Having tested positive for HCV, the journalist Jane O'Brien made a request to the BTSB to put her in contact with other women in the same situation. They refused her request on grounds of patient confidentiality and privacy. [ 12 ]  She persisted through word of mouth and appeals in the media to make contact with other women affected and set up a meeting in May 1994 at the offices of the  Council for the Status for Women  with a view to forming a support group.
25 women who had tested positive for HCV attended and elected a committee for the group. [ 13 ]  They decided to name the group " Positive Action " which simultaneously stated the purpose of the group and countered the stigma associated with their HCV positive status. The group set up its office at 56 Fitzwilliam Square, Dublin. [ citation needed ]


The group quickly gathered support from the Council for the Status of Women, Rosemary Daly of the  Irish Haemophilia Society ,  Theresa Ahern  TD, Chair of the Oireachtas Women's Rights Committee,  Máire Geoghegan-Quinn  TD and President  Mary Robinson .
Dr. Geoff Dusheiko of the  Royal Free Hospital  London became their expert advisor on medical matters. When the group first published their list of grievances with their treatment and the responses of the BTSB, the Health Minister initially defended the BTSB's response [ 14 ] [ 15 ]  but following pressure in the Dáil from opposition TDs, particularly Theresa Ahern, [ 16 ]  and  Bernard Durkan [ 17 ]  he agreed to meet first with one of the founders and then in June 1994 with the full support group. [ 18 ]


Minister Howlin acknowledged the women's grievances with the BTSB's queries into their sexual history and the fact that they were being counseled by the very organization that was responsible for their infection. The Minister announced that a limited ex-Gratia expenses scheme was being operated by the BTSB to ensure that all anti-D recipients could avail of the screening, counseling and treatment services but that no consideration could be given to a full compensation scheme until the Expert Group on the BTSB had completed and published its report. [ 19 ]


Positive Action's repeated requests for the BTSB to distribute their letter to all women affected by the anti-D contamination were ignored until Michael Noonan became Health Minister. [ citation needed ]


The Fine Gael TD, Mr  Alan Shatter , called on the DPP to consider criminal prosecutions of those responsible for what he called the "blood bank scandal". [ 20 ]


The HCV National Screening program revealed many people who had tested positive for hepatitis C but who had never received an anti-D injection. Many of these were men and women who had never had children but who had had at some point in their lives received blood transfusions supplied by the BTSB. These included people who had been in accidents, had surgical operations or were suffering from other illnesses such as haemophilia or kidney disease and need regular blood transfusions, which prior to 1994 had not been screened for hepatitis C (and several other viruses). [ 21 ]


Inspired by the actions of the women of Positive Action, a group of men and women met in  Liberty Hall  on 22 April 1995 with a view to organizing and making representations based on their specific needs and circumstances. They called their group  Transfusion Positive [ 22 ]  and held their first official meeting on 13 May 1995, in Powers Hotel on  Kildare Street , Dublin. Unlike the mothers who had received anti-D injections from known infected batches, it was much more difficult to prove categorically the source of infection for those who had had transfusions or had secondary infections from transfusion patients who had been infected. [ citation needed ]


On 5 March 1994, Minister for Health Brendan Howlin announced the establishment of an Expert Group under the leadership of   Miriam Hederman O'Brien , with the following terms of reference: [ 3 ]


1. To examine and report to the Minister for Health on the following matters:


2.  To make recommendations to the Minister for Health on the above matters and on any other matters relation to the Blood Transfusion Service Board which the Group considers necessary.


The other members of the Expert Group were:


The Minister's decision to use an Expert Group rather than a Tribunal of Inquiry was influenced by the public outrage at the costs of the  Beef Tribunal  which with costs in excess of €27 million was at that time the most expensive inquiry in the history of the state.
The Expert Group format should establish the facts and make recommendations in a much quicker and cost-efficient manner.
The Expert Group met with and gathered evidence from senior management and technical staff of the BTSB, the NDAB, the department of health and from various medical experts and bodies both in Ireland and abroad.
Its remit did not extend to interviewing the infected women or their representatives although it did make some observations on their treatment and counselling.


On 27 January 1995, the Expert Group delivered their report to the new Minister for Health,  Michael Noonan  T.D.
 [ 23 ]  who subsequently had it published.


The report [ 3 ]  clearly laid out the events that led to the 1977 contamination of anti-D and also those leading to the second contamination in 1991.
(It also found that there had been infections with hepatitis during every year that anti-D was used – i.e., 1970–1994.) [ 24 ]


The report highlighted operational and procedural shortcomings in the BTSB's response to each case and in its general operations:


It also noted that while staff of the BTSB had at all times been courteous, they had not always been forthcoming with details:


Some of our queries were answered in a manner which, although accurate, required considerable supplementary probing on our part before we felt reasonably confident that we had adequate information about the circumstances into which we were inquiring. ...


The account which we have given and the inferences which we have drawn are on the basis of the information we have received. [ 3 ]


Indeed, some of the information they received would be amended during the course of the subsequent Tribunal of Inquiry.
The difficulties the Expert Group had obtaining information from BTSB staff had been reported in the press and were known to Minister Howlin. [ 25 ]


In Dáil debates following the publication of the Expert Group's report, during which there were calls for dismissals and resignations at the BTSB, Michael Noonan TD, the new Minister for Health adopted a defensive position, going so far as to express full confidence in the board of the BTSB, 9 of whom had been appointed since 1993. [ 26 ]


Following publication of the Expert Group's report Positive Action entered into negotiations with the Department of Health for appropriate compensation (medical and financial). [ 10 ]
Negotiations ceased in September 1995 [ 27 ]  and resumed on 1 November 1995 at the request of the Department of Health.


As a result, the following were introduced: [ citation needed ]


Positive Action criticized the "ad hoc" nature of the proposed tribunal, which meant that any government could take a decision to simply wind it up without a vote in the Dáil. [ 28 ]
They demanded that any compensation tribunal should be established on a statutory basis by an act of the Oireachtas.
They felt that the purpose of the tribunal was to enable the state to never admit its culpability in the case and to force women to accept smaller sums than would be awarded through a judicial process.
Positive Action held a meeting in December 1995 at which 91% of members voted to reject and boycott the compensation tribunal. [ 29 ]


Transfusion Positive, the group representing people who had contracted hepatitis C through blood transfusions (rather than anti-D) from the BTSB also voiced concerns over the tribunal's requirement to prove infection "on the balance of probabilities". [ 27 ]


In December 1995, despite the misgivings of the representative groups, the government announced the establishment of the tribunal to award compensation to those infected with hepatitis C through BTSB products (anti-D and transfusions) under the chairmanship of former  Supreme Court  judge  Mr. Justice Seamus Egan . [ 30 ]


The tribunal chairman would adjudicate on cases together with two other members selected from a panel that included Ms. Alison Cross BL, Ms. Sheila Cooney Solicitor and Ms. Eileen Leyden BL. [ 27 ]


In February 1996, the tribunal made its first compensation awards to two women whose cases were accelerated due to their terminal illness, [ 31 ]  one of whom died within weeks of the award. [ 32 ]


At the end of February 1996 only 72 women had applied to the compensation tribunal [ 33 ]  and some 400 had issued writs against the BTSB in the courts.


The government announced that the closing date for applications to the compensation tribunal would be 17 June 1996.


Positive Action re-iterated their rejection of the tribunal claiming the government was using it to discourage women from taking legal action to expose the truth. [ 34 ] [ 35 ]


Fearing they might miss out on all compensation members of Positive Action group took legal advice.
Some members chose to apply to the tribunal while simultaneously initiating legal action against the BTSB.


Throughout the following weeks stories began to emerge of an aggressive legal strategy being pursued by lawyers acting for the Department of Health and opposition politicians accused the government of trying to bully the women into settling with the compensation tribunal. [ 36 ]


Over the following months the media reported on various awards made by the compensation tribunal. [ 37 ] [ 38 ]


By February 1997, the compensation tribunal had received 1,664 applications, of which 1,512 were primary claimants, 86 were dependents and 66 carers. [ 39 ]
In the 267 cases heard to that point, the tribunal had made 169 lump sum awards, 96 provisional awards and had disallowed two claims.


In subsequent years several of the awards made or denied by the tribunal were challenged in the High Court, most of which were reviewed by  Mr. Justice Bernard Barton .


On 28 July 1995, lawyers acting for a HCV-positive Donegal woman with advanced liver disease who had received anti-D treatments during her 12 pregnancies made an application to the High Court to pursue for damages against the BTSB and the Irish State using an assumed name. [ citation needed ]


It was proposed that to protect the woman and her family from the stigma associated with the hepatitis C, she would take the case using the name "Bridget Roe". [ 40 ]
Ms. Susan Stapleton, Solicitor said the woman wished to use an alias because she desired to protect her privacy, not merely as a means of preventing embarrassment to her but also to prevent real injustice to her. [ 41 ]


In January 1996, the Attorney General challenged the woman's right to take such a case using a false name. [ 42 ]
On 14 February 1996, Miss Justice Laffoy ruled that to do so would contravene Article 34 (1) of the Constitution. [ 43 ]


The woman decided to continue with her case for damages against the BTSB, the NDAB, the Minister for Health, the Attorney General and the Irish State using her real name Brigid Ellen McCole.
Given the advanced nature of her disease and poor prognosis, her legal team applied to the High Court to set a date for her action to be heard in June 1996.
While adjudicating on the issue on 26 April, Mr Justice Costello, President of the High Court, asked if granting the request would mean 400 similar applications would follow and fixed 8 October as the date for the trial, which was expected to take six weeks
. [ 44 ]


On 23 April the Oireachtas Select Committee on Social Affairs wrote to the BTSB requesting that it send a delegation to meet the Select Committee on Social Affairs on Thursday 2 May and discuss the hepatitis C issue.
The Chief Executive of the BTSB wrote a response saying it would not be appropriate for board could to enter into such discussions while Mrs. McCole's action was pending in the High Court. [ citation needed ]


In June 1996 Mrs. McCole's legal team applied to the High Court for discovery of files held by the BTSB, which contained information relevant to Mrs. McCole's case.
Ms. Justice Laffoy ruled that the woman was entitled to seek information from the board's employees relating to the case dating back to 1976 and gave the BTSB until 19 July to answer certain questions about its documentation.
On 23 July Mr Donal O'Donnell SC, for the BTSB, said the BTSB was conducting an extensive search through a great volume of files and asked for an additional two to three weeks more to submit an affidavit concerning the discovery of documents.
Miss Justice Laffoy said that it was an awkward situation for the BTSB and that she had no option but to grant its request
. [ 45 ]


From files eventually disclosed by the BTSB, Mrs. McCole's legal team uncovered significant details that had not been shown to the Expert Group's investigation: [ citation needed ]


Based on these revelations, Mrs. McCole's legal team formulated a long list of questions which it sent to the BTSB and as it became increasingly unlikely that they would ever come to trial, leaked them also to the press
. [ 46 ]


After attending a family wedding in Donegal in August 1996, Mrs. McCole was transferred to St. Vincent's Hospital in Dublin, where it quickly became clear that she was dying.
The legal teams acting for the plaintiffs contacted Mrs. McCole's team to negotiate a settlement.
On 20 September they wrote a letter of apology to Mrs. McCole and admitted liability in the case.
In a series of letters Counsel for the BTSB offered £175,000 in compensation from the BTSB compensation tribunal provided the McCole family would agree never to sue them following their mother's death
. [ 47 ]


If Mrs. McCole died without accepting this offer, the maximum compensation her family might win in the courts would be £7,500.
Counsel for the BTSB also threatened her with legal costs if she did not accept the offer
. [ 48 ]


When her doctors told her she would not live to the trial date, Mrs. McCole saw she had run out of time.
Negotiations continued while she was on her deathbed where on 1 October 1996, she accepted the board's full admission and offer of £175,000
. [ 49 ]
She died the next day.


The fact that the 1991 contamination of anti-D was not publicly announced until the report of the Export Group undermined confidence in the commitment of the BTSB and Department of Health to full transparency.
The legal case taken by Brigid McCole had led to the discovery of additional facts (such as the scope of the Therapeutic Substances Act, 1932 and the labelling of Patient X's blood tests as "infective hepatitis") which had been kept from the Expert Group and contributed further to the public disquiet.
However, Minister Michael Noonan resisted all calls for a full Judicial Inquiry into the affair until. His position changed after Mrs. McCole died. [ citation needed ]


In a statement to Dáil Éireann on 3 October 1996, [ 50 ]
Minister Noonan revealed that the BTSB had agreed to admit liability in the McCole case on 20 September but when  Maire Geoghegan-Quinn  demanded an full judicial Inquiry, he cited the huge legal costs and lack of clarity that resulted from the  Beef Tribunal .


A few days later, the Minister had received a letter from the family of Brigid McCole in which they listed a series of questions they expected the Minister to answer.


On 8 October, the minister brought a motion before the Dáil to institute a tribunal of Inquiry into the entire controversy.
The terms of reference for this tribunal were based in large part on the questions submitted in the McCole family's letter. [ 51 ]
He stated that he had previously felt such a tribunal unnecessary because he expected the McCole case in the High Court to clarify any issues outstanding from the Expert Group's investigation but given the death of Mrs. McCole, that case could no longer proceed. [ 52 ]


Under  Justice Thomas Finlay , this tribunal commenced on 5 November 1996 and sat for a total of 27 days, with the press reporting daily on hearings. Although the Expert Group's report had established most of the facts of the case, the reporting of first-hand testimonies and cross examinations of victims, [ 53 ] [ 54 ]  BTSB staff, [ 55 ] [ 56 ] [ 57 ] [ 58 ]  independent experts, [ 59 ] [ 60 ] [ 61 ]  civil servants [ 62 ]  and politicians [ 63 ] [ 64 ]  had a huge impact on public opinion.


One of the first witnesses to appear before the tribunal was 27-year old Bríd McCole, [ 51 ] [ 65 ]  daughter of the late Brigid McCole who said it was her "mother's dying wish that the truth of now she suffered and the circumstances surrounding it would be revealed".


At the final hearings on 4 February 1997, Justice Finlay expressed his deep admiration for those victims who had given evidence and for the manner in which they had contributed to the tribunal with rare courage and great moderation. [ 66 ]


At the final hearings of the tribunal, counsel for the tribunal, Mr James Nugent SC said that would not be appropriate for the tribunal to send its report to the DPP or to recommend prosecutions in the hepatitis C scandal.
This opinion was echoed by  Mr. Frank Clarke SC , counsel for the public interest, by Mr Patrick Hanratty, counsel for the NDAB and by Mr Paul Gallagher SC representing the BTSB. [ 67 ] [ 68 ]


On behalf of the BTSB, Mr Paul Gallagher SC issued an apology to all those who had become infected with hepatitis C due to the BTSB's negligence, repeated wrong decisions and breach of protocols. [ 69 ]
Counsel for the Department of Health used the final sitting to voice a comprehensive defense of the department's actions throughout the controversy. [ 66 ]


Mr. Justice Thomas Finlay then took another four weeks to finalize his report and submit it to the Minister for Health who had it published on 11 March 1997. [ 70 ]


Amongst the findings in the report were:


Responsibility for these failures lay to a major extent with 3 named employees of the BTSB:


The report made many recommendations, which included re-structuring the BTSB and moving from its out-dated facilities at Pelican House.


Following the tribunal findings, Positive Action again lobbied for a statutory compensation tribunal with power to award exemplary and punitative damages.
In May 1997 the bill to establish this statutory compensation tribunal, [ 71 ]  was passed in the Oireachtas, and included provision for a reparation fund of 20% of the tribunal award for exemplary and punitive damages or the option of a hearing on such damages.


The speed and efficiency with which Thomas Finlay's BTSB Tribunal conducted its business, restored confidence in the tribunal as a mechanism of resolving great controversies in the public interest. [ 72 ]


Following the tribunal Cecily Cunningham was the only employee of the BTSB to be sacked and later took an action for unfair dismissal against them. [ 4 ]  Dr. Terry Walsh had retired but both he and Ms. Cunningham would be called before the  Lindsay Tribunal  examining the contamination of BTSB's products for the treatment of haemophilia with HIV and hepatitis C.


Walsh and Cunningham were arrested in 2003. [ 73 ]  Walsh died before facing court, and charges against Cunningham were dropped in 2009. [ 74 ]


In a series of heated Dáil debates that followed the death of Brigid McCole, [ 50 ] [ 75 ] [ 76 ]
the influence of the Government on the BTSB's legal strategy towards her case and those of other women seeking compensation came under scrutiny.


Minister Noonan's attempt to describe Mrs. McColes acceptance of an  ex gratia  payment from the ad-hoc compensation tribunal as a negotiated settlement were attacked by opposition TDs who pointed out her acceptance came only when she realized she had hours to live and might otherwise get no compensation for her family.
The minister faced many questions about his knowledge of and influence on the BTSB's legal strategy, its admission of liability, the scheduling of the McCole case in the High Court and the retirement of senior managers from the BTSB without ever facing sanction. [ citation needed ]


In his statement to the Dáil on 16 October 1996, [ 76 ]
Mr. Noonan suggested that Mrs. McCole's legal team had not properly represented her interests asking:
"Would not the solicitors for the plaintiff have served their client better if they had advised her to go to the compensation tribunal early this year?
Was it in the interest of their client to attempt to run her case not only in the High Court, but also in the media and the Dáil simultaneously?"


This course of argument caused outrage amongst opposition TDs and in the public gallery of the Dáil where representatives of Positive Action stood in protest and left.
The minister returned to the house later that evening to issue an unreserved apology, [ 77 ]  for any offense his statement may have caused but the episode would dog him for the remainder of his political career. [ 78 ] [ 79 ]


While neither Brendan Howlin T.D. nor Michael Noonan T.D. were responsible for the Department of Health or any of its client organizations (BTSB/NDAB) when the contaminations occurred, their management of the crises and treatment of victims was subject to severe criticism by witnesses to the tribunal of inquiry chaired by Justice Finlay. [ 80 ] [ 81 ] [ 82 ]


In June 1997 the new Fianna Fáil Minister for Health, Mr.  Brian Cowen  TD released the McCole papers. [ 48 ]
These revealed that the BTSB had information since 3 April 1995 that they were negligent, had no defence in the McCole case, but continued to fight her application for anonymity and sent her a threatening letter on her death bed. [ citation needed ]


The government sent the Finlay Report to the DPP who responded on 6 October 1997 with the decision that no criminal prosecutions would be forthcoming as a result of the report. [ citation needed ]


The McCole family wrote first to the new Minister for Health [ 83 ]  and subsequently to the  Garda Commissioner , Patrick Byrne [ 84 ]  to demand an investigation. A Garda investigation began in late November 1997 which in 2003 resulted in charges being brought against two former employees of the BTSB - Dr. Terry Walsh and Ms Cecily Cunningham (Dr. Jack O'Riordan had since died) - on seven counts of Grievous Bodily Harm.


Both Dr. Walsh [ 85 ]  and Ms. Cunningham [ 86 ]  sought court injunctions to prevent their prosecutions but failed.


While their court cases were pending, the untimely death of Dr. Terry Walsh [ 87 ]  was announced and the case against Ms. Cecily Cunningham was dropped by the DPP due to the deaths of crucial witnesses.


In January 2002,  RTÉ  broadcast a four-part TV drama series called  No Tears [ 88 ]  based on the story of the anti-D contamination and the scandals that ensued.


Written by Brian Phelan the drama was based on real events but did not use the real names of any of the parties involved and through artistic license amalgamated aspects and experiences of different people into composite characters.
It starred the  Oscar -winning actress,  Brenda Fricker  as Gráinne McFadden (based very closely on Brigid McCole),  Tina Kellegher  as Monica O'Callaghan (based on Jane O'Brien) and  Mark Lambert  as "The Minister for Health".
Most other characters were composites of real women and families that were impacted by the contamination and employees of the BTSB and State Agencies who are focused on damage limitation. [ citation needed ]


Whereas, most viewers' knowledge of the story came from factual and often dry court reports and newspaper articles, the TV drama could show the emotional impact of many years of inexplicable illness on these women all over Ireland, as it first explored their back stories before the events that brought the controversy to light.
The series proved hugely popular, [ 89 ]  breaking viewing figures for an Irish-produced TV drama serial but attracted a certain amount of controversy also.


Some members of Positive Action challenged the sequence of and participants in certain events but it was whether the depiction of the Minister for Health was unfair or unduly unsympathetic that stimulated most discussion.
 [ 90 ] [ 91 ]


The family of Brigid McCole denied ever giving their "blessing" to the production. [ 92 ]


Core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase, 1 , also known as  C1GALT1 , is an  enzyme  which in humans is encoded by the  C1GALT1   gene . [ 1 ] [ 2 ]


The common core 1  O-glycan  structure Gal-beta-1-3GalNAc-R is a precursor for many extended  mucin -type O-glycan structures in animal cell surface and secreted  glycoproteins . Core 1 is synthesized by the transfer of  Gal  from  UDP -Gal to GalNAc-alpha-1-R by core 1 beta-3-galactosyltransferase (C1GALT1). [ 2 ]


C1GALT1 is associated with the  T-Tn antigen  system. [ 3 ]


There is some evidence that mutations in the  C1GALT1  gene may be associated with  kidney disease . [ 4 ]


This article on a  gene  on human  chromosome 7  is a  stub . You can help Wikipedia by  expanding it .


1HZF ,  4FXG ,  4FXK ,  4XAM


ENSG00000244207 ENSG00000206340 ENSG00000244731 ENSG00000227746


NM_001252204 NM_007293


NP_001239133 NP_009224


Complement C4-A  is a kind of the  Complement component 4   protein  that in humans is encoded by the  C4A   gene . [ 5 ]


This gene encodes the acidic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic  lupus  erythematosus and  type I diabetes mellitus . [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]  Excess production due to a copy number that is higher than normal has shown a high probability of a causal relationship with  schizophrenia  and  bipolar disorder  with psychosis, which could explain the hereditary nature of these illnesses. [ 12 ]  This gene localizes to the  RCCX locus  within the major  histocompatibility complex (MHC) class III  region on chromosome 6. [ 13 ] [ 14 ]  Varying  haplotypes  of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. [ 5 ]  Each copy of the gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization, [ 15 ]  can be of one of two types:  C4A  and  C4B . [ 16 ]  Each gene contains 41 exons and has a dichotomous size variation between approximately 22 kb and 16 kb, with the longer variant being the result of the integration of the endogenous retrovirus HERV-K(C4) into intron 9. [ 14 ]


This article on a  gene  on human  chromosome 6  is a  stub . You can help Wikipedia by  expanding it .


Cadaveric blood transfusion  is the  transfusion  of blood from a dead body to a living person.


In 1929, surgeon Vladimir Shamov of  Kharkiv ,  USSR , reported the experimental use of cadaveric  blood  and demonstrated the absence of toxicity. Russian surgeon  Sergei Yudin  pioneered the transfusion of cadaveric blood and performed this successfully for the first time on March 23, 1930. Yudin also reported his first seven  clinical   transfusions  with cadaveric blood at the Fourth Congress of  Ukrainian  Surgeons at Kharkiv in September 1930. The discovery that cadaveric blood could be stored safely provided time for both  serological  tests and  bacteriological  examinations. Cadaveric blood was never used widely, even in Russia. From these studies, however, developed a variety of means and methods for the collection, preservation, and storage of blood for transfusion, all of which may be grouped under the umbrella term " blood bank ". Although cadaver blood transfusion did not catch on in the  United States , physician  Bernard Fantus  modified the Soviet idea by preserving blood from healthy living persons. Drawing on earlier work involving preservatives and anticoagulants, Fantus added the element of refrigeration and in 1937 established the first blood bank in the United States at  Chicago's   Cook County Hospital .  [ 1 ]


1POZ ,  1UUH ,  2I83 ,  4PZ3 ,  4PZ4


NM_001202555 NM_001202556 NM_001202557


NP_001189484 NP_001189485 NP_001189486


The  CD44 antigen  is a  cell -surface  glycoprotein  involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the  CD44   gene  on chromosome 11. [ 5 ]  CD44 has been referred to as HCAM (homing  cell adhesion molecule ), Pgp-1 (phagocytic  glycoprotein -1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.


CD44 is expressed in a large number of mammalian cell types.  The standard  isoform , designated CD44s, comprising  exons  1–5 and 16–20 is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v.  Some  epithelial cells  also express a larger isoform (CD44E), which includes exons v8–10. [ 6 ]


CD44 participates in a wide variety of cellular functions including  lymphocyte  activation,  recirculation and homing,  hematopoiesis , and  tumor   metastasis .


CD44 is a receptor for  hyaluronic acid [ 7 ]  and internalizes metals bound to hyaluronic acid [ 8 ] [ 9 ]  and can also interact with other  ligands , such as  osteopontin ,  collagens , and  matrix metalloproteinases  (MMPs).  CD44 function is controlled by its posttranslational modifications. One critical modification involves discrete sialofucosylations rendering the selectin-binding glycoform of CD44 called HCELL (for Hematopoietic Cell E-selectin/L-selectin Ligand). [ 10 ]  (see below)


Transcripts for this  gene  undergo complex  alternative splicing  that results in many functionally distinct  isoforms ; however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis.  Splice variants of CD44 on colon cancer cells display sialofucosylated HCELL glycoforms that serve as P-, L-, and E-selectin ligands and fibrin, but not fibrinogen, receptors under hemodynamic flow conditions pertinent to the process of cancer metastasis. [ 11 ] [ 12 ]


CD44 gene  transcription  is at least in part activated by  beta-catenin  and  Wnt signalling  (also linked to tumour development).


The HCELL glycoform was originally discovered on human hematopoietic stem cells and leukemic blasts, [ 10 ] [ 13 ] [ 14 ] [ 15 ]  and was subsequently identified on cancer cells. [ 12 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ]  HCELL functions as a "bone  homing  receptor", directing migration of human hematopoietic stem cells and  mesenchymal stem cells  to bone marrow. [ 14 ]    Ex vivo glycan engineering of the surface of live cells has been used to enforce HCELL expression on any cell that expresses CD44. [ 20 ]  CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen. [ 11 ] [ 21 ]


The protein is a determinant for the  Indian blood group system .


In addition, variations in CD44 are reported as cell surface markers for some breast and prostate  cancer stem cells . In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics [ 22 ]  and has been seen as an indicator of increased survival time in  epithelial   ovarian cancer  patients. [ 23 ]


Endometrial cells in women with  endometriosis  demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells. [ 24 ]


CD44 variant  isoforms  are also relevant to the progression of  head and neck squamous cell carcinoma . [ 25 ] [ 26 ]


Monoclonal antibodies  against CD44 variants include  bivatuzumab  for v6.


CD44 is a multistructural and multifunctional  cell surface molecule  involved in  cell proliferation ,  cell differentiation ,  cell migration ,  angiogenesis , presentation of  cytokines ,  chemokines , and growth factors to the corresponding  receptors , and docking of  proteases  at the  cell membrane , as well as in signaling for  cell survival . All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of  cancer cells . Experiments in animals have shown that targeting of CD44 by  antibodies ,  antisense  oligonucleotides, and CD44-soluble proteins markedly reduces the malignant activities of various  neoplasms , stressing the therapeutic potential of anti-CD44 agents.


High levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia. [ 27 ]  Furthermore, because  alternative splicing  and  posttranslational modifications  generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach. [ 28 ]


In many cancers ( renal cancer  and  non-Hodgkin's lymphomas  are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome. [ 29 ]  On the contrary, in some neoplasms CD44  upregulation  is associated with a favorable outcome. This is true of  prostate cancer , where the  transcript variant  CD44v5 (includes the fifth 'v5' exon) is associated with better prognosis (increased time to recurrence following surgery). [ 30 ] [ 29 ]  In prostate cancer, the exclusion of the v5 exon through alternative splicing was associated with the presence of RNA binding protein  KHDRBS1  and became included in the presence of increased  YTHDC1  or  metadherin  expression. [ 30 ]


In other cases different research groups analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers. [ 29 ]


CD44 has been shown to  interact  with:


1CDQ ,  1CDR ,  1CDS ,  1ERG ,  1ERH ,  2J8B ,  2OFS ,  2UWR ,  2UX2 ,  4BIK


P13987 Q6FHM9


NM_001127227 NM_203329 NM_203330


NM_181858 NM_001368215


NP_976074 NP_976075 NP_976076 NP_000602.1 NP_001120695.1 NP_001120697.1 NP_001120698.1 NP_001120699.1 NP_976074.1 NP_976075.1 NP_976076.1


NP_862906 NP_001355144


CD59 glycoprotein , also known as  MAC-inhibitory protein  (MAC-IP),  membrane inhibitor of reactive lysis  (MIRL), or  protectin ,  is a  protein  that in humans is encoded by the  CD59   gene . [ 5 ]  It is an  LU domain  and belongs to the  LY6 / uPAR / alpha-neurotoxin   protein family . [ 6 ]


CD59 attaches to host cells via a  glycophosphatidylinositol  (GPI) anchor.  Cholesterol-containing microdomains aid in CD59 activity by stimulating a "pinch point" in the lipid membrane during MAC assembly to prevent pore-formation and inhibit lysing. [ 7 ]  When  complement  activation leads to deposition of C5b678 on host cells, CD59 can prevent  C9  from polymerizing and forming the  complement membrane attack complex . [ 8 ]  It may also  signal  the cell to perform active measures such as  endocytosis  of the CD59-C9 complex. [ 6 ]  Endocytosis of this complex leads to the destruction of the ion channel formation that this complex provides to the MAC. These ion channels are used for transfer of different ions to maintain the correct concentration of minerals inside and outside of the membrane, and without this correct maintenance, severe symptoms and diseases can occur such as neuron degeneration and  Alzheimer's disease . [ 9 ]


Mutations affecting GPI that reduce expression of CD59 and  decay-accelerating factor  on  red blood cells  result in  paroxysmal nocturnal hemoglobinuria . [ 10 ]  GPI mutation and consequent reduction in CD59 expression results from a cysteine to tyrosine missense mutation, which prevents disulfide bridge formation, ultimately disrupting tertiary protein structure and preventing proper GPI-CD59 complex binding. [ 11 ]


Viruses  such as  HIV , human  cytomegalovirus  and  vaccinia  incorporate host cell CD59 into their own  viral envelope  to prevent lysis by complement. [ 12 ]  Additionally, CD59 has been investigated as a target for immunotherapy when treating certain cancers such as breast cancer. Researchers have found that once CD59 had been targeted, there is an upregulation in fas and caspase-3, creating an increase in apoptosis and tumor growth suppression in MCF-7 cells. [ 13 ]


P48509 Q6ZNZ0


NM_139030 NM_001039490 NM_004357 NM_139029


NM_001111049 NM_001111050 NM_009842


NP_004348.2 NP_620598.1 NP_620599.1


NP_001104519 NP_001104520 NP_033972


CD151 molecule  ( Raph blood group ), also known as  CD151   ( C luster of  D ifferentiation  151 ), is a human  gene . [ 5 ]


The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. It is involved in cellular processes including cell adhesion and may regulate integrin trafficking and/or function. This protein enhances cell motility, invasion and metastasis of cancer cells. Multiple alternatively spliced transcript variants that encode the same protein have been described for this gene. [ 5 ]  Abnormalities in CD151 have been implicated in a form of epidermolysis bullosa. [ 6 ] [ 7 ]


CD151 has been shown to  interact  with  CD46 . [ 8 ]


This  membrane protein –related article is a  stub . You can help Wikipedia by  expanding it .


Cis AB  is a type of rare  mutation  in the  ABO gene . It happens when the  transferase   allele  contains a mix of  amino acids  from either A or B alleles, producing a bifunctional  enzyme  that can produce both types of  antigens , usually with one weaker than the other. This results in a serum test result much like the standard, separate (trans) AB phenotype, although the weaker antigen can occasionally fail to be detected. It complicates the basic inheritance pattern (as the allele comes from one parent only) and blood-transfusion compatibility matching for  ABO blood typing .


Different DNA mutations of either type A or Type B alleles change amino acids in enzyme transferase A or B, homologous enzymes differing in only four of 354 amino acids (R176G, G235S, L266M, and G268A). A single change in ABO gene DNA could switch type B to type A and then, a new hybrid enzyme can produce both weak B and A2 (in serum test, A2B, and A2B3). The most common mutation is an A105  allele  variation in  exon  7  nucleotide  position G803C changing  glycine  (type A) to  alanine  (type B). Another 8 alleles are reported in  BGMUT , most recently in China and Taiwan. Some Cis-AB carriers need components like washed red blood cells or autotransfusion of serum and blood.


Cis-AB type was studied first in humans in Japan (Shikoku Island) and South Korea (Gwangju area) where this rare type is more common (Chinese coast provinces and Taiwan also), although it is seen in a few European families (from France, Spain, Belgium, Germany, and Poland). In the year 2004, the  American Red Cross  described a family in Nebraska with a father of type cis-AB negative, a mother type O and their baby of type cis-AB. Since then, several cases in the United States have been reported. [ 1 ]  Antigen expression is weaker than A1 or B.


When one parent carries a Cis AB allele, the other allele can be any of O, A or B. The phenotype of this parent is always AB, but the children will inherit either the AB or the other allele from this parent.


ABO inheritance is generally derived assuming the children are not the rare  Bombay phenotype , which would require both parents to be carriers of it.


When testing paternity or maternity by ABO blood group alone, it is possible to have a paradoxical result in the rare instance that a cis-AB  genotype  is involved. [ citation needed ]  For example, (scenario 1.1 above) a child of a cis AB individual (who will test as a regular AB phenotype) and an O individual will be either AB or O instead of the usual A or B (see diagram above). [ citation needed ]


If the child of an AB and an O individual is O (the green-colored offspring in the scenario 1 image above), then a rare alternative possibility is that the parents were carriers (heterozygous) for the  Bombay phenotype  (Hh) and the child is a Bombay (hh) homozygous by genotype thus expressing  Bombay phenotype  also called O h  where, despite the presence of the ABO alleles, the substrate from which those antigens are made is not made and thus A, B and even O antigen are not expressed at all and are completely absent from the red cells.


The  Cohn process , developed by  Edwin J. Cohn , is a series of purification steps with the purpose of extracting  albumin  from  blood plasma . The process is based on the differential  solubility  of albumin and other plasma proteins based on  pH ,  ethanol  concentration, temperature, ionic strength, and protein concentration. [ 1 ] [ 2 ]  Albumin has the highest solubility and lowest  isoelectric point  of all the major plasma proteins. This makes it the final product to be precipitated, or separated from its solution in a solid form. Albumin was an excellent substitute for human plasma in World War Two. When administered to wounded soldiers or other patients with blood loss, it helped expand the volume of blood and led to speedier recovery. Cohn's method was gentle enough that isolated albumin protein retained its  biological activity . [ 3 ]


During the operations, the  ethanol concentration change from zero initially to 40%. The pH decreases from neutral at 7 to more acidic at 4.8 over the course of the fractionation. The temperature starts at room temperature and decreases to −5 degrees Celsius. Initially, the blood is frozen. There are five major fractions. Each fraction ends with a specific precipitate. These precipitates are the separate fractions. [ 4 ]


Fractions I, II, and III are precipitated out at earlier stages. The conditions of the earlier stages are 8% ethanol, pH 7.2, −3 °C, and 5.1% protein for Fraction I; 25% ethanol, pH of 6.9, −5 °C, and 3% protein. The albumin remains in the supernatant fraction during the solid/liquid separation under these conditions. Fraction IV has several unwanted proteins that need to be removed. In order to do this, the conditions are varied in order to precipitate the proteins out. The conditions to precipitate these proteins are raising the ethanol concentration from 18 to 40% and raising the pH from 5.2 to 5.8. Finally, albumin is located in fraction V. The precipitation of albumin is done by reducing the pH to 4.8, which is near the pI of the protein, and maintaining the ethanol concentration to be 40%, with a protein concentration of 1%. Thus, only 1% of the original plasma remains in the fifth fraction. [ 4 ]


However, albumin is lost at each process stage, with roughly 20% of the albumin   lost through  precipitation  stages before fraction V. In order to purify the albumin, there is an extraction with water, and adjustment to 10% ethanol, pH of 4.5 at −3 °C. Any precipitate formed here is done so by filtration and is an impurity. These precipitates are discarded. Reprecipitation, or repetition of the precipitation step in order to improve purity, is done so by raising ethanol concentration back to 40% from the extraction stage. The pH is 5.2 and it is conducted at −5 °C. Several variations of Cohn fraction were created to account for lower cost and higher yield. Generally, if the yield is high, the purity is lowered, to roughly 85–90%. [ 4 ]


Cohn was able to start the Plasma Fractionation Laboratory after he was given massive funding from the government agencies and the private pharmaceutical companies. This led to the fractionation of human plasma. Human plasma proved to have several useful components other than albumin. Human  blood plasma fractionation  yielded  human serum albumin , serum gamma  globulin ,  fibrinogen ,  thrombin , and blood group globulins. [ 5 ]   The fibrinogen and thrombin fractions were further combined during the War  into additional products, including liquid  fibrin sealant , [ 6 ]  solid  fibrin  foam and a fibrin film. [ 7 ]
Gamma globulins are found in Fractions II and III and proved to be essential in treating measles for soldiers. Gamma globulin also was useful in treatment for polio, but did not have much effect in treating mumps or scarlet fever. Most importantly, the gamma globulins were useful in modifying and preventing infectious hepatitis during the Second World War. It eventually became a treatment for children exposed to this type of hepatitis. [ 5 ]


Liquid fibrin sealant was used in treating burn victims, including some from the attack at Pearl Harbor, to attach skin grafts with an increased success rate. [ 6 ]  It was also found  helpful at re-connecting or anastomosing severed nerves. [ 6 ]   Fibrin foam and thrombin were used to control blood vessel oozing especially in liver injuries and near tumors. It also minimized bleeding from large veins as well as dealing with blood vessel malformations within the brain. Fibrin film was used to stop bleeding in various surgical applications, including neurosurgery. [ 6 ]  However, it was not useful in controlling arterial bleeding. [ 5 ]   The first fibrinogen/fibrin based product capable of stopping arterial hemorrhage  was the "Fibrin Sealant Bandage" or "Hemostatic Dressing (HD)" invented by  Martin MacPhee  at the American Red Cross in the early 1990s, and tested in collaboration with the U.S. Army. [ 8 ] [ 9 ]


The Gerlough method, developed in 1955 improved process economics by reducing the consumption of ethanol. Instead of 40% in certain steps, Gerlough used 20% ethanol for precipitation. This is especially used for Fractions II and III. In addition, Gerlough combined the two fractions with IV into one step to reduce the number of fractionations required. While this method proved less expensive, it was not adopted by industry because of this combination of fractions II, III, and IV, for fear of mixing and high impurities. [ 10 ]


The Hink method developed in 1957. This method gave higher yields through recovery of some of the plasma proteins discarded in the Fractions of IV. The improved yields, however, balanced by the  lower purities obtained,  within the 85% range. [ 10 ]


The Mulford method, akin to the Hink, used the fractions II and III supernatant as the last step before finishing and heat treatment. The method combined fractions IV and V, but in this case, the albumin would not be as pure, although the yields may be higher. [ 10 ]


Another variation was developed by Kistler and Nitschmann, to provide a purer form of albumin, even though   offset by lower yields. Similar to Gerlough, the Precipitate A, which is equivalent to Cohn’s Fraction II and III, was done at a lower ethanol concentration of 19%, but the pH, in this case, was also lower to 5.85. Also similar to Gerlough and Mulford, the fraction IV was combined and precipitated at conditions of 40% ethanol, pH of 5.85, and temperature of −8 degrees C. The albumin, which is recovered in fraction V, is recovered in Precipitate C at a pH adjustment to 4.8. Similar to the Cohn Process, the albumin is purified by extraction into water followed by precipitation of the impurities at 10% ethanol, pH 4.6, and −3 degrees C. Akin to the Cohn Process, the precipitate formed here is filtered out and discarded. Then Precipitate C (fraction V) is reprecipitated at pH 5.2 and stored as a paste at −40 degrees C. [ 10 ]  This process has been more widely accepted because it separates the fractions and makes each stage independent of each other.


Another variation involved a heat ethanol fractionation. It was originally developed to inactivate the hepatitis virus. In this process, recovery of high yield, high purity albumin is the most important goal, while the other plasma proteins are neglected. In order to make sure the albumin does not denature in the heat, there are stabilizers such as sodium octanoate, which allow the albumin to tolerate higher temperatures for long periods. In heat ethanol, the plasma is heat treated at 68 degrees C with sodium octanoate with 9% ethanol at pH of 6.5. This results in improved albumin recovery with yields of 90%, and purities of 100%. It is not nearly as expensive as cold ethanol procedures such as the Cohn Process. One drawback is the presences of new antigens due to possible heat denaturation of the albumin. In addition, the other plasma proteins have practical uses and to neglect them would not be worth it. Finally, the expensive heat treatment vessels offset the lower cost compared to the cold ethanol format that do not need it. For these reasons, several companies haven not adopted this method even though it has the most impressive results. However, one prominent organization that uses it is the German Red Cross. [ 10 ]


The latest variation was developed by Hao in 1979. This method is significantly simplified compared to the Cohn Process. Its goal is to create high albumin yields as long as albumin is the sole product. Through a two-stage process, impurities are precipitated directly from fractions II and III supernatant at 42% ethanol, pH 5.8, temperature −5 degrees C, 1.2% protein, and 0.09 ionic strength. Fraction V is precipitated at pH 4.8. Fractions I, II, III, and IV are  coprecipitated  at 40% ethanol, with pH of 5.4 to 7.0, and temperature −3 to −7 degrees C. Fraction V is then precipitated at pH 4.8 and −10 degrees C. The high yields are due to a combination of a simplified process, with lower losses due to coprecipitation, and use of filtration. Higher purities were also achieved at 98% because of the higher ethanol levels, but the yields were lowered with the high purity. [ 10 ]


More recent methods involve the use of  chromatography . [ 11 ]


The Cohn process was a major development in the field of blood fractionation. It has several practical uses in treating diseases such as hepatitis and polio. It was most useful during the Second World War where soldiers recovered at a faster rate because of the transfusions with albumin. The Cohn Process has been modified over the years as seen above. In addition, it has influenced other processes with the blood fractionation industry. This has led to new forms of fractionation such as chromatographic plasma fractionation in ion exchange and albumin finishing processes. In general, the Cohn Process and its variations have given a huge boost to and serve as a foundation for the fractionation industry to this day. [ 12 ]


However, the process has not been studied well because it is archaic. Most importantly, it has never been modernized by manufacturing companies. The cold ethanol format may be too gentle to kill off certain viruses that require heat inactivation. Since this process remains unchanged for so long, several built-in inefficiencies and inconsistencies affect the economics of the process for pharmaceutical and manufacturing companies. [ 12 ]   One exception to this was the application in Scotland of continuous-flow processing instead of batch processing. This process was devised at the Protein Fractionation Centre (PFC), the plasma fractionation facility of the Scottish National Blood Transfusion Service (SNBTS). This process involved in-line monitoring and control of pH and temperature, with flow control of plasma and ethanol streams using precision gear pumps, all under computerised feedback control . As a result, Cohn Fractions I+II+III, IV and V were produced in a few hours, rather than over many days. The continuous-flow preparation of cryoprecipitate was subsequently integrated into the process upstream of Cohn Fractionation. [ 13 ]


Nevertheless, this process still serves as a major foundation for the blood industry in general and its influence can be seen as it is referred to in the development of newer methods. Although it has its drawbacks depending on the variation, the Cohn Process’ main advantage is its practical uses and its utility within pharmacological and medical industries. [ citation needed ]


Cold autoimmune hemolytic anemia  caused by  cold-reacting antibodies . Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize  autoimmune hemolytic anemia .


A common complaint among patients with  cold agglutinin disease  is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.


Cold agglutinin-mediated acrocyanosis differs from Raynaud phenomenon. In  Raynaud phenomena , caused by  vasospasm , a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease.


Other symptoms


Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.


Classic chronic cold agglutinin disease is idiopathic, associated with symptoms and signs in relation to cold exposure.


Causes of the monoclonal secondary disease include the following:


Causes of polyclonal secondary cold agglutinin disease include the following:


Cold agglutinins, or cold autoantibodies, occur naturally in nearly all individuals. These natural cold autoantibodies occur at low titers, less than 1:64 measured at 4 °C, and have no activity at higher temperatures. Pathologic cold agglutinins occur at titers over 1:1000 and react at 28-31 °C and sometimes at 37 °C.


Cold agglutinin disease usually results from the production of a specific  IgM  antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on red blood cells (RBCs). Cold agglutinins commonly have variable heavy-chain regions encoded by VH, with a distinct idiotype identified by the 9G4 rat murine monoclonal antibody.


AIHA can be classified as  warm autoimmune hemolytic anemia   or cold autoimmune hemolytic anemia, which includes  cold agglutinin disease  and  paroxysmal cold hemoglobinuria . These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA. [ 1 ]


Cold agglutinin disease may be managed successfully using protective measures (clothing) alone in most cases. Special protective clothing is sometimes necessary in extreme cases. Therapy is directed at serious symptoms and the underlying disorder, if any is found.


Keep in mind that the idiopathic variety of cold agglutinin disease is generally a benign disorder with prolonged survival and spontaneous exacerbations and remissions in the course of the disease. Acute post infectious syndromes usually resolve spontaneously.
Anemia is generally mild. Only patients who have serious symptoms related to anemia or have a Raynaud type syndrome that constitutes a threat to life or quality of life require active therapy. The presence of an associated malignancy requires specific therapy.


Cold agglutinin disease is so uncommon in children that no specific recommendations for therapy are available. Intravenous immunoglobulin (IVIG) was used successfully in an infant with IgA-associated autoimmune hemolytic anemia.


Splenectomy is usually ineffective for the treatment of cold agglutinin disease because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy.


Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor.


A hematologist-oncologist working in collaboration with a blood banker is helpful in complicated cases of cold agglutinin disease.
Careful planning and coordination with multiple personnel are needed if patients are to undergo a procedure during which their body temperature could fall.


The  Colton antigen system  ( Co ) is present on the membranes of  red blood cells  and in the tubules of the  kidney [ 1 ]  and helps determine a person's  blood type . The Co  antigen  is found on a  protein  called  aquaporin-1  which is responsible for water  homeostasis  and urine concentration. [ 2 ]


The Co antigen is important in  transfusion medicine . 99.8% of people possess the Co(a)  allele . Individuals with Co(b) allele or who are missing the Colton antigen are at risk for a  transfusion reaction  such as  hemolytic anemia  or  alloimmunization . Antibodies against the Colton antigen may also cause  hemolytic disease of the newborn , in which a pregnant woman's body creates antibodies against the blood of her fetus, leading to destruction of the fetal blood cells. [ 3 ]


ImpactLife ,  formerly  Community Blood Services of Illinois,  is a  blood center  located in  Urbana, Illinois .


ImpactLife provides lifesaving blood products to more than 123 hospitals in a four-state region. Headquartered in Davenport, Iowa, with distribution hubs and donor centers in Iowa, Illinois, Missouri, and Wisconsin.


In addition to its headquarters, ImpactLife has regional distribution hubs in central Illinois (Peoria, Illinois and Springfield, Illinois), eastern Illinois (Urbana, Illinois); southeastern Iowa (Ottumwa, Iowa), the St. Louis region (Earth City, Missouri) and southern Wisconsin (Madison, Wisconsin).


[ 1 ]  ImpactLife collects blood at 19 fixed site donor centers and at more than 5,000 mobile blood drives held each year.


ImpactLife is licensed and regulated by the  U.S. Food and Drug Administration  and holds membership in  America's Blood Centers , the  American Association of Blood Banks  and participate in the  National Marrow Donor Program .


1GKG ,  1GKN ,  1PPQ ,  2Q7Z ,  2MCY ,  2MCZ ,  5FO9


NM_000573 NM_000651 NM_001381851


NP_000564 NP_000642 NP_001368780


Complement receptor type 1  ( CR1 ) also known as  C3b/C4b receptor  or  CD35  (cluster of differentiation 35) is a  protein  that in humans is encoded by the  CR1   gene . [ 3 ] [ 4 ]


This gene is a member of the  regulators of complement activation  (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The gene encodes a monomeric single-pass type I membrane  glycoprotein  found on  erythrocytes ,  leukocytes , glomerular  podocytes ,  hyalocytes , and splenic follicular  dendritic cells . The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas,  mesangiocapillary glomerulonephritis ,  systemic lupus erythematosus  and  sarcoidosis . Mutations in this gene have also been associated with a reduction in  Plasmodium falciparum  rosetting, conferring protection against severe malaria. Alternate allele-specific splice variants, encoding different isoforms, have been characterized. Additional allele specific isoforms, including a secreted form, have been described but have not been fully characterized. [ 3 ]


In primates,  CR1 serves as the main system for processing and clearance of complement  opsonized   immune complexes . It has been shown that CR1 can act as a negative regulator of the  complement  cascade, mediate  immune adherence  and  phagocytosis  and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of  erythrocytes  in normal individuals and is also decreased in pathological conditions such as  systemic lupus erythematosus  (SLE),  HIV  infection, some  haemolytic anaemias  and other conditions featuring  immune complexes . [ 5 ]   In mice, CR1 is an alternatively spliced variant of the complement receptor 2 (CR2) gene.


Certain  alleles  of this gene have been statistically associated with an increased risk of developing late-onset  Alzheimer's disease . [ 6 ] [ 7 ]


In humans, the  CR1  gene is located on the long arm of chromosome 1 at band 32 (1q32) and lies within a complex of immunoregulatory genes. In 5'-3' order the genes in this region are: membrane cofactor protein – CR1 – complement receptor type 2 – decay-accelerating factor – C4-binding protein.


Factor H , another immunoregulatory protein, also maps to this location. [ 8 ]


The canonical Cr2/CD21 gene of subprimate mammals produces two types of complement receptor (CR1, ca. 200 kDa; CR2, ca. 145 kDa) via alternative mRNA splicing. The murine Cr2 gene contains 25 exons; a common first exon is spliced to exon 2 and to exon 9 in transcripts encoding CR1 and CR2, respectively. A transcript with an  open reading frame  of 4,224 nucleotides encodes the long isoform, CR1; this is predicted to be a protein of 1,408 amino acids that includes 21 short consensus repeats (SCR) of ca. 60 amino acids each, plus transmembrane and cytoplasmic regions. Isoform CR2 (1,032 amino acids) is encoded by a shorter transcript (3,096 coding nucleotides) that lacks exons 2–8 encoding SCR1-6. CR1 and CR2 on murine B cells form complexes with a co-accessory activation complex containing CD19, CD81, and the fragilis/Ifitm (murine equivalents of LEU13) proteins. [ 9 ]


The  complement receptor 2  (CR2) gene of primates produces only the smaller isoform, CR2; primate CR1, which recapitulates many of the structural domains and presumed functions of Cr2-derived CR1 in subprimates, is encoded by a distinct CR1 gene (apparently derived from the gene Crry of subprimates).


Isoforms CR1 and CR2 derived from the Cr2 gene possess the same C-terminal sequence, such that association with and activation through CD19 should be equivalent. CR1 can bind to C4b and C3b complexes, whereas CR2 (murine and human) binds to C3dg-bound complexes. CR1, a surface protein produced primarily by  follicular dendritic cells , appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection. [ 10 ]


The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38  exons  spanning 133kb encoding a  protein  of 2,039  amino acids  with a predicted molecular weight of 220 kDa. Large  insertions  and  deletions  have given rise to four structurally variant  genes  and some alleles may extend up to 160 kb and 9 additional exons. The  transcription  start site has been mapped to 111 bp upstream of the  translation  initiation codon ATG and there is another possible start site 29 bp further upstream. The  promoter  region lacks a distinct  TATA box  sequence. The gene is expressed principally on  erythrocytes ,  monocytes ,  neutrophils  and  B cells  but is also present on some  T lymphocytes ,  mast cells  and  glomerular podocytes .


The encoded protein has a 47 amino acid  signal peptide , an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The  leader sequence and 5'-untranslated region  are contained in one exon. The large extracellular domain of CR1, which has 25 potential  N-glycosylation  sites, can be divided into 30 short consensus repeats (SCRs) (also known as  complement control protein  repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 and 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.


The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C.  To date the atomic structure have been solved for SCRs 15–16, 16 & 16–17.


Four known human alleles encode proteins with predicted molecular weights of 190 kDa, 220 kDa, 250 kDa and 280 kDa. [ 5 ]  Multiple size variants (55–220 kDa) are also found among non-human  primates  and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55–70 kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are  glycosylphosphatidylinositol  (GPI) anchored, are expressed on erythrocytes and the 220-kDa CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.


The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100–1000 molecules per cell. Two  codominant   alleles  exist – one controlling high and the other low expression.  Homozygotes  differ by a factor of 10–20:  heterozygotes  typically have 500–600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.


Plasmodium falciparum  erythrocyte membrane protein 1  (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as  rosetting , is believed to be a strategy used by the  parasite  to remain sequestered in the  microvasculature  to avoid destruction in the  spleen  and  liver . Erythrocyte rosetting causes obstruction of the  blood  flow in  microcapillaries . There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes. [ 5 ]


The  Knops antigen  was the 25th blood group system recognized and consists of the single  antigen   York  (Yk) a with the following allelic pairs:


The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old  Caucasian  woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of  American  Caucasians and  Africans  respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with  Europeans  and while the frequency of McC (b) was similar between Africans from the United States or  Mali , the Sl (b) phenotype is significantly more common in Mali – 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected – presumably due to malaria. 80% of  Papua New Guineans  have the  Helgeson   phenotype  and  case–control studies  suggest this phenotype has a protective effect against severe  malaria .


Convalescent plasma  is the blood plasma collected from a survivor of an infectious disease.  This plasma contains  antibodies  specific to a pathogen and can be used therapeutically by providing passive immunity when transfusing it to a newly infected patient with the same condition. Convalescent plasma can be transfused as it has been collected or become the source material for hyperimmune serum or anti-pathogen monoclonal antibodies; the latter consists exclusively of  IgG , while convalescent plasma also includes  IgA   and  IgM . Collection is typically achieved by  apheresis , but in low-to-middle income countries, the treatment can be administered as convalescent whole blood.


Specific  antibodies  to a pathogen are thought to be the primary driver of clinical benefit from convalescent plasma. [ 1 ]  In the case of viral pathogens, the subset of antibodies that retain most of the activity is the one that drives viral neutralization, i.e. neutralizing antibodies, which can be quantified in a  viral neutralization assay . This belief is based on dose-response clinical studies demonstrating that clinical benefit is directly related to the content of neutralizing antibodies, [ 2 ] [ 3 ] [ 4 ] [ 5 ]  and mechanistic studies that have established the antiviral activity of antibodies in convalescent plasma. [ 6 ] [ 7 ]   In addition to higher antibody concentrations being more effective, the timing of therapy is essential.  Preparations are typically most effective when given prophylactically or early in the disease course (i.e. until pathogen replication persists or until the infected host's endogenous immune response develops). [ 8 ]


In addition to antibodies, convalescent plasma includes a mix of many different proteins and nonprotein factors that can occur in healthy individuals as well as develop in parallel with convalescence. These compounds may affect infection, coagulation, and inflammation independently of the effect of anti-pathogen antibodies. [ 1 ]  Because convalescent plasma therapy is generally safe, [ 9 ]  and the effects of neutralizing antibodies dominate the therapeutic response, the current understanding of these potential additional effects is limited and constitutes an area of ongoing research. [ 1 ]


In 1890,  Emil von Behring  and  Shibasaburo Kitasato  used convalescent serum obtained from large mammals to treat infectious diseases and found that it was particularly effective at preventing and treating  diphtheria . [ 10 ]  Convalescent serum and plasma differ in that the former has all the coagulation components intact, but both are comparable regarding their antibody content.  Hence, the older literature is focused on serum while today most preparations use plasma.  Following the discovery by von Behring and Kitasato, antibody therapy garnered support worldwide as a treatment for infections. Von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901 for his discoveries. [ 10 ]


Before the development of  antimicrobial treatment  in the 1930s, antibody therapy in the form of serum therapy were the primary means of treating many bacterial and viral infections. [ 11 ]  This treatment appears to have reduced the mortality of  meningococcal meningitis , [ 12 ]   pneumonia , [ 13 ]  and  erysipelas . [ 14 ]   Additionally, antibody therapy seems to have been used successfully to prevent infection after exposure to  measles , [ 15 ] [ 16 ] [ 17 ]   mumps , [ 18 ]  and  chickenpox . [ 19 ]


The 1918  Spanish influenza  pandemic was caused by an H1N1 influenza virus of avian origin, and around 500 million people, or one-third of the world's population, became infected with this virus. [ 20 ]   The Spanish influenza pandemic was the first pandemic in which convalescent plasma was used as a therapy. A 2006 meta-analysis of eight studies from the Spanish influenza pandemic, including 1,703 patients, found that infected patients who received convalescent plasma had a 21% lower absolute mortality risk than patients not treated with convalescent plasma (16% vs. 37%). [ 21 ]  Consistent with the general treatment principles of antiviral therapy, the most significant clinical and mortality benefits were noted among patients receiving convalescent serum in the early stages of the disease course. [ 21 ]


After the introduction of  antibiotics , the use of convalescent serum or plasma as a therapy for infectious diseases has been restricted mainly to replacement therapy for patients with immunoglobulin deficiencies [ 11 ]  or in the context of viral epidemics or pandemics for which no widely available antiviral could be repurposed. Modern use has also included several randomized controlled trials providing conclusive evidence of efficacy. Selected viral epidemics or pandemics in which convalescent plasma has been used are reviewed below.


First identified in 1958,  Argentine hemorrhagic fever  is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. [ 22 ]  Convalescent plasma has been used during Argentine hemorrhagic fever epidemics; a double-blind, randomized clinical trial conducted from 1974 to 1978 demonstrated that patients treated with convalescent plasma within eight days of disease onset had a 15.4% lower absolute mortality rate than patients who received control plasma without neutralizing antibodies to Argentine hemorrhagic fever virus (1.1% vs. 16.5%). [ 23 ]  Comparable results were described in subsequent outbreaks of Argentine hemorrhagic fever. [ 24 ]


In 2003, a novel coronavirus  SARS-CoV-1  led to an epidemic of the  severe acute respiratory syndrome . [ 25 ]  Convalescent plasma was used to treat SARS; [ 26 ]  in a retrospective analysis from Hong Kong that included 80 patients, early convalescent plasma treatment (14 days between the onset of symptoms and the transfusion date) was associated with an improved prognosis vs late transfusion (after 14 days since symptom onset) in terms of a higher hospital discharge rate by day 22 (58% vs 16%). [ 27 ]  A review and meta-analysis that included eight observational studies (214 total patients) with SARS found a mortality benefit associated with convalescent plasma treatment. [ 28 ]  Further studies were not conducted because the pandemic was extinguished.


In 2009, a particular influenza strain  A(H1N1)pdm09  that evaded seasonal flu vaccines caused an influenza pandemic, which was referred to as the  swine flu pandemic . Convalescent plasma was used to treat individuals with severe  H1N1  infections requiring intensive care. [ 29 ]  Despite usage very late in the disease course, patients treated with convalescent plasma had reduced respiratory viral burden, reduced serum cytokine responses, and reduced mortality. [ 29 ]


Middle East respiratory syndrome  (MERS) is a viral respiratory infection caused by the Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is believed to have originated from bats. [ 30 ]  The first identified case occurred in June 2012 in Jeddah, Saudi Arabia, and most cases have occurred in the Arabian Peninsula. [ 30 ]  Convalescent plasma therapy has been used to treat MERS with mixed results; initial case reports and case series in the MERS epidemic failed to show a clinical benefit for patients transfused with convalescent plasma containing uncharacterized neutralizing antibody titers. [ 31 ]  Consistent with the principle that higher antibody content in convalescent plasma results in improved efficacy, a subsequent study demonstrated that transfusion of convalescent plasma containing a high MERS-CoV neutralizing antibody titer resulted in detectable concentrations of antibodies in the blood of the recipient ( seroconversion ). However, seroconversion was not achieved in patients who received convalescent plasma with a low neutralizing antibody titer. [ 32 ]  These findings highlight a challenge of convalescent plasma therapy, namely, that recovered survivors of viral diseases may not produce high-titer neutralizing antibodies, and thus not all convalescent plasma is equally potent. [ 33 ]


Ebola virus disease  was discovered in 1976 when two consecutive outbreaks of fatal hemorrhagic fever occurred in different parts of Central Africa. [ 34 ]  Convalescent plasma treatment was used during the 2013–2016 Ebola outbreak; a small nonrandomized study in Sierra Leone revealed significantly longer survival for patients treated with convalescent whole blood compared to patients receiving standard treatment. [ 35 ]  Furthermore, two patients with Ebola who were transferred to the U.S. were treated with convalescent plasma, and an experimental  small interfering RNA  drug, and both survived their infections. [ 36 ]


In 2019, a novel coronavirus,  severe acute respiratory syndrome coronavirus 2  (SARS-CoV-2), causing  coronavirus disease 2019  (COVID-19) spread rapidly around the globe after first being identified in Wuhan, China. [ 37 ]  In early 2020, convalescent plasma started to be used in isolated cases and small series in China [ 38 ]  and Italy. [ 39 ]  Convalescent plasma therapy was deployed at scale in the United States through a Mayo Clinic-led  Expanded Access Program for convalescent plasma [ 40 ]  and a subsequent Emergency Use Authorization issued by the United States Food & Drug Administration. [ 41 ]  Data from the Expanded Access Program demonstrated that among patients who were not mechanically ventilated, patients transfused with high-titer convalescent plasma had lower mortality than patients who received low-titer convalescent plasma (14.2% vs. 22.2%). [ 5 ]  Relatively early during the pandemic, several randomized controlled trials concluded that convalescent plasma therapy was not effective for COVID-19, [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ]  but most of them focused on patients already seropositive or late in the disease course [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ]  and/or used plasma units with insufficient antibody levels. [ 44 ] [ 47 ]  Furthermore, there were methodological problems with some of the major trials raising concerns about the validity of negative results with regards to convalescent plasma efficacy. [ 48 ]  Randomized controlled trials that instead focused on administering high-titer convalescent plasma early after diagnosis found that convalescent plasma treatment reduced hospital admission by ~50-80%, [ 4 ] [ 49 ]  which is in line with results achieved with monoclonal antibodies and small chemical antivirals. [ 50 ]  Similarly, a randomized controlled trial that administered high-titer convalescent plasma in patients requiring mechanical ventilation found an absolute reduction in mortality of 14% in patients who received convalescent plasma within 48 hours of the initiation of mechanical ventilation. [ 51 ]  Meta-analyses found that convalescent plasma treatment is associated with a mortality benefit, [ 52 ]  particularly if it contains high antibody levels, is administered early, and in immunocompromised patients. [ 53 ]  An epidemiologic analysis of convalescent plasma use and mortality in the United States showed a strong inverse correlation, providing strong evidence of efficacy at a population level. [ 54 ]  From this data, it was estimated that the deployment of convalescent plasma had resulted in approximately 100,000 fewer deaths than had no plasma been used in the USA. [ 54 ]


In the post-vaccine COVID-19 pandemic, a resurgence in the usage of convalescent plasma occurred starting in the spring of 2022, when the SARS-CoV-2 variant Omicron sublineages proved non-responsive to all anti-spike monoclonal antibody treatments authorized, [ 55 ] [ 56 ]  and concerns emerged about contraindications and chronic exposure to small-chemical antivirals which had never been studied in immunocompromised patients at that point. Considering the urgent need to treat immunocompromised patients who were not protected after vaccination, the United States Food & Drug Administration re-authorized convalescent plasma for these patients; [ 57 ]  accordingly, convalescent plasma was recommended in guidelines issued by the Infectious Disease Society of America [ 58 ]  and the European Conference on Infections in Leukemia. [ 59 ]  In the context of the wide deployment of COVID-19 vaccines, a unique product that can be collected from convalescent vaccinees, dubbed “hybrid plasma” or “Vax-plasma” has been of interest; [ 60 ]  such double status creates heterologous immunity able to cross-react against any SARS-CoV-2 variant so far. [ 61 ]


An online petition was launched on April 27, 2022, [ 62 ]  asking the World Health Organization to revise its guidelines issued in December 2021, [ 63 ]  which discouraged convalescent plasma usage based on the evidence available until July 2021. [ 63 ]


In the European Directorate for the Quality of Medicines and HealthCare guidelines for blood component manufacturing, no monography exists for convalescent plasma yet as of 2022. Outside clinical trials, the only way thus far to prescribe convalescent plasma is so-called compassionate usage, a procedure which requires authorization by a local ethical committee. In the United States, the use of convalescent plasma for the treatment of COVID-19 remains under Food & Drug Administration Emergency Use Authorization.


Cryoprecipitate , also called  cryo  for short, or Cryoprecipitate Antihemophilic factor (AHF), is a frozen  blood product  prepared from  blood plasma . [ 1 ]  To create cryoprecipitate,  Plasma  is slowly thawed to 1–6 °C. A cold-insoluble precipitate is formed, which is collected by centrifugation, resuspended in a small amount of residual plasma (generally 10–15 mL) and then re-frozen for storage. Cryoprecipitate contains fibrinogen, Factor VIII, Factor XIII and vWF. In many clinical contexts, use of cryoprecipitate has been replaced with use of  clotting factor  concentrates (where available), but the whole form is still routinely stocked by many hospital  Blood bank . Cryo can be stored at −18 °C or colder for 12 months from the original collection date [ 1 ]  or up to 36 months in Europe if stored below -25 °C. [ 2 ]  After thawing, single units of cryo (or units pooled using a sterile method) can be stored at 20–24 °C for up to 6 hours. If units of cryo are pooled in an open system, they can only be held at 20–24 °C for up to 4 hours. [ 3 ]  Presently cryo cannot be re-frozen for storage after it is thawed for use if it is not transfused.


Compatibility testing ( Cross-matching ) before transfusion of cryoprecipitate are not necessary. However, cryoprecipitate should preferably be ABO compatible with the recipient's red cells. ABO-incompatible cryoprecipitate can be used with caution, particularly with large volumes. If a large volume of ABO-incompatible cryoprecipitate can be used with caution, particularly with large volumes. If a large volume of ABO-incompatible cryoprecipitate is used, the recipient may develop a positive direct antiglobulin test and, very rarely, mild haemolysis. Matching for RhD type is not necessary.


Medical uses for giving cryoprecipitate include: [ 3 ]


Cryoprecipitate should not be used to treat haemophilia, von Willebrand’s disease or deficiencies of Factor XIII or fibronectin except in cases where alternative therapies are unavailable.


A typical adult dose is 10 units of whole blood-derived cryoprecipitate, equivalent to a fibrinogen dose of approximately 3−4 g.


Adverse effects reported with the usage of cryoprecipitate include hemolytic  transfusion reactions , febrile non-hemolytic reactions, allergic reactions (ranging from  urticaria  to  anaphylaxis ), septic reactions,  transfusion related acute lung injury , circulatory overload, transfusion-associated  graft-versus-host disease , and  post-transfusion purpura . [ 4 ] [ 5 ]


Each unit (around 10 to 15 mL) typically provides: [ 6 ]


Cryoprecipitate also contains  fibronectin ; however there are no clear indications for fibronectin replacement.


US standards require manufacturers to test at least four units each month, and the products must have a minimum of 150 mg or more of fibrinogen and 80 IU of factor VIII per unit. [ 7 ] [ 8 ]  European standards require 140 mg or more of fibrinogen, 70 IU of factor VIII and 100 IU of vWF per unit.


While the current method for producing cryoprecipitate was developed by Judith Graham Pool from  Stanford University  in 1964, it was initially approved in 1971 by the  U.S. Food and Drug Administration  under the name  Cryoprecipitated AHF  for the Hoxworth Blood Center  University of Cincinnati Medical Center .


The term  cryosupernatant  (also called  cryo-poor plasma ,  cryoprecipitate depleted ,  cryoprecipitate reduced plasma ) refers to  plasma  from which the  cryoprecipitate  has been removed. It is used to treat  thrombocytopenic purpura . [ 1 ]


The resulting plasma has reduced levels of  factor VIII  (FVIII),  von Willebrand factor  (VWF),  factor XIII  (FXIII),  fibronectin  and  fibrinogen .  While the levels of FVIII are greatly reduced, levels of fibrinogen can be as much as 70% of original levels. [ citation needed ]


Cryosupernatant plasma can be used when replacement of FVIII is not required, [ 2 ]  and is indicated for plasma exchange for patients with  thrombotic thrombocytopenic purpura  (TTP) [ 1 ]  as well as for treatment of  hemolytic-uremic syndrome  (HUS) by plasma exchange, when plasma exchange is indicated. [ 3 ]


Damage control surgery  is surgical intervention to keep the patient alive rather than correct the  anatomy . [ 1 ] [ 2 ]
It addresses the  "lethal triad"  for critically ill patients with severe  hemorrhage  affecting  homeostasis  leading to  metabolic acidosis ,  hypothermia , and increased  coagulopathy . [ 3 ]


This lifesaving method has significantly decreased the morbidity and mortality of critically ill patients, though complications can result.
It stabilizes patients for clinicians to subsequently reverse the physiologic insult prior to completing a definitive repair. While the temptation to perform a definitive operation exists, surgeons should avoid this practice because the deleterious effects on patients can result in them succumbing to the physiologic effects of the injury, despite the anatomical correction.
The leading cause of death among trauma patients remains uncontrolled hemorrhage and accounts for approximately 30–40% of trauma-related deaths. [ 4 ]


While typically  trauma surgeons  are heavily involved in treating such patients, the concept has evolved to other sub-specialty services.
A multi-disciplinary group of individuals is required: nurses, respiratory therapist, surgical-medicine intensivists, blood bank personnel and others.


Damage control surgery can be divided into the following three phases: Initial laparotomy, Intensive Care Unit (ICU) resuscitation, and definitive reconstruction. Each of these phases has defined timing and objectives to ensure best outcomes. The following goes through the different phases to illustrate, step by step, how one might approach this. There are clearly different approaches throughout the country, and no one way is necessarily correct. However, the ability to evaluate objectively the differences and then choose the one that fits your team is important. [ citation needed ]


This is the first part of the damage control process whereby there are some clear-cut goals surgeons should achieve. The first is controlling hemorrhage followed by contamination control, abdominal packing, and placement of a temporary closure device. [ 5 ]  Minimizing the length of time spent in this phase is essential.


For groups (i.e., trauma centers) to be effective in damage control surgery, a multi-disciplinary team is critical. The approach to caring for such critically ill patients is dependent on nurses, surgeons, critical care physicians, operating room staff, blood bank personnel, and administrative support. In addition to having the right team in place is having a prepared team. The more facile the team is enhances the ability for centers to effectively implement damage control surgery. This is referred to by some as damage control ground zero (DC0). [ 6 ]  The ability to mobilize personnel, equipment, and other resources is bolstered by preparation; however, standardized protocols ensure that team members from various entities within the health care system are all speaking the same language. This has been seen during implementation of complex processes such as the  massive transfusion protocol  (MTP).


Controlling of hemorrhage as discussed above is the most important step in this phase. Eviscerating the intra-abdominal small bowel and packing all four  abdominal quadrants  usually helps surgeons establish initial hemorrhagic control. Depending up on the source of hemorrhage a number of different maneuvers might need to be performed allowing for control of aortic inflow. Solid organ injury (i.e., spleen, kidney) should be dealt with by resection. When dealing with hepatic hemorrhage a number of different options exist such as performing a  Pringle maneuver  that would allow for control of hepatic inflow. [ 7 ]  Surgeons can also apply manual pressure, perform  hepatic packing , or even plugging penetrating wounds. Certain situations might require leaving the liver packed and taking the patient for angio-embolization or if operating in a hybrid operating room having perform an on table  angio-embolization . Vessels that are able to be ligated should, and one should consider shunting other vessels that do not fall into this category. This has been described by Reilly and colleagues when they shunted the superior mesenteric artery to decrease the length of time in the operating room. [ 8 ]


Once hemorrhage control is achieved one should quickly proceed to controlling intra-abdominal contamination from hollow-viscus organs. The perception might be that one could quickly perform an  anastomosis . This should not be attempted in the damage control setting. The key is to simply prevent continued intra-abdominal contamination, and to leave patients in discontinuity. A number of different techniques can be employed such as using staplers to come across the bowel, or primary suture closure in small perforations. Once this is complete the abdomen should be packed. Many of these patients become coagulopathic and can develop diffuse oozing. It is important to not only pack areas of injury but also pack areas of surgical dissection. There are various methods that can be used to pack the abdomen. Packing with radiopaque laparotomy pads allow for the benefit of being able to detect them via x-ray prior to definitive closure. As a rule abdomens should not be definitively closed until there has been radiologic confirmation that no retained objects are present in the abdomen.


The final step of this phase is applying a temporary closure device. Numerous methods of temporary closure exist, with the most common technique being a negative-vacuum type device. Regardless of which method one decides to use it is important that the abdominal fascia is not reapproximated. The ability to develop  abdominal compartment syndrome  is a real concern and described by Schwab. [ 9 ]


On completion of the initial phase of damage control, the key is to reverse the physiologic insult that took place. This specifically relates to factors such as acidosis, coagulopathy, and hypothermia ( lethal triad ) that many of these critically ill patients develop. When developing a strategy to best care for these patients, the same principles of having a multi-disciplinary team that work together in parallel for the same result apply. The intensivist is critical in working with the staff to ensure that the physiologic abnormalities are treated. This typically requires close monitoring in the intensive care unit, ventilator support, laboratory monitoring of resuscitation parameters (i.e., lactate).


In using a number of different resuscitation parameters, the critical care team can have a better idea as to which direction is progressing. The first 24 hours often require a significant amount of resources (i.e., blood products) and investment of time from personnel within the critical care team. In many circumstances, especially trauma patients, require that other specialties address a variety of injuries. Moving the patient early on, unless absolutely necessary,  can be detrimental. Certain circumstances might require this, and the patients should continue to receive care from the critical care team during the entire transport period. As the literature begins to grow within the field of damage control surgery, the medical community is continuously learning how to improve the process. Certain pitfalls have also become evident, one of which is the potential to develop abdominal compartment syndrome.


In some cases, temporary abdominal closure itself or underlying conditions may contribute to abdominal compartment syndrome, causing increased intraabdominal pressure and compromising organ perfusion. [ 10 ]  Temporary abdominal dressings with high negative pressures can be a cause of recurrent abdominal compartment syndrome and one should not hesitate to turn off the dressing's suction when evaluating a patient with signs of recurrent abdominal compartment syndrome. [ 11 ]


While it might sound counterintuitive since the fascia is left open during the placement of these temporary closure devices, they can create a similar type process that leads to abdominal compartment syndrome. If this occurs the temporary closure device should be taken down immediately. [ citation needed ]


The third step in damage control surgery is addressing closure of the abdomen. Definitive reconstruction occurs only when the patient is improving. At this point in process the critical care team has been able to correct the physiologic derangements. The optimization typically takes 24 to 48 hours, depending on how severe the initial insult is. Prior to being taken back to the operating room it is paramount that the resolution of acidosis, hypothermia, and coagulopathy has occurred. [ citation needed ]


The first step after removing the temporary closure device is to ensure that all abdominal packs are removed. Typically the number of packs has been documented in the initial laparotomy; however, an abdominal radiograph should be taken prior to definitive closure of the fascia to ensure that no retained sponges are left in the abdomen. Once the abdominal packs are removed the next step is to re-explore the abdomen allowing for the identification of potentially missed injuries during the initial laparotomy and re-evaluating the prior injuries. Attention is then turned to performing the necessary bowel anastomosis or other definitive repairs (i.e., vascular injuries). [ citation needed ]


An attempt should be made to close the abdominal fascia at the first take back, to prevent complications that can result from having an open abdomen. The concern for early closure of the abdomen with development of compartment syndrome is a real one. A method to pre-emptively evaluate whether fascial closure is appropriate would be to determine the difference in peak airway pressure (PAP) prior to closure and the right after closure. An increase of over 10 would suggest that the abdomen be left open. [ 9 ]  As mentioned above, it is important to obtain an abdominal radiograph to ensure that no retained sponges are left intra-operatively.


Considering that not all patients can undergo definitive reconstruction at first return, there are other options that surgeons can consider. Data would suggest that the longer the abdomen is left open from initial laparotomy the higher the rate of complications. [ 12 ]  After about one week, if surgeons can't close the abdomen, they should consider placing a Vicryl mesh to cover the abdominal contents. This lets granulation occur over a few weeks, with the subsequent ability to place a split-thickness skin graft (STSG) on top for coverage. These patients clearly have a hernia that must be fixed 9 to 12 months later.


Damage control resuscitation has had a dramatic impact on how care for critically ill patients is administered. [ citation needed ] . The core principles of resuscitation involve permissive hypotension, transfusion ratios, and massive transfusion protocol. The resuscitation period lets any physiologic derangements be reversed to give the best outcome for patient care.


Typical resuscitation strategies have used an approach where aggressive crystalloid and/or blood product resuscitation is performed to restore blood volume. The term permissive hypotension refers to maintaining a low blood pressure to mitigate hemorrhage; however, continue providing adequate end-organ perfusion [Duchesene, 2010]. The key is to prevent exacerbation of hemorrhaging until definitive vascular control can be achieved, the theory being that if clots have formed within a vessel then increasing the patient's blood pressure might dislodge those established clots resulting in more significant bleeding. Permissive hypotension is not a new concept, and had been described in penetrating thoracic trauma patients during World War I by Bickell and colleagues demonstrating an improvement in both survival and complications. [ 13 ]


Subsequent animal studies have shown equivalent outcomes with no real benefit in mortality  [ 4 ]  Recently there has been further data in trauma patients that has demonstrated increased survival rates [Morrison, 2011]. Cotton and colleagues found that the use of a permissive hypotension resuscitation strategy resulted in better outcomes (increased 30-day survival) in those undergoing damage control laparotomy. This would not be used in situations where patients might have injuries such as a traumatic brain injury considering that such patients are excluded from the studies.