Therapeutic aphr is an Exc ttt that selectively eliminates the abnormal cells/substances in the blood associated with or inducing certain disorders.
PLASMAPHERESIS
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
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.
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.
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.
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.
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.
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 HB “S” 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.
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 (1–
Hct)
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.
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...
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.
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.
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.
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
%.
[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.
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.
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 depletion: TPE 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.
[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.
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.
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.
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.
COMMENTS