Physical

Delayed hemolytic transfusion reactions

Hemolysis is usually extravascular, but in rare cases a component of intravascular hemolysis is present.

Most cases manifest during the second week after transfusion, but the reaction can occur from 24 hours to 3 months after the transfusion.

Many patients are asymptomatic, and the condition is oftentimes detected only by laboratory testing.^[7]

In some patients, fever and/or chills (50%), jaundice (10%), pain (3%), and dyspnea (1%) can occur.

Rarely, cases may be complicated by renal failure (6%) or disseminated intravascular coagulation (1%).

In patients with sickle cell disease, a DHTR can precipitate a sickling crisis.^[8]

Refractoriness to platelet transfusions

Frequently, patients with refractoriness to platelet transfusion are asymptomatic and diagnosed by laboratory methods; however, failure to achieve hemostatic levels of platelets may preclude these patients from important procedures, including bone marrow transplantation. Alloimmunization should be avoided in candidates for bone marrow transplantation.

Preexisting bleeding resulting from thrombocytopenia may persist after transfusion of an appropriate therapeutic dose of platelets.^[9]Rarely, spontaneous bleeding may occur after prophylactic transfusion of platelets.

Causes

Alloimmunization to blood antigens occurs after the following:

Transfusion
Pregnancy
Transplantation
Sharing intravenous needles (rare)

Differential Diagnoses

Henrichs KF, Howk N, Masel DS, Thayer M, Refaai MA, Kirkley SA, et al. Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence. Transfusion. 2011 Sep 2. [QxMD MEDLINE Link]. [Full Text].
Gilson CR, Zimring JC. Alloimmunization to transfused platelets requires priming of CD4+ T cells in the splenic microenvironment in a murine model. Transfusion. 2011 Oct 7. [QxMD MEDLINE Link].
Mishima Y, Tsuno NH, Matsuhashi M, Yoshizato T, Sato T, Ikeda T, et al. Effects of universal vs bedside leukoreductions on the alloimmunization to platelets and the platelet transfusion refractoriness. Transfus Apher Sci. 2014 Nov 11. [QxMD MEDLINE Link].
Cid J, Lozano M, Ziman A, West KA, O'Brien KL, Murphy MF, et al. Low frequency of anti-D alloimmunization following D+ platelet transfusion: the Anti-D Alloimmunization after D-incompatible Platelet Transfusions (ADAPT) study. Br J Haematol. 2014 Oct 4. [QxMD MEDLINE Link].
Buetens O, Shirey RS, Goble-Lee M, Houp J, Zachary A, King KE. Prevalence of HLA antibodies in transfused patients with and without red cell antibodies. Transfusion. 2006 May. 46(5):754-6. [QxMD MEDLINE Link].
Friedman DF, Lukas MB, Jawad A, Larson PJ, Ohene-Frempong K, Manno CS. Alloimmunization to platelets in heavily transfused patients with sickle cell disease. Blood. 1996 Oct 15. 88(8):3216-22. [QxMD MEDLINE Link].
Heddle NM, Soutar RL, O'Hoski PL, Singer J, McBride JA, Ali MA. A prospective study to determine the frequency and clinical significance of alloimmunization post-transfusion. Br J Haematol. 1995 Dec. 91(4):1000-5. [QxMD MEDLINE Link].
Telen MJ, Afenyi-Annan A, Garrett ME, Combs MR, Orringer EP, Ashley-Koch AE. Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival. Transfusion. 2014 Dec 1. [QxMD MEDLINE Link].
Kerkhoffs JL, Eikenboom JC, van de Watering LM, van Wordragen-Vlaswinkel RJ, Wijermans PW, Brand A. The clinical impact of platelet refractoriness: correlation with bleeding and survival. Transfusion. 2008 Sep. 48(9):1959-65. [QxMD MEDLINE Link].
Allen DL, Samol J, Benjamin S, Verjee S, Tusold A, Murphy MF. Survey of the use and clinical effectiveness of HPA-1a/5b-negative platelet concentrates in proven or suspected platelet alloimmunization. Transfus Med. 2004 Dec. 14(6):409-17. [QxMD MEDLINE Link].
Novotny VM. Prevention and management of platelet transfusion refractoriness. Vox Sang. 1999. 76(1):1-13. [QxMD MEDLINE Link].
Slichter SJ, Davis K, Enright H, Braine H, Gernsheimer T, Kao KJ, et al. Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood. 2005 May 15. 105(10):4106-14. [QxMD MEDLINE Link].
Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007. 2007:172-8. [QxMD MEDLINE Link].
Poon MC. The evidence for the use of recombinant human activated factor VII in the treatment of bleeding patients with quantitative and qualitative platelet disorders. Transfus Med Rev. 2007 Jul. 21(3):223-36. [QxMD MEDLINE Link].
Schonewille H, Haak HL, van Zijl AM. Alloimmunization after blood transfusion in patients with hematologic and oncologic diseases. Transfusion. 1999 Jul. 39(7):763-71. [QxMD MEDLINE Link].
Werch J. Use of Rh immune globulin when transfusing large volumes of Rh-positive cells. Am J Clin Pathol. 1999 May. 111(5):712. [QxMD MEDLINE Link].
Werch J, Todd C. Resolution by erythrocytapheresis of the exposure of an Rh-negative person to Rh-positive cells: an alternative treatment. Transfusion. 1993 Jun. 33(6):530-2. [QxMD MEDLINE Link].
Wahl S, Quirolo KC. Current issues in blood transfusion for sickle cell disease. Curr Opin Pediatr. 2009 Feb. 21(1):15-21. [QxMD MEDLINE Link].
The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997 Dec 25. 337(26):1861-9. [QxMD MEDLINE Link].
Friedberg RC. Clinical and laboratory factors underlying refractoriness to platelet transfusions. J Clin Apher. 1996. 11(3):143-8. [QxMD MEDLINE Link].
Blumberg N, Heal JM, Gettings KF. WBC reduction of RBC transfusions is associated with a decreased incidence of RBC alloimmunization. Transfusion. 2003 Jul. 43(7):945-52. [QxMD MEDLINE Link].
Delaflor-Weiss E, Mintz PD. The evaluation and management of platelet refractoriness and alloimmunization. Transfus Med Rev. 2000 Apr. 14(2):180-96. [QxMD MEDLINE Link].
Kekomaki R. Use of HLA- and HPA-matched platelets in alloimmunized patients. Vox Sang. 1998. 74 Suppl 2:359-63. [QxMD MEDLINE Link].
Kickler T, Herman JH, eds. Current issues in platelet transfusion therapy and platelet alloimmunity. Bethesda, Md: AABB Press; 1999.
Legler TJ, Fischer I, Dittmann J, Simson G, Lynen R, Humpe A. Frequency and causes of refractoriness in multiply transfused patients. Ann Hematol. 1997 Apr. 74(4):185-9. [QxMD MEDLINE Link].
Pineda AA, Vamvakas EC, Gorden LD, Winters JL, Moore SB. Trends in the incidence of delayed hemolytic and delayed serologic transfusion reactions. Transfusion. 1999 Oct. 39(10):1097-103. [QxMD MEDLINE Link].
Sayeh E, Sterling K, Speck E, Freedman J, Semple JW. IgG antiplatelet immunity is dependent on an early innate natural killer cell-derived interferon-gamma response that is regulated by CD8+ T cells. Blood. 2004 Apr 1. 103(7):2705-9. [QxMD MEDLINE Link].
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Table 1. Human Platelet-Specific Antigen Systems

Platelet Antigen System	Protein Antigen	Synonyms	Alleles	Antigen Frequency
HPA-1	GPIIIa	Pl^A,Zw	HPA-1a = Pl^A1 HPA-1b = Pl^A2	97% 26%
HPA-2	GPIb	Ko, Sib	HPA-2A HPA-2b	99% 14%
HPA-3	GPIIb	Bak, Lek	HPA-3a HPA-3b	85% 66%
HPA-4	GPIIa	Pen, Yuk	HPA-4a HPA-4b	>99% < 1%
HPA-5	GPIa	Br, Hc, Zav	HPA-5a HPA-5b	99% 20%

Table 2. Frequent Clinically Significant RBC Antibodies

Antigen	System	Frequency Among All Detected Alloantibodies	Frequency of Antigen (Whites)	Frequency of Antigen (Blacks)	Potency*
E	Rh	16-40%	30%	22%	4%
K	Kell	5-40%	9%	2%	9%
D	Rh	8-33%	85%	92%	70%
c	Rh	4-15%	80%	96%	4%
Jk(a)	Kidd	2-13%	77%	92%	0.14%
Fy(a)	Duffy	4-12%	66%	10%	0.46%
C	Rh	2-10%	68%	27%	0.22%
e	Rh	2-3%	98%	98%	1%
Jk(b)	Kidd	2%	74%	49%	0.06%
S	MNSs	1-2%	55%	31%	0.08%
s	MNSs	< 1%	89%	94%	0.06%
*Percentage of antigen-negative recipients who become alloimmunized if transfused with antigen-positive units

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Author

Douglas Blackall, MD, MPH Professor of Pathology, St Louis University School of Medicine; Medical Director, Glennon Children’s Hospital Laboratory; Medical Director, St Louis University Hospital Blood Bank

Douglas Blackall, MD, MPH is a member of the following medical societies: Academy of Clinical Laboratory Physicians and Scientists, American Association of Blood Banks

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Eyal Oren, MD

Eyal Oren, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

Charles H Kirkpatrick, MD

Charles H Kirkpatrick, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Physicians, American Society for Clinical Investigation, Clinical Immunology Society, American Federation for Clinical Research

Disclosure: Received consulting fee from Dyax for consulting.

Acknowledgements

Samuel R Marney, Jr, MD Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine

Samuel R Marney, Jr, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, and Tennessee Medical Association

Disclosure: Nothing to disclose.

Jorge L Sepulveda, MD, PhD Associate Professor of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine; Chief, Pathology and Laboratory Medicine Service, Philadelphia Veterans Affairs Medical Center

Jorge L Sepulveda, MD, PhD is a member of the following medical societies: Academy of Clinical Laboratory Physicians and Scientists, American Heart Association, and College of American Pathologists

Disclosure: Nothing to disclose.