PLASMA

DERIVATIVES
Dr Siti Salmah Noordin
TTS 502
9/10/2018
Topics to be covered
• Plasma preparation
• Plasma fractionation process
➢
Cohn fractionation
➢
Method of purification
➢
Viral reduction
• Plasma derivative and its application
• 1940s : Plasma fractionation developed by Dr. Edwin Cohn during Second
World War
*involves modifying the pH, ethanol concentration and temperature to
separate proteins through precipitates into five “fractions” (I-V).
• 1950s: IMIG
• 1960: purification to develop FVIII and FIX for haemophilia treatment
• 1980s:IVIG and alpha-1 protease inhibitor (A1PI)
• 1990: Malaysia start its fractionation program through contract
fractionation

Source :http://marketingresearchbureau.com/plasma-industry/history-of-plasma-fractionation/
PLASMA PREPARATION
Preparation of RBC, plasma, and platelets

Whole Blood.
Hold at 22°C for up to 8 hrs

Soft Spin

Packed RBC at 2 Platelet Rich Plasma (PRP)

± 2°C

Hard Spin

FFP stored at -25°C

Platelet (or plt poor Rapid freezing within 1 hour below
plasma; PPP) at 22 ± -30°C / -25 °C
2°C
 FFP at -25°C

-Thaw at 2-6 °C for 16-24 hours.

-Centrifuge
-Hard spin at 2-6°C

Cryosupernatant
Cryoprecipitate at -25°C
(supernatant
cryoprecipitate-poor
plasma at -25°C)
• Plasma products:
➢
Storage of palsma products (i-v) : 36 months at or below – 25 ºC @ 3 months at – 18 ºC to – 25 ºC (Council of
Europe, 19th edition)

i. Fresh Frozen Plasma (FFP)

➢
Contains all coagulation factors
ii. Cryoprecipitate
➢
Contain Fibrinogen, FVIII, FXIII, fibronectin and vWF
iii. Cryosupernatant
➢
Contain most clotting factors in similar amounts to FFP but is deficient in FVIII, fibrinogen, VWF (the high
molecular weight multimers are more thoroughly removed than the smaller multimers), F XIII and fibronectin

iv.Plasma frozen within 24 hours of phlebotomy (PF24 or “FP24”)

➢
Frozen within 24 hours after collection
➢
FV levels equal to those in FFP, while FVIII and Protein C levels decline 20-25%
v. Plasma frozen within 24 hours of phlebotomy held at room temperature up to
24 ➢hours after phlebotomy (PF24RT24)
Only from apheresis plasma collections
➢
Held up to 24 hrs at room temp before freezing
➢
Decreased FV, FVIII

vi. ➢Thawed Plasma

After thawing, mostly FFP expired 24 hours later
➢
Thawed FFP/FP24/PF24RT24 may be relabeled as “Thawed Plasma”
➢
Stored at 1-6°C for up to 5 days
➢
Indications are essentially identical to FFP, despite a decrease in FV and FVIII (FVIII decreased
~40-50% by 5 days of storage)

vii.➢ Liquid Plasma / Never frozen plasma

Plasma separated from whole blood
➢
Stored at 1-6°C, not frozen for 26 days
➢
Liquid plasma had a better capacity to form a clot and generate thrombin compared with thawed
plasmaMajority of clotting factors and inhibitors retained more than 88% of their
initial activities at day 26. (Matijevic et al. Better hemostatic profiles of never-frozen liquid plasma compared with thawed fresh
frozen plasma. J Trauma Acute Care Surg; 2013)
PLASMA FRACTIONATION
• Fractionation is separation and processing of human plasma into a range of products
for therapeutic use.
• Requires pooling of 10,000 to 50,000 plasma donations
• Options for plasma fractionation:
➢
Domestic fractionation plant
✓
Full fractionation by building and operating a plasma fractionation facility
✓
E.g: Thailand, Australia, Japan, China, South Korea, India

➢
Contract fractionation
✓
Send local collected plasma to established fractionators
✓
E.g: contract-fractionate to CSL-Behring,Australia - Hong Kong, Malaysia, New Zealand, Singapore, and Taiwan
→albumin, IVIG, factor VIII and factor IX are manufactured and returned to the country of origin.
✓
System regulated by country where the fractionation plant is situated

➢
Sell plasma
✓
Fractionator purchases plasma
✓
Provides product from plant but not necessarily from the country of plasma origin
• Types of plasma for fractionation (WHO, Recommendation for production, control and regulation of human plasma
for fractionation,2007)

➢
Recovered plasma (35% of plasma fractionation collection)
✓
Plasma collected from whole blood donation
✓
Frozen within 24h after collection or after 24 hours (till max 72h) after collection

➢
Apheresis plasma/ source plasma (65% of plasma fractionation collection)
✓
Obtained by apheresis machine (technique: centrifugation or filtration).
✓
Donors are either paid to donate as often as twice a week or a voluntary non-renumerated donor
➢
Hyperimmune (antibody-specific) plasma- can be obtained from:
✓
Individuals selected from the normal population by screening of plasma units for antibody titres (Screening
may be random, or may be informed by knowledge of history of recovery from an infectious disease — for
example varicella).
✓
Individuals with a high titre of a specific antibody resulting from prophylactic immunization.

✓
Volunteers recruited to a panel for a targeted immunization programme→ requires clinical and ethical
consideration.

*All plasma needs to be kept at least at -20°C

Volume of recovered and source plasma (X 1000kg)
Source : WHO, Recommendations
for the production, control
and regulation of human
plasma for fractionation ; 2007
Plasma fractionation flowchart

Plasma reception by Quarantine of plasma

ship establishment in cold room (-20°C or Preparation of
colder) plasma batch
- Usually pack of -Documentation, QC
2,000-4,000L plasma and additional testing

Quarantine and Aseptic Pooling and large Conditioning of

plasma packs
quality control dispensing scale processing

Checks of
production batch, Labelling and Boxing and
records and packaging shipment
documentation
Plasma fractionation process

• Initially relies on Cohn fractionation

using sequential precipitation steps, at
negative temperatures, different
ethanol concentrations and various
pH, to segregate bulk plasma proteins
by differential solubility.

• Modern fractionation methods relies

on cryoprecipitation combined with an
integrated ethanol fractionation ⁄
chromatography process, followed by
aseptic filtration and filling, and freeze
drying.
• The Cohn methods use 5 variables:
I. Ethanol concentration ranging from 8% to 40%
II. pH levels between 4.5 and 7.4
III. Temperature ranges from -3°C to -6°C
IV. Ionic strength differentials from 0.01 to 0.14
V. Protein concentration- from 0.8-5.1%
• As the ethanol concentration or pH is changed,
different protein fractions are obtained.
• Ethanol is removes by lyophilisation (freeze-drying)
or ultra-filtration.
• Alcohol fractionation is now combined with glycine
precipitation or polyethylene glycol, and with other
separation methods such as chromatography to
isolate specific proteins, such as coagulation factors
and protease inhibitors
• Plasma pools are thawed slowly at 1° to 5°C to produce cryoprecipitate.
The cryoprecipitate is usually recovered by centrifugation.
• The cryo-supernatant or cryo-poor plasma may be treated with a chromatographic media
to capture the factor IX complex or antithrombin (AT) before it enters the Cohn process.
• There it goes through a series of precipitations as the ethanol concentration is
increased in steps from 8% to 40% at specific combinations of pH, ionic strength,
protein concentration, and cold temperature.
• The precipitates and supernatants are separated either by the traditional continuous-flow
centrifugation or in large-scale filter presses.
• Fraction I (first precipitate): factor VIII, fibrinogen, and other poorly soluble proteins.
• Fractions II and III are precipitated together: immunoglobulins. Because many of the
fraction I proteins are removed in the cryoprecipitate, some manufacturers do not
produce a separate fraction I. Instead they collect a combined fraction I + II + III.
• Fraction IV, produced from the supernatant of fraction (I+)II + III, is sometimes
produced in two subfractions.
➢
Fraction IV-1: vitamin K-dependent clotting factors, AT and α1-proteinase inhibitor
➢
Fraction IV-4: transferrin, haptoglobin, and some of the albumin.
• Fraction V: albumin.
Cohn
Fractionation
Process
Fracti
on Fraction Fraction Fraction Fraction Fraction
variab I II III IV V
les
Ethano
8 25 18 40 40
l %:
pH: 7.2 6.9 5.2 5.8 4.8
Tempe
rature −3 −5 −5 −5 −5
(°C)
Protein
fractio 5.1 3 3 3 1
n (%):

Rossi’s Principles of Transfusion Medicine 5 th edition.

Chapter 27. page 304
• Others Cohn fractionation process modification:
➢
Gerlough method: used 20% ethanol for precipitation instead of 40% and
combined of fractions II, III, and IV
➢
Mulford method: used the fractions II and III supernatant as the
last step before finishing and heat treatment and combined
fractions IV and V
➢
Kistler and Nitschmann method:
Precipitate: A B C
Ethanol %: 19 40 40
pH: 5.85 5.85 4.8
Temperature (°C) −3 −8 −8
Modification from Combined Fraction II
Fraction IV Fraction V
Cohn and III
• Methods for plasma purification (Thierry Burnouf, Modern Plasma Fractionation;
Transfusion Medicine Reviews, 2007, 21, 2: 101-117)
Viral reduction
T. Burnouf. Plasma fractionation, ISBT Science Series, 2012

• Two types of approaches can reduce the risks of viral contamination:

➢
Viral inactivation treatments: viruses are destroyed and become non-
infectious.
➢
Viral removal treatments: viruses are separated from the protein
fraction through a purposely implemented partitioning.
• In the plasma fractionation industry, at least one viral inactivation step
is required, the second being based on either inactivation – distinct
from the first one- or removal.
A. Viral inactivation
• Solvent detergent (SD)
➢
Protein solutions are incubated for 4 to 6 hours at 24-37°C in the presence of 0.3% to 1% Tri-n-butyl
phosphate (TnBP) and 1% Tween-80 or Triton X-100.
➢
Inactivate lipid-enveloped virus (e.g: HIV, HBV, HCV).
➢
The SD agents are removed by chromatographic adsorption or specific precipitation of proteins, or

selective adsorption on hydrophobic chromatographic support.

• Pasteurization
➢
It is a heat treatment of protein solutions for 10 hours at 60°C, that denatures viral protein and viral
replication.
➢
Inactivate both enveloped and non enveloped viruses (e.g: parvovirus B19, HAV)
➢
Need stabilizers (e.g: sugars, polyols, amino acids) to avoid heat-induced protein denaturation,
neoantigenicity, and precipitation.
➢
Stabilizers may be removed subsequently following pasteurization by ultrafiltration, protein
precipitation, or chromatography
• Low pH incubation
➢
Usually performed at pH 4, at 30°C -37°C for more than 20 hours
➢
Useful for IVIG
➢
Inactivate most lipid-enveloped viruses.

• Caprylic (octanoic) acid

➢
Used only for some IVIG preparations, which are purified and incubated at <pH6
➢
Inactivate lipid-enveloped viruses

• Lyphophilization (dry-heat)
➢
Applied to some coagulation factor concentrates viral reduction treatment.
➢
Performed at 80°C for 72 hours or at 100°C for 30 minutes, generally in the presence of
protein stabilizers.
B. Viral removal
• Nanofiltration
➢
Using 15- to 75-nm multi-layers membranes, or equivalent systems, to remove viruses mostly by
a sieving mechanism.
➢
It is used to complement the core viral inactivation treatment and to provide enhanced safety
against non-enveloped viruses or other resistant infectious agents.

• Non-dedicated virus removal that incidentally occurs during protein

precipitation, chromatography, or filtration steps, contributes to lowering virus
load.
E=
enveloped
virus
NE= non
enveloped
virus
Plasma derivatives or plasma-
derived medicinal products (PDMPs)

• Definition
ISBT 128 defines Plasma Derivatives as, "A product that contains
concentrated fractions of plasma proteins that have been separated using
physico-chemical or other fractionation processes. It is made from pooling
plasma from large numbers of donors and is traced based on the lot or batch
number of the pooled product”.

-ISBT 128 is a global standard for the identification, labelling, and information transfer of medical
products of human origin (including blood, cells, tissues, milk, and organ products) across international
borders and disparate health care systems.
-ISBT 128 encodes information about biological products in a manner that allows the information to be
transferred from one computer system to another in a way that is unambiguous and accurate
Market for PDMPs
Demands for PDMPs
Supply for PDMPs

Source:
https://ipfa.nl/UserFile
s/File/WS%202015/IP
FA%20Cape%20Tow
n%202015/Proceedin
gs%20Publicly%20Pu
blished/1_4_Robert_a
mended.pdf
PDMPs Indications
Replacement
therapy
- e.g: factor
concentrates,
albumin

Immune-
modulating PDMPs Antagonist
therapy indications - PCC, aPCC
- eg: IVIg

Drug delivery
- eg: fibrin
glue
Types of available PDMPs

Coagulation/
Antibody
Albumin anticoagulation Other protein
products
factors

Albumin 4%, Single factor

Immune globulin: 4.5%, 5%
concentrate: factor (F) II,
FV, FVII, FVIII, FIX,FX,
IVIg, SCIg, IMIg FXIII fibrinogen, von Alpha-1 antitrypsin
- iso-osmotic Willebrand factor,
antithrombin, protein C

Hyperimmune
globulin: RhIg, Albumin 20% or Combination of
25% coagulation factors: C1-esterase
Tetanus Ig, Rabies Prothrombin complex
Ig, HBIg, CMV Ig, inhibitor
concentrate
varicella Ig
-hyperosmotic
1) Albumin

• Most abundant protein in blood - accounting for

approximately 50% of total plasma protein
• Human serum albumin is a small protein with a
molecular weight of 66.5 kDa, consisting of a single
chain of 585 amino acids
• Derives from Cohn fraction V and is available in saline
containing 4%, 4.5%, 5%, 20% or 25% protein ,of which
not less than 95% is albumin
• Pasteurized for at least 10 h at +60°C → pasteurization
inactivates both enveloped and non-enveloped viruses
• Indications:
i. Albumin 4%, 4.5% or 5%
➢
Plasma expander →Normal colloid osmotic pressure is 28 mmHg and albumin accounts for 21.8
mmHg. Each gram of albumin attaches 18 g of water
➢
Replacement fluid for therapeutic plasma exchange
➢
Postoperative volume resuscitation after cardiac surgery (may only be used if 3 L crystalloid
has been administered within a given 24-hour period without an adequate hemodynamic response )

ii. Albumin 20% or 25%

➢
Large volume paracentesis (> 5L removed) in patients with cirrhosis
➢
Maintenance of serum albumin levels (e.g major hepatic resection; (>40% resected), post-
operative hurt/lung/liver transplant, nephrotic syndrome)
➢
Management of fluid shifts as an osmotic agent in severely burned patients and liver diseases with
ascites (e.g in hepatorenal syndrome)
2) Antibody production / Immunoglobulin (Ig)

• IgG products are now more often prepared from the supernatant of fraction III
or the precipitate II+III
• Human Ig preparations contain mostly IgG, very little IgM, but variable
amounts of IgA.
• The WHO has established the following production criteria for IVIG :
1. Each lot should be derived from plasma pooled from at least 1,000 donors.
2. It should contain at least 90% intact IgG with the subclasses present in ratios
similar to normal pooled plasma.
3. IgG molecules should maintain biological activity such as complement
fixation.
4. It should be free from contaminants of prekallikrein activator kinins, plasma
proteases and preservatives.
5. It should be free from infectious agents
Evolution in the production of commercialized intravenous immunoglobulins

Benjamin Chaigne, Luc Mouthon. Mechanisms

of action of intravenous immunoglobulin.
Transfusion and Apheresis Science
Volume 56, 2017
• Routes of administration for Ig: intramuscular (IMIg) or intravenous (IVIg)
or subcutaneous (SCIg) or oral

• Examples of hyperimmune globulin:

➢
Human Hepatitis B immunoglobulin
➢
Human Hepatitis A immunoglobulin
➢
Human varicella immunoglobulin
➢
Human rabies immunoglobulin
➢
Human rubella immunoglobulin
➢
Human tetanus immunoglobulin
➢
Human measles immunoglobulin
➢
Ig for Norovirus or Rotavirus (especially for post-transplant recipient)
• Dose:
- As replacement agent (in immunodeficiency patients): 200–400 mg/kg, given
approximately 3-weekly
- As immunomodulatory agent (e.g. in treatment of ITP or Kawasaki’s):
high dose’ IVIG (hdIVIG) at 2 g/kg/month
• Mechanism of action of Ig:
i. Protects against infection: hyperimmune globulins provide
specific passive immunity
ii. Anti-inflammatory and immunomodulatory effects
(https://www.uptodate.com/contents/overview-of-intravenous-immune-globulin-
ivig-therapy)
- Interaction with/blocking of Fc receptors on phagocytic cells in
the spleen and liver such as splenic macrophages
- Inhibition of dendritic cell differentiation and maturation
- Reduction of proinflammatory subsets of peripheral blood
monocytes (CD14+CD16++) and suppression of cytokine
production by these cells
- Blockade of Fas ligand-mediated apoptosis by anti-Fas antibodies
in the IVIG
- Supply of anti-idiotypic antibodies directed against idiotypes on
circulating autoantibodies → downregulation of antibody production
- Solubilization and clearance of immune complex deposits and/or
inhibition of the binding of active complement components such
as C4b and membrane attack complex to target tissues
3) RhIG is a high-titer IgG, anti-D Ig
• IM or IV preparations
• Half life: 3 weeks
• Indications:
➢
Used primarily in the prophylaxis of Rh immunization either through blood
transfusion (RhD-ve recipient transfused with RhD+ve blood)
or through pregnancy (RhD-ve mother carrying an RhD+ve fetus).
- RhIG should be given within 72hrs of the transfusion or delivery.
*20-25g (100-125iu) of RhIg is capable to suppress primary
immunization by 1mL RhD positive red cells.

➢
In RhD +ve patients with ITP
→RHIg binds to D-positive red cells, and thus block Fc receptors
→ interferes with platelet destruction in ITP
Coagulation Proteins
1) Factor VIII concentrate
• Indication : Haemophilia A (deficiency in FVIII; an X-linked disorder)
• Mostly purified from cryoprecipitate
• Undergoes viral inactivation typically by solvent detergent (SD) or
pasteurization.
• Subsequently undergoes chromatography by anion exchange, monoclonal
antibody affinity (using anti-FVIII or anti-VWF murine antibodies), or
immobilized heparin affinity to remove protein contaminants (such as
fibrinogen or fibronectin).
• Alternatively, some freeze-dried preparations are subjected to heat treatment
at 80°C or 100°C to inactivate non-enveloped viruses.
• Recovery of FVIII, as expressed per litre of plasma, is usually comprised
between 100 and 200 IU (1 IU = physiological activity present in 1ml plasma).
• Two types of FVIII -depends on factor purity:
➢
High purity: >50 units/mg (contain only FVIII)
➢
Intermediate purity: <50 units/mg (Also contain other proteins such as von Willebrand Factor). E.g.,
Alphanate [Grifols], Humate [CSL-Behring], Wilate [Octapharma]).
• Factor purity is commonly defined as specific activity (International Units of
clotting activity per milligram of protein)
* Lower purity associated with allergic reaction
• Half life FVIII is 8-12 hours
• Other types of FVIII is recombinant FVIII (e.g: Recombinate (Baxter Bioscience) and
Koginate (Cutter Biological/ Miles)
• Dose (e.g in haemophilia patient):
FVIII dose IU/kg = Desired factor rise % x Body weight(kg)
2
*1 IU/dL of FVIII per kg body weight can be expected to increase the plasma
FVIII concentration by approximately 2%
2) Prothrombin complex concentrate (PCC)
• Contain mixture of vitamin K-dependent coagulation factors in which FII, FIX,
FVII, and FX and proteins C and S have a low specific activity between 0.5
and 2 IU/mg.
*Few products contain also factor VII (FVII), but usually at levels lower than that
of FIX.
• Manufactures involve adsorption of cryo-poor plasma.
• Associated with risk of thromboembolism
• Indications:
➢
Haemophilia B (FIX deficiency)
➢
Urgent overwarfarinization reversal or patient bleeding on warfarin
➢
For haemophilia A patient with inhibitor
• Examples of PCC:
➢
3-factor PCC (contain FII, FIX,FX) : Prothrombinex, Profilnine
➢
4-factor PCC (contain FII, FVII, FIX,FX): Beriplex, Octaplex
➢
Activated PCC (contains non-activated FII and FIX as well as trace
amounts of FVIIa and FXa): factor eight bypassing agent; FEIBA
• Dose (IU /kg)
= Desired rise % of FIX X Body weight (Kg)
Other PCC products are also available in different countries. PCCs containing heparin are contraindicated in patients with
heparin-induced thrombocytopenia. The potency of each PCC vial is according to the FIX activity except for FEIBA, which is
dosed according to FVIII bypassing activity unit. Data are shown based on the prescribing information for each product;
actual factor contents may vary for each vial.
PC/PS protein C/protein S, N.Q. not quantified.
3) Factor IX concentrate
• Isolated by chromatographic purification of the PCC
• Mean specific activity range from 100 to 150 IU/mg and a yield between 200
and 300 IU/L of plasma
• Half life : 18-24 hours
• Indication : Haemophila B
Human derived factors concentrate

52
Recombinant factor concentrate

53
Indication and guidelines for factor replacement

54
 4) Fibrinogen concentrate
• Contain fibrinogen (factor I) in lyophilized powder for reconstitution
• Produced from pooled human plasma using the Cohn/Oncley cryoprecipitation
procedure and undergone viral inactivation steps by solvent/detergent exposure
or pasteurisation
• Indicated as prophylaxis and therapy of haemorrhage in congenital
afibrinogenaemia / hypofibrinogenemia and acquired hypofibrinogenemia (e.g: liver
failure, disseminated intravascular coagulation, massive transfusion and cardiac
surgery)
• Four fibrinogen concentrates are currently available: Haemocomplettan/ RiaSTAP (CSL
Behring, Marburg, Germany), FIBRINOGENE T1 and Clottagen (LFB, Les Ulis,
France), Fibrinogen HT (Benesis, Osaka, Japan) and FibroRAAS (Shangai RAAS,
Shangai, China)
• Dose (mg/kg body weight) = [Target level (mg/dL) - measured level (mg/dL)]

1.7 (mg/dL per mg/kg body weight

Or when fibrinogen level is unknown: 70 mg/kg body weight

• Complications: allergy/ thrombosis
 Fibrin Glue
• Contain freeze dried fibrinogen-rich and purified thrombin concentrates.
• Fibrinogen is prepared by precipitation methods from cryoprecipitate, or
from the Cohn fraction I
* Fraction I may also contain fibronectin, VWF, or factor XIII (FXIII).
• Fibrinogen is virally inactivated by solvent detergent, pasteurization, vapor-heat
treatment, and/or nanofiltration.
• Indications:
➢
Hemostasis in diffuse bleeding – all surgery (e.g: orthopaedic, maxillofacial, ENT, Urology
➢
Adhesive- adhesion/ gluing for skin graft parenchyma in surgery on the kidney, liver, spleen and
pancreas, spongiosa grafting when packing bone cavities and defects, pleurodesis in spontaneous
pneumo thorax, fixation of skin grafts and flaps,
➢
Sealant- coating and sealing of vascular prostheses, tympanoplasty, sealing of the lens after
injuries with perforations, sealing of suture lines to prevent leakage of intestinal anastomoses,
additional sealing of sutured microvascular anastomoses,
 5) Antithrombin
• Antithrombin (AT) inactivates five of the activated
coagulation factors (IIa, IXa, Xa, XIa, XIIa).
• AT concentrates is produced from cryo-supernatant
or cryo-poor plasma with ion exchange
chromatography to remove the PCC components,
followed by capture of AT on immobilized heparin.
Also produce from fraction IV-1 by affinity
chromatography and adsorption
• Viral inactivate by heat-treated or solvent/detergent
treated, nanofiltered or pasteurization in the
presence of sodium citrate or a combination of
sucrose and glycine
• Indication:
-prevention or treatment of thromboembolic disorders
in patients with hereditary antithrombin deficiency.
The treatment aim is to maintain AT activity in the 80–
120% range.
- in acquired AT deficiency such as liver cirrhosis
who are to undergo surgery and patients in hepatic
coma or pre-coma.
• Administration of 1 UI/kg of body weight
increases plasma AT activity by 1.4%.
• Half life: 3.8 days
 6) Protein C
• Protein C is a serine protease that inhibits
activated FV and FVIII. Activated protein C
also stimulates fibrinolysis by neutralizing the
inhibitor of tissue plasminogen activator.
• It requires co-factor which is protein S
• A plasma-derived protein C concentrate Purpura
(eg :CEPROTIN is prepared by anion fulminans
exchange chromatography, solvent/detergent
treatment, and affinity chromatography.
• Indicated in treatment for congenital protein
C deficiency as a
➢
Treatment of acute episodes of venous
thrombosis and purpura fulminans
➢
Prophylaxis of thrombotic events
• Half life: 4.4 to 15.8 hour
C1- Esterase Inhibitor (C1-INH)
• C1-INH is a positive acute-phase
plasma glycoprotein
• Function as regulating the
complement cascade system,
regulation of the contact
(kallikrein-kinin) amplification
cascade, and participates in the
regulation of the coagulation and
fibrinolytic systems.
• C1-NH is synthesized and secreted
primarily by hepatocytes, but is
also produced by monocytes,
fibroblasts, macrophages,
microglial cells, endothelial cells,
and some other cell.
• Deficiency of C1-NH causes
hereditary angioedema (HAE)
• HAE
- an autosomal dominant
- typically manifests as acute attacks with nonpruritic,
nonpitting, subcutaneous, or submucosal edema, with
the most frequently affected areas including the arms,
legs, hands, feet, bowels, genitalia, trunk, face, tongue,
and larynx
• C1-NH is purified by chromatography from the cryo-
supernatant or cryo-poor plasma after extraction of
the PCC and,potentially, AT.
• It is virally inactivated by pasteurization, vapor heat,
or SD, possibly combined with nanofiltration
®
• Indication of C1-NH (e.g Berinert , Cinryze™):
-treatment of acute facial and abdominal HAE attacks
-routine prophylaxis of HAE in adolescent and adult
patients;
- ACE inhibitor-induced angioedema.
• Half life: 36-48 hours
THANK YOU