Therapeutic Apheresis

Basic Principles, Techniques and Practical considerations

Outlines
Definitions Mechanism of Action Technology (ies) Use Practical Considerations Apheresis Math

Apheresis
Derives from Greek, to carry away A technique in which whole blood is taken and separated extracorporealy, separating the portion desired from the remaining blood. This allows the desired portion (e.g., plasma) to be removed and the reminder returned.

Apheresis- Mechanism of Action

Large-bore intravenous catheter connected to a spinning centrifuge bowl Whole blood is drawn from donor/patient into the centrifuge bowl The more dense elements, namely the red cells, settle to the bottom with less dense elements such as white cells and platelets overlying the red cell layer and finally, plasma at the very top.

Apheresis: Principles of Separation

Platelets (1040) Lymphocytes (1050-1061) Monocytes (1065 - 1069) Granulocyte (1087 - 1092) RBC
Torloni MD

Torloni MD

Torloni MD

Centrifugal Separation

Cobe
WB WBC PRBC Plasma

Torloni MD Torloni MD

a m as Pl

ts ele at Pl

ff y Bu

at Co

lls Ce d Re

Principals of Apheresis
WBC WBC Plasma Plasma
ts yte tele hoc tes s Pla ymp nocy locyte L M o nu Gra
Torloni MD

Separate blood components is based on density with removal of the desired component
RBC WBC Plasma

Torlo ni MD

RBC RBC

Cobe Spectra

Graphics owned by and courtesy of Gambro BCT

Apheresis- Mechanism of Action

Apheresis- Mechanism of Action

Large-bore intravenous catheter connected to a spinning centrifuge bowl Whole blood is drawn from donor/patient into the centrifuge bowl The more dense elements, namely the red cells, settle to the bottom with less dense elements such as white cells and platelets overlying the red cell layer and finally, plasma at the very top.

Plasmapheresis: Fluid Dynamics

Apheresis- Mechanism of Action (Cont.)
In plasmapheresis, the plasma layer is collected into a collection bag, and the red cells and buffy coat layers are returned to the patient mixed with plasma substitute (NS, 5% albumin) Since all current apheresis equipment uses advanced microcomputer technology, you can adjust the system to collect platelets/red cells/white cells/pbmc
42 L

INTRACELLULAR K
28 L

EXTRACELLULAR EXTRACELLULAR Na
14 L
INTERSTITIAL INTERSTITIAL INTRAVASCULAR INTRAVASCULAR

10 L

4L

Plasma Exchange : Mathematical Models

L L y y m m p p h h a a tt ii c c Catabolism s s

INTRAVASCULAR
Interstitial Intracellular

Modified from: Weinstein, Apheresis:Principles and Practice- AABB press

Apheresis: Automated Processing Technology

Continuous flow Automated centrifugal cell separators allow large of blood to be processed in a short period of time Discontinuous flow: Haemonetics MSC plus, V50, V30 Continuous flow: Cobe spectra, CS 3000, Fresnius AS 104 Cobe Frezaenius Intermittent flow

Haemonetics Fenwal (Baxter)

Definitions
Plasmapheresis: plasma is removed and replaced w/plasma substitute (N.S. and/or 5% albumin) Plasma exchange: plasma is removed and exchanged w/allogeneic plasma TPE: therapeutic plasma exchange

Use of Apheresis
Collection - facilitate collection of a blood component (plt, wbc) from an allogeneic donor Therapy (therapeutic apheresis): *removing undesired substances like antibodies, lipids *reducing excess wbc/plt in pts w/myeloproliferative disorders *automated exchange of sickled rbc *collection of hematopoietic progenitor cells

Use of Apheresis (cont.)

TPE assures the immediate removal of abnormal substances from the circulation, which are either: *present in plasma *or tightly bound to plasma proteins

Abnormal Substances Removed From the Circulation by TPE

1) Paraproteins (Waldenstorms Macroglobulinemia) 2) Autoantibodies (Myasthenia Gravis, Goodpastures syn.) 3) Lipids (LDL in familial hypercholesterolemia; phynatic acid in refsums disease 4) Toxins or drugs (that are bound to albumin) 5) Circulating immune complexes (CIC) 6) Soluble mediators of inflammatory response (activated complement component, vasoactive substances)

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications

Venous Access
*Apheresis require large bore venous catheters to sustain the flow rates required (50-100 ml/min) Type of catheters:17 gauge therumo butterflies/ double lumen dialysis catheters 10-13.5 fr (Shiley, Quinton, Vascath, Permacath) *Location: Peripheral: anticubital central: femoral/subclavian/jugular arteriovenous shunt/fistula *Number of lines: intermittent flow devices (draw and return via the same line): single line continuous -flow devices : separate lines

Venous Access (cont.)

Planned/occasional procedure - peripheral line and removal after the procedure Few days/ bed rest- femoral line (risk of infection/thrombosis) Multiple procedures for a long period of time - neck central vein or artriovenous shunt/fistula Do not forget: *Dressing change *Flush

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal Constituents Removed Anticoagulation Patient History and Medications Extracorporeal Volume Frequency and number of procedures

Replacement Fluid
Must be FDA approved to use w/blood products [ get mixed w/rbc before the return phase] Replacement solutions: *Crystalloids normal saline 0.9% *Colloids 5% albumin; plasma

Replacement Fluid
*The primary function of the replacement

Replacement Fluid (cont.)

*With the exception of TTP, the success of therapeutic apheresis procedures seldom depends on the composition of the replacement solution that is used *Type used depends on: Procedure performed Diagnosis of patient Coagulation status

fluid is to maintain intravascular volume **additional features: - Restoration of important plasma proteins - Maintenance of colloid osmotic pressure - Maintenance of electrolyte balance

Replacement Fluids
TTP/HUS
FFP Cryodepleted FFP Mixtures : Albumin /FFP Albumin /FFP 5% Human Albumin Albumin/Saline (70% /30%)

Comparison of Replacement Fluids

Replacement Fluid Crystalloid Advantage
Low cost Hypoallergenic No infectious risk Iso-oncotic No infectious risk Immunoglobulins Coagulation factors Iso-oncotic

Disadvantage
Hypo-oncotic No coagulation factors No immunoglobulins 2-3 volumes required Higher cost No coagulation factors No immunoglobulins Infectious risk Citrate Allergic reactions ABO compatibility

Neurological
GBS, MG, Stiff-man CIDP

Renal
(RPGN, FSGS)

5% Human Albumin Albumin/Saline (70% /30%)

Albumin Plasma

Post Transplant

5% Human Albumin Albumin/Saline (70% /30%) Consider adding FFP at the end if post op

Patients with hepatic failure, coagulopathy, pre-op or post-op use FFP or finish with FFP

Replacement Fluid and Balance

3 choices of fluid balance: 1) 100% fB isovolemic volume replaced=volume removed 2) <100% fB hypovolemic (dry) - volume replaced < volume removed 3) >100% fB hypervolemic (wet) - volume replaced > volume removed

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications

Normal/abnormal Constituents Removed

TPE: One volume exchange removes about 63%- 65% of most plasma constituents A single two-volume exchange removes about 86% of plasma constituents Increasing the volume beyond 1-1.5 volumes has very little impact on removal of plasma constituents

Volume of Patient Plasma Exchanged (PEX)

1pv= 63%, 2 vol=86% , 3 vol=95%

Volume of Patient Plasma Exchanged (PEX)

Little advantage beyond 1.0-1.5 volumes 1pv= 63%, 2 pv=86% , 3 pv=95% Removal of IgG and IgM by plasma exchange: measure intravascular amount total body removal 1.0 PEX vol. 1.5 PEX vol. 2.0 PEX vol. 28% 35% 39% 48% 59% 65% IgG 45% IgM 76%

Coagulation factors:

Normal Constituents Removed

Most coagulation factors are lost at the same rate Rapidly synthesized;replacement usually is 2-3 days following exchange Practical: measure PT/PTT/Fibrinogen every 2-3 days (rather then daily)

Platelets:
25-30% per procedure Endogenous synthesis replaces lost platelets within 2-4 days (except hypoplastic/aplastic marrow) Lab work (esp. chemistry): not immediate postprocedure; allow equilibrium intra/ extravascular space

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications Heparin

Anticoagulation
Anticoagulation-citrate-dextrose solution (ACD-A) Combination of ACD-A and Heparin

Anticoagulation
Anticoagulation citrate Dextrose (ACD): Found in human cells, plant cells, and citrus fruits Chelates positively charged calcium ions (ionized calcium) and blocks calcium-dependent clotting factor reactions Works extracorporeally Metabolized in the liver almost immediately upon return Side effects: hypocalcemia. small pts, large vol. of citrated blood, liver dysfunction Heparin: Prevents conversion of fibrinogen to fibrin and prothrombin to thrombin Systemic anticoagulation Metabolized slowly 1-2 hours Individual sensitivity and elimination rates

Anticoagulation

Apheresis Procedural Elements (+ Practical Considerations):

Venous Access Replacement Fluid Normal/abnormal Constituents Removed Anticoagulation Patient History and Medications Frequency and Number of Procedures Complications

Patient History and Medications

Does patient have a disease which is amenable to treatment by the requested apheresis procedure Does the patient/donor capable of sustaining the fluid shifts associated with apheresis Certain medications, most notably antibiotics and anticoagulant can be removed by apheresis - should be given immediately after the procedure Angiotensin-converting enzymes (ACE) inhibitors

ACE inhibitors
A.C.E.

ACE inhibitors

A.C.E. Inhibitor

Angiotensin I

Angiotensin II
Angiotensin I

Vasoconstriction

Angiotensin II

No vasoconstrictive effect

ACE inhibitors and Pheresis

ACE Inhibitor Kinase I & II
XII Prekalikrein
XII a

Angoitensin-converting enzymes (ACE) inhibitors Block conversion of angiotensin I to angiotensin II Also, inhibit the breakdown of bradykinin In the setting of apheresis, activation of bradykinin in the extracorporeal circuit; potent vasodilator profound hypotension Ace-inhibitors must withheld for at least 24 hours before apheresis C/I in immunosorba column (prosorba column) risk of anaphylaxis

Patient History and Medications

X
Kallikrein

wn do ks nin ea yki r d B ra B

H.M.W.K 1- Activation of XII 2- Inhibition of Kinase II

Bradykinin

Vasodilatation

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications

Frequency and Number of Procedures

Depends on: Disease being treated Patient signs and symptoms Lab values

Interval between Exchanges : Why we do what we do...

Target and Goals of TPE

Substance Substance Volume Volume Treated Treated (ml/kg) (ml/kg) Treatment Treatment Interval Interval (hours) (hours) Number Number of of Treatments Treatments

Alteration in Blood Constituents by a 1- PV Exchange

Constituent Constituent Autoantibodies Autoantibodies Immune Immune complexes complexes Paraproteins Paraproteins Cryoproteins Cryoproteins Toxins Toxins TTP TTP // HUS HUS 40 40 60 60 40 40 60 60 40 40 60 60 40 40 60 60 40 40 60 60 40 40 24 24 48 48 24 24 48 48 24 24 24 24 48 48 24 24 72 72 24 24 4 4 6 6 treat treat to to response response treat treat to to response response treat treat to to response response treat treat to to response response to to remission remission Clotting factors Fibrinogen Immuneglobulins Paraproteins Liver Enzymes Bilirubin C3 Platelets
Modified from : Weinstein, in McLeod, Apheresis, Principles and Practice, AABB press 1997

% % decrease decrease 25 50 63 63 20 30 55 60 45 63 25 30

% % recovery recovery 48 48 hrs hrs post post exchange exchange 80 100 65 45 Variable 100 100 60 100 75 100

From McLeod B, Apheresis, Principles and Practice (R. Weinstein ) p 271, AABB Press 1997

Apheresis Procedural Elements (+ Practical Considerations):

Venous access Replacement fluid Normal/abnormal constituents removed Anticoagulation Patient history and medications Frequency and number of procedures Complications

Complications
Hypocalcemia (citrate toxicity) Vasovagal
Pallor, sweating, Slow pulse, Low BP Nausea/ vomiting, syncope, convulsions

Hypotension
ACE inhibitors increase risk

Bleeding
Decrease in clotting factors (40-70%) Decrease in platelets (1050%)

Vascular access
Hematoma, thrombosis Central lines: sepsis, thrombosis

Infection Anxiety/ hyperventilation

Tingling, diaphoresis, tachycardia, seizures

Allergic/ anaphylactic

Complications
1) Hypotension S/S: lightheadedness dizziness faintness Treatment: head of bed, foot of bed Give NS Monitor VS pulse rate shallow breaths perspiration S/S: B/P nausea

Complications
2) Vasovagal syncope
pulse feeling of apprehension, distress, doom

Treatment: same as hypotention

Complications
3) Hypocalcemia
S/S: Parasthesia, perioral tingling Chills/vibrations of chest wall Severe citrate toxicity - tetany, heart rhythm disturbances Treatment: AC flow rate to the patient Decrease blood flow rate Give Ca tables (Tums) Give dairy products For severe citrate toxicity stop procedure, IV Calcium

Complications
4) Allergic reaction: Etiology: blood products/ ethylene oxide/ACE inhibitors S/S: hives
rash swelling (eyes,lips, tongue) breathing difficulties

flushing, hypotension (m/p ACE inhibitors) burning eyes, periorbital edema (m/p ethylene oxide) Treatment: Pause procedure Give medication per order: Antihistamines, corticosteroids, epinephrine Discontinue procedure if no improvement

10

Complications
5) Other side effects: *Vascular access: hematoma, phlebitis, infection *Air embolism *Loss of blood components: *Thrombocytopenia (30% decrease) *Hypofibrinogenemia (50% decrease)

Journal of Clinical Apheresis 16:3, 130

Journal of Clinical Apheresis 16:3, 130

Request for TA

Evaluate the patient

-Does the patient most likely have the diagnosis? -Are other reports of treatments of equal efficacy? -Will TA harm the patient?

I/ II

III Review new literature

NC

IV

Review literature Apply McLeods criteria

Consider: Volume status Cardiovascular stability Vascular access Impact of TA on other treatments

ASFA Category

Favorable

Risk/ Benefit
Unfavorable

Category I/II

Category III

Not Categorized

Category IV

Accept Treatment Plan

Deny

11

 Rationale Impact

Evaluation of a new patient for TA

Based on the diagnosis and history, review the pathophysiology of disease and results of previous studies Benefits and risks of the procedure

Technical issues
Anticoagulant, access, replacement fluid, volume processed

End-point
Monitoring of treatment and criteria for discontinuation

Timing and location

Therapeutic Apheresis Math

Blood/Plasma Volume Total Blood Volume (TBV): -Height -Weight -Sex Plasma Volume -TBV x (1-Hct)

Blood Volume Calculations

TBV - Nadlers Formula

TBV - Gilchers Rule of Five

12

Estimated Blood Volume

TBV Adjustments

Plasma Volume Calculation

Blood/plasma Volume Calculations

Determine patient tolerance/safety Calculating % of extracorpreal volume

Calculate treatment dose

Cytoreduction and PBSC collections TPE and RBC Exchange replacement fluid volumes

Extracorporeal Volume (ECV)

The amount of blood outside the patients body at any given time Should not exceed 15% of patient's total estimated blood volume Depend on the technology used, it varies between 131-284 ml Cobe spectra set volume: TPE 170ml RBC exchange 170ml PBSC 285ml

Treatment Dosage
A typical order for plasmapheresis: Perform plasmapheresis Remove 3L of plasma (based on 1PV exchange; regular size 70kg patient; PV ~40 mg/kg) Replacement per disease : for example Replace 100% with 12 units FFP (`250 x 12 =3L) Or replace 100% with 3L 5% albumin (each alb. 250cc =12 bottles) Frequency : per disease: for example TTP: daily; GBS: QOD x 5 treatments

13

RBC exchange Treatment dosage - FCR

Fraction Cell Remaining (FCR): desired HbS divided by patients pre HbS For example: desired HbS 30%; patients pre HbS:100% FCR: 30/100 =0.3 desired HbS 30%; patients pre HbS:60% FCR: 30/100 =0.6 The lower the FCR more exchange needed

RBC exchange Treatment dosage RBC volume to be exchanged

The cobe spectra will use 3 parameters to calculate volume of RBC needed: - RBC volume of the patient - Hct of the RBC units: the lower the Hct you will need more units - Desired FCR 1X RBC volume exchange FCR 35-40% 2X RBC volume exchange FCR 15-20% 3X RBC volume exchange FCR 5-10%

Treatment Dosage - RBC Exchange

Patient blood volume = 4000; Hct 30% Patient RBC volume = 1200 ml You need to raise Hgb A from 0 to 70% (FCR=30%) 1 X RBC vol. Exchange Average unit Hct is 60% (each unit ~350 ml) 1200/.60 = 2000 ml 2000/350 = 6 units

14