Simple Plasma Exchange Research Articles

Recurrent localized fever caused by cryoglobulinemic vasculitis following hemodialysis: A case report.

Post-dialysis fever is commonly reported in patients undergoing hemodialysis (HD). However, it is often challenging to identify the underlying cause owing to the wide variety of potential factors that can lead to fever. In this case, a 66-year-old Japanese man experienced recurrent fever after HD treatment. Initially, antibiotics were prescribed to treat pneumonia, but it was later discovered that the pneumonia was an alveolar hemorrhage caused by cryoglobulinemic vasculitis. It is believed that cryoglobulin was sensitized by cold exposure owing to the dialysate temperature, which resulted in fever being experienced only after HD. Although treatment for vasculitis required prednisolone and rituximab, simple plasma exchange and a dialysate temperature of 37.5°C dramatically suppressed the occurrence of post-dialysis fever. Cryoglobulinemia should be considered as a potential cause of fever, as it may be a common occurrence in patients undergoing HD and could be overlooked as a possible cause of localized fever following HD treatment.

Effectiveness and safety of plasma exchange for anti-MDA5 antibody-positive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease refractory to intensive immune suppression therapy: A case series.

Clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) with rapidly progressive interstitial lung disease (RP-ILD) is often refractory for intensive immunosuppression. In this study, we verified the effectiveness and safety of plasma exchange (PEx) for this lethal disease. We retrospectively examined the clinical course and adverse effect (AE) of 12 patients with anti-MDA5 Ab-positive CADM between January 2017 and December 2021 in our hospital. Five out of six patients treated with simple PEx using fresh frozen plasma or 5% albumin survived with or without home oxygen therapy. Multiple PEx (15-20 times) were required to achieve satisfactory improvement as well as remission of CADM. The AEs caused by PEx were resolved using conventional methods. PEx might be a promising option for controlling the disease activity of anti-MDA5 Ab-positive CADM with severe RP-ILD and may contribute to better survival.

Establishment of an adverse effect prevention protocol on plasma exchange using fresh frozen plasma prior to ABO-incompatible living donor kidney transplantation at our hospital.

Simple plasma exchange (PE) with fresh-frozen plasma replacement allows antibody removal for ABO-incompatible living donor kidney transplantation, but is associated with a high incidence of allergic reactions. We developed, implemented, and evaluated a protocol for safe preoperative PE. The protocol comprised pretreatment (125 mg methylprednisolone infusion, 400 mg acetaminophen and 30 mg diphenhydramine orally) with a replacement fluid rate < 20 mL/min. Allergic reaction incidence was investigated in controls who underwent ABO-incompatible living donor kidney transplantation between 2016 and March 2020 (group C) and patients who underwent the protocol and procedure between April 2020 and February 2023 (group N). Ten (group C) and 19 (group N) patients performed 11 and 30 sessions of PE, respectively. Allergic reactions occurred in 81.8% and 36.7% (p = 0.014), respectively, with an odds ratio of the protocol was 0.056 (95% CI 0.0059-0.5380, P = 0.013). Our protocol resulted in a significantly lower incidence of allergic reactions.

Meta-analysis of the therapeutic value of plasma exchange simple or combined with dual plasma molecular adsorption system for liver failure

Objective: To systematically analyze the serological parameters, effective rate and survival rate of patients with liver failure after simple plasma exchange treatment and half-dose plasma exchange combined with dual plasma molecular adsorption system. Methods: Randomized controlled trials published in the full-text articles of Pubmed, Embase, Web of Science, The Cochrane Library, Wanfang, Weipu, CNKI, and other journals from June 2020 were retrieved. Revman 5.3 software was used to conduct the meta-analysis after the literature quality evaluation. Results: A total of 10 studies involving 884 cases were selected. Among them, 425 and 459 were treated with combination and simple plasma exchange therapy. The levels of TBIL (MD=-28.58, 95% CI: -37.42～-19.75, P<0.000 01) and ALB (MD=-2.00, 95%CI:-2.61～-1.39, P<0.000 01) were lower in the combined treatment group than those in the simple treatment group, and the difference was statistically significant. HGB (MD=5.96, 95%CI: 1.52-10.40, P=0.009), effective rate (OR=1.92, 95%CI: 1.29-2.85, P=0.001), and survival rate (OR=1.63, 95%CI: 1.13-2.36, P=0.009) were higher in the combined treatment group than those in the simple treatment group, and the difference was statistically significant.The two treatment methods had good curative effects for the improvement of ALT, AST, DBIL, PTA, INR, and PLT levels (P＜0.05), and there was no statistically significant difference between them (P＞0.05). Conclusion: Half-dose plasma exchange combined with dual plasma molecular adsorption system therapy not only effectively improves hyperbilirubinemia, efficacy, and survival rate while significantly reducing plasma dosage, but it also has fewer adverse effects on hemoglobin depletion in patients with liver failure than simple plasma exchange therapy.

Use of double filtration plasmapheresis for the treatment of acquired thrombocytopenic thrombotic purpura.

Double filtration plasmapheresis (DFPP) could be an alternative method to simple plasma exchange plasmapheresis in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). In a retrospective single center case series, we studied clinical presentation, management care, and prognosis of aTTP patients from our academic center treated with DFPP and IV infusion of fresh frozen plasma (FFP) between 2009 and 2018. Nine patients were included for 11 episodes. Median age was 38 years old (IQR 26-53) with 78% women. Six episodes (55%) required admission to the ICU, four of which required mechanical ventilation. Median FFP volume transfused was 35.2 mL/kg/d of session. Response was complete for nine episodes (82%). Four patients presented an early relapse, two a late relapse. Four patients died: one had an active untreated HCV infection, and two were over 80-year-old polymorbid patients. DFPP seems to be an efficient method of therapeutic plasmapheresis in TTP when combined with FFP transfusion and immunosuppressive treatments.

SAT-084 DIFFERENCE IN RATE OF DECLINE OF ISOAGGLUTININ TITERS BETWEEN SELECTIVE PLASMA EXCHANGE WITH AND WUTHOUT FRESH FROZEN PLASMA BEFORE ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION

Isoagglutinins removal by apheresis and immunosuppressive therapy are generally performed at pre-transplant desensitization of ABO-incompatible kidney transplantation. Selective plasma exchange (SePE) is a new simple plasma exchange (PE) modality that enables removal of small and medium-sized molecules without removing larger molecules, such as coagulation factors. Since 2015, we have always performed SePE using albumin solution in patients with a low isoagglutinin titers, or we added this approach in patients in whom the isoagglutinin titers was sufficiently decreased by double-filtration plasmapheresis (DFPP) and/or simple PE. However, although this procedure is advantageous in that it has fewer adverse effects, it also removes about 30% of coagulation factors, such as fibrinogen and factor XIII, and this is problematic in the perioperative period. Thus, we currently perform SePE using fresh frozen plasma (FFP) as part of the replacement fluid in patients with a decline of coagulation factors. We have had a favorable impression clinically with regard to the decline of the antibody titer with use of FFP. In this study, we examined if this impression was supported by a significant difference in outcomes.

Efficacy of selective plasma exchange as pre-transplant apheresis in ABO-incompatible kidney transplantation

BackgroundSelective plasma exchange (SePE) is a new simple plasma exchange (PE) modality that enables removal of small and medium-sized molecules without removing larger substances such as coagulation factors. In this study, we examined the efficacy of SePE for removal of isoagglutinins in pre-transplant desensitization for ABO-incompatible (ABOi) kidney transplantation.Materials and methodsA case series study was performed in 15 ABOi kidney transplant recipients (KTRs) who underwent SePE alone (7 cases) and SePE in combination with double-filtration plasmapheresis or simple plasma exchange (8 cases). The target processed plasma volume (PV) was set at 2 PV, and 5% albumin solution was used as the substitution fluid in all SePE sessions. Changes in isoagglutinin titers (IgG and IgM) and serum IgG, IgM, and fibrinogen levels were examined. We also compared the decrease in isoagglutinin titers between SePE and conventional methods (PE and double-filtration plasmapheresis).ResultsA total of 29 sessions of SePE were performed in the 15 KTRs. Isoagglutinin titers were controlled to ≤ 1:16 in all patients except for 2 with high isoagglutinin titers, and there were no cases of antibody-mediated rejection. SePE led to a median twofold decrease in isoagglutinin titers (IgG and IgM), with median IgG, IgM, and fibrinogen removal rates of 64.2, 11.7, and 25.5%, respectively. Side effects occurred in only 4 of the 29 sessions. Neither titer decreased after SePE in 30% of the sessions. However, the reductions in isoagglutinin titers in patients undergoing SePE were significantly less than those in patients treated with conventional methods.ConclusionBecause SePE is less efficient in removing isoagglutinins compared to conventional methods, the use of SePE alone should be limited to patients with low isoagglutinin titers, and SePE in combination with conventional methods should be used for patients with high isoagglutinin titers. SePE may be a useful treatment option, if applied in appropriate cases, due to its lower cost (about half the price of PE using fresh frozen plasma in Japan) and fewer side effects. However, care is required because about 25% of fibrinogen is removed during SePE.

Clinical Characteristics and Therapeutic Effects of Hospitalized Patients Who Underwent Simple Plasma Exchange

Clinical Characteristics and Therapeutic Effects of Hospitalized Patients Who Underwent Simple Plasma Exchange

Plasma exchange combined with double plasma absorption therapy improve the prognosis of acute-on-chronic liver failure

Objective: To compare the efficacy and safety of plasma exchange (PE) combined with double plasma absorption and simple PE in the treatment of acute-on-chronic liver failure. Methods: We retrospectively analyzed 251 cases of acute-on-chronic liver failure treated with artificial liver treatment since January 2015. Changes in clinical manifestations, laboratory tests, and complications of the patients before and after different modes of treatment were compared and short-term efficacy was tracked. In accordance with different data, t-test, Pearson's chi-squared test and Fisher's exact test were used for statistical analysis. Results: The effectiveness of low-volume PE combined with double plasma molecular adsorption system (DPMAS) and equal amount of PE combined with DPMAS was significantly better than simple PE (83.7%, 84.05% and 82.15 vs 55.6%, P < 0.05) in early stage of liver failure. In late-stage of liver failure, there was no significant difference in the treatment efficiency of each group (P > 0.05). Bilirubin and bile acid levels were significantly decreased in combined treatment groups than that to simple PE group (P < 0.05). PTA and albumin improvement rate of DPMAS PE groups were significantly lower than that of simple PE group (P < 0.05). There was no statistical difference in adverse reactions between each group. Conclusion: PE combined with DPMAS improves the treatment efficiency of early hepatic failure and decrease dosage of plasma when compared with simple PE. A beforehand DPMAS treatment after PE treatment can improve the adverse effects of DPMAS on blood coagulation function and albumin levels.

Prediction of immunoglobulin M reduction via therapeutic dose of simple plasma exchange and double filtration plasmapheresis using membrane separation in patients with hyperviscosity syndrome caused by Waldenstrom macroglobulinemia.

Plasma exchange (PE) and double filtration plasmapheresis (DFPP) are known as effective treatment options for hyperviscosity syndrome (HVS) caused by Waldenstrom macroglobulinemia. Nonetheless, few data are available for the relation between the prescribed dose of apheresis and the reduction rate of target molecule immunoglobulin M (IgM), especially in the modality using membrane separation. This study was conducted to establish a model to predict the IgM reduction rate by the dose of simple PE and DFPP using membrane separation in patients with HVS and to compare the consumption of albumin between PE and DFPP. We retrospectively analyzed data of total 17 sessions of PE and DFPP with various therapeutic doses performed for five patients at our institution. We used linear regression analysis to examine the relation between the ratio of processed plasma volume to estimated circulating plasma volume (X) and the reduction rate of IgM (Y). Regression analysis revealed that Y is expressed by X as the following equation: Y = 0.35X + 0.095. The total usage of albumin for replacement fluid was lower in DFPP than in PE (21.5 g vs 150 g per session), although the treatment efficacies of both modalities are similar. The dose of PE and DFPP using membrane separation can predict IgM reduction rate in the HVS patients. Predicted IgM reduction rates based on our model are lower than those calculated using a known theoretical model. In terms of the amount of use of albumin, DFPP is preferred to PE.

Short-term effect of additional apheresis on visual acuity changes in patients with steroid-resistant optic neuritis in neuromyelitis optica spectrum disorders.

To evaluate temporal changes in visual acuity in patients with steroid-resistant optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) after apheresis. Retrospective observational study, clinical case series SUBJECTS AND METHODS: We reviewed the medical charts of 15 eyes of 9 consecutive patients with ON in NMOSD who underwent apheresis between March 2010 and September 2017. All patients were seropositive for anti-aquaporin 4 (AQP4) antibody and resistant to steroid pulse therapy. Apheresis was performed by either simple plasma exchange or/and immune adsorption therapy. Twelve eyes (80%) showed improvement with logMAR > 0.3 at 1month after apheresis. Within 1month after apheresis therapy, logMAR on average significantly decreased, the magnitude of change being greatest within the first week. Thereafter visual acuity became stable in 10 of the 11 eyes, until 12months. However, two eyes (12%) showed recurrence of visual acuity reduction 3months after the cessation of apheresis. There were a few serious complications during and after apheresis, but these were completely treatable. Additional apheresis therapy rapidly improves the visual acuity of steroid-resistant seropositive AQP4 ON.

Treatment of rapidly progressive anti-GBM antibody-type glomerulonephritis with combination therapy involving simple plasma exchange and selective plasma exchange: a case report

Treatment of rapidly progressive anti-GBM antibody-type glomerulonephritis with combination therapy involving simple plasma exchange and selective plasma exchange: a case report

Selective Plasma Exchange for Critically Ill Patients Accompanied With Thrombocytopenia.

Selective plasma exchange is a blood purification therapy in which simple plasma exchange is performed using a selective membrane plasma separator (pore size of 0.03 µm). Seven critically ill patients accompanied with thrombocytopenia were treated with selective plasma exchange using fresh frozen plasma. The total bilirubin levels and prothrombin time international normalized ratios decreased significantly after treatment. The total protein, albumin, and fibrinogen levels increased significantly after treatment. Selective plasma exchange may be a useful blood purification therapy for removing causal substances and retaining coagulation factors in patients accompanied with thrombocytopenia.

Plasma Adiponectin Levels in Acute Liver Failure Patients Treated with Plasma Filtration with Dialysis and Plasma Exchange.

Plasma filtration with dialysis (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside of the hollow fibers. Improvement of hypoadiponectinemia is considered to be a useful therapeutic approach for ameliorating fatal conditions including cardio-metabolic and infectious disease. We investigated the effects of PDF in comparison to PE in terms of plasma adiponectin (APN) changes in patients with acute liver failure. Seventeen patients with liver failure were studied; PDF was performed 55 times and PE 14 times. Plasma APN levels increased significantly after PDF, while decreasing significantly after PE. PDF appears to be among the most useful blood purification therapies in acute liver failure cases in terms of increasing APN levels.

Removal Characteristics of Immunoglobulin G Subclasses by Conventional Plasma Exchange and Selective Plasma Exchange.

Selective plasma exchange (SePE) using a selective membrane separator is a modified method of simple plasma exchange (PE). Immunoglobulin G (IgG) subclass distribution is one of the important immunological characteristics of IgG. However, there is little information regarding the removal characteristics of IgG subclasses by SePE and conventional PE. Here, we investigated the removal ratio of IgG subclasses by PE and SePE in seven patients with immunological disorders. When the mean processed volume was 0.88 plasma volume (PV) (corresponding to 2.12 L), the mean percent reductions by PE were as follows: IgG, 63.2%; IgG1, 64.5%; IgG2, 64.0%; IgG3, 61.4%; and IgG4, 69.5%. When the mean processed volume was 1.18 PV (corresponding to 2.98 L), the mean percent reductions by SePE were as follows: IgG, 51.6%; IgG1, 55.3%; IgG2, 52.0%; IgG3, 53.7%; and IgG4, 64.6%. In both PE and SePE, using albumin solution as the supplementary fluid, IgG was effectively eliminated regardless of IgG subclasses.

Clinical Study of Simple Plasma Exchange in the Treatment of Severe Autoimmune Hepatitis

&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Plasma Exchange (PE) in the treatment of severe autoimmune hepatitis and the clinical outcome of the clinical data were retrospectively analyzed. The clinical efficacy and safety of single plasma exchange (PE) in the treatment of autoimmune hepatitis were also evaluated. &lt;strong&gt;Method: &lt;/strong&gt;The PE group of 22 patients was given conventional treatment of combined treatment of patients with simple PE while 21 cases of the control group were treated with comprehensive treatment. The efficacy of PE group and control group were compared within 2 weeks. &lt;strong&gt;Results&lt;/strong&gt;&lt;strong&gt;: &lt;/strong&gt;The clinical symptoms of 22 patients in PE group were significantly improved (&lt;em&gt;p &lt;/em&gt;&amp;lt; 0.05); in total bilirubin (TBIL), (AST), (INR), (ALT) where the PE group (17/22) 77.27%, and control group (10/21) 47.62%. The difference was statistically significant (&lt;em&gt;p &lt;/em&gt;&amp;lt; 0.05). &lt;strong&gt;Conclusion: &lt;/strong&gt;Pure plasma exchange (PE) is an effective method for the treatment of severe autoimmune hepatitis (AIH).&lt;/p&gt;

Clinical application of blood purification (artificial liver) in treatment of acute liver failure in children

To investigate the clinical application, indication, timing and prognosis of blood purification (artificial liver, BP) in treatment of acute liver failure in children. Artificial liver was used to treat 30 cases of pediatric acute liver failure (PALF), who were hospitalized in pediatric intensive care unit of Bayi Children's Hospital Affiliated to Beijing Military Command General Hospital, during March 2010 to July 2013. Simple plasma exchange (PE) mode was used for PALF without complications, while PE combined with continuous veno-venous hemodiafiltration (CVVHDF) mode was used for PALF with cerebral edema and/or hepatorenal syndrome and/or serious abnormality of electrolyte and acid-base balance. Sixteen cases survived and restored hepatic function, with a survival rate of 53.3%. Single PE therapy could significantly decrease total bilirubin (TBIL) from (293.96 ± 214.52) µmol/L to (155.64 ± 140.97) µmol/L (P = 0.033), increase prothrombin time activity (PTA) from (34.50 ± 18.34) % to (60.50 ± 33.97) % (P = 0.013), while it did not significantly influence ammonia from (156.43 ± 67.23) µmol/L to (124.03 ± 62.58) µmol/L (P = 0.156) and alanine transarninase (ALT) from (752.53 ± 1 291.84) U/L to (132.00 ± 98.57) U/L (P = 0.066). PE + CVVHDF therapy could significantly ameliorate TBIL from (326.90 ± 233.85) µmol/L to (157.53 ± 125.31) µmol/L (P = 0.033), ALT from (1 476.64 ± 1 728.18) U/L to (169.38 ± 207.18) U/L (P = 0.019), ammonia from (215.83 ± 83.92) µmol/L to (141.25 ± 63.09) µmol/L (P = 0.022) and PTA from (36.68 ± 23.13)% to (71.75 ± 50.50) % (P = 0.044). Prothrombin time (PT) from (29.71 ± 17.75)s to (16.27 ± 6.38)s (P = 0.008) , ALT from (1 574.11 ± 1 775.96) U/L to (145.81 ± 113.89 ) U/L (P = 0.003) , TBIL from (233.16 ± 219.70) µmol/L to (75.19 ± 86.07) µmol/L (P = 0.012) , ammonia from (182.75 ± 90.07) µmol/L to (101.81 ± 37.14) µmol/L (P = 0.002) and PTA from (38.38 ± 20.39)% to (83.13 ± 41.68)% (P = 0.001) in survived cases significantly ameliorated after BP therapy. TBIL from (394.04 ± 192.80) µmol/L to (249.34 ± 113.97) µmol/L (P = 0.023) in died cases declined significantly after BP therapy, while alteration of PT, ALT, ammonia , and PTA had no statistical significance (P > 0.10) after BP therapy. PE + CVVHDF therapy could significantly ameliorate not only TBIL and PTA but also ammonia and ALT compared with single PE therapy. The decline of only an index like TBIL or ALT after BP therapy could not improve the prognosis. The inconsistency between serum bilirubin and ALT levels was an important factor that suggested poor prognosis of ALF, and it might increase survival rate to use BP therapy before that inconsistency emerged.

Efficacy of continuous plasma diafiltration therapy

Acute liver failure (ALF) is a critical illness with high mortality. Plasma diafiltration (PDF) is a blood purification therapy in which simple plasma exchange is performed using a selective membrane plasma separator while the dialysate flows outside the hollow fibers. While several studies demonstrated that PDF therapy is a useful blood purification therapy for patients with ALF, PDF therapy is often difficult to employ in ALF patients complicated with multiple organ failure, especially in those with unstable hemodynamics. Furthermore, it is likely to re-occur immediately after PDF therapy. We developed continuous PDF (CPDF) as a new concept in PDF therapy, and assessed its efficacy and safety in ALF patients compared with conventional plasma exchange (PE) plus continuous hemodiafiltration (CHDF) therapy in this study.

Abstract 349: Effects of Continuous Plasma Diafiltration Therapy in Septic Shock With Acute Liver Failure

Background: Plasma diafiltration (PDF) is blood purification therapy in which simple plasma exchange is performed using a selective membrane plasma separator while the dialysate flows outside the hollow fibers. Several studies demonstrated that PDF therapy is one of the most useful blood purification therapies for use in cases of acute liver failure or severe sepsis. However, PDF therapy is very difficult to undergo in septic shock patients with acute liver failure because of unstable hemodynamics. Moreover, it is likely to deteriorate in acute liver failure immediately after PDF therapy. We have experienced that continuous PDF (CPDF) therapy can undergo in unstable patients with acute liver failure. Therefore, we evaluated the effects of CPDF therapy in septic shock patients with acute liver failure. Hypothesis: We hypothesis that CPDF therapy has beneficial effects for septic shock patients with acute liver failure. Methods: Nine patients (M/F 7/2, mean age 55 years) with septic shock, who combined acute liver failure, renal failure and respiratory failure, underwent CPDF therapy. The CPDF therapy was undergone for 7 days. Primary outcomes were changes in hemodynamics and inflammatory responses after CPDF therapy, and secondary outcomes were changes in liver functions and SOFA scores at 7 days after therapy and survival rate at 14days after therapy. Results: In primary outcomes, hemodynamics in all patients improved at one day after CPDF therapy. WBC counts improved (22,634 to 9,893; p&lt;0.05), C-reactive protein levels decreased (11.0 to 2.0 mg/dL; p&lt;0.05), and procalcitonin levels decreased (31.6 to 2.9 ng/mL; p&lt;0.05) at 7days after CPDF therapy. In secondary outcomes, total bilirubin decreased (8.3 to 3.4 mg/dL; p&lt;0.05) and PT-INR did not decreased (1.22 to 1.19) at 7 days after CPDF therapy. SOFA scores decreased (13.0 to 8.0; p&lt;0.05) at 7 days after CPDF therapy. All patients recovered and discharged in ICU. Conclusion: In the present study, CPDF therapy significant improved hemodynamics, inflammatory responses and severity in septic shock patients with acute liver failure.

The effect of different apheresis modalities on coagulation factor XIII level during antibody removal in ABO-blood type incompatible living related renal transplantation

Apheresis therapy is used to remove pathogenic antibodies within the recipient blood during ABO-incompatible living related renal transplantation (LRRT). Factor XIII (FXIII) is a coagulating factor. Its deficiency reportedly engenders perioperative bleeding. This study compared apheresis modalities from the perspective of the FXIII level. Cases 1–3 were treated only with double-filtration plasmapheresis (DFPP) without (case 1) or with (cases 2 and 3) fresh frozen plasma (FFP) supplementation. Cases 4 and 5 were treated with simple plasma exchange (PEx) with FFP supplementation for the last session. Cases 1–3 showed a marked (case 1, 8.6%) or moderate (case 2, 26.2%; case 3, 28.4%) decrease in FXIII on the day before the procedure after the last apheresis session, although cases 4 (81.9%) and 5 (66.2%) did not. Case 1 experienced perioperative bleeding. The last session is usually performed the day before the surgical procedure. Therefore, FXIII elimination by DFPP might cause bleeding complications because of its slow recovery. The fact warrants that the last apheresis modality during the course might be PEx from the viewpoint of FXIII depletion.