IN THE NAME OF

IN THE NAME OF GOD

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 theGreek 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 andreplaced 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

RBC PlasmaWBC PLT

Sickle Cell Dis.Malaria

LeukemiasCell Therapies

Thrombocytosis

TTPGuillain Barre Syn.Myasthenia GravisGoodpasture’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 TPETPE 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 Th2suppression of IL-2 and IFN- γ production

Mechanism of action DisordersRemoval of autoantibody Myasthenia gravis

Removal of alloantibody Rh alloimmunization in preg.

Removal of immune complex Systemic lupus erythemotosus

Removal of monoclonal protein

Hyperviscosity syndrome

Removal of toxin Mushroom poisoning

Replacement of specific plasma factor

Thrombotic thrombocytopenic purpura

Possible mechanisms of TPE

TECHNIQUES OF SEPARATING PLASMA FROM WHOLE BLOOD

Plasmapheresis is performed by 2 fundamentally different techniques: Devices separating based on density:

centrifugationor

Devices separating based on size: filtration

centrifugation apheresiswhole blood is spun so that the 4 majorblood 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 platelets4-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 andintensivist

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 circumstances.”

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


• 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


• 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

American Society of Hematology 2012

Medications reportedly removed by TPEBasiliximabCeftriaxoneCeftazidimeChloramphenicolCisplatinDiltiazemα IFN-

IVIGPalivizumabPropoxyphenePropranololRituximabTobramycinVerapamilVincristine


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.


Treating volumes beyond 1.5 plasma volumes removes smaller, less clinically important amounts of pathologic substance present in theplasma while prolonging the procedure and exposing the patient to more replacement fluid

and anticoagulant,increasing: risk of complications without increasing benefit to the patient.

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

AlbuminAdvantages: 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 accessOrperipheral 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 TPEI for:

TTP and atypical HUS due to autoantibody to factor H

II for: CAPS

III for: hematopoietic stem cell

transplant–associated thrombotic microangiopathy

TTPclassic “pentad”

pathophysiologic process :deficiency ofADAMTS-13 (aka, von Willebrand factor[VWF]–cleaving proteinase)VWF- and platelet-rich microthrombicongenital and acquiredADAMTS-13 inhibitors and proteolytic inactivatorsincluding :interleukin-6, plasma-free hemoglobin, IgG autoantibody, Shiga toxin,plasmin, thrombin, and granulocyte elastase

TPE in TTPremove 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 &AtypicalThe “triad” of HUS is thrombocytopenia, microangiopathic hemolytic anemia, and .renalFailureIn atypical HUS, in addition to the typical “triad” , .patients have neurologic abnormalitiesCurrently, the ASFA does not recommend TPE

(category IV )for typical HUS

Crit Care Clin 28 (2012) 453–468

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.

DICMany case series and observational studiessuggest that TPE might have a beneficial effect in DIC.

TPE is thought to normalize the blood coagulation to homeostasis milieu by removing tissue factor andplasminogen 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.

sepsisthe 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 ErythematosusThe ASFA gives a category II recommendation for TPE :in severe SLE such as withcerebritis 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 DISORDERSThe ASFA gives a category I recommendation for TPE in acute inflammatory demyelinating

polyneuropathy (Guillain-Barre syndrome) ,chronic inflammatory demyelinatingpolyradiculoneuropathy, pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections and Sydenham’s chorea, multiple sclerosis,

and myasthenia gravis

Frequency of proceduresDuration 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 VIEWHemophagocytic Lymphohistiocytosis: Pathologic Hyperactive Inflammation(HLH)HLH is a syndrome of pathologic hyperactiveinflammation 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

Secondary HLH &familial/primaryEpstein-Barr virus is the most commonly recognized .infection associated with secondary HLHTPE 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 ofTPE in HLH.

Documents

IN THE NAME OF