Implications of HLA in Transfusion Related Immune Complications Like TRALI and Platelet Refractoriness
Meenakshi Singh, Selma D’Silva and Anisha Navkudkar
HLA and Immunogenetics Laboratory, Department of Transfusion Medicine, Tata Memorial Hospital, India
Submission: February 01, 2018; Published: February 09, 2018
*Corresponding Author: Meenakshi Singh, HLA and Immunogenetics Laboratory, Department of Transfusion Medicine, Tata Memorial Hospital, India, Email: email@example.com
How to cite this article: Meenakshi S, Selma D’S, Anisha N. Implications of HLA in Transfusion Related Immune Complications Like TRALI and Platelet
Refractoriness. Blood Res Transfus J. 2018; 1(5) : 555574. DOI:10.19080/IJCSMB.2018.01.555574
Transfusion-related acute lung injury (TRALI) is defined as a new acute lung injury (ALI) that develops during or within 6 hours of transfusion and is a leading cause of transfusion-related morbidity and mortality . The causative antibodies in TRALI may be directed against class I or II human leukocyte antigens (HLA) or human neutrophil antigens (HNA). It may also be caused by lipid products from the cellular breakdown, which accumulates in stored blood products and prime, activate neutrophils. TRALI can occur in patients undergoing repeated platelet transfusions and has mortality rates between 6-20%. Thus, it is important to identify these cases and address the issues related to the patients and implicated donors.
There are two working hypotheses - the ‘two hit’ model and leukocyte antibodies (HLA antibodies). The ‘two-hit’ model mentions neutrophil priming as an initial requirement which can be a consequence of hematologic malignancy . The introduction of neutrophil-binding antibodies, cytokines, and bioactive lipids from the transfused product, may lead to activation of the primed and sequestered neutrophils. Silliman et al.  mentioned that the patients with acute leukemia undergoing induction chemotherapy appeared to be at greater risk of developing TRALI. Another hypothesis suggests that transfused HLA antibodies may induce TRALI by direct contact with susceptible endothelial cells of the lung capillaries. It has been postulated that the transfused HLA Class I antibody binds to its cognate antigen present on the pulmonary endothelium. Passively transfused HLA Class II antibodies are also known to cause TRALI by activation of monocytes which lead to neutrophil activation . A short duration of the clinical episode may reflect the paucity of entrapped neutrophils. A recent study has demonstrated that donors serum positive for HLA class II antibodies, may induce monocytes and possibly platelets to secrete a variety of inflammatory mediators which subsequently activate neutrophils .
Previously, we have reported a 35 years old female with acute myeloid leukemia with prolonged neutropenia and thrombocytopenia secondary to chemotherapy-induced marrow suppression . She was transfused with multiple platelets (single donor platelets) as she had prolonged thrombocytopenia and developed dyspnoea after one such transfusion. TRALI was diagnosed after excluding other causes of ALI. The Panel reactive antibodies (PRA) of the patient revealed HLA Class I and Class II antibodies. The implicated donor was a registered voluntary platelet donor with the hospital and his sample was sought immediately after this event for laboratory workup. The donor-specific antibody test between recipient and donor pair was positive with a high mean fluorescence intensity (MFI) value for Class I antibodies 10370 and class II antibodies 3454. The HLA typing of the implicated donor was A*02,*03; B*51,*58; DRB1*03,*04. Serum of implicated donor demonstrated HLA Class I antibodies and HLA class II antibodies. Therefore, the mechanism in the patient was a combination of the above factors. The patient had a haematological malignancy with superadded entercolitis which made her susceptible to TRALI by the two-hit model. The donor-derived HLA-A*02 antibodies by binding the pulmonary capillary endothelium may have facilitated the sequestration and activation of neutrophils despite a low ANC. A short duration of the clinical episode may reflect the paucity of entrapped neutrophils. There was also an evidence of HLA Class
II antibodies in the implicated donor.
Based on this observation it is suggested that the laboratory
workup of all cases of TRALI should be performed to reduce the
potential for further cases due to the implicated donor. Baseline
PRA of repeat male donors should be studied to prevent TRALI
due to passive transfer of antibodies. It is also important to
perform PRA status of oncology patients at their 1st hospital visit
to enable provision of epitope matched platelet transfusions to
prevent the development of refractoriness.
Platelet refractoriness is the repeated failure to obtain
acceptable responses to platelet transfusions . Two
consecutive platelet transfusions with corrected count increment
(CCI) below 7,500 within 10-60 minutes after transfusion is an
evidence of refractoriness .
Patients who are refractory as a result of HLA
alloimmunization are given HLA-matched or crossmatched
platelets. But these HLA matched donors can be potential
candidates for stem cell harvest in future and patients can
develop antibodies to minor antigens causing graft rejection.
Another alternative is to provide platelets from donors matched
at HLA-epitope level. This is based on the concept that HLA
antibodies are produced for epitopes that can be structurally
defined as eplets, which are present on different HLA alleles.
The causes of platelet refractoriness can be subdivided into
immune and non-immune. Alloimmunization against HLA Class I
antigens has remained the major immune cause of refractoriness
of thrombocytopenic patients to random donor platelet (PLT)
transfusions. Non-immune platelet consumption is associated
with fever, sepsis, disseminated intravascular coagulation (DIC),
splenomegaly and intravenous antibiotics (especially antifungal
drugs such as amphotericin B) etc.
HLA epitope matching is expected to benefit platelet
transfusion outcome and increase the number of compatible
donors for refractory patients. It could lead to new strategies for
HLA mismatch permissibility to reduce alloimmunization and
thus increase platelet survival. Human leukocyte antigen (HLA)
mismatches are important risk factors for HLA alloimmunization
and cause an increase in the interval of platelet transfusions.
It is known that HLA antibodies recognize epitopes instead
of antigens, thus it has become evident that donor-recipient
compatibility should be assessed at the epitope level . A
computer algorithm called HLA Matchmaker considers each
HLA antigen as a series of small configurations of polymorphic
residues, referred to as eplets, as essential components of
HLA epitopes. By quantifying the total number of antibodyaccessible
eplet mismatches (EMMs) between donor and
patient, the probable success of the donor-recipient mismatch
can be estimated . The program evaluates the total number
of triplet mismatches between the donor and recipient HLA
collection. The triplet algorithm has helped to define the
relative immunogenicity of mismatched triplets by analysis of
serologic reactivity patterns of highly allosensitized patients.
The program can identify the subset of highly immunogenic
mismatches (HIMMs) . Validation of this algorithm has been
done previously for the prediction of kidney transplant survival
. It is hypothesized that platelet donors matched at the
epitope level must be considered compatible, even if donor HLA
antigens appear mismatched by conventional criteria. Hence,
HLA Matchmaker should be applied at the time of HLA matching
at epitope level rather than after failure of HLA-matched platelet
transfusion. This hypothesis can be best tested by a prospective
follow-up of platelet increments. The number of mismatched
eplets (EMMs) has been shown to correlate with the CCIs of PLTrefractory
patients with lesser; the mismatch more is the CCI
HLA epitope matching approach in immune refractory
patients can have very impressive 1 hour CCI results. It can be
expected to benefit platelet transfusion outcome and increase
the number of compatible donors for refractory patients.
Because the HLAMM algorithm provides a quantitative method
to measure donor-recipient mismatches, this method can be
used for donor selection which will expand the available donor
pool while improving PLT transfusion outcomes.
HLA plays a crucial role in certain aspects of Transfusion
Medicine. The main function of the HLA molecules is to present
antigenic peptides to the immune system and thus regulate the
induction of immune responses. HLA antigens and antibodies
are responsible for some of the serious clinical complications
of blood transfusion. HLA alloimmunisation, TRALI, platelet
refractoriness, Febrile Non-Haemolytic Transfusion Reactions
(FNHTR) etc are some of the complications of blood transfusion
where HLA plays a crucial role . This article highlights the
HLA related immune mechanisms responsible for complications
of transfusions and ways to detect and avoid the same.