Double Filtration
Plasmapheresis (DFPP)
賴俊夫醫師
台大醫院內科部腎臟科
台大醫院急性腎衰竭研究群 NSARF
Renal Division, Department of Internal Medicine,
National Taiwan University Hospital
NTUH Study group on Acute Renal Failure
Plasma therapy in CVS
(TPE, DFPP, ECP)
賴俊夫醫師
內科部腎臟科
March 25, 2011
血漿治療
Plasma – 血漿
 Apheresis – 分離; Exchange – 交換
 血漿分離術 (Plasmapheresis)

 將血液中血球與血漿分離，以移除血漿中較大
分子量的有害成份

血漿置換術 (Plasma exchange)
 將血漿取出體外，去除血漿中的有害物質，再
換以正常人的血漿。
Molecular weight of removed substances by blood purification therapy
離心式血漿分離
補充液
Centrifugal Separation Plasma Exchange
空心纖維膜血漿分離
 治療性血漿交換術
(TPE, Therapeutic Plasma
Exchange)

輸注他人血漿，以補充移除的血漿
 雙重血漿分離術
(DFPP, Double Filtration
Plasmapheresis)

利用兩個人工腎臟，減少移除的血漿量
空心纖維膜血漿分離
補充液
補充液
FFP, Plasmanate, Lacted Ringer’s
Membrane
Separation
Plasma
Exchange
HF-400
Plasmacure
TM
Plasma seperator
(ASAHI KURARAY MEDICAL CO., LTD)
Evaflux
TM
(KURARAY MEDICAL INC.)
Plasma fractionator
雙重過濾血漿分離術
補充液
N/S
0.2μm
0.03μm
去除血漿中有害成分(分離
血漿的10%，約血流的3%)
KPS-8800Ce
血漿移除量
1 plasma voulem = BW X (1/13) X (1-Hct)
Plasma volume
Volume exchanged
Immunoglobulin
exchange( Ve/EPV )
( Ve, ml )
or other substance
eg. 60kg, Hct 40%
removed (MRR,%)
0.5
1,400
39
1.0
2,800
63
1.5
4,200
78
2.0
5,600
86
2.5
7,000
92
3.0
8,400
95
血漿補充量
視血漿移除量多寡
 Plasma exchange

 移除2


plasma volume 5600 cc 血漿
22U FFP + 5 plasmanate + 3 Ringer’s
Double filtration plasmapheresis移除量
 移除1.5
plasma volume 4200 cc 血漿血漿量
x10% = 420cc

3U FFP, or 500cc Ringer’s, or albumin
血漿補充液之選擇
好處
白蛋白
(雙重血漿分離術)
新鮮冷凍血漿
(血漿分離術)
壞處
較不易感染肝炎
價格昂貴
室溫保存
不含凝血因子
無
不含免疫球蛋白
ABO 血型考量
含凝血因子
較有感染肝炎,愛滋病疑慮
較不易出血
較易發生過敏反應
含免疫球蛋白
需
生理食鹽水
便宜
補充量大時不適用
代用血漿
便宜
半衰期短
ABO-血型相合
治療機轉
血漿移除
 血漿輸注

可能的治療機轉
血漿移除

移除血漿中可能的致病因子: TPE, DFPP
 Antibodies
(Anti-GBM Ab disease; MG)
 Immune complex (SLE)
 Cryoglobulin (Cryoglobulinemia)
 Myeloma protein (Myeloma nephropathy(
 Endotoxin, cytokine (Sepsis)
 Poison or drug
 Cholesterol, LDL-c
可能的治療機轉
血漿輸注

補充血中缺乏之因子: TPE only
 Anti-thrombotic
or fibrinolytic factor (HUS/TTP)：
removal of auto-antibodies to vWF multimers
cleaving enzyme + infusion of vWF multimers
cleaving enzyme

免疫調控 (Immunomodulation)
 Removal
of complement products (SLE)
 Effect of immune regulation (Transplantation)
 Improvement in RE function (cyroglobulinemia)
健保給付之適應症

58008C血漿置換術（2475點）
Plasma exchange：限下列病患實施










1.SLE，CNS involvement
2.Myasthenia gravis crisis
3.Macroglobulinaemia
4.RPGN
5.Goodpasture's disease
6.Multiple myoloma
7.Guillain-Barre syndrome
8.Thrombocytopenic Purpura
9.其他經專案向保險人申請同意實施者
58016C二重過濾血漿置換療法（2475點）
Double filtration plasmapheresis：施行本項之適應症請依
支付標準58008C「血漿置換術」之規定辦理。
Applications of plasmapheresis
ASFA guidelines
e.g. SLE lupus nephritis
ASFA guidelines
Traffic
Accident
Transfer
to NTUH
Cardiac echo:
LVEF 19%
8/14 8/15 8/16
8/23
VV-ECMO
LM dissection
s/p POBAS
Desaturation
PCWP 40 mmHg
Dilate LV
8/31 9/1
9/5 9/6
Extubation
9/15
LV Drain
Cardiac cath:
No ISRS
10/5
LV Assist Device
Remove
VV-ECMO
10/20
10/25
檢查項目
數值
37℃
B cell
1:32 Positive Negative
37℃
T cell
1:32 Positive Negative
4℃
B cell
1:32 Positive Negative
4℃
T cell
1:32 Positive Negative
Donor:楊XX
數值
1:32 Positive
1:32 Positive
1:32 Positive
說明
37℃
37℃
4℃
檢查項目
B cell
T cell
B cell
4℃
T cell
1:32 Positive Negative
11/3
Panel reactive antibody:
Anti-HLA class I: 61%
Anti-HLA class II: 72%
標準值
標準值
Negative
Negative
Negative
說明
Donor:鄭XX
Rituximab (Mabthera)
200 mg
Bortezomib (Velcade)
3.5 mg
Solu-Medrol
1000 mg
Intravenous immunoglobulin
45 gm
R-anti-thymocyte globulin
25 mg
Plasma Exchange
Hypotension, Bradycardia
11/3
11/4
11/6
11/8
11/10
11/12
Donor
11/12
檢查項目
數值
標準值
37℃
B cell
1:8 Positive Negative
4℃
T cell
1:2 Positive Negative
說明
Double Filtration Plasmapheresis
37℃ T cell
1:2 Positive Negative
3L/session, 1.2x plasma volume
4℃
B cell
1:4 Positive Negative
total 5 course
Donor:侍XX
Isoproterenol
Millisrol
Dopamine
Primacor (Milrinone)
Bosmin
3000
Graft failure ?
2500
CO: 2.23
CI: 1.48
2000
1500
1000
CVVH
500
11/11
11/12
Transplant
11/13
DFPP
11/14
11/15
11/16
Massive bloody
pleural effusion
DFPP
IVIG
11/17
IVIG
Solu-Medrol
FK506
Cellcept
11/18
11/19
PT
PTT
sec
sec
26.6
39.1

Definition


Exposure of the immune system to antigen (transplant
organ) sufficient to generate an immune response
Antibody
 ABO
 Anti-HLA
 Non-HLA
• Blood transfusions
• Pregnancy
• Previous organ transplant
• Placement of a ventricular device
Approximate 30% incidence of antibody production (PRA >
10%) after LVAD placement
J Heart Lung Transplant 2002; 21: 1218-24
Prevent rejection
Humoral Response
Donor selection
Recipient
Desensitization
Cellular Response
Immunosuppressive
agents
Human Immunology 2005;66:334-42
Examples of desensitization
J Heart Lung Transplant 2009;28:213-25
Pre-heart transplant plasmaheresis
for sensitized patients (high PRA)


1.5 plasma volume
plasmapheresis + 20g
5% IVIG, then heart
transplant
1.5 plasma volume
plasmapheresis qod
(followed by 20g 5%
IVIG )X 5 sessions. Then
a single plasmaphereis
with IVIG at the time of
surgery
J Heart Lung Transplant 1999;18:701
Clin Transplant 2006;20:476-84
HLA class I
HLA class II
Clin Transplant
2006;20:476-84
Clin Transplant
2006: 20: 476–484
On-pump TPE for XM heart
transplant
High blood flow and thus increased
pheresis rate to shorten treatment time
than standard setting of TPE/DFPP
 3 plasma volume within 60-90min
 Especially need to watch out [Ca]

J Extra Corpor Technol 1999;31:177-83
J Heart Lung Transplant 2008;27:1036-9
Comparative long-term outcome
5-year patient survival
1-year rejection-free survival
523 heart transplant, 95 PRA>10%, 21/95 desensitization, 74 untreated
Survival: no significant difference
Rejection: significant decrease in desensitized patients
(Treated with PP+IVIG+Rituximab)
Clin Transplant. 2010 Oct 25
Proposed protocol for
desensitization
Solumedrol 500mg
IVIG 15g (heart lung machine)
Bortezomib (Velcade) IV slow push
IVIG 30g slowing infusion
Solumedrol 500mg + Rituximab (Mabthera) IV drip
RATG + FK506
D-9
D-7
D-5
D-3
D-1 OP day D1
D3
D5
TIW
1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 2 PV 1.5 PV 1.5 PV1.5 PV
DFPP DFPP DFPP DFPP DFPP DFPP TPE DFPP DFPP DFPP
IVIG IVIG IVIG IVIG IVIG (OR)
Initial Ab X(1-78%)5
=0.0005 initial amount
residual Ab X(1-86%)
Extracorporeal photopheresis
T-cell
B-Cell
Primary prophylaxis
N Engl J Med 1998;339:1744-51
Clin Transplantation 2000;14:162-6
Secondary prophylaxis
J Heart Lung Transplant 2006;25:283-8
Extracorporeal photopheresis
(ECP)


Leukapheresis-based immunomodulatory therapy.
Mechanism:
 causes apoptosis of the treated and abnormal T cells
 induces monocytes to differentiate into dendritic cells
capable of phagocytosing and processing the
apoptotic T-cell antigens
 may cause a systemic cytotoxic CD8+ T-lymphocyte–
mediated immune response to the processed
apoptotic T-cell antigens
 induce antigen-specific regulatory T cells, which may
lead to suppression of allograft rejection or GVHD
ECP Procedures





3 basic stages: (1) leukapheresis, (2) photoactivation, and (3)
reinfusion. The process takes 3-4 hours to complete.
Blood (225 mL) is passed through 3 cycles of leukapheresis, or 125
mL of blood is passed through 6 cycles, depending on the patient's
hematocrit value and body size. At the end of each leukapheresis
cycle, the red blood cells and plasma are returned to the patient.
The collected WBCs (including approximately 5% of the peripheral
blood mononuclear cells) are mixed with heparin, saline, and 8methoxypsoralen (8-MOP), which intercalates into the DNA of the
lymphocytes upon exposure to UVA light and makes them more
susceptible to apoptosis when exposed to UVA radiation.
The mixture is passed as a 1-mm film through a sterile cassette
surrounded by UVA bulbs for 180 minutes, resulting in an average
UVA exposure of 2 J/cm2 per lymphocyte.
The treated WBC mixture is returned to the patient.
UVAR XTS (Therakos, USA)
ECP Complications




Hypotension may occur in some patients during
the collection phase of the treatment.
Low-grade fevers, likely due to the release of
cytokines.
Some patients with cutaneous T-cell lymphoma
(CTCL) may experience an increase in pruritus
or redness.
No immunosuppression, opportunistic infections,
or neoplasia has been associated with
extracorporeal photopheresis.
Acute AMR after heart transplant
Anti-B-memory and/or
plasma cells agents
Am J Transplant 2007;7:2064-74
Transplant Rev 2009;23:34-46
Transplant Rev 2009;23:34-6
血漿分離術之併發症

血管通路
 血胸、氣胸、後腹腔出血

抗凝劑
 出血

Hypothermia
 Hyperthermia
blanket , Warm lamp, Warmer
血漿分離術之併發症

血漿內成份的移除
 血漿量
低血壓、急性心衰竭 (3-6%)
 血漿膠體滲透壓降低導致水腫

 藥物

Volume distribution 較小者易被移除
酶

Cholinesterase


麻醉藥物代謝減慢
GOT/GPT, LDH, CPK下降
血漿分離術之併發症

血漿輸注 (Plasma exchange)
 過敏反應 (5%)
 蕁麻疹、氣管痙攣、低血壓、肺水腫
 Premedication: antihistamine, steroid
 感染
 HBV:1/200-1/300
 HIV:1/40000-1/1000000
 CMV: asymptomatic
 低血鈣症 (1%) : Infusion CaCl2 : 2% 20 c.c/hr
 冷凍血漿常使用Citrate作為抗凝劑所引起
 抽筋、寒顫、嘴部發麻、噁心、心律不整等。
 代謝性鹼中毒：Citrate所引起
血漿分離術之併發症

非血漿輸注：
 球蛋白流失：感染
 凝血因子流失(DFPP)：出血
TPE vs DFPP

Mechanism
 TPE:
Plasma removal + plasma infusion
 DFP: Plasma component removal

Indication
 DFPP:
not suitable for Hepatic failure, TTP/HUS,
refractory bleeding problems

Complication
– 較常見, besides=>exposure to more antigens
 DFPP – 凝血因子缺乏
 TPE
Treatment
Disease
Product
Option 1
Option 2
ABO-mismatched renal transplantation
DFPP
PE
Cascadeflo
Plasmaflo
Allogenic renal transplantation
DFPP
PE
Cascadeflo
Plasmaflo
Rapidly progressive glomerulonephritis (RPGN) DFPP
PE
Cascadeflo
Plasmaflo
Henoch-Schulein purpura nephritis
DFPP
PE
Cascadeflo
Plasmaflo
Systemic lupus erythematosus (SLE)
IA
DFPP
Immusorba
Cascadeflo
Arteriosclerosis obliterans (ASO)
DFPP
Cascadeflo
Plasmaflo
Focal glomerulosclerosis
DFPP
Cascadeflo
Plasmaflo
Acute renal failure
CRRT
CUREFLO
Disease
Treatment
Product
Option 1
Option 2
Systemic lupus erythematosus (SLE)
IA
DFPP
Immusorba
Cascadeflo
Rheumatoid arthritis (RA) with vasculitis
IA
DFPP
Immusorba
Cascadeflo
Disease
Treatment
Option 1
Option 2
Product
Arteriosclerosis obliterans (ASO)
DFPP
Cascadeflo
Plasmaflo
Familial hypercholesterolemia (FH)
DFPP
Cascadeflo
Plasmaflo
Asahi Kasei Kuraray Medical Co., Ltd.
Disease
Treatment
Option 1
Acute renal failure(ARF)
CRRT
Fulminant hepatitis (FH)
CRRT
Hemolytic uremic syndrome (HUS)
PE
Disease
Product
Option 2
CUREFLO
PE
CUREFLO
Plasmaflo
Plasmaflo
Treatment
Product
Option1
Option 2
Myasthenia gravis(MG)
IA
DFPP
Immusorba
Cascadeflo
Guillain-Barr? syndrome (GBS)
IA
DFPP
Immusorba
Cascadeflo
Chronic inflammatory demyelinating =olyneuropathy(CIDP) IA
DFPP
Immusorba
Cascadeflo
Multiple sclerosis (MS)
IA
DFPP
Immusorba
Cascadeflo
Lambert-Eaton myasthenic syndrome(LEMS)
PE
Miller-Fisher syndrome(MFS)
IA
Plasmaflo
DFPP
Immusorba
Cascadeflo
Asahi Kasei Kuraray Medical Co., Ltd.
Disease
Treatment
Option 1
Product
Option 2
Pemphigus
DFPP
PE
Cascadeflo
Plasmaflo
Pemphigoid
DFPP
PE
Cascadeflo
Plasmaflo
Toxic epidermal necrolysis (TEN)
DFPP
PE
Cascadeflo
Plasmaflo
Systemic sclerosis (SS)
IA
DFPP
Immusorba
Cascadeflo
Disease
Treatment
Product
Option 1
Option 2
Multiple myeloma
DFPP
PE
Cascadeflo
Plasmaflo
Primary macroglobulinemia
DFPP
PE
Cascadeflo
Plasmaflo
Thrombotic thrombocytopenic purpura (TTP)
DFPP
PE
Cascadeflo
Plasmaflo
Hemophilia
PE
Cryoglobulinemia
DFPP
Disease
Age-related macular degeneration(AMD)
Plasmaflo
PE
Treatment
Option 1
DFPP
Option 2
Cascadeflo
Plasmaflo
Product
Rheofilter
Plasmaflo
Asahi Kasei Kuraray Medical Co., Ltd.
Disease
Treatment
Option 1
Product
Option 2
Ulcerative colitis (UC)
LCAP
Cellsorba
Crohn's disease (CD)
LCAP
Cellsorba
Severe acute pancreatitis
CRRT
CUREFLO
Post-operative hepatic failure
CRRT
Acute hepatic failure
CRRT
CUREFLO
Primary biliary cirrhosis
PA
Plasorba
Hyperbilirubinemia
PA
Plasorba
Fulminant hepatitis
CRRT
Chronic hepatitis C
DFPP
PA
CUREFLO
PE
Plasorba
CUREFLO
Plasmaflo
Cascadeflo
Plasmaflo
Treatment
Disease
Severe blood-type incompatible pregnancy
Disease
Sudden sensorineural hearing loss (SSHL)
Option 1
Option 2
DFPP
PE
Treatment
Option 1
DFPP
Option 2
Product
Cascadeflo
Plasmaflo
Product
Rheofilter
Plasmaflo
Asahi Kasei Kuraray Medical Co., Ltd.
Flow limitation of TPE/DFPP
300X40%=120cc/m=7.2L/hr => 3 plasma volume in 70mins
150X30%=45cc/m=2.7L/hr≒1 plasma volume/hr
200X30%=90cc/m=5.4L/hr=> 2 plasma volume in 60+mins
Qb 50-150cc/m
Plasma flow
≦40% Qb
MaxTMP
100mmHg
補充液
N/S
MaxTMP
50mmHg
Waste fluid
flow ≦30%
plasma flow
Summary





Plasmapheresis is a rational therapy for AMR and
sensitized candidates, while the solid evidence is still
lacking.
Both TPE and DFPP could offer the ability of removing
circulating antibody.
DFPP may decrease the risk of antigens exposure and
complications from blood component infusion
(hypocalcemia, allergic reaction…)
No well-defined standard protocol and we could
developed our protocol
Rate of plasma flow may be the main limitation
Thanks for your attention!
賴俊夫醫師
MVPN: 51652
E-mail: s821052@yahoo.com.tw
Better choice: MARS or Prometheus
Other choice: TPE + CVVHDF
合併使用 IVIG 須待血漿置換術後再給予, 以免血漿置換術時遭移除
Renal transplantation




70’-80’ CR/CS: effective for all rejection
80’ RCT: not effective, even in so called
“vascular pathology”
Since late 80’: DSA, C4d, development of Banff
criteria, better anti-rejection medications ->
effective for AMR
Since 90’:
 AMR:
removing circulating DSA
 Pretransplant incompatible graft: desensitization of
donor specific HLA or ABO antibody
Renal transplantation uncertainties


Lack multi-center randomized controlled trial
New methods for detecting XM antibody
 higher
laboratory sensitivity
 clinical specificity ?

Criteria for desensitization
 XM methods: cytotoxic
 DSA detection
XM, flow XM
 C4d deposition
 Quantification of antibody, threshold?
 ABO, MHC class I, class II ? DR ? DP,DQ?
Others?