International Perspective

When I first moved overseas from the United States, I brought the perspective of my American training and experience.  I saw everything in my new blood bank through those eyes.

Yet, most of my staff were not American or even North American.  Few were even native in English, and most of those  were not American.  They had different qualifications, many of which would not have been accepted by the American schemes.  Still, they functioned well.

I also worked with the US military technologist staff during Gulf War One.  Some did not even have a Bachelor’s degree;  yet, they performed the work well.

I used many technologies that were not yet (or never) US FDA approved such as gel or glass bead typings and pooled buffy coat platelet production.  There were rare reagents I could buy off the shelf (e.g. anti-Tja/PP1Pk).

Later, I adopted pathogen-reduction technology (Mirasol), automated component production (Atreus then Reveos), and platelet additive solution.  I achieve a level of good manufacturing practice that would have been difficult to achieve by the FDA-approved methods.

My perspective had changed.  In the Middle East, I studied many frameworks and came to the conclusion that the best approach was to customize them to our local needs.  My particular experience was to start with one framework, i.e. Council of Europe CE, and then localize it.

To do this, I could not use an American turnkey blood bank software for either the donor or patient operations.  I needed a flexible system that could be customized to my needs.  Again, I chose a CE-marked system, Medinfo Hematos IIG that had already been adapted to many frameworks.

It is much easier to work solely within one system such as FDA.  However, if I had done that, I would have lost so much flexibility and not had a system optimized for local conditions.  I would not have used Mirasol, Reveos, Diamed, and many other reagents.

One big disappointment at such international meetings is the perspective by one country’s regulatory agency that they feel its regulations and framework will work well overseas.  I would wager that those people were not well acquainted with international conditions.

Another frustration was attending another international meeting in which the presenters apologized for the source of information since it came from a foreign country (France) and not their own (United States).

No country has a monopoly on what is best for everyone.  To share our experiences and compare is so valuable.  No one assume his way is the best.  In my career, I have had the richest experiences studying other perspectives and my organizations have benefited greatly from the exchange.  We can all learn from each other.  We are citizens of the world.

Therapeutic Apheresis Volume Calculations

You can get the values off the therapeutic apheresis machine, but in the middle of the night when you have to write orders, it is convenient to estimate the volumes (whole blood, plasma, RBCs).  These are the values from my lectures to hematology fellows while I was at HMC Doha:

Whole Blood:

Weight in kg X 70 ml/kg = whole (whole) blood volume adult

Weight in kg X 85 ml/kg =whole blood volume for child (prepubertal)

Weight in kg X 100 ml/kg = whole blood volume for neonates/premature

Example:  70 kg adult has 4900 ml blood volume (I round up to 5 liters)

Plasmacrit + hematocrit = 1.00 in fractions (100%), ignore buffy coat volume

Plasmacrit = 1- hematocrit

Plasma volume:

Plasma volume = whole blood volume x plasmacrit = whole blood volume X (1-hematocrit)

RBC volume:

RBC volume = whole blood volume x hematocrit

Estimates for blood components:

The volumes will depend on the original amount collected (e.g. 450 vs 500 ml),  original preservative solution used (e.g. CPD), use of automated component production such as Terumo Atreus or Reveos, use of RBC additive solution (e.g. SAGM), leukodepletion, platelet additive solution, pathogen inactivation.

At HMC Doha, the average values were:

300 ml for leukodepleted RBCs in SAGM prepared by Reveos

300 ml for platelet pools in Mirasol and platelet additive solution (residual WBC < 1E6)

300 ml for plateletpheresis concentrate (2.4E11) in Mirasol and platelet additive solution

250 ml for leukodepleted, pathogen inactivated plasma

Summary of Accomplishments at HMC 2011-2020

I resigned from HMC on 16/4/20.  Here are a set of my major accomplishments during that period. None of my work after this date has any relationship to HMC.

2011

Established automated component production using Atreus technology, plasma and platelet pathogen inactivation (Mirasol)—made HMC component production Good Manufacturing System GMP compliant

Adopted non-PCR-based NAT technology (Grifols/Novartis Tigress) and Qatar becomes world reference site for this

Based on the above, Qatar can now completely process all whole blood into blood components (red cells, platelets, and plasma) in as little as 5 hours from collection!

2011-2020:

Prepared policies and procedures for the hospital blood banks/transfusion services, blood donor center, therapeutic apheresis, and laboratory information systems to bring HMC in compliance with the Council of Europe, international AABB, and other standards.  I customized our own standards for our local needs based on them.

2012-2013

Implemented custom build of the multilingual blood bank computer system (Medinfo) for both patient and donor services, including development of interfaces to all production equipment including Atreus and Mirasol (world’s first) and a direct link to Ministry of the Interior to obtain patient demographics in English and Arabic—Qatar became the world’s first site to combine fully-interfaced, automated component production with pathogen inactivation:  Qatar becomes world reference site for this.

2013-2014

Built, validated, and implemented laboratory build of hospital information system, Cerner Millennium

2015

Replaced and updated Atreus with Reveos automated component production to allow faster throughput and capacity with a full bidirectional interface (world’s first), introduced platelet-additive solution PAS with pathogen inactivation (Mirasol)—Medinfo interfaces updated to Reveos for all equipment:  this doubles the capacity to process whole blood into components using the same physical space

2015-2019

Updated dedicated blood bank software Medinfo Hematos IIG by several versions using Division Head, LIS, and internally trained Super Users—at great cost savings to HMC by not using outside consultants (e.g. Dell Consulting)

2019

Established column absorption technology using Terumo Optia therapeutic apheresis machine for treatment of ABO-incompatible renal transplants:  I validated using the Ortho Vision MAX to perform ABO antibody titers for this system and correlated it with the reference method at Karolinska Institutet in Stockholm (manual gel) to bring rapid throughput and labor savings—Qatar being the first-site in the world to do this.  We saved money by using the same apheresis machine to use this column absorption technology (no need for second machine to use the columns)

2020

Expedited setup (two weeks total) of COVID-19 convalescent plasma production, initially manual and then fully integrated into the Medinfo computer system as a customized module with separate quarantine collection, production, and transfusion service functions

Other:

I was awarded two HMC Star of Excellence Awards:

2013—Liver Transplantation Transfusion Support

2019—ABO-Incompatible Renal Transplantation Support

TRALI/TACO Policy and Process

The following was my process at HMC Doha for TRALI/TACO.  It includes proactive measures to minimize the risk of TACO and the procedure for surveillance and workup of such cases.

In the Medinfo blood bank computer system, we did not prepare plasma or platelets from female donors.  If approved by a transfusion medicine physician, a manual override was made in exceptional cases (e.g. mother donating platelets for her child in neonatal alloimmune thrombocytopenia cases.).  In some other countries, they do HLA antibody testing to allow females to donate platelets.

I emphasize that the diagnosis of TRALI and/or TACO is clinical, but the transfusion medicine physicians must always consider the possibility whenever there is an adverse effect associated with progressive respiratory distress.

Principle:

Since TACO and TRALI are major causes of serious adverse effects from transfusions, this policy outlines actions being pro-actively taken to mitigate the risks in Transfusion Medicine.  TACO and TRALI may be difficult to distinguish so this policy addresses both.

Objectives:

  1. Implement measures to minimize TRALI and TACO
  2. Track cases of transfusion-associated acute lung injury TRALI and TACO
  3. Develop algorithms for suspected cases of TRALI and TACO

Tracking:

  1. All transfusion reactions are reviewed by the Division Head, Transfusion Medicine or his designee on a STAT basis, 24 hours a day, 7 days a week
  2. Any reactions with respiratory distress are reported as “rule-out TRALI/TAC” to the clinician
  3. All transfusion reactions are recorded in Medinfo HIIG for tracking and reporting.

Risk Management:

  1. Female blood donors routinely are only used for making RBC components (i.e. not for FFP, cryoprecipitate, or platelets).
  2. RBCs are in additive solution SAGM so only 35 ml residual plasma is present per unit.
  3. All platelet components are in platelet additive solution with only 35 ml residual plasma per component.
  4. All platelets and plasma are pathogen-inactivated which may reduce the risk of TRALI.
  5. If the female has a rare phenotype (e.g. IgA deficient, rare platelet antigen typing) she will only be considered for a directed donation of platelets or FFP/cryoprecipitate for that special-needs patient if she does not have HLA antibodies (anti-human-neutrophil antibody testing to be implemented in such cases when it is available on-site).
  6. Solvent-detergent treated plasma SDP is available for patients with a confirmed or suspected history of TRALI.
  7. All cellular components are leukodepleted (< 1E6 residual WBCs/component as per CE Standards) in the blood bank at the time of production.
  8. Blood bank computer system Medinfo Hematos IIG limits the number of components released at any one time (excluding emergencies).

Notifications:

  1. Transfusion Medicine TM will notify the outside blood supplier of any units implicated or associated with TRALI.
  2. A transfusion medicine physician will notify the most responsible physician of any workup results suggesting the possibility of TRALI/TACO.
  3. TM will notify all donors of their disqualification from blood donation based on the following algorithm.

Algorithm for Diagnosis and Management of Donors:

  1. Evaluation of the Donor and Recipient in Suspected TRALI:
    1. The medical technologist will process all transfusion reactions as STAT and immediately contact the TMS Director or physician designate with the results.
    2. The medical technologist will convey information to the TMS Director or designate about ALL blood components issued recently, especially in the last 6 hours prior to the event.
    3. The TMS Director or designate will specifically check if there is evidence of respiratory distress listed on the transfusion reaction investigation form.  If so, he will contact the responsible clinician immediately for further assessment.
    4. If the signs and symptoms suggest ALI (see Table 1 above), the TMS Director or designate will inquiry about the left atrial pressure to rule out left-sided heart failure as a cause for the pulmonary edema.
    5. Based on the clinical information, the TMS Director or designate may elect to order any or all of the following tests if available:
      1. Quarantine all remaining components from possibly implicated/associated donor(s) while the workup is in progress.
      2. Recipient HLA, platelet, and/or granulocyte antibody screen, or a crossmatch between recipient plasma/serum and donor leukocytes
      3. Donor HLA and/or platelet antibody screen, granulocyte antibody screen, crossmatch donor plasma/serum and recipient leukocytes, inter-donor crossmatch between plasma/serum of one and leukocytes of another donor.
      4. The usual algorithm to be followed is as follows:
        1. Consult patient medical record and clinical care physician to determine if the diagnosis of TRALI is likely.
        2. Check all components transfused within 6 hours prior to the onset of symptoms.’
        3. Immediately quarantine other components from the same donations and contact outside blood suppliers if indicated.
        4. Obtain donor antibody testing of only highly suspect cases, based on the clinical manifestation and initial diagnostic tests:
          1. If multiple units transfused within hours, only investigate components donated by multiparous females and/or last two units transfused.
          2. First test for presence of HLA class I and class II antibodies in donor components.
          3. If antibody positive, HLA type recipient’s lymphocytes to detect corresponding antigen or perform crossmatch with donor plasma and recipient lymphocytes.
          4. If HLA antibody negative, proceed with neutrophil-specific antibody testing of donor plasma.
        5. If matching antigen-antibody identified or if positive crossmatch, defer implicated donor immediately.
        6. If no such concordance found or if crossmatch is negative, donor eligible to continue donating.
        7. If no antibodies found in donor plasma, test recipient plasma for antibodies to HLA class I and II antigens:
          1. If recipient antibody positive, HLA type donor’s lymphocytes to detect corresponding antigen or perform crossmatch with recipient plasma and donor lymphocytes.
          2. If recipient HLA antibody negative, proceed with neutrophil-specific antibody testing of recipient plasma
  2. Donor Disposition:
    1. For donors implicated in TRALI or associated with multiple events of TRALI, one or more of the following options may be selected at the discretion of the Head, Transfusion Medicine or designate:
      1. Defer donor from donation
      2. Divert plasma for fractionation or discard plasma from future whole blood donations from that Blood and Apheresis Donor Main Questionnaire
      3. Manufacture no platelet or plasma components from that donor
      4. Wash or freeze/deglycerolize RBCs from that donor
      5. Permanently defer the donor from future plasmapheresis or plateletpheresis donations
      6. Evaluate the previous donations from that Blood and Apheresis Donor Main Questionnaire  Avoid giving the same recipient future transfusions from the same donor implicated in TRALI
      7. If the implicated unit(s) are from another facility, that blood center should be notified to initiate a workup for possible TRALI in the donor.
  3. Interpretation:
    1. The diagnosis of TRALI is not clear-cut:
      1. The AABB interim standard does not apply.  It is at the discretion of the TMS Director or designate whether to conduct donor assessments.
    2. The donor is associated with a single event of TRALI:
      1. This applies where the diagnosis of TRALI has been established based on clinical and radiographic findings:
      2. Each donor from each and every component associated with TRALI must be identified and traced.
      3. Co-components from the current donation and components from previous donations should be evaluated for recipient complications.
      4. The donors medical history should be evaluated for previous pregnancies, transfusions or other events that may have resulted in antibody development.
      5. Based on the results of this investigation, the Head, Transfusion Medicine or designate should decide:
        1. Whether to perform laboratory testing
        2. Whether to discard the remaining blood components from the donor
        3. Whether to allow or indefinitely defer the donor
    3. The donor is associated with multiple events of TRALI:
      1. This applies where the diagnosis of TRALI has been established based on clinical and radiographic findings:
      2. Each donor from each and every component associated with TRALI must be identified and traced.
      3. Co-components from the current donation and components from previous donations should be evaluated for recipient complications.
      4. The donors medical history should be evaluated for previous pregnancies, transfusions or other events that may have resulted in antibody development.
      5. Based on the results of this investigation, the TMS Director or designate should decide:
        1. Whether to perform laboratory testing
        2. Whether to discard the remaining blood components from the donor
        3. Whether to allow or indefinitely defer the donor
    4. Triage based on laboratory testing for TRALI:
      1. The donor associated with TRALI is antibody-negative:
        1. The donor may continue to donate.
      2. The donor associated with TRALI is antibody-positive but the specificity is NOT directed against a recipient antigen by either antigen typing or crossmatching (i.e. the donor is NOT implicated in TRALI—see definition above):
        1. Indefinitely defer the donor from all donations OR
        2. Allow donation of washed/frozen-deglycerolized RBCs only
      3. The donor is implicated in TRALI (see definition above):
        1. Indefinitely defer the donor from all donations OR
        2. Allow donation of washed/frozen-deglycerolized RBCs only
      4. The recipient has antibodies implicated in TRALI (determined by crossmatch or antibodies directed against specific HLA class I, HLA class 2, and/or human neutrophil antigens):
        1. The recipient must receive leukodepleted blood components
    5. TACO
      1. TACO is due to cardiac overload.  Our mitigations are to restrict release of the number of components outside emergency events.

References:

  1. AABB Association Bulletin 14-02, TRALI, Bethesda, MD, USA
  2. Han Y. and Goldfinger D., Transfusion Medicine TM 07-5 (TM-297) Checksample, American Society for Clinical Pathology, Chicago, IL, USA. July 2007
  3. Goldman M, Webert, KE, Arnold DM, et al., Transfusion Med Rev  2005; 19:2-31.
  4. Fung YL, Goodison KA, Wong JK, Minchinton RM., Investigating Transfusion-Related Acute Lung Injury (TRALI), Intern Med J. 2003 Jul;33(7):286-90.
  5. Standards for Blood Banks and Transfusion Services, Current Edition, AABB, Bethesda, MD, USA
  6. AABB Association Bulletin #05-09, Transfusion-Associated Acute Lung Injury, 11/8/05
  7. AABB Association Bulletin #05-04, Proposed Interim Standard for Deferral of Donors Implicated in TRALI, 9/3/05.
  8. TRM.42110, CAP Transfusion Medicine Checklist, 15/6/09

Processes and Software Building: Updated Convalescent COVID-19 Plasma Production

After the initial manual setup of the CCP program, the Medinfo process was set up.  The following workflow shows the production of CCP from the raw apheresis collection, including division into aliquots based on the total volume.  The plasma volumes were kept within the range for riboflavin pathogen inactivation (Mirasol).

The usual safeguards for production were also in effect for CCP.  The product could not be labelled without all criteria (donor screening, collection, marker testing) being met.  Furthermore, the inter-depot and transfusion service processes still applied.  However, all steps were done in quarantine at a location separate from the regular processes.  Also, the actual ordering and release of CCP was restricted to the quarantine hospital blood bank site.

The following outline the production process:

Processes and Software Building 8: Reveos and Mirasol

Automated Component Processing:  Reveos and Mirasol Pathogen-Inactivation

The production instruments have more complicated interfaces than the testing equipment discussed in the previous post:

In the collection area (on-site or remote), the cvolume of the whole blood and collection time are recorded in Medinfo and based on the rules, production may only occur within specified volume and collection time.  Otherwise, Medinfo will block further processing.

The ISBT unit number of the whole blood units are read by the Reveos.  Only those units passing the collection criteria will proceed to separation.

In about 20 minutes, the Reveos machine will simultaneously process four units of whole blood into packed RBCs, leukodepleted plasma, buffy coat platelets, and residual buffy coat.  The volumes of the RBCs, plasma, and platelets are recorded in Reveos.  For the platelets, the platelet yield index is also provided.

Within Medinfo, these parameters are compared to criteria of acceptability according to the manufacturer.  Volumes for the platelets and plasma must be within certain ranges to permit pooling and pathogen inactivation and additive solution.  Medinfo will not permit these subsequent procedures if the values are out of range and the intermediate components will be discarded.

Here is a sample of Reveos acceptable ranges for component volumes:

E4207 – Whole Blood CPD 450 mL

Volume Consequences

< 400 mL Discard

400 – 500 mL OK

> 500 mL Discard

E5259 – Leukodepleted Packed Red Blood Cells

Volume Consequences

< 230 mL Discard

230 – 330 mL OK

> 330 mL Discard

E2807 – Platelets Concentrate 20-24°C

Volume Consequences

< 20 mL Discard

20 – 55 mL OK

> 55 mL Manual decision

E2555 – FP24:  Plasma Frozen <= 24h

Volume Consequences

< 170 mL Discard

170 – 360 mL OK

> 360 mL Manual decision

All these production parameters are permanently stored in Medinfo as part of the production record of that unit.  The actual location (bucket) of the whole blood unit in the Reveos is also available.

RBCs are manually leukodepleted and the final volumes recorded in Medinfo based on weight.  Based on the platelet yield index, platelets are pooled and the final volume recorded.   Those permissible volumes are next treated with platelet additive solution PAS and then pathogen inactivated.  The acceptable volumes are based on the process used, e.g. platelets in plasma versus platelets in PAS.

How a sophisticated blood bank software like Medinfo enforces good manufacturing process at all stage of production will be a future topic.

To Be Continued:

26/6/20

Active Inventory Management: Further Discussion

Yesterday’s post showed my active blood inventory management scheme for my previous position in Qatar.  I thought today I would elaborate on how I adjust the inventory based on critical shortages and planning for disasters and other major events.

I always review the critical shortages to check for atypical usage (e.g. a disaster situation) or production issues (equipment breakdown, shortage of donors during holiday period).

If it is due to increased utilization, I try to adjust the critical and desirable inventories upward to cover the shortfall for future events.  However, it is not always possible if the event is a one-of-a-kind situation unlikely to recur.  Also, I must take into account the available resources (supplies, kits, manpower, equipment) to see if I can cope with the increase.

If it is due to resource issues, I see if I can bolster those by recommending increases or improving utilization of what is available.

Very important is through-put:  How quickly can I produce components from whole blood or apheresis components?  This was one of the major reasons we shifted away from PCR to other NAT testing with single-well processes since to minimize the need to make additional runs (Grifols Panther System).  Also, automated component processing can greatly speed production (one Reveos can process four whole blood units in about 23 minutes or about 12 units in 75 minutes.)  Those staff can be busy with other tasks while the machines are working.

In the system I developed in Qatar, we could complete processing into components (RBCs, buffy coat platelet pools, leukodepleted plasma)–Reveos 3C Program, all marker and immunohematology testing, leukoreduction of the pools and RBCs, Mirasol pathogen inactivation, and platelet additive solution in as little as five hours!!  There is great need for speed in a place that must be 100% self-sufficient in all blood components. We could even further reduce the total processing time if we only made RBCs and plasma, Reveos 2C Program

In rapid turn-around events, it is most helpful to have a robust blood bank computer system that can scale to the challenge.  Also, it must mercilessly enforce all the rules starting with donor qualification, screening, collection through testing and production.  At times of emergency, it is difficult to meet Good Manufacturing Processes manually.

After each major shortage, I recommend a “post-mortem” analysis of the situation with senior donor and quality staff to analyze our processes and see if we can further optimize them for the future.  A report is prepared and reviewed by me as the Division Head/Medical Director of the Blood Bank.  If possible, we implement our recommendations.  If not, I request additional resources from the Administration.

As regards Disaster Planning, I always asked Administration how many victims did they want to save?  When I got the response, I always try to adjust inventory by two extra RBCs and one adult platelet dose (> 2E11) per salvageable victim.  This may come at the expense of increased wastage, especially in a region that cannot export the excess, unused stock.

The exasperating issue is that I didn’t get a clear answer on this last point.  What number should I use?  I made a spreadsheet showing calculations for a variety of endpoints, e.g. 100, 500, 1000 treatable victims and sent this to Administration to consider.