Plasma exchange-A useful adjunct therapy to red cell exchange in patients with sickle cell disease and multiorgan dysfunction.

BACKGROUND: Urgent red cell exchange (RBCx) is indicated for many complications of sickle cell disease (SCD), including acute chest syndrome, stroke, and hepatic/splenic sequestration. Many who receive RBCx remain hospitalized and develop further complications, including multiple organ dysfunction syndrome (MODS), a leading cause of death in intensive care units. Therapeutic plasma exchange (TPE) has been advocated as an effective treatment of MODS, but its role in SCD compared with RBCx alone is not well studied. METHODS: We identified all ICU encounters from 2013 to 2019 involving RBCx procedures for MODS or SCD crisis that progressed to MODS, a total of 12 encounters. Data regarding hospital length of stay (LOS), survival, number of TPE procedures following RBCx, and procedure characteristics were collected. Surrogate laboratory markers of end-organ damage and disease severity scores were recorded at the time of admission, post-RBCx, post-TPE, and at discharge. RESULTS: Eight encounters involved RBCx followed by TPE (TPE group) while four involved RBCx alone (RBCx group). The TPE group had a higher SOFA score at ICU admission (9.5 vs. 7.0), greater predicted mortality, and a statistical trend toward higher disease severity scores following RBCx relative to the RBCx group (p = 0.10). The TPE group showed a significantly greater decrease in SOFA score between RBCx and discharge (p = 0.04). No significant difference in mortality or hospital LOS was observed between the groups. CONCLUSION: The findings suggest TPE may be considered as an adjunct treatment for patients with acute complications of SCD that progress to MODS, especially in cases where there is no significant improvement following RBCx.

Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is a serious adverse drug reaction caused by transient antibodies against platelet factor 4 (PF4)/heparin complexes, resulting in platelet activation and potentially fatal arterial and/or venous thrombosis. Most cases of HIT respond to cessation of heparin and administration of an alternative non-heparin anticoagulant, but there are cases of persisting HIT, defined as thrombocytopenia due to platelet activation/consumption for greater than seven days despite standard therapy. These patients remain at high risk for thrombotic events, which may result in limb-loss and mortality. Intravenous immunoglobulin (IVIg) has been proposed as an adjunct therapy for these refractory cases based on its ability to saturate FcγRIIa receptors on platelets, thus preventing HIT antibody binding and platelet activation. We describe 2 cases of persisting HIT (strongly positive antigen and functional assays, and persisting thrombocytopenia >7 days) with rapid clinical response to IVIg. We performed in-vitro experiments to support IVIg response. Healthy donor platelets (1 × 10e6) were treated with PF4 (3.75 µg/mL) for 20 min followed by 1-hour incubation with patients' sera. Platelet activation with and without addition of IVIg (levels equivalent to those reached in a patient after treatment with 2 gm/Kg) was evaluated in the PF4-dependent P-selectin expression assay (PEA). A significantly decreased platelet activation was demonstrated after the addition of IVIg to both patient samples, which correlated well with the rapid clinical response that each patient experienced. Thus, our study supports the use of IVIg as an adjunct therapy for persisting HIT.

Contribution of whole platelet aggregometry to the endovascular management of unruptured aneurysms: an institutional experience.

BACKGROUND: Stent-assisted coiling of intracranial aneurysms is an efficient alternative treatment to surgical clipping but requires prolonged antiplatelet therapy. Some patients are non-responsive to aspirin and/or clopidogrel. OBJECTIVE: To analyze the implications of this assessment using the 'whole blood aggregometry (WBA) by impedance' technique. MATERIALS AND METHODS: The Southwestern Tertiary Aneurysm Registry was reviewed between 2002 and 2012 for patients with unruptured aneurysms treated with stent-assisted coiling. The study population was divided into patients who were tested preoperatively for platelet responsiveness to aspirin and clopidogrel ('tested' patients) and those who were not ('non-tested'). Where necessary, tested patients received additional doses of antiplatelet drugs to achieve adequate platelet inhibition. Endpoints included the incidence of non-responsiveness, the rates of thrombotic and hemorrhagic complications, and the rates of permanent morbidity and mortality. RESULTS: A total of 266 patients fulfilled our selection criteria: 114 non-tested patients who underwent 121 procedures, and 152 tested patients who underwent 171 procedures. The two groups did not vary significantly in patient age, gender, and aneurysms location. Aspirin non-responsiveness was detected in 3 patients (1.75%) and clopidogrel non-responsiveness in 21 patients (12.3%). Non-tested patients had an 11.6% rate of thrombotic complications with a 4.1% permanent morbidity or mortality rate versus 2.3% and 0.6% in tested patients (p=0.0013). The incidence of hemorrhagic complications was similar between the two groups. CONCLUSIONS: Preoperative platelet inhibition testing using WBA can be useful to assess and correct antiaggregant non-responsiveness, and may reduce postoperative mortality and permanent morbidity.

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. SUMMARY: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP.

Developing a multidisciplinary Young Women's Blood Disorders Program: a single-centre approach with guidance for other centres.

INTRODUCTION: Bleeding from the reproductive tract in women is a natural event, generally occurring with menstruation and childbirth. Women with an underlying bleeding disorder may experience heavy menstrual bleeding (HMB) and thereby, unacceptable blood loss. Up to 20% of US women with abnormal uterine bleeding and a normal gynaecological exam may have an underlying bleeding disorder corresponding to almost 2-3 million American women. These females face many obstacles in achieving optimum medical care for their problems. A haematologist may not evaluate these women as they are treated symptomatically. Recognition of an underlying bleeding disorder is not straightforward and many come to attention after serious bleeding events. Although mortality from HMB is uncommon, the true burden of HMB is its impact on health-related quality of life. To address these issues, women with HMB require a comprehensive approach to their care. METHODS: These reasons compelled us to institute a multidisciplinary Young Women's Blood Disorders (YWBD) Program at our institution. RESULTS: Herein, we describe the process of developing this program involving paediatric haematology, adolescent medicine and paediatric/adolescent gynaecology, and the expertise of a laboratory coagulationist, a nutritionist and nursing professionals. We also describe our experience with patient selection, the role of each specialty in the program, our approach to testing, the coordination of care and overall management of this patient population. Lastly, we propose metrics that could be followed in justifying the support of such a program. CONCLUSIONS: There is a growing need to offer comprehensive care to women with HMB and blood disorders. The YWBD program at our institution appears to be successful in delivering optimal care to young women affected with HMB.

New strategies for effective treatment of vitamin K antagonist-associated bleeding.

Vitamin K antagonists have been used as oral anticoagulants in the treatment and prevention of thromboembolic events for over half a century. Although vitamin K antagonists are effective in the management of thromboembolic events, the need for routine monitoring and the associated risk of bleeding has resulted in the development and licensing of direct oral anticoagulants for specific clinical indications. Despite these developments, vitamin K antagonists remain the oral anticoagulants of choice in many clinical conditions. Severe bleeding associated with oral anticoagulation requires urgent reversal. Several options for the reversal of vitamin K antagonist exist, including vitamin K, prothrombin complex concentrates and plasma. In this manuscript, we review current evidence and provide physicians with treatment strategies for more effective management of vitamin K antagonist-associated bleeding.

IgA antiphospholipid antibodies are an independent risk factor for thromboses.

Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin and anti-beta(2)-glycoprotein I antibodies, mostly IgG isotype) are strong risk factors for thrombosis. Because a paucity of information on IgA isotype exists in the literature, we retrospectively evaluated the thrombotic significance of IgA antiphospholipid antibodies. We included 472 patients with clinical information on thrombotic events and complete laboratory work-up for antiphospholipid antibodies syndrome. Odds ratios (OR) of various antiphospholipid antibodies for thrombosis were calculated by univariate and multivariate analyses. Lupus anticoagulant alone was detected in 57 (12%) patients, ELISA-based antibodies (IgG, IgM, IgA) against cardiolipin, phosphatidylserine or beta(2)-glycoprotein-I alone were detected in 131 (28%) patients, whereas 80 (17%) patients had both. Antibody isotype distribution was IgG 32%, IgM 60% and IgA 56%. Univariate analysis showed a statistically significant risk of thrombosis in patients with elevated titres of IgA of any ELISA-based antiphospholipid antibodies (OR 1.77). Stepwise logistic regression (multivariate) analysis identified elevated titres of any ELISA-based IgA antiphospholipid antibodies as an independent risk factor for thrombosis (OR 1.6) in the entire cohort, and in the subgroup of patients without concurrent presence of lupus anticoagulant (OR 1.8). IgA antiphospholipid antibodies appear to be a significant independent risk factor for thrombosis, thereby meriting evaluation in patients with unexpected thrombosis.

Acute hemolytic transfusion reaction secondary to anti-Fy3.

A hemolytic transfusion reaction due to anti-Fy3 is reported in an African American patient with no history of sickle cell disease. This 82-year-old African American woman received two units of RBCs for anemia (Hab 7 g/dL) on admission for a left hip fracture. On hospital Day 7, the patient underwent left hip endoprosthesis surgery; she received two units of RBCs on the second postoperative day due to Hb of 6.1 g/dL. Her urine was dark during surgery and postoperatively. Her posttransfusion plasma was red. Her Hb dropped from 8.4 to 6.4 g/dL over 24 hours after the transfusion. Her total bilirubin rose to 4.0 mg/dL, with and LDH value of 1558 U/L and a haptoglobin of 10.9 mg/dL. Both the antibody detection test and the DAT were positive. An anti-Fy3 was identified in the serum and in the eluate. To the best of our knowledge, this is the first case of acute intravascular hemolysis due to anti-Fy3 in a patient without sickle cell disease.

An anti-CD45RO immunotoxin kills HIV-latently infected cells from individuals on HAART with little effect on CD8 memory.

CD4+ CD45RO+ T cells are the major latent viral reservoir in HIV-infected individuals and hence a major obstacle in curing the disease. An anti-CD45RO immunotoxin (IT) can decrease the number of both productively and latently infected CD4+ T cells obtained from HIV-infected individuals with detectable viremia. In this study, we determined whether this IT could also kill latently infected replication-competent CD4+ T cells obtained from infected individuals without detectable plasma viremia. Our results demonstrate that ex vivo treatment with the anti-CD45RO IT significantly reduced the frequency of these cells. In contrast, the IT had only a modest effect on the cytomegalovirus-specific memory responses of CD8+ T cells. These results suggest that purging latent cells from infected individuals on highly active antiretroviral therapy with the anti-CD45RO IT might reduce the HIV latent reservoir without seriously compromising CD8+ T cell memory responses.

Consanguineous hemolytic uremic syndrome secondary to Escherichia coli O157:H7 infection treated with aggressive therapeutic plasma exchange.

We describe the successful management of an elderly husband and wife with Escherichia coli O157:H7 associated hemolytic uremic syndrome (HUS) treated with aggressive therapeutic plasma exchange (TPE) with replacement with fresh frozen plasma. Following twelve TPEs (three 1.5 volume; nine 1 volume), the husband's platelet count increased from 45 x 10(9)/L to 183 x 10(9)/L. Following ten 1.5 volume TPEs, the wife's platelet count increased from 30 x 10(9)/L to 193 x 10(9)/L. This is the first known occurrence of E. coli O157:H7 associated HUS in an elderly husband and wife successfully treated with aggressive TPE. We conclude that early, aggressive TPE should be considered and may be life-saving for E coli O157:H7 associated HUS in the elderly.

Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) usually occurs after infection with Shiga toxin-producing bacteria. Thrombotic thrombocytopenic purpura, a disorder with similar clinical manifestations, is associated with deficient activity of a circulating metalloprotease that cleaves von Willebrand factor at the Tyr842-Met843 peptide bond in a shear stress-dependent manner. We analyzed von Willebrand factor-cleaving metalloprotease activity and the status of von Willebrand factor in 16 children who developed HUS after Escherichia coli O157:H7 infection and in 29 infected children who did not develop this complication. Von Willebrand factor-cleaving metalloprotease activity was normal in all subjects, but von Willebrand factor size was decreased in the plasma of each of 16 patients with HUS. The decrease in circulating von Willebrand factor size correlated with the severity of thrombocytopenia and was proportional to an increase in von Willebrand factor proteolytic fragments in plasma. Immunohistochemical studies of the kidneys in four additional patients who died of HUS demonstrated glomerular thrombi in three patients, and arterial and arteriolar thrombi in one patient. The glomerular thrombi contained fibrin but little or no von Willebrand factor. A decrease in large von Willebrand factor multimers, presumably caused by enhanced proteolysis from abnormal shear stress in the microcirculation, is common in HUS.

Massive blood transfusion.

Pediatricians in the hospital setting must frequently treat children who require massive transfusion (MT) in a variety of clinical situations ranging from major trauma to neonatal hyperbilirubinemia. After identifying the need for massive transfusion, the pediatrician must select the appropriate blood components. Different blood components have specific temperature, preservative, and time requirements for their storage. Changes, termed storage lesions, occur over time in blood components during storage; biochemical changes include decreased levels of 2,3-DPG, a decrease in pH, and an increase in supernatant potassium (K+) with a concurrent decrease in intracellular K+. These changes may affect the function and the viability of components. Additionally, physical changes such as deformation of the red cell membrane occur during storage. Knowledge of these storage lesions is necessary for the pediatrician to make the most appropriate decisions regarding the preparation and selection of components during MT. Serious complications of MT include hemostatic abnormalities, biochemical/metabolic abnormalities, hypothermia, mechanical injury and the effect of Rh incompatibility, each of which has a specific management response. Pediatricians need to be aware of the potential complications associated with massive transfusion, to take measures to prevent them when possible, to anticipate additional transfusion requirements, and to know how to manage them in the pediatric patient.

Successful large volume leukapheresis on a small infant allogeneic donor.

We successfully performed a hematopoietic stem cell apheresis on the smallest allogeneic donor reported to date, a 6.1 kg female. After placement of a dialysis catheter in the left femoral vein, the COBE Spectra was primed with one unit of paternal whole blood. Heparin and anticoagulant citrate dextrose, solution A (ACD-A) were slowly administered to the patient. Ionized calcium levels were checked hourly and calcium gluconate was given for hypocalcemia. Coagulation parameters were checked throughout the procedure. We collected 4.4 x 10(6) CD34+ cells/kg (recipient). The donor tolerated the procedure well and was discharged the following day. Five months later, the child manifests no obvious late effects.

Role of A and B blood group antigens in the expression of adhesive activity of von Willebrand factor.

ABO (H) blood group antigens are covalently linked to the oligosaccharide side-chains of von Willebrand factor (VWF). In this study, we investigated the role of the A and B antigens in the expression of VWF adhesive activity. VWF of type A, B or O was purified from fresh frozen plasma. Presence of A or B antigen on the VWF was confirmed by enzyme-linked immunosorbent assay (ELISA) and by immunoblotting with monoclonal anti-A or anti-B. The A or B antigen was also detected in the 48/52-kDa fragment of the respective VWF after trypsin digestion. Removal of A antigen with alpha-N-acetylgalactosaminidase or B antigen with alpha-galactosidase did not affect its multimer size or antigenic level, but decreased the ristocetin cofactor (RCoF) activity of the respective VWF by 33-39% (P < 0.01-0.002). Removal of A or B antigen from VWF did not affect the binding of the VWF to immobilized type III collagen. A and B antigens were not detected in platelet VWF. These results indicate that AB structures play a role in platelet aggregating activity of VWF.

Heparin-induced coagulopathy associated with staphylococcal protein A immunoadsorption treatment columns: an in vitro and in vivo analysis.

BACKGROUND: The staphylococcal protein A (SPA) column used to treat refractory autoimmune and alloimmune thrombocytopenia and rheumatoid arthritis patients is primed with heparin to prevent possible fibrin clot formation when the patient's plasma is passed through the column. A BMT patient with refractory alloimmune thrombocytopenia had prolonged activated partial thromboplastin times (aPTTs) at the end of SPA column treatments. This observation led to in vivo and in vitro analysis of the kinetics of heparin elution from the SPA column. STUDY DESIGN AND METHODS: Two patients with refractory rheumatoid arthritis, who were treated on five occasions with the SPA column (as a part of a national trial) primed with 5000 U of heparin, were monitored for aPTT and heparin in their plasma. In addition, two in vitro analyses were performed with FFP for heparin elution from the SPA column. RESULTS: The in vivo studies showed the presence of 0.3 to 1.5 U per mL of heparin in patients' plasma at the end of the SPA column treatments that corresponded with the prolonged aPTTs. The in vitro studies showed that 82 to 85 percent heparin (approx. 4400 U) was eluted from the SPA column during rather than before the procedure. CONCLUSION: Patients undergoing SPA column treatments, especially those with thrombocytopenia, may be at increased risk of bleeding as a result of the presence of a significant amount of heparin in their circulation during the entire period of SPA column treatment.