Plasma exchange for the management of refractory pruritus of cholestasis: A report of three cases and review of literature.

BACKGROUND: Intractable pruritus of cholestasis leads to significant morbidity. Therapeutic plasma exchange (TPE) has been shown to be an effective alternative in the setting of refractory pruritus associated with cholestatic liver disease based on several individual reports. Due to rarity of this approach to intractable pruritus, the literature is sparse and therefore TPE, as a treatment for refractory pruritus is currently not in the apheresis guidelines. We present three additional patients with severe intractable pruritus of cholestasis successfully treated with plasma exchange to add to the mounting literature showing this as an effective and safe adjunctive therapy. METHODS: Three patients underwent serial plasma exchange procedures to control pruritus. Frequency of plasma exchange was three times a week, with slow taper upon improvement of pruritus. Total bile acid levels were assessed before procedures. RESULTS: All three patients had an intractable pruritus with different underlying etiologies of cholestasis. All three patients showed significant improvement in pruritus, with none or minimal pruritus in one patient with primary biliary cirrhosis. Pre procedure bile acids levels were decreased initially, but showed rebound increase upon tapering of plasma exchange, without increased pruritus. No serious side effects or complications were observed. CONCLUSION: Our results in conjunction with the published literature show that severe and intractable pruritus associated with cholestasis could be successfully treated with TPE, irrespective of the underlying disease, and can be done safely.

Novel Application of Extracorporeal Photopheresis as Treatment of Graft-versus-Host Disease Following Liver Transplantation.

A 48-year-old man with hepatitis C virus (HCV) cirrhosis complicated by hepatocellular carcinoma underwent liver transplantation. His course was complicated by fever, diarrhea, abdominal pain, and pancytopenia. He developed a diffuse erythematous rash, which progressed to erythroderma. Biopsies of the colon and skin were consistent with acute graft-versus-host disease. Donor-derived lymphocytes were present in the peripheral blood. The patient was treated with corticosteroids and cyclosporine; however, he had minimal response to intensive immunosuppressive therapy. Extracorporeal photopheresis was initiated as a salvage therapy. He had a dramatic response, and his rash, diarrhea, and pancytopenia resolved. He is maintained on minimal immunosuppression 24 months later.

Comparison of Spectra Optia and COBE Spectra apheresis systems' performances for red blood cell exchange procedures.

BACKGROUND: Spectra Optia (Terumo BCT, Lakewood, CO) was FDA approved for red blood cell exchange (RBCx) procedures in January 2014 and is expected to replace COBE spectra (Terumo BCT) very soon in the USA. The performance characteristics of these devices for Isovolemic Hemodilution (IHD-RBCx) procedure were compared in this study. METHODS: A total of 114 IHD-RBCx procedures from 19 patients were analyzed. For every patient, three procedures on each device with similar pre-procedure hematocrits were compared. Pre and post procedure laboratory parameters compared were hemoglobin S (HbS), hematocrits (Hct), platelet counts and fraction of cells remaining (FCR). Statistical analysis was performed using t-test adjusted by the Holm-Bonferroni method to reduce family-wise error rate. RESULTS: There were no significant differences between these two devices in regards to HbS, Hct, FCR and platelet counts (p = > 0.05). However, rinseback volume (124.2 ± 8.9 ml) and normal saline replacement volume during IHD phase (296.1 ± 97.2 ml) were lower in Spectra Optia as compared to COBE Spectra (337 ± 33.8 ml and 326.6 ± 105.2 ml, p value <0.001 and 0.030 respectively). Spectra Optia had a longer run time (107.1 ± 15.9 min vs 123.8 ± 19.6 min, p value <0.001) overall. CONCLUSIONS: Performance characteristics of Spectra Optia for HbS, Hct and FCR were similar to COBE Spectra for IHD-RBCx. IHD-RBCx procedure on Optia required less normal saline replacement volume and rinse back volume but with overall longer procedure run time.

Thrombosis, Microangiopathies, and Inflammation.

Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia. There are several disorders with varied etiopathogenesis, both genetic and acquired, that result in TMA. The neutrophils play an important role in inflammation and thrombosis through the formation of neutrophil extracellular traps (NETs). NETs are formed in response to a variety of stimuli including infections, chemical factors, and platelet activation. The classic TMA, thrombotic thrombocytopenic purpura (TTP) is caused by a severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type-I motif, member 13), mostly acquired due to autoantibodies, whereas atypical hemolytic uremic syndrome (aHUS) is mostly attributed to genetic defects in complement pathway regulatory proteins. The management of these well-known disorders has evolved over the last decade. Similarly, there is also better understanding of diverse and unusual clinical presentations of both of these conditions. Since there are many other causes of TMAs, which may mimic some of the clinical features of TTP or aHUS, it is essential to thoroughly investigate each patient so that appropriate therapy can be offered. This review focuses on some important developments in understanding of etiopathogenesis, diagnosis, and treatment of more commonly encountered TMAs.

Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: A retrospective review.

INTRODUCTION: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is an increasingly recognized form of autoimmune encephalitis. Conventional treatments include therapies such as corticosteroids, intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE). Although TPE is regularly used for treatment of anti-NMDA receptor antibody encephalitis, the American Society for Apheresis has given it a category III recommendation only. Earlier administered immunotherapies in tumor-negative patients may facilitate faster recoveries, but it remains unclear whether or not TPE is superior to steroids and/or IVIG. METHODS: We retrospectively evaluated 10 of 14 patients that received steroids and TPE with modified Rankin scores and subjectively assessed the point of largest sustained improvement in all 14 patients. RESULTS: In the patients that received both steroids and TPE at our institution during the same hospitalization (only 10 of 14 patients), 7/10 patients after TPE had improved with the modified Rankin score versus 3/10 patients after steroids. The average modified Rankin score improvement after steroids in this group was -0.1 as compared with 0.4 after TPE. Based on subjective chart review analysis during which all 14 patients were assessed, the largest sustained improvement occurred immediately following the third-fifth exchange in 9/14 patients, whereas only 2/14 patients appeared to have had significant benefit immediately following steroids. CONCLUSIONS: This is compelling preliminary data that suggests that corticosteroids may not be as effective compared to steroids followed by TPE. Given the importance of time-sensitive treatment, more formal studies may illuminate the ideal first-line treatment for anti-NMDA receptor antibody encephalitis.

Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. CASE REPORT: We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. CONCLUSION: Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.

Therapeutic plasma exchange in the management of sepsis and multiple organ dysfunction syndrome: a report of three cases.

Sepsis with multi organ dysfunction syndrome (MODS) is the most common cause of death in patients in noncoronary intensive care units. Currently, there are no specific treatments that reduce mortality in patients with sepsis and MODS. We report three patients who received therapeutic plasma exchange (TPE) for sepsis with MODS who completely recovered. The first patient, a 3-year-old male presented with Methicillin-resistant Staphylococcus aureus-associated respiratory, renal, coagulation, hepatic, and neurologic dysfunction. After 5 TPEs, the patient fully recovered. The second patient was a 36-year-old pregnant female who developed MODS at 22 weeks of gestation. She had developed respiratory, hepatic, renal, cardiovascular, neurologic, and coagulation dysfunction following pneumonia and concurrent urinary tract infection resulting in an intrauterine fetal demise. After 8 TPEs, the patient was discharged home with only mild residual hepatic dysfunction. The third patient, a 50-year-old female with a history of seizure disorder, was found unresponsive in over 100°F heat and diagnosed with Staphylococcus aureus-associated MODS. Her respiratory, coagulation, neurologic, renal, and hepatic systems were affected. The patient underwent 6 TPEs after which she had marked improvement. In conclusion, TPE may be an effective adjunct therapy in MODS by possibly removing toxic mediators and replacing deficient factors using donor plasma.

Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP).

The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.

Isovolemic hemodilution-red cell exchange for prevention of cerebrovascular accident in sickle cell anemia: the standard operating procedure.

Red blood cell exchange is an accepted superior therapy to simple chronic transfusion, due to minimal risk of iron overload, for secondary prevention of cerebrovascular accidents in selected patients with sickle cell anemia. Recently, we described our experience of Isovolemic Hemodilution-Red Blood Cell Exchange (IHD-RBCx), a two-step modification of the conventional RBCx with several advantages, including cost reduction. We are describing our standard operating procedure for IHD-RBCx with COBE Spectra apheresis system to make it widely available to the apheresis centers interested in implementing this procedure.

Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage.

OBJECT: Intracerebral hemorrhage (ICH) is the most serious bleeding complication of vitamin K antagonist (VKA) therapy, carrying a high mortality. Rapid reversal of VKA in ICH is critical. Plasma therapy, the standard of care in the US, is not optimal. The ideal prothrombin complex concentrate (PCC) containing all vitamin K-dependent factors (VKDFs) is not available in the US. Therefore, the authors developed a Trauma Coumadin Protocol (TCP) consisting of a 3-factor PCC available in the US (which contains insufficient factor VII [FVII]) with a low-dose recombinant FVIIa to rapidly reverse VKA. METHODS: Forty-six patients treated with the TCP were retrospectively analyzed. Fourteen patients had pre- and post-TCP plasma samples collected to assess their VKDF increment. Eleven patients had measurable intraparenchymal hematomas, which were evaluated for expansion. RESULTS: The mean pre- and post-TCP international normalized ratios (INRs) were 3.4 (median 2.9) and 1.0 (median 0.9), respectively. Once corrected, INR was maintained at < 1.3 during a patient's hospital stay. The pre-TCP median values of FII, FVII, FIX, and FX were 28%, 21%, 45%, and 20%, respectively; post-TCP median values increased to 144%, 417%, 102%, and 143%, respectively. Four of the 11 patients with measurable intraparenchymal hemorrhage had expansion at 24 hours after TCP. One patient probably (8 hours post-TCP) and 1 patient possibly (3 days post-TCP) had thrombotic complications. CONCLUSIONS: The TCP was very effective in rapidly reversing VKA-associated coagulopathy; however, this protocol should be used cautiously in patients at high risk for thrombosis.

Advantages of isovolemic hemodilution-red cell exchange therapy to prevent recurrent stroke in sickle cell anemia patients.

Chronic simple hypertransfusion (every 3 to 4 weeks) effectively prevents secondary stroke in children with sickle cell anemia but leads to iron overload despite chelation therapy. Conventional red blood cell exchange (C-RBCx) has advantages over simple transfusion: no net iron gain and less frequent hospital visits. However, C-RBCx requires more red blood cell units, an apheresis instrument and skilled personnel; it is also more expensive. We developed a modified procedure where isovolemic hemodilution precedes RBCx (IHD-RBCx) to decrease RBC units required and to increase the interval between procedures. Twenty patients underwent IHD-RBCx over a period of 7 years. IHD-RBCx required 11% fewer RBC units and increased inter-procedure interval from 37 to 53 days compared to C-RBCx. The median number of annual procedures decreased from 9.8 to 7.0 per patient, resulting in estimated savings of more than $4.5 million over 10 years for 20 patients while providing improved care. Five patients have discontinued chelation therapy; three while on C-RBCx and two while on IHD-RBCx. No adverse events occurred related to the isovolemic hemodilution phase and no patients had recurrent stroke. IHD-RBCx is a safe, efficient, and cost effective therapy for secondary prevention of stroke in patients with sickle cell anemia.

Coagulation factor levels in neurosurgical patients with mild prolongation of prothrombin time: effect on plasma transfusion therapy.

OBJECT: Neurosurgical patients often have mildly prolonged prothrombin time (PT) or international normalized ratio (INR). In the absence of liver disease this mild prolongation appears to be due to the use of very sensitive PT reagents. Therefore, the authors performed relevant coagulation factor assays to assess coagulopathy in such patients. They also compared plasma transfusion practices in their hospital before and after the study. METHODS: The authors tested 30 plasma specimens from 25 patients with an INR of 1.3-1.7 for coagulation factors II, VII, and VIII. They also evaluated plasma orders during the 5-month study period and compared them with similar poststudy periods following changes in plasma transfusion guidelines based on the study results. RESULTS: At the time of plasma orders the median INR was 1.35 (range 1.3-1.7, normal reference range 0.9-1.2) with a corresponding median PT of 13.6 seconds (range 12.8-17.6 seconds). All partial thromboplastin times were normal (median 29.0 seconds, range 19.3-33.7 seconds). The median factor VII level was 57% (range 25%-124%), whereas the hemostatic levels recommended for major surgery are 15%-25%. Factors II and VIII levels were also within the hemostatic range (median 72% and 118%, respectively). Based on these scientific data, plasma transfusion guidelines were modified and resulted in a 75%-85% reduction in plasma orders for mildly prolonged INR over the next 2 years. CONCLUSIONS: Neurosurgical patients with a mild prolongation of INR (up to 1.7) have hemostatically normal levels of important coagulation factors, and the authors recommend that plasma not be transfused to simply correct this abnormal laboratory value.

Rinseback during red blood cell exchange with COBE Spectra does not affect fraction of cells remaining or post-exchange hematocrit.

CaridianBCT currently does not recommend rinseback with its COBE Spectra cell separator during red blood cell (RBC) exchange procedure, as the machine's software does not take into account the "rinseback" when calculating the fraction of cells remaining (FCR, and therefore target hemoglobin S (HbS) value) and postexchange hematocrit (Hct). To our knowledge, no study has investigated the effect of rinseback on these laboratory values. Therefore, we performed pre- and postrinseback evaluations of FCR and Hct in 22 consecutive combined Isovolemic Hemodilution/Red blood cell (IHD-RBCx) exchange procedures in sickle cell anemia patients with stroke currently enrolled in our institution's chronic RBC exchange program. The pre- and-post rinseback values for HbS were 9.9 ± 4.66 and 10.7 ± 4.83 (P = 0.56) with corresponding FCRs of 22.6 ± 8.57 and 24.7 ± 8.75 (P = 0.44), and for Hct were 32.4 ± 2.93% and 32.2 ± 3.19% (P = 0.79), respectively. Since there was no significant difference in the "pre" and "post" values, we conclude that rinseback can be used during RBC exchange without any concern for significantly affecting Post Exchange HbS and Hct and possibly not waste 53 mL of precious red cell mass in the rinseback.

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.

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.