Plasmapheresis
DR KAMRAN FAZEL.MD.FCCM
Since antiquity, mankind has hypothesized there
are bad substances called
“humors”
that accumulate in the blood of sick patients
and that the removal of these humors would
make patients feel better.
Bloodletting, the practice of draining blood
from sick patients,has been around since the
Egyptians, dating back 1000 years BC. The
practice of bloodletting peaked in the
18th century and evolves with modern
technology to this day.
Apheresis is a procedure that is used in the
treatment of patients with a variety of illnesses.
The term apheresis comes from the
Greek origin meaning “removal of”. All
apheresis procedures involve
removing components from the blood.
Efficient apheresis procedures have been
developed over the last 15 years.
Blood has 4 major components: red blood cells,
white blood cells, platelets, and plasma.
With modern machinery, blood can be
separated into each of these 4 components.
Thus, if a particular blood component is causing
harm, it can be selectively removed and
replaced with the same blood component from
healthy donors.
History of modern plasmapheresis
• 1909 Fleig / France
– Auto & heterotransfusion of washed corpuscles
• 1914 Abel / U.S.
– Use the term of Plasmapheresis in his paper
– Prolonged the life of dog with bilateral nephrectomy by
plasmapheresis
• 1959 Michael Rubinstein was the first person to use
plasmapheresis to treat an immune-related disorder
when he "saved the life of an adolescent boy with
thrombotic thrombocytopenic purpura (TTP) at the old
Cedars of Lebanon Hospital in Los Angeles
1970 -Invention of cell separator machine
Apheresis in Clinical Practice
Sickle Cell Dis.
Malaria
RBC
Thrombocytosis
WBC
PLT
Leukemias
Cell Therapies
Plasma
TTP
Guillain Barre Syn.
Myasthenia Gravis
Goodpasture’s Syn.
Waldenstrom’s
Plasmapheresis
is an apheresis procedure that separates
and removes the plasma component
from a patient.
Plasma exchange is when plasmapheresis is
followed by replacement with fresh
frozen plasma infusion
To apply this treatment to patients
appropriately
it is essential to understand:
1-the methods to remove plasma
2- its effects on normal plasma constituents
3-the role of replacement fluids in the
treatment
4-and the risks associated with the procedure.
Mechanism of action of plasma
exchange
Removes pathologic substances such as pathologic
Abs, immune complexes,and cytokines is the major
mechanism of action of TPE
TPE may have an immunomodulatory effect beyond
the removal of Ig:
Reported effects of TPE on immune function
include:
T-cell modulation with a shift from in the Th1/Th2
balance with a shift toward Th2
suppression of IL-2 and IFN- γ production
Possible mechanisms of TPE
Mechanism of action
Disorders
Removal of autoantibody
Myasthenia gravis
Removal of alloantibody
Rh alloimmunization in
preg.
Removal of immune complex Systemic lupus
erythemotosus
Removal of monoclonal
Hyperviscosity syndrome
protein
Removal of toxin
Mushroom poisoning
Replacement of specific
plasma factor
Thrombotic
thrombocytopenic purpura
TECHNIQUES OF SEPARATING PLASMA
FROM WHOLE BLOOD
Plasmapheresis is performed by 2
fundamentally different techniques:
Devices separating based on density:
centrifugation
or
Devices separating based on size:
filtration
centrifugation apheresis
whole blood is spun so that the 4 major
blood components are separated out into layers
by their different densities.
Centrifugation apheresis is commonly
performed by blood bankers.
centrifugation apheresis
Advantages:
1-Capable of performing
cytapheresis
2-No heparin requirement
3-More efficient removal of
all plasma components
Disadvantages:
1-Expensive
2-Requires citrate
anticoagulation
3-loss of platelets
4-usually requires a
consultation to another
service such as a blood
banker
Centrifugal Separation
Filtration plasmapheresis
whole blood passes through a filter to separate
the plasma components from the larger
cellular components of red blood cells, white
blood cells,and platelets.
commonly performed by nephrologists and
intensivist
Membrane apheresis
Advantages:
1-fast and efficient
2-No citrate requirements
Disadvantages:
1-Removal of substances
limited by sieving
coefficient of membrane
2-Unable to perform
cytapheresis
3-Requires high blood flows
, central venous access,
heparin
4-Limiting use in bleeding
disorders
Membrane
Separation
Dialysis & Transplantation 2009 February: 1-4
2010, ASFA published its updated comprehensive
“Guidelines
• Category I: “Disorder for which apheresis is accepted as
first-line therapy,either as a primary stand-alone
treatment or in conjunction with other modes of
treatment.”
• Category II: “Disorders for which apheresis is accepted as
second-line therapy,either as a stand-alone treatment or
in conjunction with other modes of treatment.”
• Category III: “Optimum role of apheresis therapy is not
established. Decision -making should be individualized.”
• Category IV: “Disorders in which published evidence
demonstrates or suggests apheresis to be ineffective or
harmful. Internal Review Board approval is desirable if
apheresis treatment is undertaken in these
Diseases and disorders treated with
plasma exchange. ASFA categoryI
Acute inflammatory demyelinating polyradiculopathy
(Guillain-Barré Syndrome)
ANCA-associated rapidly progressive
glomerulonephritis/vasculitis
(Wegener granulomatosis)
Dialysis independent
Alveolar hemorrhage
Antiglomerular basement membrane disease
(Goodpasture syndrome)
Dialysis independent
Alveolar hemorrhage
Diseases and disorders treated with
plasma exchange. ASFA categoryI
• Chronic inflammatory demyelinating
polyradiculopathy
• Cryoglobulinemia
• Focal segmental glomerulosclerosis (recurrent)
• Hemolytic uremic syndrome
• Autoantibody to factor H
• Hyperviscosity in monoclonal gamopathies
• Symptomatic
• Prophylactic for rituximab treatment
Diseases and disorders treated with
plasma exchange. ASFA categoryI
•
•
•
•
Paraproteinemic polyneuropathies
IgG/IgA
IgM
Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal
infections (PANDAS)
• Renal transplantation, Ab-mediated rejection
• Thrombotic thrombocytopenic purpura
TPE & removal of plasma
• Significant declines in factor V (FV), FVII, FVIII, FIX, FX,
and VWF activity occurs.
• Activities of FVIII, FIX, and VWF return to normal
within 4 hours after TPE
• whereas the remaining coagulation factors achieve
pre-TPE activity levels by 24 hours.
• The exception to this is fibrinogen, which reaches 66%
of pre-apheresis levels by72 hours
• Additional substances removed include:
inhibitors of coagulation such as antithrombin and
the pseudocholinesterase necessary for metabolism
of some drugs
• Theoretically, the removal of inhibitors of
coagulation could predispose patients to
thrombosis, but this has not been demonstrated
definitively
• Reports of prolonged neuromuscular blockade due
to decreased pseudocholinesterase activity have
been reported
The removal of Abs from the patient can result in:
false negative tests for:
infectious diseases, autoantibodies,
alloantibodies,and enzyme and coagulation factor
activity.
Samples for such testing should be collected before
the initiation of TPE
Medications reportedly removed by TPE
Basiliximab
Ceftriaxone
Ceftazidime
Chloramphenicol
Cisplatin
Diltiazem
IFN- α
IVIG
Palivizumab
Propoxyphene
Propranolol
Rituximab
Tobramycin
Verapamil
Vincristine
American Society of Hematology 2012
For each 1-1.5 plasma volume exchanged,
approximately 60%-70% of substances
present in the plasma at the start of that
plasma volume will be removed.
routine practice is to exchange only 1-1.5
plasma volumes during a TPE.
American Society of Hematology 2012
Treating volumes beyond 1.5 plasma volumes
removes smaller, less clinically important
amounts of pathologic substance present in the
plasma while prolonging the procedure and
exposing the patient to more replacement fluid
and anticoagulant,increasing :
risk of complications without increasing benefit
to the patient.
American Society of Hematology 2012
one-third of the replacement fluid
administered at the beginning of the
TPE will be present by the end, with
the majority having been removed.
Administering plasma as a
replacement fluid at the beginning of
a TPE results in exposure of the
patient to blood products without
benefit.
Exchange Fluids
• 5% Albumin
– Best choice
– Dilute only with saline
• Combination of saline and albumin
• FFP
• Cryopoor plasma
Albumin
Advantages:
1-No risk of hepatitis
2-Stored at room
temperature
3-Allergic reaction are rare
4-No concern about ABO
blood group
5-Depletes inflammation
mediators
Disadvantages:
1-Expensive
2-No coagulation factors
3-No immunoglobulins
70% albumin and 30% saline.
majority of the albumin being given
at the end of the procedure
to avoid hypovolemia from
redistribution of the crystalloid
FFP
Advantages:
1-Coagulation factors
2-Immunoglobulins
Disadvantages:
1-Risk of hepatitis, HIV,
transmission
2-Allergic reaction
3-Hemolytic reaction
4-Must be ABO
compatible
5- citrate load
vascular access ?
central venous access
Or
peripheral vascular access
Studies examining the complication rates of
apheresis procedures :
the frequency of complications due to the
placement of central venous catheters exceed
the frequency of complications directly
related to the procedure.
(hemopneumothorax)
Central venous access has also been identified
as a major risk factor for complications of TPE
in other studies
Complications of plasmapheresis
•
•
•
•
•
•
4-25%
Minimal reactions 5%
Mod reactions 5-10%
Severe reactions <3%
Mortality rate 3-6 per 10000 procedures
The majority of deaths is anaphylaxis
associated with FFP, PTE , vascular perforation
Indications for emergency plasmapheresis
• Anti-GBM disease and /or/pulmonary hemorrhage in
Goodpasture syn.
• Hyperviscosity syn with signs and symptoms suggesting
impending stroke or loss of vision
• TTP/HUS
• Factor 8 inhibitor in patients requiring surgery
• Respiratory insufficiency in G-B syn
• MG with respiratory distress not responding to
medication
• Acute poisoning
THROMBOTIC MICROANGIOPATHIES
Thrombotic thrombocytopenic purpura
(TTP)
hemolytic uremic syndrome (HUS)
disseminated intravascular coagulation
(DIC)
catastrophic antiphospholipid syndrome
(CAPS)
ASFA category for TPE
I for :
TTP and atypical HUS due to autoantibody
to factor H
II for :
CAPS
III for :
hematopoietic stem cell
transplant–associated thrombotic
microangiopathy
classic “pentad”
TTP
pathophysiologic process :
deficiency ofADAMTS-13 (aka, von Willebrand
factor[VWF]–cleaving proteinase)
VWF- and platelet-rich microthrombi
congenital and acquired
ADAMTS-13 inhibitors and proteolytic inactivators
including :interleukin-6, plasma-free hemoglobin, IgG
autoantibody, Shiga toxin,plasmin, thrombin, and
granulocyte elastase
TPE
in
TTP
remove the large and ultra-large VWF
- ADAMTS-13inhibitors and proteolytic
inactivators, and
replenish ADAMTS-13.
the recommended TPE replacement fluid is
plasma or plasma with cryoprecipitate removed
(ie, the plasma portion that is depleted with
ultra-large VWF and large plasma VWF).
HUS:Typical &Atypical
The “triad” of HUS is thrombocytopenia,
microangiopathic hemolytic anemia, and
renalFailure.
In atypical HUS, in addition to the typical “triad” ,
patients have neurologic abnormalities.
Currently, the ASFA does not recommend TPE
(category IV) for typical HUS
We recommend consulting nephrology and
hematology to send the appropriate ADAMTS-13,
VWF, and complement studies.
In addition, TPE should be initiated until the results of
biomarkers can differentiate the diagnoses.
Because the underlying pathology is the deficiency of
complement H activity, the recommended TPE
replacement fluid is either plasma or albumin. We
recommend plasma as the replacement fluid since it
has normal factor H activity.
Crit Care Clin 28 (2012) 453–468
DIC
Many case series and observational studies
suggest that TPE might have a beneficial effect in DIC.
TPE is thought to normalize the blood coagulation to
homeostasis milieu by removing tissue factor and
plasminogen activator inhibitors type I and by
replacing antithrombin III, protein C,and
coagulation factors.
Currently, the ASFA does not have a specific
recommendation for TPE in DIC.
sepsis
the ASFA gives a category III recommendation
DIC has been shown to be one of the major
contributing mechanisms to multiorgan failure in
critically ill patients.
Thus, there is a biologic plausibility that the beneficial
treatment effect of TPE in sepsis with multiorgan
failure could be from reversing DIC .
Systemic Lupus Erythematosus
The ASFA gives a category II recommendation for TPE
in severe SLE such as with:
cerebritis or diffuse alveolar hemorrhage.
The ASFA does not recommend TPE
(category IV) for SLE-associated nephritis.
TPE is thought to remove autoantibodies,
complement, interferon alpha, and immune
complexes.
The recommended TPE replacement fluid is either
plasma or albumin.
NEUROLOGIC DISORDERS
The ASFA gives a category I recommendation for TPE
in acute inflammatory demyelinating
polyneuropathy (Guillain-Barre syndrome),
chronic inflammatory
demyelinatingpolyradiculoneuropathy, pediatric
autoimmune neuropsychiatric disorders
associated with streptococcal infections and
Sydenham’s chorea, multiple sclerosis,
and myasthenia gravis
Frequency of procedures
Duration of therapy
• Anti- GBM disease :2 plasma volume daily for 7
consecutive days
• TTP-HUS :1.5 plasma v. for first 3 treatments
followed by 1 plasma v. until plt is normalized
and LDH level below 400iu/l
• Cryuoglobulinemia:1 plasma v. 3 times weekly
for 2-3 weeks
• RPGN: 4 days for the first week
• Hyperviscosity syn: daily 1 plasma v for 2-5
days
(HAND BOOK OF DIALYSIS 2007)
FUTURE VIEW
Hemophagocytic Lymphohistiocytosis:
Pathologic Hyperactive Inflammation(HLH)
HLH is a syndrome of pathologic hyperactive
inflammation due to unchecked immune
activation.
multiorgan failure with the following
clinical criteria
(1) fever
(2) splenomegaly
(3) cytopenia
(4) Hypertriglyceridemia
(5) hemophagocytosis in bone marrow spleen, lymph
nodes, or liver
(6) low or absent NK-cell activity
(7) ferritin greater than 500 ng/mL, and
(8) elevated serum CD 25
familial/primary&Secondary HLH
Epstein-Barr virus is the most commonly recognized
infection associated with secondary HLH.
TPE has been reported in many small case series to be
beneficial in calming the cytokine storm and to
provide hematologic support in patients with
primary and secondary HLH.
Currently, the ASFA has not commented on the use of
TPE in HLH.