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PLASMAPHERESIS

Therapeutic aphr is an Exc ttt that selectively eliminates the abnormal cells/substances in the blood associated with or inducing certain disorders.

 

PLASMAPHERESIS

 

 Abbreviations (Read twice please, to facilitate your reading):

 

o   A/S: albumin-saline

o   AABB: the American Association of Blood Banks

o   AB: antibody(s)

o   ACEi: angiotensin converting enzyme inhibitor. 

o   ACEi: angiotensin-converting enzyme inhibitors

o   ALI: acute lung injury

o   anti-GBM AB disease: anti-glomerular basement membrane antibody disease. 

o   Anti-GBM AB disease: anti-glomerular basement membrane antibody disease

o   APA: antiphospholipid syndrome

o   Aphr: Apheresis.

o   APO: acute pulmonary edema

o   aPTT: activated partial thromboplastin time

o   ASFA: American Society for Apheresis

o   Auto-AB: Autoantibodies

o   Aza: Azathioprine  

o   C: complement

o   CAG: Canadian Aphr Group

o   CBC: complete blood count

o   CMV: cytomegalovirus

o   Cph: cyclophosphamide.

o   Ctr: citrate

o   CVC: central venous catheter

o   d: daltons

o   Dphn: diphenhydramine

o   DX: dialysis

o   ECP: erythrocytapheresis

o   Ecz: Eculizumab

o   EO: ethylene oxide

o   EOD: every-other-day.

o   Exc: extracorporeal

o   FDA: Food and Drug Administration

o   FFP: Fresh Frozen Plasma

o   FSGS: focal segmental glomerulosclerosis

o   GI: gastrointestinal

o   GLCD: glucocorticoids

o   GN: glomerulonephritis

o   HBV: Hepatitis B virus

o   Hct: hematocrit

o   HCV: Hepatitis C virus

o   HDX: hemodialysis

o   HES: hydroxyethyl starch

o   Hf: hemofiltration

o   HIV: Human immunodeficiency virus.

o   HTLV: human T-lymphotropic virus

o   HV: Hyperviscosity

o   Hypo-Ca+Hypocalcemia

o   Ig: immunoglobulin

o   im/m: immunosuppressive

o   IVIG: Intravenous immune globulins

o   LL: light chains

o   LN: lupus nephritis

o   MG: Myasthenia gravis

o   mm: mucous membrane

o   MM: multiple myeloma

o   MR: Mortality rates

o   MS: multiple sclerosis

o   MW: molecular weight

o   NS: Normal saline

o   PE: plasma exchange (s).

o   PF24: Plasma Frozen Within 24 hs After Phlebotomy

o   Pred: prednisone

o   PT: prothrombin time.

o   PV: plasma volume

o   RBCs: red blood cells

o   RES: reticuloendothelial system

o   RF: renal failure

o   Rf: replacement fluid

o   Rtx: Rituximab  

o   SLE: systemic lupus erythematosus

o   Sms: symptoms

o   SOB: Shortness of breath

o   SOT: solid organ transplants

o   TA: Therapeutic apheresis

o   TPE: Therapeutic plasma exchange

o   TPN: Total parenteral nutrition

o   TRALI: transfusion-related acute lung injury

o   TTP: thrombotic thrombocytopenic purpura

o   ttt: treatment

o   tx: Transfusion

o   VWF: von Willebrand factor

o   WBC: white blood cell count

o   WM: Waldenström macroglobulinemia

 

TA is an Exc ttt that selectively eliminates the abnormal cells/substances in the blood associated with or inducing certain disorders. It can also be applied to provide cells or plasma constituents presented in subtherapeutic levels. I shall revise the indications for which TA is provided with practical guide for performing Aphr. Many indications are currently applied via TA therapy.

 

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TERMINOLOGY: describing Aphr & TA related procedures:

o   Apheresis (Aphr): A general term for removal = "taking out" a target cell/substance from blood. Aphr may include Plasm-Aphr (plasma) & cyt-Aphr (blood cells).

o   Pheresis: The term "pheresis," is NOT currently applied.

o   Plasm-Aphr: denote selective elimination of plasma separated from blood via centrifugation /filtration. Plasm-Aphr is mostly performed to collect plasma from a healthy blood donor for tx (i.e., donated plasma). 

o   Therapeutic Aphr (TA): denotes plasma replacing with another fluid e.g., colloid, crystalloid, or allogeneic plasma; or eliminating or replacing of abnormal or excessive cells to achieve certain clinical benefits.

o   TPE: Was historically applied synonymously with "TA" as in the past only “plasma” was provided as Rf. However, now TPE is used directly for procedures involving sole replacement with “plasma”. TPE is also referred to as PE or therapeutic Plasma-Aphr and involves removing ptn plasma with replacing with allogeneic/autologous plasma. According to US/FDA, plasma eliminated during PE must not be re-used for tx to another ptn.

o   Therapeutic cyt-Aphr (hem-Aphr): Denotes selective elimination of abnormal blood cell (s) (e.g., sickled cells [ECP, RBC exchange]) or excessive quantities of cells (e.g., platelets [thrombocyte-Aphr], WBCs [leukocyt-Aphr]).

o   Dialysis (DX): A diffusion-dependent ttt best applied for removing fluids or small molecules (e.g., uremic toxins, certain drugs) from the blood through a dialyzer. Fluids can be removed via filtration (convection); while solutes can be eliminated by diffusion.

o   Plasma filtration: A technique separating plasma from cellular constituents with a greatly permeable filter (plasma filter) via a DX or Hf machine. 

 

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INDICATIONS

Rationale/benefits of TA: The basic technique of TA is that elimination/lowering the levels of certain pathological agents from plasma, prevents further destruction or reversing pathological process (see table 1). This pathological substance could be an auto-AB, immune complexes, cryoglobulin, myeloma LC, endotoxin, cholesterol-carrying lipoprotein, etc... TA process may involve the passage of venous blood through an Exc device separating blood into its major constituents (cells & plasma), shunting most of the targeted pathological cells or plasma onto a discarding room, and returning most of the remained blood into the ptn, in addition to Rf & normal cell(s), with short-acting anticoagulation (commonly Ctr).

Suggested Rf include the ptn's own plasma from which the harmful substance has been eliminated or healthy donated allogeneic plasma, colloid, or crystalloid. In certain cases, using allogeneic plasma is preferrable as it supplies the required proteins and other agents. However, donor’s plasma should only be provided as Rf in certain settings e.g., TTP with ADAMTS13 deficiency. In the other settings, use of the proper non-plasma Rf removes unnecessary exposing to an allogeneic plasma. Considering the target substance for elimination, one of the following settings, at least, should be available for TPE to be considered as a reasonable therapeutic option:

o   Have sufficient long ½-life so that Exc elimination is more fast than endogenous clearance.

o   It should show acute toxicity and/or resisting the conventional therapies, so that the rapid removal from the extracellular fluid via TA is highly indicated.

o   It should be large enough, (MW > 15,000 d), so that it could not be easily eliminated via less expensive purifying techniques e.g., Hf or high-flux HDX.

TA is highly efficacious for the eliminating pathological auto-AB. IgG has an average MW > 150,000 d & ½-life of almost 21 d. So, even if im/m therapy may immediately hold the new AB formation, the plasma level would decline only by 50 % within 21 ds. Such a delay may not be accepted with an aggressive Auto-AB behavior like that observed in anti-GBM AB disorder.

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TA own many other potential benefits including de-loading the RES that can trigger the endogenous elimination of the circulating toxin(s), enhancing lymphocyte clones to stimulate cytotoxic therapy, with possible reinfusion of large plasma volume and lowered risk of volume overloading. Infusing allogeneic plasma is specifically crucial in acquired (autoimmune) or congenital TTP. In acquired, autoimmune TTP, TPE plasma administration as the Rf could be lifesaving. Here, TPE works both by eliminating the very high MW VWF multimers & Auto-AB to the ADAMTS13 protease that cleaves VWF multimers, in addition to supplying additional ADAMTS13. For certain indications, TA can be dealt as 1st line therapy (e.g., TTP, acute Guillain-Barré syndrome), whilst in others e.g., LC cast nephropathy in MM, Aphr may be required to be supplemented with other established ttt s e.g., chemotherapy to halt AB formation. 

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Common indications of TA: In the US, most TA procedures are introduced for neurological, immunological, or hematological diseases. A collaborative study by AABB & ASFA showed: > one ½ of all procedures were proceeded for neurological disorders e.g., Guillain-Barré syndrome or MG. The CAG has reported increasing indications of TA for hematological disorders constituting 55 % of all TA procedures applied in 2003; application of TA for neurological disorders had declined from 50 % in 1988 to 40 % in 2003. This alteration is reflecting the increased application of evidence-based medicine and the progress in pharmacological ttt that may reflect Aphr replacement as standardized ttt in certain setting, e.g.,

1)    HV

2)    Renal disorders    

3)    Acquired (autoimmune) TTP 

4)    Neurologic syndromes.

Historically, MS, SLE, and rheumatoid arthritis were managed via TA, but this attitude usually was not dependent upon evidence from RCT. The advent of this complex/expensive ttt in the absence of sufficiently supporting evidence triggered the evolution of evidence-based guidelines instead of the anecdotal reports or data relying upon small series or uncontrolled studies. 

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Indications of therapeutic cyt-Aphr: In contrary to the routine TA, therapeutic cyt-Aphr can be applied to limit the abnormally higher cell counts, removing abnormal cells, or, as in acute sickle cell disorder, removing cells that contain sickled HB, replacing them with normal RBCs from healthy donors. The provided CBC will show whether declined cell counts have been reached. With RBC exchange applied in sickle cell disease, the HB and % of HBS” can be determined to assess Aphr efficacy.

o   In hyperleukocytosis, the targeted post-cyt-Aphr WBC is <100,000/microL.

o   In thrombocytosis, the targeted platelets’ count is <1,000,000/microL.

ASFA therapeutic categories: A standard review of TA indications depending upon literature review (s) is currently publishing every 2-3 ys by the ASFA. Settings were assigned to 1-4 categories according to the evidence magnitude of clinical efficacy as recognized by peer-reviewed literature assessment. The guidelines were not mandating TA for situations that is clearly not efficacious, nor excluding ptns from managed by TA with certain possible benefit (s). Considering its complexity/expense, however, the guidelines may provide a definite framework for decision-guiding. ASFA categories’ summary available in the 2019 guidelines. Certain diseases for which an evidence was re-evaluated for the 2019 update may include TA for devastating APA that was changed from category II to category I. Many settings were elevated from category III to category II, including thyroid storm, lipoprotein Aphr for FSGS, and immunoadsorption for acute episodes in MS.  These categories were recognized as follows:

o   Category I: Disorders with Aphr is the " 1st line ttt”, either as sole ttt or conjugated with other modalities, e.g., Guillain-Barré syndrome or acquired autoimmune TTP, & ECP in complicated sickle cell disease e.g., with stroke. 

o    II: Aphr can be accepted as “2nd line ttt," either as a sole ttt or conjugated with others, e.g., life-threatening hemolytic anemia (cold agglutinin dis.) or Lambert-Eaton myasthenic syndrome.

o   III: " role of Aphr is not established." Decision of ttt should be individualized, e.g., TPE for hypertriglyceridemic pancreatitis or Exc photopheresis for nephrogenic systemic fibrosis. 

o   IV: evidenced Aphr as ineffective/harmful" e.g., active rheumatoid arthritis.

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TECHNOLOGY

TPE is mostly performed via centrifugation device known as Aphr instruments that is used for collecting blood constituents in healthy donors. These tools may offer more advantage for selective cell elimination (cyt-Aphr).

Venous access: Effective TA may require patent vascular access that may be 2 large, durable peripheral veins or centrally placed dual-lumen catheter, rigid enough to afford the desired blood flow pressure; the proper lines are Aphr/DX catheters. A radiographic-confirmed catheter placing is crucial to halt perforation of any adjacent tissue/organ and also because cardiac arrhythmias may be induced via Ctr anticoagulation that binds ionized Ca+, is infused near by the SA node. Peripheral veins may offer avoiding sequalae related to a CVC but can be associated with slower blood flow with prolonged procedure timing that may make peripheral access non beneficial or inducing discomfort to the ptn. It may be reasonable to insert a CVC to manage conditions warranting many procedures along a long period of time.

Exchange volumes: The standardized practice is mostly proceeded via 1-1.5 PV exchanges/procedure. Exchanging the 1st 1-1.5 plasma volumes eliminates the greatest concentration of the target substance that decreasing the amount of elimination in the next exchange sessions. One single PV exchange in an average-sized adult subject consumes about 3 L of Rf. Generally, large MW components equilibrate smoothly between the vascular space & interstitium. So, calculating the rate of elimination via TA can be focused on the 1st order kinetics. One single PV exchange can decline the plasma macromolecule values by 60 %, and an exchange = 1.4 times the PV can decline the plasma levels by 75 %. The following formula could be applied to assess the PV in most adults:

Estimated PV (L) = 0.07 x wt (kg) x (1Hct)

The American Red Cross Comp. of tx Guidelines, 3rd edit., provides a function for assessment of total blood, RBCs, & PV.

Exchanging > 1-1.5 PV in a single ttt will prolong procedure time, challenging ptn tolerance, and elevates its cost. E.g., cell separators can proceed in one completed volume exchange in 1.5-2 h.s; 2-3 PE will double/triple the timing warranted to complete the procedure.

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Replacement fluids (Rf s): The ptn's fluids eliminated via Aphr should be replaced immediately to prevent severe volume depletion. 5 % albumin, Saline, or a combined A/S are mostly the Rf of choice. Optimal option usually varies according to the clinical situation. 5 % albumin is currently used for many conditions; saline for HV; and combined albumin/saline if cost is considered. The 5 % albumin or combined crystalloid-colloid (i.e., A/S) as the preferred Rf, instead of saline alone. We advise plasma only be provided as the Rf for situations that plasma constituents are essential for achieving certain therapeutic target (e.g., TTP). The concentration of 25 % albumin should Not be provided unless it is diluted to a level of 5 %.

 

o   5 % albumin: The major advantage of 5 % albumin: markedly lowered risk of transmitted pathogen & anaphylactic reaction. However, a post-Aphr dilutional coagulopathies due to depleted coagulation factors and a net depletion of Ig can be observed.

o   Albumin/saline (A/S): If combined colloid + crystalloid solutions are used, colloid amount should not be < 50 % of the totally infused Rf. The proper Rf may consist of 1:1 of 5 % albumin to whole blood and a 2:1 ratio of Saline to whole blood for the remainder, e.g., if a 3000 mL exchanged and 1500 mL of 5 % albumin is given, 3000 mL of saline should be provided to replace the other 1500 mL of ptn fluid.

o   Saline: NS alone is not enough to provide suitable oncotic pressure leading to evident edema and/or hpt. So, 5 % albumin or combined A/S are preferred. However, for certain reasons saline may be used, e.g., albumin is not available or allergic.

o   Plasma: Plasma can be provided in the form of FFP, PF24, Thawed Plasma, etc... 

 

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Plasma is replacing the proteins eliminated by Aphr so that greater depletion of coagulation factors or Igs would not be observed with successive daily procedures. However, other sequalae are more common with plasma compared with albumin (see below).

Aphr schedule: The TA schedule is primarily depending upon the nature of the target substance and by the desiring endpoint (e.g., clinical improvement or reduction in the level of the pathologic entity). In immunological, paraproteinemia, or HV states, Ig compartmental shifting, particularly IgG/IgM, must be assessed, where TA only considered an adjuvant role as those ptns are currently receiving concomitant chemotherapeutics or im/m therapy.

o   IgM: Almost 75 % of IgM being intravascular. So, only 1-2 sessions are for IgM decline.

o   IgG: Only 45 % of IgG is intravascular, and within 48 hs, plasma IgG can return to 60 % of its pre-Aphr level. The produced IgG amount is also characterized by a "rebound" phenomenon, and cessation of TPE after several procedures can result in pre-ttt or even higher levels of IgG, especially if the ptn is not on im/m therapy. Consequently, a more rigorous regimen involving several TA procedures and the institution of im/m therapy are crucial to reduce IgG levels significantly.

If - due to concurrent im/m therapy- we assume a negligible Ig production rate, with the rate of extra- to intravascular equilibration is 1-2 %/h., then 5 separate sessions along 7-10 ds are required to eliminate 90 % of the total initial Ig body burden. Additional ttt (s) may be needed with new AB production. The AABB generally recommends for situations requiring TA: one exchange be provided every 2nd or 3rd d., each one composed of 1-1.5 plasma volumes for, totally 3-5 procedures, with following Exceptions:

o   Acquired TTP: TPE is provided on daily bases. 

o   Goodpasture's syndrome: TPE provided daily or EOD. 

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Lab evaluation: is usually depending upon:

1)    The type of Rf.

2)    The targeted endpoint of therapy,

3)    The No. of planned procedures, &

For plasma-free TA, a baseline CBC, Ig values, and coagulation & electrolyte profiles should be provided. With serial or several closely spacing procedures were planned, more frequent lab assessment may be required. Ptn on therapeutic cyt-Aphr, the proper cell count will recognize the magnitude of cyt-Aphr adequacy.

 

 

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Complications of TA

 

 

TA is an Exc ttt separating blood components (plasma and/or cellular constituents) from the ptn's blood for ttt of disorders in which a pathological agent in the blood causing morbidity. TPE informs the selective elimination of a ptn’s plasma with replacing with another fluid; cyt-Aphr denotes selective elimination of abnormal/excessive No. of blood cells.

OVERVIEW

The basic concept of TA is that eliminating certain pathological material (or cells, in cyt-Aphr) will limit organ/tissue damage, permitting reversing the pathological process. To halt volume depletion during TA, the eliminated volume of plasma should be replaced via plasma, colloid, or crystalloid. However, certain sequalae varying according to whether the Rf is allogenic (donor) plasma or was an albumin.

o   Donor plasma is preferrable in TTP as it provides the ADAMTS13 enzyme.

o   Donor plasma should be prohibited if Aphr is strictly removing a protein or another agent.

The frequency/types of TA sequalae are usually depending on the general ptn’s condition, the frequency of procedures, Rf, and the inlet to the venous access. Review: the reported sequalae from > 15,000 TPE ttt(s): adverse events were eventually more commonly seen with plasma compared to albumin replacement (20 vs 1.4 %). In therapeutic cyt-Aphr, levels of target cells have been lowered. If ECP is applied as ttt/prophylaxis for sickle cell disease, RBCs obtained from donors -ve for sickle cell trait are currently used for replacing. Other cyt-Aphr types, however, e.g., leuk-Aphr for hyperleukocytosis or platelet Aphr thrombocytosis usually not requiring Rf. In TA with Ctr-containing anticoagulant, Ctr-induced hypo-Ca+; metabolic alkalosis or vascular access-related complications can be observed. If blood products (plasma or RBCs) were used, the risk of Ctr-related sequalae is usually greater due to the impact of Ctr that is currently added to blood components during collection. Moreover, ptns receiving blood products for Rf are at risk of tx complications with tx-transmitted pathogens. For TPE, if albumin and/or crystalloid is used as Rf, ptns may also be at risk of depleted coagulation factors or Ig.

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o   Any Rf: Ctr-related hypo-Ca+ Sms (Ctr bound ionized (free) Ca+), used for anticoagulation, including [paresthesia, nausea & vomiting, muscle cramp, chest pain, Hpt, and, in severe cases, tetany or arrhythmias e.g., prolonged QT].  

o   Non-plasma Rf for PE: may induce hypo-k+, declined coagulation factors and/or Ig level, or Hpt if the ptn receiving an ACEi.  

o   Donor plasma or RBC exposure: Allogeneic (donor) plasma/RBCs may induce severe sequalae, e.g., hemolytic tx reaction (if out-of-group products are given), severe anaphylaxis, or TRALI, with higher risk of tx-transmitted pathogens. Blood products should follow the standard regulations. Any alteration in ptn's status (e.g., SOB, seizures, chest pain, & Hpt not responding to 1-2 fluid boluses) should invite TPE withdrawal and assessment for the Sms etiology. The overall incidence of TPE MR = 0.03-0.05 %.  

 

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[1] ANY Rf

Ctr-induced hypo-Ca+: Generally, a solution of Na+ Ctr is provided as an anticoagulant for the Exc procedures. Ctr can bind to ionized Ca+ constituting soluble Ca+ Ctr, declining the ionized (possibly total) SCa+ levels. Ptns with normal hepatic function, Ctr is usually metabolized within 1.5 hs. However, with prolonged TPE) or RBCs exchange procedure, Sms of Ctr toxicity can be frequently observed if not alleviated. Earlier Sms of Hypo-Ca+ may include peri-oral & lower extremity paresthesia or numbness. Intense reaction may include tetany, prolonged QT interval, arrhythmias, or Hpt.

ECG monitoring with intra-procedural assessment of ionized Ca+ values may be mandated in ptns receiving IV Ca+, and showing Sms, or being at risk of severe Ctr sensitivity, including ptns with altered sensorium or pediatric ptns who are cannot express early Sms of Hypo-Ca+. Plans limiting Ctr-induced Hypo-Ca+   may include:

o   Firstly, slow down the rate of exchange that may be enough to induce Sms resolution.

o   Slowly IV infusion of one 10 mL ampule (10 % Ca+ Cl-) over 15-30 min., beginning 15 min. after TPE start. Repeated the infusion if the procedures last > an hour.

AAK experience: this regimen declines symptomatic hypo-Ca+ incidence from 9.1 % to 1 %.

JLF: oral Ca+ supplements can alleviate/possibly treat mild hypo-Ca+, reserving IV Ca+ for ptns who cannot consume oral Ca+ or for severe hypo-Ca+ or Sms not improving with oral Ca+. 5-10 mL of 10 % Ca+ gluconate given IV over 10-15 min can reduce Sms if oral Ca+ is not efficacious; muscle contraction may ensue if Ca+ Cl- or Ca+ gluconate is provided fast.

Alternate approach: IV Ca+ gluconate, provided as continuous infusion of 10 mL of 10 % Ca+ gluconate per 1000 mL, can halt Ctr intoxication.

Ctr-induced metabolic alkalosis: Metabolized extra Ctr may generate HCO3, with its excretion is confined by Rf. Ctr-related metabolic alkalosis in subjects with kidney impairment can be controlled by HDX. Ptns with RF requiring TA may need HDX after the procedure to correct acid-base, electrolyte, & fluid balancing as required.  

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Removing medications: appropriate drug elimination via TPE should be expected for medications that’re greatly protein-bound, with minute distribution volume, and so, mainly limited to the intravascular space, and also for therapeutic AB.

1)    Pred/prednisolone: NOT lowered, whilst Cph & Aza can be eliminated to some extent.

2)    Therapeutic AB e.g., Rtx & Ecz are totally removed, a problem that can be limited by providing the drug after the procedure.

3)    TPN fluids must be infused after the procedure.

4)    IVIG is not commonly infused after TPE, but if a ptn undergoing TPE is ttt with IVIG (e.g., for severe infection), the IVIG must be administrated after the procedure.

 

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CVC complications: may include infectious episodes, pain, nerve injury, thrombotic sequalae, perforation, dissecting hematoma, embolic complications, or A/V fistula. Many of these may be also seen with peripheral venous access. Application of peripheral venous access may prevent some of the complications seen with CVC, but this cannot be easily applied due to the slow blood flow via peripheral catheterization that prolongs the timing needed for the procedure causing more ptn discomfort. Confirmed the correct placing of the vascular access is a standardized practice to limit many of these sequalae and is also recommended by the AABB cellular therapeutic standards.

[2] NON-PLASMA Rf

Hypok-K+: Non-plasma Rf can induce a 25 % decline in the post-Aphr plasma K+, due to dilutional impact. In subjects at risk for K+ depletion (e.g., owing to depletion, dilutional effect, or Ctr-induced alkalemia), K+ level should be monitored immediately post-Aphr with rapid K+ correction.  

Hypo-Ca+: The largely infused volumes of albumin may have a role in Hypo-Ca+ evolution. Study: 32 ptns receiving 10 % pentastarsh (type of HES) vs 5 % albumin during 1st ½ of an Aphr procedure. The mechanism of Hypo-Ca+ could be binding of Ca+ to the infused albumin. The risk of Hypo-Ca+ was less with pentastarsh than with albumin (hypo-Ca+ Sms in 8 vs 33 %).

Coagulation factor depletionTPE with albumin/other non-plasma Rf leads to frequent losses in coagulating factors predisposing to bleeding tendency. After a single PV exchange, PT may rise by 30 % and the aPTT may be doubled; these alterations may return to normal after 4 hs. However, more intense/Longley-lasting alterations can result from several exchanges provided shortly in timing (e.g., 3 or more ttt (s)/wk). In ptn requiring several TPE procedures, a baseline evaluation of coagulating status by assessing the PT, aPTT, and/or fibrinogen level should be provided before commencing TPE; with repeated testing daily or EOD. Ptns at risk of bleeding (e.g., after kidney biopsy for anti-GBM disease), one or more L. of plasma (3-4 units of plasma/L) may be instituted as the Rf that should be provided by the end of the procedure. An alternate is to permit the coagulating factor level to be normalized before commencing the procedures with risk of bleeding, e.g., waiting 24 hs after the last TPE ttt before getting off a large-bored vascular access.

Ig depletion: Repeated TPE with a non-plasma Rf will commonly depleting ptn's Igs, leading to lowered serum IgG & other Ig values. The indication for monitoring serum IgG is currently depending upon several factors, e.g., frequency of the procedures, number of the exchanged blood volumes in each procedure, immune status of the ptn, and the ptn's ability to provide Igs.

Removing Igs & C may induce immunodeficiency, making the ptn vulnerable for infections. Reports about TPE for GN therapy suggested a rise in opportunistic infection rates. However, these ptns received im/m agents and were frequently granulocytopenic. Trial: 86 ptns with LN to TPE or im/m agents, TPE was not complicated with a higher risk of infection and ptns were not more vulnerable to infection. With aggressive TPE, e.g., 2-3 plasma volumes replacements per procedure and/or successive daily sessions, with no plasma replacing, a baseline IgG values should be monitored. Ptns with IgG level falling < 500 mg/dL and having a systemic infection, or at risk of severe infection, we can provide a single infusion of IVIG; 100-400 mg/kg, despite IgG replacing has not been assessed in this setting.

ACEi-related complications: Rarely, Sms resemble anaphylaxis, e.g., flushing, Hpt, abdominal cramps, and other GI Sms, have been observed during TPE in ptns on ACEi therapy. These Sms have been reported if albumin was given as a Rf and the ptn had received an ACEi within 24-30 h of TPE. Report: 299 consecutive ptns performing TPE, these Sms occurred in all 14 ptns receiving an ACEi vs only 7 % in those not receiving an ACEi. The explanation of these Sms is not clear; one possible cause is higher kinin generation that has been accused to induce the angioedema seen with ACEi therapy. According to these observations, it has been advised that ACEi be withdrawn for 24 hs before TPE if the ptn can afford a transient discontinuation. Managing this sequala is mainly supportive. With future planned TPE, a different lot of albumins should be provided, as kinin levels are varying among different albumin lots.

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[3] DONOR PLASMA/RBCs EXPOSURE

Anaphylactic reaction:  to plasma have been observed as a serious complication and possible cause of death with TPE therapy. These reactions have been observed in up to 21 % of ptns usually with pyrexia, rigor, urticarias, wheezes, and Hpt. Cardiopulmonary collapsing is rare.  Management may include antihistamines, epinephrine, GLCD, or more aggressive agents, according to Sms intensity.

Anaphylaxis may be attributed to the finding of anti-IgA AB in ptn with IgA-deficiency reacting with IgA present in donor plasma. With anaphylaxis attributed to anti-IgA, it is crucial to provide plasma obtained from IgA-deficient donors that could be available from the registered rare donors, and it may be difficult to provide enough number of plasma units to apply several TPE sessions.  If plasma from an IgA-deficient donor is not available, we may provide a non-plasma Rf e.g., albumin.  Rarely, AAK author has the ability to use pre-ttt ephedrine, GLCD, and Dphn in a ptn with a history of anaphylactic complications to plasma and so successful TPE for TTP within 2 pregnancies have been performed.

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Hives: In contrary to anaphylactic reactions, allergy characterized by urticaria and/or pruritus can often be managed by transient withdrawal of the procedure, Dphn or GLCD (if needed), with strict monitoring of the ptn with worsened Sms. The procedure can be resumed if Sms alleviated. Allergic Sms e.g., hives are considered to be due to pre-formed IgE AB in the recipient/donor reacting with a substance in the donor/recipient, resp (e.g., donor peanut allergy, with hives stimulation due to recently consumed peanut by the recipient).  

TRALI (tx-related ALI): It is a type of ALI often induced by AB in donor plasma reacting with "cognate" or "matching" Ags on ptn neutrophils that may result in leukoagglutination in the pulmonary circulation & non-cardiogenic pulmonary edema. TRALI typically presented as abrupt onset of hypoxic respiratory insufficiency, and bilateral pulmonary infiltrations on chest radiology within few hours of blood product exposition. Ttt is supportive, but with clinical deterioration, ptn may need to be intubated.

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Infection with plasma/RBC:  per-unit risk of tx-acquired viral infection in US [table (2)].  

POSSIPLE COMPLICATIONS

Sms observed during Aphr may be due to volume shifting, metabolic sequalae, or reaction to plasma/RBCs. The BP, temperature, and other vital Sns should be monitored during Aphr, e.g., every 10-15 min according to the ptn’s hemodynamic status. In symptomatizing ptn we may consider the following:

[1] SOB: Causes may include:

1)    Tx-related ALI should be considered if plasma was provided as a Rf.  

2)    APO due to fluid overload.

3)    Bronchospasm, hives, or mm swelling could be a Sn of an impending anaphylaxis that can be attributed to plasma or RBCs-contained plasma.

4)    Air embolism: bubbles in the line or pulmonary emboli (inadequate anticoagulation). This’s unlikely as sensors can identify clotting with triggering alarm to alert the staff.

5)    Rarely: SOB, wheezes, chest pain, and Hpt resistant to fluid bolus (s) may be related to C-mediated via bio-incompatible membrane effect or EO sensitivity (membrane sterilant).

[2] Hypotension (Hpt): Causes of Hpt may include:

1)    Ctr-related hypo-Ca+ with any blood product, but more evident with plasma.

2)    Diminished intra-vascular volume can complicate any procedure that can be explained by the presence of about 200 mL of ptn blood within the Aphr kit tubing & centrifuge. The exact amount is usually provided by the manufacturer. With recent flow techniques, the Exc volume is often not > 15 % of the ptn's intravascular volume; however, techniques using interrupted flow technology may experience greater Exc volume. The following maneuvers can resume BP toward its baseline if Hpt is mainly caused by fluid shifting:

1.    Slow down the procedure, or

2.    Enhancing the returning rate

3.    Add more infusion to the intravascular volume,

3)    Coronary events e.g., acute coronary syndrome may occur with Hpt & chest pain. If ptn has such Sms, the procedure should be halted and ptn assessed for cardiac ischemia.

4)    Vasovagal attacks: not commonly seen but may present as Hpt associated with bradycardia, sweeting, syncopal episodes, and/or GI Sms. Lowering ptn's head, providing ammonium salt, and transient cessation of the procedure are usually effective. Moderate fluid bolus (s) with NS can also alleviate ptn's Sms if the extra fluids can be tolerated.


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 MORTALITY

The reported MR for TPE is 3-5 per 10,000 (0.03-0.05 %). In > 50 TPE-related deaths since 1989, respiratory or cardiac sequalae were most common. Cardiac arrhythmias are frequently reported, particularly in ptns receiving plasma. The culprit etiology was a decreased ionized Ca+ levels, but a cause-related-effects relation has not been shown. Among respiration-related deaths, acute respiratory distresses & Sms of non-cardiogenic APO were seen shortly prior to death; these ptns have also received plasma. Anaphylactic reaction, vascular sequalae, hepatitis, septic complication, and thrombosis were less commonly inducing causes of mortality. Considering the recent progress in donor testing, HIV, hepatitis, and other tx-transmitted infections, are considered rare causes of complications.



Table (1) Pathological agents eliminated via TPE

 

 

Pathologic agent

Diseases

Igs

HV syndrome

WM

MM

Auto-AB

MG

Anti-GBM AB disease

SLE

Systemic vasculitis

Factor VIII inhibitors

TTP

Lipoproteins

Hypercholesterolemia

WBCs

Hyperleukemic leukostasis

Platelets

Severe thrombocytosis

Abnormal RBCs

Sickle cell disease (pain crisis, acute chest syndrome, stroke)

Circulating immune complexes

Immune complex GN

SLE

Systemic vasculitis

Protein-bound substances & toxins

Thyroid storm

Amanita phalloides toxins

Hyperparasitemia

Malaria, babesiosis

 

 

 

Table (2) Viral & bacterial infections after blood products tx.

 

 

 

No

Whole Blood

Plasma products

(Solvent inactivated)

Plasma products

(Partially inactivated)

Platelets

Reduced CMV risk

(SOT/BM Tx)

(1)

1)    HCV (1:1.2 million)

1)    HCV

1)    Hepatitis A virus

Septic tx

1:50,000-1:80,000 /Aphr units

1)    seronegative cellular components (RBCs/ platelets) or

2)    leukoreduced components.

(2)

2)    HBV (1:1 million)

2)    HBV

2)    Hepatitis E virus

(3)

3)    HIV (1:1.5 million)

3)    HIV

3)    Parvovirus B19

(4)

4)    HTLV (1:2.7 million)

 

 

 

 

References:

1.     ​Stramer SL, Notari EP, Krysztof DE, Dodd RY. Hepatitis B virus testing by minipool nucleic acid testing: Does it improve blood safety? Transfusion 2013; 53:2449.

2.     Kleinman S, Reed W, Stassinopoulos A. A patient-oriented risk-benefit analysis of pathogen-inactivated blood components: Application to apheresis platelets in the United States. Transfusion 2013; 53:1603. 

 



 

 

 

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Therapeutic aphr is an Exc ttt that selectively eliminates the abnormal cells/substances in the blood associated with or inducing certain disorders.
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