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Investigation: an investigation was conducted for this retrospective review of the existing literature using medline (pubmed) from inception to (b)(6) 2021 regarding tpe's impact on hemostasis.These include tpe's effects on platelets, coagulation proteins, fibrin formation, and cytokines.The authors highlighted the impact on hemostasis of the extracorporeal circuit, circuit anticoagulant, replacement fluid, number of tpe procedures, tpe schedule, and timing of the tpe procedure relative to invasive procedures.They also reviewed studies evaluating bleeding complications associated with tpe, highlighting the main risk factors as demonstrated in the literature.The review consisted of 36 journals using three devices, amicus, cobe spectra, and spectra optia.Both cobe spectra and spectra optia reportable adverse events will be documented in this investigation since the authors did not directly link the adverse events to the devices.The authors listed adverse events by categories and some without specific number of occurrences.Another study of 12 plasmapheresis donors showed persistent platelet activation, as measured by expression of p-selectin (0.7 ± 0.4 vs 45.3 ± 24.1%, p <.05), activated conformation of gpiib/iiia (0.8 ± 0.7 vs 55.4 ± 17.8%, p <.05), and platelet microparticle formation (0.4 ± 0.1 vs 11.6 ± 5.8%, p <.05), which persisted for up to 48 hours.Platelet microparticle release contributes to propagation of thrombotic processes and promotes clotting in the extracorporeal circuit.As a result, the extracorporeal circuit typically requires a circuit anticoagulant.In a study of 85 patients undergoing 225 tpe procedures, compared to citrate, heparin was associated with more bleeding complications (11.8% vs 0%).In another study of 1034 patients undergoing 9611 tpe procedures, bleeding complications were reported in 13 procedures, of which 85% (11/13) occurred with unfractionated heparin or low-molecular-weight heparin.In this study, bleeding complications were noted in 2 procedures without circuit anticoagulation.The finding of bleeding in the absence of anticoagulation is further demonstrated in a study of 44 patients undergoing 367 tpe procedures.Despite the absence of circuit anticoagulation, bleeding complications occurred in six cases (2%).The occurrence of bleeding in the absence of anticoagulation is likely due to the consumptive coagulopathy that develops when extracorporeal circuits are run without anticoagulation.When used as the only replacement fluid, 5% albumin does not restore coagulation proteins depleted during tpe.Thus, 5% albumin has been associated with increased hemostatic abnormalities following tpe, including prolongation of the clotting time and clot formation time in whole blood clotting assays.A study of 18 patients undergoing 179 tpe procedures measured blood component recovery between tpe procedures.With increasing intervals of one to four days between procedures, the index of recovery for both fibrinogen and platelet improved (0.81 ± 0.06 vs 1.09 ± 0.17 and 0.93 ± 0.05 vs 1.25 ± 0.15, respectively).In this study, the average time to fibrinogen and platelet recovery was 3 and 2 days, respectively.In six patients undergoing tpe, there was a cumulative effect of pre- to post-tpe factor level decrease when tpe was performed daily or every other day.Nevertheless, after three to four procedures, the slope of pre- to post-tpe factor level decrease leveled out.This study may suggest that after two to four procedures, coagulation factor levels enter into a steady state.The timing of the tpe procedure can affect bleeding outcomes in patients undergoing invasive procedures or receiving therapeutic anticoagulation.Tpe-induced coagulopathy could be aggravated by hemodilution and blood loss during invasive procedures.One bleeding complication (hemorrhagic stroke) occurred but was thought to be related to the underlying disorder not the tpe procedure.At a single center, bleeding complications after kidney biopsy were five times higher in tpe-treated vs nontreated patients (5.17% vs 1.03%, replacement fluid unknown).Bleeding complications associated with cvc use are noted in a number of studies.In a study of 381 tpe procedures in 63 patients, severe complications occurred in four patients with cvc (6%).Three out of four (75%) were bleeding complications, including arterial laceration, hemopneumothorax, and sternocleidomastoid hematoma.Another study of 44 patients undergoing 367 tpe procedures reported bleeding complications in six procedures with cvc (1.63%), including one major bleed requiring surgical intervention.These studies and others in the literature suggest that, when coupled with tpe-associated coagulopathy, cvcs have the potential to precipitate bleeding complications during line placement or removal.The effects of therapeutic anticoagulation on bleeding could be amplified by tpe-induced hemostatic effects.Tpe's hemostatic effects are strongly related to its removal of both procoagulant and anticoagulant proteins.Tpe also removes cytokines that may have indirect effects on hemostasis.Additionally, tpe inadvertently removes platelets, which further impacts hemostasis.Naturally occurring anticoagulants removed during tpe include antithrombin and protein c.As summarized in table 1, studies demonstrate that tpe decreases both antithrombin and protein c activity levels.Studies consistently show that tpe also decreases naturally occurring procoagulants, including fibrinogen and factors v, vii, viii, ix, x, xi, xii, and xiii (see table 1).Most decreases are transient, with factor levels returning to pre-tpe levels within 24-48 hours.The exception, however, is fibrinogen, which returns to baseline levels within 96 hours.Inadvertent removal of platelets tpe-associated coagulopathy could be exacerbated by removal of platelets, which can be lost in the plasma bag, and also clotting in the centrifuge bowl.Table 2 summarizes the effects of tpe on platelets levels.As shown in table 2, tpe can deplete platelet counts by up to 53%.Though transient, tpe-associated thrombocytopenia can both impair hemostasis and contribute to bleeding risk.Tpe-induced coagulation abnormalities can be demonstrated by several clotting assays, including the prothrombin time (pt), activated partial thromboplastin time (aptt), and thrombin time (tt).These assays can be prolonged by several variables, including, tpe-associated depletion of factors v, vii, viii, ix, x, xi, xii, prothrombin, and fibrinogen (see table 1).Table 3 summarizes the studies that demonstrate tpe's effects in prolonging the pt, international normalized ratio (inr), aptt, and tt.Table 4 summarizes studies evaluating tpe's effects on rotational thromboelastometry (rotem).Four studies assessed the effects of tpe on whole blood clotting assays.Three of these studies used albumin as the replacement fluid and one used plasma.Blood samples were collected no more than 30 minutes after the tpe procedure to measure changes in clotting time, clot formation time, and maximum clot firmness.Across all studies, clotting time and clot formation time increased, while maximum clot firmness decreased.These changes were each statistically significant in 2/3 studies for which p values were calculated.Taken together, these studies show that individual tpe-related coagulation abnormalities affect whole blood clotting in aggregate.Pediatric patients may be at higher risk for tpe-associated complications due to venous access limitations, extracorporeal volume relative to patient total blood volume, lower body weight, and challenges in anticoagulation management.Pediatric studies summarizing tpe-associated effects on coagulation are shown in table 3b.Similar to findings in adults, tpe with albumin replacement is associated with an increase in inr, pt, aptt, and tt.Tpe is also associated with decreased fibrinogen and antithrombin levels.As with adults, bleeding complications in the pediatric population are typically associated with risk factors such as cvc, anticoagulant therapy, and hypofibrinogenemia (see table 6).Bleeding rates appear to be on par with or lower than what is seen in adults (0-3%); however, pediatric studies suggest a higher use of plasma as replacement fluid.In five studies that evaluated pediatric complications of tpe, four studies reported plasma only replacement of 70% or greater.Pediatric bleeding rates may be higher with albumin use.In one pediatric study of 11 patients undergoing 66 procedures, bleeding complications were reported in 36% and hematomas in 27%; however, the replacement fluid was not reported.Since this is a retrospective review of the existing literature using medline (pubmed) from inception to november 9, 2021 regarding tpe's impact on hemostasis, the disposable sets were not available for return.Since this is a retrospective review of the existing literature using medline (pubmed) from inception to november 9, 2021 regarding tpe's impact on hemostasis, the lot numbers were not provided; therefore, a disposable lot history search could not be conducted.According to therapeutic apheresis: a physician's handbook, apheresis procedures require anticoagulation to prevent clotting of blood in the extracorporeal circuit.Citrate has become the anticoagulant of choice in this setting.It anticoagulates by chelating calcium ions and blocking calcium-dependent platelet activation and clotting-factor reactions.The challenge is to strike a balance between adequate anticoagulation and potential toxicity; achieving that balance requires an understanding of calcium metabolism and the effects of citrate infusion on calcium homeostasis.According to therapeutic apheresis: a physician's handbook, information on constituent clearance during tpe can be helpful in anticipating adverse effects.Table 2 contains a list of constituents including fibrinogen and clotting factor where as much as 2/3 or 1/4 to 1/2 may be removed, respectively.For example, rapid re-equilibration of potassium reduces the apparent efficiency of removal so much that patients rarely become hypokalemic during tpe, even when replacement solutions contain no potassium.Glucose and bicarbonate also are maintained during tpe.Most non-immunoglobulin proteins recover to nearly 100% baseline within 48 to 72 hours after tpe.A notable exception is fibrinogen, which is discussed in detail below.When plasma is exchanged with a non-plasma replacement solution, coagulopathy caused by dilution of coagulation factor is a potential problem.The prothrombin time and activated partial thromboplastin time rise and fibrinogen falls to an extent related to the intensity of the exchange.Despite these hemostatic alterations, hemorrhagic complications of dilutional coagulopathy are seldom encountered unless a patient is hemostatically compromised before treatment.Routine supplementation of replacement fluids with plasma or other sources of clotting factors is not recommended for nonbleeding patients whose baseline coagulation is normal.As mentioned earlier, redistribution and ongoing synthesis raise levels of most coagulation factors rapidly in the hours following an exchange.Fibrinogen is usually replaced more slowly and might be considered the rate-limiting factor determining the frequency of procedures performed without replacement of coagulation factors.However, the production of this acute-phase protein varies greatly among patients.Fibrinogen levels may decrease somewhat below 100 mg/dl if several procedures are performed on consecutive days.A level near 100 mg/dl is generally sufficient for hemostasis unless the individual has another hemostatic challenge.If fibrinogen decreases a great deal below 100 mg/dl, some physicians will then increase the interval between procedures of will use plasma replacement during the last part of the procedure to avoid a potential bleeding diathesis.Fresh frozen plasm (ffp) is the preferred source of fibrinogen, and it supplies other coagulation factors as well.Ffp is seldom required, though, if tpe is performed at intervals of 72 hours or greater.Hemorrhage is rarely reported in patients undergoing a tpe series without plasma replacement if there is no underlying predisposition to bleeding.According to therapeutic apheresis: a physician's handbook, adverse effects related to vascular access are a frequent concern.Hemorrhage or pneumothorax or both may complicate cvc insertion, while thrombosis and infection are the most frequently observed complications of prolonged central venous access.During a dressing change, the site should be cleaned and observed for signs of infection such as redness, swelling, drainage, and foul odor.If an infection is suspected, cvc removal should be considered, and the patient should be treated for infection as appropriate.The cause of a cvc flow problem may sometimes be difficult to determine, although patient repositioning will sometimes improve flow.A common situation is that the cvc can be flushed without resistance but does not yield blood return; this scenario may be the result of kinking, poor positioning, intralumenal clots, or venous thrombosis.Blocked cvcs can sometimes be cleared with a fibrinolytic agent such as tpa.The placement of a cvc is considered by some to be the greatest risk related to the apheresis procedures, and it should be avoided if the procedure can be performed using peripheral iv.According to therapeutic apheresis: a physician's handbook, with current centrifugal technology, reductions in platelet count are usually modest, and levels quickly return to baseline.In a severely thrombocytopenic patient, however, such a loss may mask the beginning of platelet recovery.Similarly, the small amount of red cells lost in the apheresis circuit may be more apparent in an anemic patient who has meager production capacity and who is receiving multiple procedures.Although generally well tolerated, the large-volume leukocytapheresis for stem cell collections in patients often results in a decline in hematocrit and platelet count, particularly because some red cells and platelets are incidentally removed with the stem cells.Article citation: soares ferreira júnior, a, hodulik, k, barton, kd, onwuemene, oa.2021.Hemostatic effects of therapeutic plasma exchange: a concise review.Journal of clinical apheresis.2022:1-21.Doi: 10.1002/jca.21973 root cause: a root cause assessment was performed for the activation of platelets.According to the authors "platelet microparticle release contributes to propagation of thrombotic processes and promotes clotting in the extracorporeal circuit." a root cause assessment was performed for the bleeding complications.The authors stated that "heparin was associated with more bleeding complications (11.8% vs 0%).In another study of 1034 patients undergoing 9611 tpe procedures, bleeding complications were reported in 13 procedures, of which 85% (11/13) occurred with unfractionated heparin or low-molecular-weight heparin.In this study, bleeding complications were noted in 2 procedures without circuit anticoagulation.The finding of bleeding in the absence of anticoagulation is further demonstrated in a study of 44 patients undergoing 367 tpe procedures.Despite the absence of circuit anticoagulation, bleeding complications occurred in six cases (2%).The occurrence of bleeding in the absence of anticoagulation is likely due to the consumptive coagulopathy that develops when extracorporeal circuits are run without anticoagulation.The timing of the tpe procedure can affect bleeding outcomes in patients undergoing invasive procedures or receiving therapeutic anticoagulation.Tpe-induced coagulopathy could be aggravated by hemodilution and blood loss during invasive procedures.One bleeding complication (hemorrhagic stroke) occurred but was thought to be related to the underlying disorder not the tpe procedure.At a single center, bleeding complications after kidney biopsy were five times higher in tpe-treated vs nontreated patients (5.17% vs 1.03%, replacement fluid unknown)." a root cause assessment was performed for the hemostatic abnormalities.The authors stated that "when used as the only replacement fluid, 5% albumin does not restore coagulation proteins depleted during tpe.Thus, 5% albumin has been associated with increased hemostatic abnormalities following tpe, including prolongation of the clotting time and clot formation time in whole blood clotting assays." a root cause assessment was performed for the blood component recovery between tpe procedures.The authors stated that "in six patients undergoing tpe, there was a cumulative effect of pre- to post-tpe factor level decrease when tpe was performed daily or every other day.Nevertheless, after three to four procedures, the slope of pre- to post-tpe factor level decrease leveled out.This study may suggest that after two to four procedures, coagulation factor levels enter into a steady state." a root cause assessment was performed for the tpe-induced coagulopathy.The authors stated that "tpe-induced coagulopathy could be aggravated by hemodilution and blood loss during invasive procedures.One bleeding complication (hemorrhagic stroke) occurred but was thought to be related to the underlying disorder not the tpe procedure.At a single center, bleeding complications after kidney biopsy were five times higher in tpe-treated vs nontreated patients (5.17% vs 1.03%, replacement fluid unknown)." a root cause assessment was performed for the bleeding complications associated with cvc use.The authors stated that "bleeding complications associated with cvc use are noted in a number of studies.These studies and others in the literature suggest that, when coupled with tpe-associated coagulopathy, cvcs have the potential to precipitate bleeding complications during line placement or removal." a root cause assessment was performed for the bleeding complications.The authors stated that "the effects of therapeutic anticoagulation on bleeding could be amplified by tpe-induced hemostatic effects.Tpe's hemostatic effects are strongly related to its removal of both procoagulant and anticoagulant proteins.Tpe also removes cytokines that may have indirect effects on hemostasis.Additionally, tpe inadvertently removes platelets, which further impacts hemostasis.Naturally occurring anticoagulants removed during tpe include antithrombin and protein c.As summarized in table 1, studies demonstrate that tpe decreases both antithrombin and protein c activity levels.Studies consistently show that tpe also decreases naturally occurring procoagulants, including fibrinogen and factors v, vii, viii, ix, x, xi, xii, and xiii (see table 1).Most decreases are transient, with factor levels returning to pre-tpe levels within 24-48 hours.The exception, however, is fibrinogen, which returns to baseline levels within 96 hours." a root cause assessment was performed for the platelet removal.The authors stated that "inadvertent removal of platelets tpe-associated coagulopathy could be exacerbated by removal of platelets, which can be lost in the plasma bag, and also clotting in the centrifuge bowl.Table 2 summarizes the effects of tpe on platelets levels.As shown in table 2, tpe can deplete platelet counts by up to 53%.Though transient, tpe-associated thrombocytopenia can both impair hemostasis and contribute to bleeding risk.¿ based on the available information a definitive root cause could not be determined but it is likely due to one or a combination of the possible causes listed below: - patient's underlying disease state - clumping in the extracorporeal system - running a lengthy procedure - inlet flow rate was set too high a root cause assessment was performed for the tpe-induced coagulation abnormalities.The authors stated that "tpe-induced coagulation abnormalities can be demonstrated by several clotting assays, including the prothrombin time (pt), activated partial thromboplastin time (aptt), and thrombin time (tt).These assays can be prolonged by several variables, including, tpe-associated depletion of factors v, vii, viii, ix, x, xi, xii, prothrombin, and fibrinogen (see table 1).Table 3 summarizes the studies that demonstrate tpe's effects in prolonging the pt, international normalized ratio (inr), aptt, and tt." a root cause assessment was performed for the tpe's effects on rotational thromboelastometry.The authors attributed the removal of clotting factors during tpe procedures as the cause for coagulation abnormalities.A root cause assessment was performed for the adverse reactions in pediatric patients.The authors stated that "pediatric patients may be at higher risk for tpe-associated complications due to venous access limitations, extracorporeal volume relative to patient total blood volume, lower body weight, and challenges in anticoagulation management.Pediatric studies summarizing tpe-associated effects on coagulation are shown in table 3b.Similar to findings in adults, tpe with albumin replacement is associated with an increase in inr, pt, aptt, and tt.Tpe is also associated with decreased fibrinogen and antithrombin levels.As with adults, bleeding complications in the pediatric population are typically associated with risk factors such as cvc, anticoagulant therapy, and hypofibrinogenemia (see table 6).Bleeding rates appear to be on par with or lower than what is seen in adults (0-3%); however, pediatric studies suggest a higher use of plasma as replacement fluid.In five studies that evaluated pediatric complications of tpe, four studies reported plasma only replacement of 70% or greater.Pediatric bleeding rates may be higher with albumin use.In one pediatric study of 11 patients undergoing 66 procedures, bleeding complications were reported in 36% and hematomas in 27%; however, the replacement fluid was not reported.".
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