ALBERT

Description: Introduction: Chronic liver disease (CLD) results in thrombocytopenia [1]. Depression of thrombopoietin (TPO) levels in CLD leads to thrombocytopenia. Thrombocytopenia increases the risk of bleeding in patients undergoing invasive diagnostic or therapeutic procedures [2]. TPO agonists have been depicted to be safe and efficacious in the treatment of thrombocytopenia due to idiopathic immune thrombocytopenia and aplastic anemia. Several studies have evaluated the use of TPO agonist versus placebo for pre-procedural treatment of thrombocytopenic patients with chronic liver disease. These studies were of limited sample sizes. We conducted a meta-analysis to determine if TPO agonists reduce the need of platelet transfusions before procedures in chronic liver disease patients. Methods: We performed a computerized search of Medline, Cochrane and Google Scholar databases through March 2019 for studies evaluating the efficacy of thrombopoietin (TPO) agonists versus placebo in the treatment of thrombocytopenia of chronic liver disease patients undergoing procedures. We screened 295 studies and only 5 of them met our inclusion and exclusion criteria. Inclusion criteria were studies with adults 〉18 years old, English literature, randomized controlled trials utilizing a TPO agonists in chronic liver disease patients. Exclusion criteria were studies with patients

Description: CASE REPORT: A 59-year-old white female with history of easy bruising for 2 years and 2 episode of RH in the last 6 month admitted to ICU with her 3rd episode of RH. Her previous w/o included a BM Bx which had shown clonal population of plasma cells kappa chain restrictive (7%) with repeatedly negative SPEP and UPEP. PFA-100 was consistent with severe platelet dysfunction. During the ICU admission platelet transfusion with multiple single donor units did not correct her PFA-100 results, which were confirmed with platelet aggregation results. Both, collagen/epinephrine and collagen/ADP closure times were prolonged (〉300 and 128 seconds respectively). The patient however did not receive any medications to explain this apparently intrinsic dysfunction. Coagulation studies including PT, aPTT and factor II, VII, VIII, IX all were within normal limit. Factor X levels were slightly decreased (45%). Patient had selective embolization of the fourth lobar artery of the right kidney. Plasma cells in the marrow showed monoclonal expression for cytoplasmic kappa light chains by both IHC and in situ hybridization. Amorphous pink material was present in the walls of blood vessels. Plasma cells stained positively with CD138. The amyloid material stained positively with Congo red and demonstrated apple green birefringence under polarized light. Skeletal survey demonstrated multiple lytic lesions. Serum free light chain measurement showed high levels of M protein (κ) with κ to λ ration of 4.30. Patient was started on treatment with pulse dose steroid and bortezomib. DISCUSSION: Amyloidosis can cause hemorrhage with multiple mechanisms including amyloid deposition (amyloid angiopathy), platelet dysfunction, coagulation factor deficiencies, abnormal fibrin polymerization and hyperfibrinolysis. Consumption of factor X by amyloid is often called a culprit for hemorrhage in amyloidosis. The slightly decreased level of factor X in this case provided a valuable clue for diagnosis, but was not likely a cause of bleeding in this patient. Amyloid induced platelet dysfunction along with amyloid angiopathy lead to life threatening hemorrhage in our patient. The mechanism of this platelet dysfunction, which also affected the transfused platelets, is not well explained. This effect on platelets complicates the clinical management. The case also illustrates the value of the free light chain assay, which is more sensitive than SPEP and UPEP. These commonly used tests to diagnose plasma cell dyscrasias are reportedly false negative in 3% of cases. CONCLUSION: Plasma cell dyscrasia has a wide variety of presentation and should be considered as a part of bleeding work up in complex cases.

Description: Introduction Venous thromboembolism (VTE), is the second leading cause of death in patients with cancer. The risk of VTE in patients with cancer is 4 to 7-fold, when compared to the general population. Even during anticoagulant treatment, the cumulative incidence of recurrent VTE is 3.5 times higher in patients with cancer than in cancer-free patients. Low-molecular-weight heparin has been the "gold standard" for the of treatment for VTE in cancer associated thrombosis, following the landmark trial by Lee et al. Methods We conducted a meta-analysis to evaluate the safety and efficacy of direct oral anticoagulants in patients with cancer. We systematically searched Medline for randomized-control clinical trials and post-hoc analyses. For each study, data on recurrent VTE, major or clinically relevant non-major bleeding (CRNMB), and major bleeding (MB) were extracted. We included randomized control trials (RCT's) where interventions consisted of direct oral anticoagulants (DOA) versus vitamin K antagonists (VKA) or low molecular weight heparins (LMWH), in which all or a part of the study population had active cancer. We excluded studies that were not comparing DOA versus VKA/LMWH or did not have a subset of active cancer patients. Results Seven studies met our eligibility criteria. Data for recurrent VTE was extractable from all 7 RCT's. There were 2178 enrolled participants total. The pooled results show evidence for a lower incidence of recurrent VTE with the use of DOA versus VKA/LMWH. The pooled risk ratio for recurrent VTE was 0.68 (95% confidence interval 0.50 to 0.93; P = 0.01). There was negligible heterogeneity among the trials (I2 = 0%; P = 0.99). Data for major bleeds was extractable from 6 RCT's, including 1952 enrolled participants total. The pooled results show no evidence for a difference in frequency of major bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 1 (95% CI 0.53 to 1.87; P= 0.99). There was moderate heterogeneity among trials (I2 = 40%; P = 0.17) Data for clinically relevant bleeding was extractable from 6 RCT's, including 1952 enrolled participants total. The pooled results show no evidence for a difference in frequency of nonmajor but clinically relevant bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 1.06 (95% CI 0.80 to 1.42; P= 0.68). There was negligible heterogeneity among trials (I2 = 27%; P = 0.24). Data for all bleeds (major or nonmajor) was extractable from all 7 RCT's. There were 2178 enrolled participants total. The pooled results show no evidence for a difference in frequency of bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 0.95 (95% CI 0.68 to 1.32; P= 0.74). There was substantial heterogeneity among trials (I2 = 65%; P = 0.02). Conclusions Our results suggest that DOACs might reduce the incidence of VTE recurrence in patients with cancer without putting them at high risk for major bleeds or clinically relevant nonmajor bleeds. Table. Table. Disclosures No relevant conflicts of interest to declare.

Description: Background: Although thousands of patients (Pts) receive chemotherapy every year in the United States, only few retrospective studies have been done to address the risk factors for chemotherapy (CT) induced neutropenia in patients with cancer. The data in androgen-independent prostate cancer (AIPC) patients is extremely scarce. We decided to perform a retrospective analysis of patients with metastatic AIPC treated with chemotherapy in an open phase II clinical trial looking for predictive factors for neutropenia. Methods: We reviewed the records of all patients with AIPC who completed at least 2 cycles of CT with cyclophosphamide 50 mg/m2, etoposide 50 mg/m2 and estramustine 280 mg orally every night for 14 days out of a 28 day-cycle. We divided the patients into 2 groups according to neutropenia grade 3–4 (Group 1) versus 0–2 (Group 2). Risk factors reviewed included age, number of organs involved with metastases, number of bone metastasis, prior radiotherapy (RT) to the prostate/pelvis, prior number of areas treated with palliative RT, prior CT regimens, baseline PSA, absolute neutrophil count (ANC) and ECOG performance status (PS). Results: See table and figures. Group 1 2 Neutropenia Grade 3–4 0–2 # of Pts 7 11 Age 68 (58–86) 63 (52–74) # organs involved 2.1 1.6 # bone metastases 10.9 9.5 RT prostate/pelvis 0.1 0.4 # palliative RT courses 1 0.6 # prior CT regimens 0.4 0.2 Baseline ANC 3.6 3.8 Baseline PS ECOG 1.3 1.4 Baseline PSA 584 (26–2268) 157 (37–65) Figure Figure Conclusions: Average age and PSA were the only risk factors that were different between the patients who developed severe neutropenia and the ones who did not, albeit not statistically significant. Studies with a larger sample size may detect clinically and statistically significant differences.

Description: Interstitial lung disease (ILD) secondary to monoclonal antibodies and tyrosine-kinase inhibitors have been reported. However, little is known about rituximab induced ILD. We report two cases of R-ILD. CASE 1: A 63 year-old man with DLBCL presented for cycle 6 of R-CHOP complaining of 10 days of dyspnea and fever. Prior to initiation of therapy, he had a normal lung exam along with computerized tomography (CT) of the chest. After three cycles of R-CHOP, repeat CT scans of the chest revealed a favorable response to treatment and continued disease-free lung fields. He had tachypnea, tachycardia, and a normal lung examination. Pulse oximetry on room air was 76%. A helical CT of the chest demonstrated diffuse bilateral pneumonitis with no evidence of pulmonary embolus. Bronchoscopy with bronchoalveolar lavage and biopsy revealed no infection. Biopsy showed evidence of alveolar damage and interstitial fibrosis. He responded to corticosteroids and was discharged home with supplemental oxygen. Two months later, he did not require supplemental oxygen. A CT scan of the chest showed almost complete resolution of his interstitial disease. Pulmonary function tests revealed a mild restrictive pattern with a severe diffusion defect. CASE 2: A 61 year-old man with DLBCL presented with 3 days of dyspnea, fever and cough. He was on cycle five, day 14 of R-CHOP. Prior to starting therapy, lung examination was normal and a CT of the chest showed no lung abnormalities. He had tachypnea, tachycardia, and inspiratory crackles on lung examination. Arterial blood gas revealed a pO2 of 45 mmHg. He was admitted to the hospital and started on broad spectrum antibiotics and corticosteroids. A helical CT of the chest revealed a diffuse interstitial lung pattern bilaterally consistent with interstitial pneumonitis and no pulmonary embolus. A bronchoscopy with bronchoalveolar lavage showed no infection. A lung biopsy could not be performed because of severe hypoxia. The patient required mechanical ventilation. After one week of intensive treatment the patient expired. DISCUSSION: Respiratory complications of rituximab include increased cough, rhinitis, brochospasm, dyspnea, and sinusitis. However, R-ILD is very rare. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include a direct injury to the lung tissues, unlikely, as well as the induction of cytotoxic substances. Rituximab acts by binding CD20+ B cells. Toxicity and efficacy are related to events after binding which include B cell signaling, complement activation, direct apoptosis, and antibody dependent cellular cytotoxicity. Complement activation and cytokine secretion, in particular, seems to be the causative factors in side effects associated with infusion reactions. Because of the increasing use of rituximab for a variety of disorders, it is important to recognize and appropriately treat possible fatal toxicities. Our patients presented with dyspnea and fever. In the absence of an infectious etiology further evaluation with a high-resolution CT scan of the chest or bronchoscopy with BAL and biopsy should be pursued. If evaluation suggests an ILD without clear evidence of infection, corticosteroids should be initiated and further treatment with rituximab discontinued. CONCLUSION: With the increasing use of rituximab and other monoclonal antibodies, clinicians must be aware of this rare but potentially fatal complication.

Description: Introduction: Development of an acquired inhibitor to factor VIII (acquired hemophilia) is a rare autoimmune phenomenon that has been associated with a variety of medical conditions such as autoimmune diseases, malignancies, drugs like penicillin and postpartum state. It often presents with acute, life-threatening hemorrhage. Interferon alpha (IFN) is an immune system modulator that is widely used for the treatment of hepatitis C and various malignancies. It is known to stimulate or exacerbate autoimmune diseases and has been described in four separate reports to be associated with the development of inhibitors to factor VIII. All but one of these four cases represented patients with underlying malignancy or congenital hemophilia A. Case Report: Our patient is a 55-year old non-hemophiliac with no prior diagnosis of cancer who developed new-onset bruising while on IFN therapy for hepatitis C. This was not evaluated or treated further at that time. Six months after completing IFN therapy, he presented to the emergency room with respiratory distress. On examination, he was found to have a large supraglottic hematoma and underwent an urgent tracheostomy for impending respiratory failure. This was followed by severe postoperative bleeding which the otolaryngologists were unable to control surgically. Laboratory testing showed a prolonged activated prothrombin time and infusion of fresh frozen plasma failed to achieve hemostasis. A hematology consultation was obtained and the patient was treated with activated recombinant factor VII (rVIIa) which resulted in prompt cessation of bleeding. Existence of factor VIII inhibitor was confirmed by abnormal mixing studies (no correction), low factor VIII activity (2.1%) and high inhibitor titer (42 Bethesda Units/ml [BU]). Following hospital discharge, inhibitor titers slowly declined to less than 1 BU after immunosuppressive therapy with steroids, alkylating agents and rituximab given sequentially over a period of nine months. The factor VIII activity has also increased to 15%. The patient has since had occasional mild to moderate soft tissue bleeding which responded well to rVIIa. Conclusion: One previous report has described a patient without a history of hemophilia or cancer who developed factor VIII inhibitor while being treated with pegylated IFN for hepatitis C. Our patient represents only the second such report and adds to the slowly growing body of literature pointing to this association. Although this data is anecdotal, we believe that the potential for such inhibitors to produce serious and even life threatening hemorrhage warrants awareness of and attention to this possibility by clinicians treating patients with IFN. Simple clinical vigilance along these lines may help identify and address this condition in a timely fashion before it has a chance to produce catastrophic bleeding.

Description: The incidence of heparin-induced thrombocytopenia (HIT) with the use of heparin (H) might be higher in cardiac patient than other populations. Sometimes, these patients require surgery with the use of extracorporeal circulation (heart-lung machine or oxygenator). Anticoagulation during this surgery is essential, and almost always done with heparin. Knowledge in this setting about alternative anticoagulants, bleeding complications, monitoring problems, and drug elimination is limited. Here, we describe our experience with the direct thrombin inhibitor argatroban for anticoagulation during cardiac surgery. CASE REPORT: A 48-year-old male presented with weakness. He was found to have new onset atrial fibrillation with rapid ventricular rate and congestive heart failure. Echocardiography and blood cultures revealed staphylococcus endocarditis affecting the mitral valve and he received antibiotics. The patient started heparin on admission, and developed thrombocytopenia six days later. HIT antibody was positive, heparin was stopped and argatroban was initiated. Platelet count normalized. After two weeks, he required the insertion of an intra-aortic balloon pump and mitral valve replacement for severe mitral regurgitation. On the day of surgery, a baseline celite activated clotting time (ACT) was 253 seconds (s). A loading dose of argatroban was given (10 mcg/kg) followed by continuous infusion of 3.0–6.0 mcg/kg/min. The ACT ranged from 423–755 s during the surgery. The patient received platelets and plasma products for adequate hemostasis of the surgical site, but had increase bleeding during the first post-operative day. Argatroban was held for 36 hours after surgery. During this period, his activated partial thromboplastin time (aPTT) ranged between 25.4 – 33.8 s. After that, argatroban was re-started and the aPTT kept between 48–55 s. On post-operative day (POD) 3, doppler studies revealed a venous thrombus in the right upper extremity. On POD 6 the patient started warfarin and continued to have a full recovery. DISCUSSION: This case exemplifies the successful use of argatroban for anticoagulation during emergent cardiac surgery where heparin was contraindicated. The ACT monitoring was adequate and there were no unexpected complications. However, our patient suffered a venous thrombosis in the early post-operative period. In addition to the surgical complications, patients with HIT are at high risk for developing both venous and arterial thrombosis. Our case highlights the need for early anticoagulation with argatroban following surgery. We speculate that the delay in starting argatroban after surgery might have predisposed the patient to have a deep vein thrombosis. Yet, it is difficult to determine when to start anticoagulation in a highly thrombophilic patient who has significant post-operative bleed. CONCLUSION: Argatroban, with ACT monitoring, can be safely used for emergent cardiac surgery in patients with HIT. The timing of post-operative anticoagulation may pose a challenge for the clinician.

Description: Introduction: Iron deficiency anemia is one of the most commonly encountered hematologic medical conditions in general practice. Oral replacement of iron can be a slow and suboptimal process, limited by low absorption rates and disease-enhanced malabsorption. When clinicians are faced with patients with large iron deficits, intravenous (IV) iron is the best option. Currently there are four IV preparations available; iron sucrose, iron gluconate, low-molecular weight iron dextran and high-molecular weight iron dextran. Upon informal questioning, we found reluctancy by many physicians to use iron dextran due to fear of allergic reactions. We examine these four preparations for clinical utility, adverse drug events (ADEs), and cost-effectiveness. Methods: We performed a systematic review and retrospective meta-analysis of studies investigating various forms of intravenous iron preparations for toxicity, ADEs, and costs. Also, we obtained actual costs of infusing intravenous iron at four hospitals in metro Louisville, KY. Results: Fourteen studies met the criteria and were reviewed. One study compared all four iron preparations, two compared three preparations and the rest compared two. Eight had a small sample size. The number of ADEs were quite small. Data from FDAderived ADE reporting of the four IV iron preparations from 2001–2003 showed a total of 1141 per 30,063,800 doses administered, yielding an ADE rate of approximately 38 per million. Absolute rate of all ADEs for iron sucrose, iron gluconate, low molecular weight iron dextran and high molecular weight iron dextran were 19.2, 18.5, 36.9, and 117.8 per million, respectively. Absolute rates of life-threatening ADEs were significantly lower at 0.6, 0.9, 3.3, and 11.3 per million respectively for iron sucrose, iron gluconate, low molecular weight iron dextran, and high molecular weight iron dextran. Based on cost differences between iron sucrose and dextran preparations, the cost to prevent one lifethreatening ADE related to the use of lower molecular weigh iron dextran was estimated to be $5.0–7.8 million. Also the cost to prevent one low-molecular weight iron dextran related death was estimated to be $33 million. These calculations are based on cost of preparations only. Estimates based on hospital-related costs incurred due to multiple infusions vs total dose infusion (TDI) puts the estimate of cost to prevent one lower molecular weight related death over $150 million. Conclusions: The perceived rate of ADEs related to infusion of IV iron preparations in medical practice has been overstated. Smaller studies with lower patient and total infusion numbers, and anecdotal evidence, tended to overestimate the frequency of life-threatening reactions. The incidence of ADEs and serious life-threatening ADEs, is exceedingly low for all IV iron preparations. In light of costs associated with the use of iron sucrose and iron gluconate vs iron dextran, we recommend that all clinicians re-assess the clinical utility of low molecular weight iron dextran for iron deficiency anemia necessitating parenteral iron replacement. Moreover, large doses of iron dextran can be safely given, thereby reducing costs associated with multiple small infusions of iron sucrose.

Description: Multiple myeloma is the most common hematological malignancy. MM can affect many organ systems; therefore, it may mimic different clinical syndromes at presentation. We report an extremely rare presentation of MM. CASE REPORT: A 62-year-old man presented with progressive cervical pain for 2 months and double vision for 2 weeks. Physical exam demonstrated a cranial nerve 6 palsy, nuchal rigidity and no other abnormalities. A magnetic resonance image (MRI) of the brain revealed a 5 cm enhancing mass in the clivus which extended into the brain stem, left internal auditory and carotid canal, nasopharynx, sphenoid and cavernous sinuses, without midline shift or hydrocephalus. MRI of the spine showed 2 small enhancing lesions in thoracic vertebrae 4 and 11. Computer tomography of the chest abdomen and pelvis demonstrated a lesion in the sternum and no other abnormalities. Technetium-99 bone scan showed uptake in the skull base mass only. Complete blood count and metabolic profile were normal except for an albumin of 3.2 g/dL. Serum protein electrophoresis with immunofixation revealed hypogammaglobulinemia without a monoclonal protein. 24 hour urine collection demonstrated monoclonal free kappa light chains. Transsphenoidal stereotactic biopsy of the mass showed an atypical plasma cell proliferation with multi-nucleation and mitotic activity, positive for kappa light chain. Bone marrow aspirate revealed 17% of the nucleated cell to be abnormal plasma cells, some with plasmablastic morphology. He improved rapidly with dexamethasone and was referred for radiotherapy. DISCUSSION: The most common neurologic complications of MM are spinal cord compression due to epidural plasmacytomas or vertebral fractures, and peripheral polyneuropathy due to the presence of antibodies directed against myelin structures or due to amyloid deposits. Brain involvement in MM is uncommon. Furthermore, neurologic symptoms due to plasmacytomas located either in the clivus and brain stem are extremely rare. A MEDLINE search from 1950 until July 2005 revealed only 9 cases of MM or plasmacytoma involving the brain stem. Since there is no published autopsy series on MM patients describing the percentage of patients with brain involvement at death, the denominator is difficult to assess. Clinically, extramedullary involvement from MM bears a poor prognosis, and has been described in cases of plasma cell leukemia. We speculate that the aggressive behavior of the MM in our patient might be consistent with the atypical phenotype of the plasma cells. CONCLUSION: The unusual presentation of this patient adds to the medical knowledge about the clinical spectrum of multiple myeloma.