Yara A. Park

Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery

BACKGROUND Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Is it HIV TTP or HIV-associated thrombotic microangiopathy?

Thrombocytopenia is a common complication of Human Immunodeficiency Virus (HIV) infection. With advanced HIV disease, the presence of both thrombocytopenia and schistocytosis are frequently observed. In such cases, the diagnosis of HIV associated TTP is often considered. This article reviews emerging concepts of HIV associated microangiopathies. It concludes that the pathophysiology, in many cases seems to be distinct from idiopathic TTP (particularly with advanced HIV disease—<100 CD4/microliter). A sine que non for successful therapy of HIV‐TMA appears to be the treatment of the underlying HIV infection.infection. J. Clin. Apheresis, 2008.

Platelet Count and Prothrombin Time Help Distinguish Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome From Disseminated Intravascular Coagulation in Adults

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) and disseminated intravascular coagulation (DIC) may have identical manifestations in adults. Because TTP-HUS is 90% fatal without plasma exchange, prompt diagnosis is essential. To test the hypothesis that routine laboratory assays can discriminate between the 2 entities, we retrospectively identified adult patients with TTP-HUS and matched each with 2 patients with DIC. Although the platelet count, prothrombin time (PT), and partial thromboplastin time were different (P < .05) between the 2 patient groups, after regression analysis, only PT and profound thrombocytopenia remained associated with TTP-HUS (P = .001 and P = .003, respectively). A platelet count of less than 20 x 10(3)/microL (20 x 10(9)/L) and a PT within 5 seconds of the upper limit of the reference interval had a specificity of 92% for TTP-HUS. Our data confirm that readily available laboratory assays in the proper clinical scenario can increase the likelihood of TTP-HUS over DIC.

Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease.

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross‐matching for future transfusions and may sometimes trigger life‐threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14–27 days). RBC antibody formation was significantly associated with the age of RBC units (P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71–7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66–35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso‐occlusive complications. Although increased echocardiography‐derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies (P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding. Am. J. Hematol. 90:691–695, 2015.

Bortezomib induces clinical remission and reduction of ADAMTS13 inhibitory antibodies in relapsed refractory idiopathic thrombotic thrombocytopenic purpura

Idiopathic Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening syndrome characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, fever, renal impairment and neurological symptoms. The activity of the von Willebrand factor cleaving metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is frequently decreased due to the presence of inhibitory autoantibodies. (Furlan et al, 1998; Tsai & Lian, 1998) Immunosuppression, commonly including corticosteroids and rituximab, (George, 2010; Scully et al, 2011) is used as an adjunct to daily therapeutic plasma exchange (TPE) to reduce further autoantibody production. Recently, the proteasome inhibitor bortezomib was reported to deplete autoantibodies in a patient with idiopathic TTP. (Shortt et al, 2013) However, the concomitant administration of rituximab creates ambiguity in this causative interpretation. Here, we report the first use of bortezomib without concomitant rituximab for successful induction of clinical remission, reduction of inhibitory antibodies, and return of ADAMTS13 activity in relapsed, refractory idiopathic TTP. A 51-year-old woman with multiply relapsed idiopathic TTP presented with haemoglobinuria and signs of TTP including MAHA and severe thrombocytopenia, but without evidence of end-organ dysfunction (renal or neurological). Her initial diagnosis was made in 2003 when she presented 10 days post-operatively from hysterectomy with neurological symptoms and was found to have severe thrombocytopenia and MAHA. She was treated with corticosteroids and TPE and rapidly achieved remission after only 4 days of therapy. When she relapsed in 2006, her only symptom was haemoglobinuria, but again was found to have severe thrombocytopenia and MAHA. ADAMTS13 activity was available and found to be undetectable with the presence of an inhibitor. During this relapse, she required more intensive immunosuppressive therapy, including rituximab and subsequent elective splenectomy. At her current presentation with relapsed idiopathic TTP, ADAMTS13 activity was again undetectable with an ADAMTS13 inhibitor titre of 3 0 Inhibitor Units. With daily TPE and immunosuppressive agents (Fig 1) her platelet counts returned to the normal range. However, each time TPE was held for a single day, her platelet count rapidly decreased and haemolysis resumed. Furthermore, her inhibitor titre persisted and she remained severely ADAMTS13-deficient, indicating a failure of immunosuppression to eradicate production of autoantibodies to ADAMTS13. Other treatment options were then considered. She had been previously treated with rituximab in 2006, was retreated with rituximab during this relapse, and we considered a second cycle of rituximab therapy. However, there is no current evidence on which to base continued use of rituximab for the treatment of TTP. In the phase II study of the efficacy of rituximab with concurrent TPE in TTP, subjects receiving rituximab were found to have depletion of circulating CD19/ 20 positive B cells by flow cytometry. (Scully et al, 2011) Extrapolating from this finding, we reasoned that if circulating CD19/20 positive B cells by flow cytometry were shown to be effectively depleted, then additional rituximab may be unlikely to be beneficial. Our patient had had effective depletion of circulating CD19/20 positive B cells by flow cytometry and therefore we decided to not give further rituximab. The monoclonal antibody directed against complement (C5), eculizumab, has been reported to have induced remission in a patient with TTP and complement dysregulation evidenced by endothelial complement deposition on skin biopsy. (Chapin et al, 2012) However, a skin biopsy in our patient suggested no evidence of complement dysregulation. Bortezomib is a highly active therapy to reduce serum immunoglobulins in multiple myeloma (MM) and in antibody-mediated rejection (AMR) in solid organ transplant rejection, (Everly et al, 2009) which suggested that the drug had potential to be utilized to deplete persistent autoantibodies in TTP. We initiated bortezomib at the standard dose for both MM and AMR (1 3 mg/m, days 1, 4, 8, 11 on a 21 day cycle). Cycle 1 started on Day 75 and TPE was subsequently weaned for the first time without a TTP exacerbation. The patient was discharged on Day 103, but continued intermittent outpatient TPE. When TPE was discontinued, an exacerbation occurred (Day 158) and a second cycle of bortezomib was given. Both cycles were associated with a rapid fall in inhibitor titre and, following the second cycle, a rise in ADAMTS13 activity. The patient remains in full remission over 120 days after discontinuation of TPE and corticosteroids. This report suggests activity of bortezomib for achieving clinical remission in idiopathic TTP, with a reduction of ADAMTS13 inhibitor titre and a rise in ADAMTS13 activity. While we cannot exclude the contribution of continuous mycophenolate mofetil (MMF) therapy, a late effect of rituximab Correspondence

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 ≥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. J. Clin. Apheresis, 2009.

ADAMTS13 activity levels in patients with human immunodeficiency virus-associated thrombotic microangiopathy and profound CD4 deficiency

Thrombotic microangiopathy (TMA) encompasses a number of disorders with hemolytic anemia and thrombocytopenia, including thrombotic thrombocytopenic purpura (TTP). A deficiency in ADAMTS13 enzyme levels, along with an inhibitory antibody, is found in most patients with idiopathic TTP. Patients with human immunodeficiency virus (HIV) infection can have a TTP‐like illness; however, it appears to have a different etiology.

Passive reporting greatly underestimates the rate of transfusion-associated circulatory overload after platelet transfusion.

Transfusion‐associated circulatory overload (TACO) is the second leading cause of reported transfusion‐related fatalities in the United States. While its occurrence has been previously investigated after red cell and plasma transfusion, no data are available regarding its association with platelet transfusion. Our goal was to determine the rate of platelet‐associated TACO at our university medical centre.

The treatment of nephrogenic systemic fibrosis with therapeutic plasma exchange.

Background: Nephrogenic systemic fibrosis (NSF), also known as nephrogenic sclerosing dermopathy (NSD), is a rare progressive fibrosing disease associated with gadolinium based dyes in patients with renal disease. The exact pathophysiology is not well understood. Accepted treatments include corticosteroids, immune modulators, PUVA, rituximab and extracorporeal photopheresis (ECP). Apheresis is utilized when symptoms continue to progress. However, the paucity of centers offering ECP can be inhibitory to care. Small case reports have been published illustrating moderate treatment success with therapeutic plasma exchange (TPE). Methods: Chart review found two patients; both were African‐American women with systemic lupus erythematosus (SLE), status post renal transplant, who had biopsy documented NSF. The patients were still symptomatic, despite maximal medical management, so they underwent TPE series for symptom management. Medical therapy with immune modulators was continued in conjunction to TPE. Response to treatment was evaluated using subjective reporting to the primary care team. Results: The patients reported significant improvements in subjective pain levels after TPE. Patient 1 reported decreased skin and contracture pain after the 3rd treatment, with similar results for a second series 6 months later. Patient 2 reported drastic improvement in pain symptoms and rarely required pain medication during hospital course. No adverse reactions occurred during treatment. Conclusions: TPE is a therapy option for patients with NSF without access to ECP. TPE was well‐tolerated, easily assessable, and effective; however the etiology of the improvement following TPE is unknown. Larger studies will help further determine the efficacy of TPE for NSF. J. Clin. Apheresis 28:317–320, 2013.

Rapid increases in parasitemia following red cell exchange for malaria

Exchange transfusion is frequently used as an adjunctive treatment of severe malaria, although the efficacy of exchange transfusion as therapy for severe malaria remains controversial. The major perceived benefit of exchange transfusion is the rapid reduction of parasite load. However, no previous report has shown the dynamic change in parasitemia shortly following an acute load reduction. We report a 20‐year‐female who developed cerebral malaria and 30% parasitemia after traveling to Africa. In addition to antimalarial treatment, red cell exchange (RCX) was begun emergently with an automated blood‐cell separator. Parasitemia dropped from 30 to 15% immediately after the procedure but rapidly increased to 25% after 50 min. The second procedure was performed 12 h after the first procedure. Her neurologic status returned to baseline on Day 2, and she was discharged on Day 6. Rapid increases in parasitemia can be observed after mechanical load reduction following RCX. J. Clin. Apheresis, 2011.