to prevent or reduce major bleeding events has the potential to reduce health care use and costs in patients with VWD. DISCLOSURES: This study was funded by Baxalta U.S. Inc., a Takeda company (Lexington, MA). The study sponsor was involved with the study design, analysis, and interpretation of data; writing of the manuscript; and the decision to publish the article. Lu, Wu, and Ewenstein are employees of Baxalta U.S. Inc., a Takeda company, and are Takeda stock owners. Farahbakhshian is an employee of Shire U.S. Inc., a Takeda company, and is a Takeda stock owner. Oladapo was an employee of Baxalta U.S. Inc., a Takeda company, at the time the analysis was completed and the manuscript developed, and is a Takeda stock owner.

Incidence and time course of neutropenia in patients treated with rituximab‐based therapy for non‐malignant immune‐mediated hematologic diseases

Incidence and time course of neutropenia in patients treated with rituximab‐based therapy for non‐malignant immune‐mediated hematologic diseases

Clinical Applications, Pitfalls, and Uncertainties of Thrombin Generation in the Presence of Platelets.

Platelet-dependent thrombin generation is a helpful tool to assess ex vivo the interaction between platelets and plasma coagulation factors in the initiation, amplification, and inhibition of thrombin generation (TG). This review article discusses the most relevant available data on the clinical applications of fluorogenic TG, the most widely used TG assay, performed in the presence of platelets, i.e., in platelet-rich plasma. With respect to prothrombotic states, arterial hypertension and obesity were the most prominent cardiovascular conditions linked to increased platelet-dependent TG. In addition, platelet-associated hypercoagulability, assessed by the TG assay, has been shown in individuals with active cancer. In terms of bleeding, platelet-dependent TG has been applied to assess bleeding risk in individuals with hemophilia, von Willebrand disease, and Glanzmann thrombasthenia as well as in subjects with other congenital or acquired coagulation factor deficiencies. In addition to risk prediction, a role of the TG assay has been suggested in monitoring antiplatelet therapy in prothrombotic conditions and replacement therapy in bleeding diathesis. Finally, for the routine clinical use and as a biomarker of disease development and progression, better standardization and clinical validation of platelet-dependent TG are still needed.

Adherence to Infectious Disease Screening and Immunization Guidelines When Treating Non-Malignant Immune-Mediated Hematologic Disorders

Background : The use of immunosuppressive therapies in the management of non-malignant immune-mediated hematologic disorders (NMIHD) leads to an increased risk of infections. Preventive strategies, such as immunization and infectious disease (ID) screening, reduce the burden of infectious complications. However, lack of compliance to available guidelines among healthcare providers (HCP) represent a major concern. The present study was performed to assess adherence by HCP to national guidelines and recommendations for the prevention of infectious complications in patients (pts) treated for a NMIHD with the goal to identify areas where interventions can be implemented to improve awareness. Methods : We retrospectively analyzed pts diagnosed with AIHA, acquired coagulation factor deficiency (ACFD), TTP, ITP, aHUS, PNH, and antiphospholipid syndrome (APS) between January 2016 and July 2018 at an academic medical center (University of North Carolina). Pts had to have received either rituximab (RTX), eculizumab, or splenectomy. Adherence to existing strategies was assessed based on available recommendations from recognized national entities (e.g. CDC, ACIP), and clinical societies (e.g. ASH) (summarized in Table 1). Immunizations considered for analysis included: pneumococcal, meningococcal and Haemophilus influenzae vaccines ('triple vaccine' if received all together). We considered 'adherence to an immunization recommendation' when, depending on the diagnosis and treatment employed, pts received all recommended vaccines at least 2 weeks prior to therapy or 4 weeks if splenectomy. Adherence to ID screening in pts receiving RTX therapy was defined as pts screened for both hepatitis B surface antigen and total core antibodies. Influenza virus and herpes zoster (HZ) immunization rates were also analyzed. Results : 269 pts from six UNC-affiliated hospitals were included. Pts clinical characteristics are summarized in Table 2. Overall, only 6% of all evaluable pts were appropriately immunized as recommended by national guidelines (5%, 8%, and 8%, for RTX, eculizumab, and splenectomy, respectively) (Table 3). Immunization rates are summarized in Figure 1. In the eculizumab group, although 92% of HCP recommended and prescribed meningococcal immunization, only 38% (n=5/13) received both vaccines (54% either, 8% none). Likewise, although 89% (n=47/53) of pts undergoing splenectomy had received a 'triple vaccine', only 11% of pts received guideline recommended vaccines (both pneumococcal and meningococcal vaccines) and only 8% were appropriately vaccinated by receiving all indicated vaccines at least 4 weeks prior to their scheduled surgery. 68% of pts treated with RTX were appropriately screened for hepatitis B, with lower rates found in young women (screening rate: 77% age &amp;gt;50 vs. 58% ≤50 years, p&amp;lt;0.01; 83% male vs. 58% female, p&amp;lt;0.01) diagnosed with TTP or APS (ITP 74%, AIHA 79%, ACFD 77% vs. TTP 46%, APS 55%, p=0.01). Lastly, 36% of pts received annual influenza virus vaccine, and 11% of eligible pts the HZ vaccine. Conclusion : To the best of our knowledge, there have been no studies conducted in the U.S. assessing adherence to infectious prevention guidelines among different NMIHD. We found that in pts with NMIHD undergoing immunotherapy or splenectomy, many pts received either incomplete recommended immunizations or the immunization was administered too close in proximity to the immunosuppressive therapy or splenectomy, both resulting in impaired immunologic response to vaccines. In addition, only two thirds of pts receiving RTX had pretreatment screening for hepatitis B infection at odds with national recommendations of 100%. Lastly, low immunization rates against influenza virus and HZ were found. Based on these results, we created infographics (supplemental figure), an "easy-to-use" pocket brochure summarizing recommendations (Table 1), and we are building immunization reminders when electronically prescribing immunotherapy, with the aim of improving HCP awareness in our health care system. Although we are unsure about other institution's compliance rate, we suspect that non-compliance to immunization is a systemic problem across the U.S. We will disseminate this data hoping to replicate this study at other academic institutions. There is an urgent need for the development of strategies to improve HCP awareness and adherence to infectious prevention guidelines! Disclosures No relevant conflicts of interest to declare.

Incidence and Time Course of Neutropenia in Patients Treated with Rituximab-Based Therapy for Non-Malignant Immune-Mediated Hematologic Diseases

Background : Rituximab (RTX) is approved for various malignant hematologic and rheumatologic disorders. A noteworthy side effect, late-onset neutropenia, has been reported in patients (pts) treated for hematologic malignancies, often in combination therapies of RTX and chemotherapy with an incidence of 3% to 27%. Conversely, the lack of prospective data and the off-label use of RTX in non-malignant immune-mediated hematologic diseases (NMIHD) limits the availability of evidence on the rate, severity and time course of neutropenia on this patient population, particularly in RTX monotherapy. The present study was performed to determine the frequency, severity, and time course of development and resolution of neutropenia in NMIHD pts treated with RTX, with the goal of providing evidence for clinicians on the safety and potential implications of RTX use in this patient population. Methods : We retrospectively analyzed patients diagnosed with autoimmune hemolytic anemia (AIHA), acquired coagulation factor deficiency (ACFD), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), and antiphospholipid syndrome (APS) between January 2013 and October 2017. Patients with a minimum of 1 laboratory visit every 8 weeks with 1-year of follow-up were included. Date of initial and last RTX infusion, RTX dosing and number of doses, and pre-treatment absolute neutrophil count (ANC) were obtained. ANCs were reviewed from first RTX infusion to at least 12 months from last infusion. For those pts who developed neutropenia, ANC nadir and date when ANC was 1 to 1.5 (mild), 0.5 to &amp;lt;1 (moderate), and &amp;lt;0.5 ˣ 103 cells/µL (severe neutropenia) was recorded. The time to recovery from neutropenia was determined from the time of first neutropenia occurrence to an ANC&amp;gt;1.5. Episodes of febrile neutropenia (FN), hospitalization, infection, and use of granulocyte-colony stimulating factor (GCSF) were also obtained. Kaplan-Meier estimators, and Log-rank Tests were applied to compare between groups. Results : 197 patients (ITP=94, TTP=34, AIHA=34, ACFD=22, APS=13) treated with RTX monotherapy (73%), or in combination with other immunosuppressant were included. Clinical features, treatment characteristics and outcomes are summarized in the table. The median age at diagnosis was 51 years (58% female) with a median ANC prior to RTX initiation of 5.6 ˣ 103 cells/µL. Most pts received RTX at 375 mg/m2 in 4 doses (83%). The 1-year estimated probability of developing neutropenia (ANC&amp;lt;1.5) was 18% (Figure 1). Of those who developed neutropenia, the median ANC nadir and time to neutropenia from initial RTX infusion was 1.2 ˣ 103 cells/µL and 4.4 months, respectively. Development of neutropenia was not statistically different by gender, age, hematologic disease type, or RTX dosing. However, RTX given for ≥ 4 doses (p=0.04), or in combination with other immunosuppressant different than steroids (p&amp;lt;0.01) were significantly associated. Severe neutropenia was frequent in pts receiving RTX in combination with other immunosuppressant (36% versus 2%) with longer time to recovery from first neutropenia occurrence to an ANC&amp;gt;1.5 (2.5 versus 1.1 months) (Figure 2) compared to pts receiving RTX alone or with steroids. No episodes of FN were reported, 3 pts were hospitalized for neutropenia workup, and 2 pts had documented infections (pneumonia and cellulitis) with uncomplicated clinical course. One pt, treated with 6-mercaptopurine, received GCSF. Conclusions : To the best of our knowledge, this is the first study reporting on the incidence, degree and time-course of development of neutropenia in patients treated with RTX for different NMIHD. Our analysis demonstrates an 18% rate of neutropenia at 1 year, mostly mild neutropenia. Conversely, RTX in combination with other immunosuppressant, as opposed to RTX alone or with steroids, represented a significant risk factor for the development of neutropenia, especially severe neutropenia with longer time to ANC recovery. The rate of hospitalizations, infections and the use of GCSF was low, even in severe neutropenia cases. In conclusion, development of neutropenia in pts treated with RTX for NMIHD is an expected but relatively benign side effect. Neutropenia is more frequent if RTX is given with other immunosuppressant other than steroids, and when the number of doses of RTX given are higher. Disclosures No relevant conflicts of interest to declare.

Estimation of the Economic Burden Associated with Major Surgery Due to Von Willebrand Disease Based on Claims Data from the USA

Background: von Willebrand disease (VWD), a rare, inherited bleeding disorder, is associated with impaired hemostasis resulting from a quantitative or qualitative deficit in von Willebrand factor. Limited information exists on the economic burden associated with major surgeries in this patient population, and real-world data may help determine the impact of these procedures. Aims: To estimate the incremental economic burden associated with major surgeries in patients with VWD compared with patients without VWD who had similar types of surgery. Methods: Accessing data from the Truven US health care database (January 2008 to December 2018), we analyzed data from patients with VWD (based on ≥2 diagnoses from different hospital admissions/physician visits, excluding laboratory and radiology orders) and patients without VWD who had undergone a major surgical procedure. The surgical procedure was defined as a medical claim associated with a major therapeutic operating room procedure (International Classification of Diseases, 9th/10th revision codes) or a major procedure (Current Procedural Terminology code). For patients with VWD, the surgical procedure had to have occurred on or after their first VWD diagnosis. Patients without VWD who had undergone major surgeries were selected from a 1% random sample of the Truven database. Patients from both groups (ie, VWD and non-VWD) were included in the study if they had continuous health care plan enrollment ≥12 months prior to (baseline period) and ≥12 months following (study period) their first major surgery, no diagnosis of acquired coagulation factor deficiency, and not undergone surgery used to reduce bleeding associated with VWD (ie, uterine ablation, nasal ablation, or hysterectomy). Patients with VWD were matched (1:1) with patients without VWD using propensity score matching. Health care resource utilization (HCRU: inpatient [IP] admission, emergency room [ER] visits, and outpatient [OP] visits) and associated costs (pharmacy or medical; adjusted to 2018 US dollars [USD] using the medical component of the Consumer Price Index) were measured over the 12-month study period. Adjusted analyses controlling for age, sex, region, health plan, index year, Charlson Comorbidity Index (CCI), comorbidity profile (anemia, anxiety, depression, fatigue, and obesity), and baseline HCRU were conducted using generalized linear regression models. Results: After propensity score matching, 2972 patients with VWD and 2972 patients without VWD who had ≥1 major surgery were selected for analysis (mean [SD] age, 40.53 [20.56] and 40.94 [20.33] years, respectively; female, 73.3% and 73.6%, respectively). Mean (SD) CCI was 0.66 (1.26) and 0.64 (1.30), respectively; and anemia, anxiety, depression, fatigue, and obesity were present in a similar proportion of each group (7−18% of patients with or without VWD). The most common major surgeries were musculoskeletal or digestive in patients with or without VWD (39.6% and 25.0% vs 37.1% and 23.4%, respectively). Patients with VWD were significantly (P&lt;0.0001) more likely to have an IP admission (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.52−1.92) or ER visit (OR, 1.41; 95% CI, 1.25−1.59) than patients without VWD. They also had significantly (P&lt;0.0001) more frequent IP admissions (incidence rate ratio [IRR], 1.47; 95% CI, 1.35−1.60), ER visits (IRR, 1.44; 95% CI, 1.31−1.59), and OP visits (IRR, 1.16; 95% CI, 1.11−1.21) than patients without VWD. Patients with VWD incurred significantly (P&lt;0.0001) higher total health care costs than patients without VWD ($50,733.89 USD vs $30,154.84 USD). The majority of costs were medical: $41,943.22 USD in patients with VWD and $26,233.83 USD in patients without VWD. Conclusions: In this large retrospective analysis of a US commercial health care database, patients with VWD incurred significantly higher HCRU and associated costs following major surgeries compared with patients without VWD who had similar surgeries. Disclosures Oladapo: Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Wu:Shire US Inc., a Takeda company: Employment, Other: a Takeda stockowner. Lu:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Farahbakhshian:Shire US Inc., a Takeda company: Employment, Equity Ownership. Ewenstein:Baxalta US Inc., a Takeda company: Employment, Equity Ownership, Other: a Takeda stock owner.

Immune-mediated acquired coagulation factor deficiencies: state-of-the-art in diagnosis and management

Recently, in Japan, the number of patients with autoimmune acquired coagulation factor deficiency (AiCFD) due to anti-coagulation factor autoantibodies has been on the rise. There are several types of such autoantibodies, which can be generated against any coagulation factor: 1) the neutralizing type binds the functional region (s) of a coagulation factor to inhibit its activity (inhibitor type) ; 2) the non-neutralizing type binds the nonfunctional region (s) of a coagulation factor and enhances its clearance from circulation (hyperclearance type) ; 3) the combination of types 1) and 2). Despite clinical manifestations of AiCFD ranging from asymptomatic laboratory abnormalities to fatal exsanguination or even to thromboembolic events, most patients with AiCFD exhibit certain bleeding symptoms. Owing to the major bleeding symptoms of AiCFD not being specific for any particular disease, laboratory tests are essential for the early diagnosis of AiCFD, selection of proper treatment, and assessment of a therapy's efficacy. Because of severe ongoing hemorrhages and anemia, most patients are administered large amounts of the deficient coagulation factors. Moreover, given the rarity of this disease, there is no standardized therapeutic modality for antibody eradication. Most patients receive corticosteroids as first-line immunosuppressive medicines; however, some patients become treatment-resistant or develop a recurrence despite achieving remission once.

Indications, Efficacy and Complications of Kcentra Use in Reversing Coagulopathy

IntroductionDirect acting oral anticoagulants are rapidly replacing warfarin, the most commonly used anticoagulant for patients with atrial fibrillation, pulmonary embolism (PE) and deep vein thrombosis (DVT). However, there is limited data on the efficacy and adverse effects of the commercial Kcentra used in these patients. Kcentra, the only approved PCC in the USA, is FDA approved for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) therapy in adult patients with acute major bleeding or need for an urgent surgery/invasive procedure. In this study we examine the indications for administration of Kcentra, efficacy of the PCC in several coagulopathies, incidence of adverse events including ischemic stroke and DVT/ PE, and overall mortality.MethodsRetrospective analysis of inpatients at UPMC Presbyterian, Shadyside and Mercy, admitted between February 2016 and 2017 was done. A total of 213 patients, with history of stroke / DVT / PE who received Kcentra were grouped based on the cause of coagulopathy, sites of bleed (CNS or non-CNS) or the clinical setting of Kcentra administration. Definitions of the International Society on Thrombosis and Hemostasis (ISTH) / Scientific and Standardization Committee were used to assess the efficacy of management. Among the patients on Warfarin, only non-CNS and prophylactic administration group were included here as those with CNS bleeding were part of an earlier study. Adverse events measured were incidence of ischemic stroke and DVT/ PE during their hospital stay.ResultsThe 213 patients who received Kcentra included those on warfarin (40%), apixaban (21%), Rivaroxaban (23%), with the remaining 16% including patients with hepatic cirrhosis, disseminated intravascular coagulation and those with coagulopathy related to heparin/ fondaparinux or antiplatelets (ASA, clopidogrel). The study group included those with CNS bleeds (33%), non-CNS bleeds (37%) and those in the prophylactic, pre-operative setting (30%). The majority of the non-CNS bleeds were patients with gastrointestinal bleeding (45%), with the rest including the musculoskeletal (31%) and intra-abdominal / intra-thoracic (16%) bleeding. Mortality was highest in patients with cirrhosis (n = 15), DIC (n = 8), and on anti-platelet medications (n = 2) at 100%, followed by 60% in patients on heparin / fondaparinux (n = 5). The mortality was markedly lower (~13%) in patients on Coumadin, Apixaban and Rivaroxaban. 2 of the patients, previously on rivaroxaban, developed multiple CNS infarcts. Thromboembolic events were significantly higher (40%) in patients with cirrhosis, with moderate effect in the Rivaroxaban group (14.5%) when compared to coumadin (2.3%) and apixaban (0%).ConclusionsKcentra was used in several off-label clinical settings, with comparable mortality among the coumadin, rivaroxaban and apixaban groups and no identifiable benefit in the setting of cirrhosis, DIC or antiplatelet medications, but with an increased incidence of deep vein thrombosis and stroke. DisclosuresNo relevant conflicts of interest to declare.

Subcapsular Hepatic Hematoma Resulting From Hepatic Microaneurysms in a Patient With Systemic Amyloidosis

A 64-year-old woman presented with acute onset of epigastric pain. Her history was significant for extensive amyloid light-chain amyloidosis and known hepatic amyloidosis substantiated by prior liver biopsy. Computed tomography of the abdomen demonstrated a large subcapsular perihepatic hematoma along the posterior margin of the left hepatic lobe measuring 19 × 6 × 13 cm (Figure A, arrow). Hepatic arteriography was performed and demonstrated hepatic microaneurysms involving the left hepatic artery (Figure B, arrows), a rare but recognized complication of systemic amyloidosis. In this case, multiple hepatic microaneurysms involving the left hepatic artery were identified on angiography. Management with left hepatic artery particle embolization resulted in enduring symptomatic resolution and hemodynamic stability. Spontaneous hemorrhage is a well-recognized manifestation of primary (amyloid light-chain) amyloidosis. Impaired platelet function, amyloid angiopathy, hyperfibrinolysis, and acquired coagulation factor deficiencies predispose to hemorrhagic events in patients with this condition. Vascular infiltration by amyloid fibrils serves as the likely basis for aneurysmal formation as supported by biopsy-proven hepatic amyloidosis. This case highlights spontaneous hemorrhage as a possible cause for acute abdominal pain and anemia in the setting of systemic amyloidosis.

Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital.

Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital.

Renal hemorrhage caused by acquired inhibitors to coagulation factors VIII and V in a hemodialysis patient.

Acquired coagulation factor deficiency is a rare bleeding disorder caused by the inhibitors to coagulation factors. We report a case of an elderly hemodialysis patient who presented with the intermittent hematuria and anemia, associated with the prolonged activated partial thromboplastin time and prothrombin time. Laboratory examination revealed undetectable factor VIII activity, decreased factor V activity, and the presence of inhibitors to these coagulation factors. The patient was diagnosed to have inhibitors to coagulation factors VIII and V simultaneously. In addition, hematuria was found to be caused by the right renal hemorrhage. Renal extravasation was treated by transcatheter arterial embolization. Oral prednisolone successfully eradicated the inhibitors. The present case highlights the importance to consider acquired coagulation factor inhibitors for bleeding symptoms, because they are sometimes life-threatening.