血漿分離術

January 29, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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: [email protected]

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  C4d deposition  Quantification of

XM, flow XM

antibody, threshold?  ABO, MHC class I, class II ? DR ? DP,DQ? Others?

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