Impact of the Hemostasis and Thrombosis Research Society trainee workshop in recruiting the next generation of nonmalignant hematologists.

The United States is facing a shortage of physicians dedicated to nonmalignant hematology to meet future needs. The Hemostasis and Thrombosis Research Society (HTRS) developed a medical education program for trainees, "HTRS Trainee Workshops: Building a Career in Hemostasis and Thrombosis" in 2016. The aim of this study is to evaluate the impact of the workshop in recruiting the next generation of nonmalignant hematologists. Two surveys (post-workshop survey and alumni survey) were conducted. The post-workshop survey occurred within 30 days of each workshop and was completed by 81.9% (n = 185) of participants. Majority of respondents reported that the workshop had a positive impact to their practice and/or research (93.0%, n = 174) and career development (87.7%, n = 164). For the alumni survey which was conducted in 2018, 73 participants responded to the survey (38.2% response rate). Of the 38 respondents who had graduated from fellowship at the time of the survey, almost all chose a career in academic medicine. 41.7% (n = 15) reported their specialty as adult nonmalignant hematology and 25.0% (n = 9) as pediatric hematology/oncology with a nonmalignant hematology focus. 41.1% (n = 30) developed collaborative professional relationships, and 78.1% (n = 57) reported that the workshop had a positive influence in their choice to pursue nonmalignant hematology as a career. 67.1% (n = 49) were actively involved in research in nonmalignant hematology, with the most common being clinical research. This survey suggests that the HTRS Trainee Workshop is meeting its goals to recruit, train, and mentor the next generation of nonmalignant hematologists.

Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: A rapid and practical approach.

OBJECTIVES: Acute hypertriglyceridemia induced pancreatitis (HTP) presents with a more severe clinical course compared to other etiologies of pancreatitis. Therapeutic plasma exchange (TPE) is a potential treatment option for lowering plasma triglycerides and possibly decreasing morbidity and mortality. However, clinical data regarding its effectiveness are limited. METHODS: We retrospectively examined the clinical data and outcomes of 13 consecutive episodes of HTP in which TPE was employed to reduce plasma triglycerides during a 15-month period. RESULTS: The TPE was initiated at a median of 19 hours from the time of presentation. We performed 1.2-1.5 volume TPEs with 5% albumin as the replacement fluid. After only one TPE procedure, the mean plasma triglycerides values decreased from 2993 mg/dl to 487 mg/dl with a reduction of 84%. All 13 patients survived with a mean length of hospital stay of 9.5 days. There were no complications related to TPE. CONCLUSIONS: One TPE procedure is an effective method for reducing plasma triglycerides and possibly decreases the length of hospital stay in patients admitted with HTP.

The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question.

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays.

Background: To overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited. Objectives: To validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay. Methods: Clinical sites enrolled healthy subjects and patients representing the intended use population; VWF activity assays were performed, and results were analyzed. The performance of the INNOVANCE VWF Ac assay was also compared between the BCS XP System and the CS-2500 and CS-5100 analyzers. Results: The INNOVANCE VWF Ac assay correlated well with the VWF:RCo assay and the automated HemosIL VWF:Ab assay, with Pearson coefficients of >.9 and a predicted bias of ≤5.0 IU/dL at VWF levels of 30 IU/dL and ≤5.8 IU/dL at the levels of 50 IU/dL, but correlation and bias were not as good when compared with the REAADS manual VWF:Ab assay. Reference ranges observed for healthy subjects correlated well with previously published findings. Reproducibility of the INNOVANCE VWF Ac assay on the BCS XP System and the CS analyzers was excellent, as was correlation among devices. Conclusion: The characteristics of the INNOVANCE VWF Ac assay regarding comparability with other VWF activity assays, reference ranges, and precision support the use of this assay for evaluation of patients with concern for von Willebrand disease.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Blood component support in acquired coagulopathic conditions: is there a method to the madness?

Acquired coagulopathies are often detected by laboratory investigation in clinical practice. There is a poor correlation between mild to moderate abnormalities of laboratory test and bleeding tendency. Patients who are bleeding due to coagulopathy are often managed with various blood components including plasma, platelets, and cryoprecipitate. However, prophylactic transfusion of these products in a nonbleeding patient to correct mild to moderate abnormality of a coagulation test especially preprocedure is not evidence-based. This article reviews the management of bleeding due to oral anticoagulants and antiplatelet agents, disseminated intravascular coagulation, chronic liver disease, and trauma.

Calculated blood loss in severe obstetric hemorrhage and its relation to body mass index.

OBJECTIVE: To evaluate total calculated blood loss at the time of severe obstetric hemorrhage. STUDY DESIGN: This is a prospective observational study of women with obstetric hemorrhage. Women who received a blood transfusion for hypovolemia and those in which a body mass index (BMI) could be calculated were included. Total blood volume lost was calculated. Blood loss was analyzed in relation to maternal size as reflected in the BMI. RESULTS: Fourteen hundred forty-three women meeting inclusion criteria delivered at our hospital between March 2002 and June 2006. The median calculated volume of blood lost was 3529 mL, and 93% of women sustained losses ≥3000 mL. The blood loss sufficient to provoke signs and symptoms of hypovolemia was proportional to the woman's BMI. CONCLUSION: Women who develop hypovolemia during childbirth have suffered very large losses of blood, and infusion of blood products is required to restore circulation and prevent further morbidity.

Prospective monitoring of plasma and platelet transfusions in a large teaching hospital results in significant cost reduction.

BACKGROUND: Plasma and platelets (PLTs) are often transfused to correct mild to moderately abnormal laboratory values. Our objective was to reduce unnecessary plasma and PLT transfusions to nonbleeding patients by prospective triage and education of end users in evidence-based hemostasis and transfusion medicine practices. STUDY DESIGN AND METHODS: Using the Parkland Memorial Hospital's transfusion service and admission database as the data source, this study comprises the comparison of transfusion data on plasma and PLT use between pre- (2000-2002) and posttriage (2003-2006) periods. Yearly transfusion and wastage data on red blood cells (RBCs), plasma, and PLTs and yearly hospital admissions, trauma visits, and surgical procedures were extracted retrospectively for the study. RESULTS: The study revealed that implementation of triage resulted in a significant reduction of plasma (60%) and PLT (25%) transfusions, saving more than $3,000,000 over 4 years. CONCLUSIONS: Prospective triage and evidence-based transfusion practice education reduced unnecessary plasma and PLT transfusions and health care costs.

Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis.

The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. Beginning with the 2007 ASFA Special Issue (fourth edition), the subcommittee has incorporated systematic review and evidence-based approach in the grading and categorization of indications. This Fifth ASFA Special Issue has further improved the process of using evidence-based medicine in the recommendations by refining the category definitions and by adding a grade of recommendation based on widely accepted GRADE system. The concept of a fact sheet was introduced in the Fourth edition and is only slightly modified in this current edition. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. The article consists of 59 fact sheets devoted to each disease entity currently categorized by the ASFA as category I through III. Category IV indications are also listed.

Whole blood in the management of hypovolemia due to obstetric hemorrhage.

OBJECTIVE: To study the use of blood products including whole blood, for the management of obstetric hemorrhage requiring transfusion. METHODS: This was a population-based, observational study of all women receiving blood for hypovolemia because of hemorrhage at the Parkland obstetrics service between March 24, 2002, and June 12, 2006. Hypovolemia was diagnosed in women who sustained hemorrhages sufficient enough to provoke hemodynamic instability. RESULTS: A total of 66,369 women gave birth during the study period, and 1,540 (2.3%) received a blood transfusion. Six hundred fifty-nine (43%) received only whole blood, 593 (39%) received only packed red blood cells, and 288 (19%) received combinations of blood products, including thawed plasma, platelets, and cryoprecipitate. The number of units transfused was similar in the whole blood and packed red blood cell groups (mean 2 units) and higher in the combination group (mean 5.5 units). Complications attributable to hypovolemia were similar in frequency in the whole blood and packed red blood cells groups, including intensive care unit admission (1%), hypofibrinogenemia (0.3%), and adult respiratory syndrome (0.5% compared with .3%). Acute tubular necrosis was more common in the packed red blood cell group (2% compared with 0.3%, P<.001). All of these outcomes were increased in the combination transfusion group. There were three maternal deaths in the cohort, two in the combination group and one in the packed red blood cells group. CONCLUSION: The risk of acute tubular necrosis is significantly reduced in women receiving whole blood transfusion for hypovolemia due to obstetric hemorrhage. LEVEL OF EVIDENCE: III.

Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose.

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States. STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison. RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001). CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.

Warfarin does not interfere with lupus anticoagulant detection by dilute Russell's viper venom time.

BACKGROUND: The dilute Russell's viper venom time (DRVVT) test is part of the diagnostic armamentarium used to detect lupus anticoagulant (LA). When testing patients on warfarin therapy, there is some concern of false positive results due to their low Factor X levels. We studied the diagnostic performance of the DRVVT ratio (DRVVT-R) to confirm the presence of LA in thrombophilia patients receiving warfarin therapy, and compared those results with a control group receiving warfarin for cardiac conditions but without thrombosis. METHODS: The DRVVT (screen, confirm, and ratio), Factors II and X assays, and PT/INR were performed in patients receiving warfarin for thrombosis and in patients with cardiac conditions but no thrombosis (control group). RESULTS: Patients on warfarin in the thrombosis group (n=22) were positive for LA by DRVVT-R (ratio >1.27 was considered positive) whereas none of the patients in the control group (n=13) were positive for LA. The median DRVVT-R was significantly higher in the thrombosis group (1.60, range 1.29-1.92) as compared to controls (1.13, range 0.79-1.23, p<0.001) even though the INRs were comparable (median 2.3 for thrombosis group versus median of 2.2 for controls, p<0.05). Similarly, FX and FII levels were not significantly different in these two groups. CONCLUSIONS: We conclude that the use of the DRVVT-R allows for diagnosis of LA in patients receiving warfarin with therapeutic INR despite their decreased Factor X levels.

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy.

Thrombocytopenia with or without microangiopathy following quinine is often referred to as quinine "hypersensitivity." When schistocytes are present it is frequently termed "quinine-associated TTP/HUS." A severe deficiency of the vWF-cleaving protease, ADAMTS13, is associated with idiopathic TTP. A previous study of patients with "quinine-associated TTP/HUS" found that ADAMTS13 activities were not abnormal in 12/12 patients. A retrospective review of TTP patients with quinine-associated thrombotic microangiopathy (TMA) for whom ADAMTS13 was measured before plasma exchange was performed. Six patients were identified. All were females (age range: 43 to 73, mean = 61.7 years) and had taken quinine for leg cramps. Four of the six experienced renal failure requiring dialysis. Five of the patients had D-Dimers levels measured, all were elevated. In four patients the levels were > or = 18 times the upper limit of normal. ADAMTS13 was normal in four patients and mildly decreased in two patients. We conclude that while thrombocytopenia and schistocytosis can be seen in quinine-associated TTP/HUS, the pathophysiology seems to be distinct from that seen in most cases of idiopathic TTP (i.e., severely decreased ADAMTS13 with an inhibitor). We recommend that a TMA in association with quinine be consistently referred to as quinine-associated thrombotic microangiopathy (quinine-TMA) to better distinguish this entity from idiopathic TTP. The use of plasma exchange in quinine-TMA is called into question.

Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia.

OBJECTIVES: To correlate optical density and percent inhibition of a two-step heparin-induced thrombocytopenia (HIT) antigen assay with thrombosis; the assay utilizes reaction inhibition characteristics of a high heparin concentration. PATIENTS AND METHODS: Patients with more than 50% decrease in platelet count or thrombocytopenia (<150 x 10(9)/L) after exposure to heparin, who had a positive two-step antigen assay [optical density (OD) >0.4 and >50 inhibition with high concentration of heparin] were included in the study. RESULTS: Forty of 94 HIT patients had thrombosis at diagnosis; 54/94 had isolated-HIT without thrombosis. Eight of the isolated-HIT patients developed thrombosis within the next 30 d; thus, a total of 48 patients had thrombosis at day 30. At diagnosis there was no significant difference in OD between HIT patients with thrombosis and those with isolated-HIT. However, OD was significantly higher in all patients with thrombosis (n = 48, 1.34 +/- 0.89), including isolated-HIT patients who later developed thrombosis within 30 d (n = 8, 1.84 +/- 0.64) as compared to isolated-HIT patients who did not develop thrombosis (0.96 +/- 0.75; P = 0.011 and P = 0.008). The Receiver Operative Characteristic Curve showed that OD >1.27 in the isolated-HIT group had a significantly higher chance of developing thrombosis by day 30. None of these groups showed significant difference in percent inhibition. Multivariate analysis showed a 2.8-fold increased risk of thrombosis in females. Similarly, thrombotic risk increased with age and OD values. CONCLUSION: Higher OD is associated with significant risk of subsequent thrombosis in patients with isolated-HIT; percent inhibition, however, was not predictive.

Urgent cardiac surgery in a patient with a remote history of heparin-induced thrombocytopenia: use of the anti-PF4/heparin ELISA confirmatory test.

The use of established heparin protocols when heparin-induced thrombocytopenia (HIT) antibodies are negative is currently recommended for the management of patients with previous HIT who require cardiac surgery. Routine preoperative testing for HIT antibodies using an anti-PF4/heparin enzyme-linked immunosorbent assay (ELISA) introduces the problem of detecting nonpathogenic HIT antibodies, which can lead to a false diagnosis of the presence of platelet-activating antibodies. Our case report demonstrates the clinical utility of a newer confirmatory procedure performed using high dose heparin. We use this procedure in situations in which pretest probability is low (remote HIT) and the anti-PF4/heparin ELISA test results are weak to moderately positive (absorbance 0.4-1.0).

Recent advances in understanding and management of acquired thrombocytopenia.

There are numerous congenital and acquired causes of thrombocytopenia. Thrombocytopenia could be a result of decreased bone marrow production, increased consumption, increased destruction, splenic sequestration or a combination of these causes. In this review, we have focused on some of the serious acquired causes of thrombocytopenia. There have been some significant advances in our understanding of the pathophysiology, diagnostic testing, and treatment of immune thrombocytopenia, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome over the past five years. These advances have resulted in a significant decrease in mortality and morbidity of patients with these disorders. Despite these advances, we are still faced with numerous unanswered questions in the pathophysiology and management of these complex thrombocytopenic disorders.

Laboratory evaluation of platelet function.

Platelets play a central role in hemostasis. Consequently, they lie at the heart of many inherited and acquired bleeding disorders and thrombotic events. The diagnosis of these disorders and monitoring of antiplatelet therapy require a thorough understanding of tests that measure platelet quantity and function. This article outlines basic concepts of platelet physiology and describes the tests that are commonly used in the clinical assessment of platelet function.