Delayed hemolytic transfusion reaction

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Delayed hemolytic transfusion reaction
Specialty Hematology and immunology
Symptoms Drop in hemoglobin level, fever, jaundice, or hemoglobinuria, as well as chills, abdominal pain, or back pain
Usual onsetGenerally up to one month
CausesTransfusion of mismatched blood types, reactivity of recipient's antibodies against donor's red blood cell proteins, or prior damage to red blood cells contained in transfusion products
Risk factors Medical malpractice, inadequate compatibility testing for blood transfusions, and negligent handling of blood products
Diagnostic method Antiglobulin test, also known as a Coombs test
Differential diagnosis Acute hemolytic transfusion reaction

Transfusion-related acute lung injury

Febrile non-hemolytic transfusion reaction

Transfusion-associated graft versus host disease

Hyperhemolysis

A delayed hemolytic transfusion reaction (DHTR) is a type of adverse reaction to a blood transfusion. [1] [2] [3] [4] DHTR is the later-onset manifestation of hemolytic transfusion reaction, which may also present as acute hemolytic transfusion reaction (AHTR) in a shorter timeframe from transfusion administration. The prevalence of AHTR has been estimated at 1 in 70,000 blood transfusions, whereas the prevalence of DHTR is thought to be underreported, although various studies estimate the prevalence of DHTR as between 1 in 800, to 1 in 11,000 transfusions. [1]

Contents

Hemolytic transfusion reactions are a possible complication from red blood cell transfusions. Hemolysis refers to the lysis (rupture) of red blood cells, and the resulting leakage of their contents. Hemolytic reactions may be immune or non-immune mediated. Immune-mediated hemolytic reactions, such as DHTR, represent a type of alloimmunity. Non-immune hemolysis may result from thermal, osmotic, or mechanical damage to red blood cells in transfusion products.

In immune-mediated DHTR, the transfusion recipient has antibodies that react with antigens on incompatible donor red blood cells, [5] prompting lysis of the red blood cells by the recipient's immune cells, such as macrophages. The severity of immune-mediated hemolytic reactions may vary based on the type and quantity of both the transfused red blood cell antigens and the recipient's antibodies against them, as well as the ability of the antibodies to activate complement or opsonization. Some recipients do not have significant pre-existing antibodies against transfused red blood cells, but then develop higher levels of such antibodies following immune stimulation by the transfused red blood cells.

While AHTR usually presents within the first 24 hours after transfusion, DHTR has the possibility to present up to 30 days later. Even though DHTR may have a lower chance of severe outcomes than AHTR, it can still be fatal or result in serious complications, and must be treated as an urgent medical issue.

Mechanism

If a person without a Kidd blood antigen (for example a Jka-Jkb+ patient) receives a Kidd antigen (Jka-antigen for example) in a red blood cell transfusion and forms an alloantibody (anti-Jka); upon subsequent transfusion with Jka-antigen positive red blood cells, the patient may have a delayed hemolytic transfusion reaction as their anti-Jka antibody hemolyzes the transfused Jka-antigen positive red blood cells. Other common blood groups with this reaction are Duffy, Rhesus and Kell. [6]

Immune-mediated hemolytic reactions may be classified as either intravascular or extravascular hemolysis. Intravascular hemolysis takes place while the red blood cells are still when the recipient's antibodies bind to the donor's red blood cells and cause complement activation. Extravascular hemolysis is produced when the recipient's antibodies opsonize the donor's red blood cells, leading to their sequestration and phagocytosis by phagocyte immune cells such as macrophages. Macrophage activation, in response to antibody-mediated targeting of red blood cells, can also increase production of cytokines that induce a systemic response that results in clinical symptoms, such as fever, chills, abdominal pain, and back pain.

Some hemolytic reactions are the product of incompatibility between different blood types of the ABO blood group system. Hemolytic reactions may also be caused by incompatibilities with Rh factors, Duffy antigens, Kell antigens, Kidd antigens, [6] and Lewis antigens.

Many people have antibodies to red blood cell antigens not found on the surface of their own red blood cells. Therefore, to use the ABO types as an example, those with type O blood are likely to have antibodies to type A and type B blood. Those with type A blood are likely to have antibodies to type B blood, and vice versa.

Antibodies against Kidd antigens may be difficult to detect because of significant variability in their molecular features, and weak in vitro expression. They have been reported to cause severe immediate or delayed hemolytic transfusion reactions, [6] with anti-Jk antibodies responsible for 13 of 44 cases of DHTR reported in the UK during 2021. [7]

Diagnosis

Symptoms may include a drop in hemoglobin level, fever, jaundice, or hemoglobinuria. [6] It is also "associated with a fall in Hb or failure to increment, rise in bilirubin and LDH and an incompatible crossmatch not detectable pre transfusion." [10]

DHTR may be diagnosed by the presence of antibodies that react to red blood cells. An antiglobulin test, also known as a Coombs test, is a type of blood test used in immunohematology. An antiglobulin test may either be direct (e.g., "direct antiglobulin test" or "direct Coombs test"), or indirect. The direct test is designed to detect antibodies already bound to the surface of red blood cells in a clinical blood sample. By contrast, the indirect test is designed to detect antibodies that are freely floating in the blood, and that display in vitro reactivity against red blood cells. Both direct and indirect Coombs tests may be useful for investigating suspected blood transfusion reactions. The indirect test may also be used to determine a patient's reactivity to foreign red blood cell antigens prior to transfusion.

Hyperhemolysis differs from DHTR in that it involves the lysis of the recipient's own red blood cells in addition to those introduced from the donor. [11]

Epidemiology

Delayed blood transfusion reaction occurs more frequently (1 in 20,569 blood components transfused in the USA in 2011) when compared to acute haemolytic transfusion reaction. [12]

Related Research Articles

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<span class="mw-page-title-main">Hemolytic anemia</span> Medical condition

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

The direct and indirect Coombs tests, also known as antiglobulin test (AGT), are blood tests used in immunohematology. The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells. Since these antibodies sometimes destroy red blood cells they can cause anemia; this test can help clarify the condition. The indirect Coombs test detects antibodies that are floating freely in the blood. These antibodies could act against certain red blood cells; the test can be carried out to diagnose reactions to a blood transfusion.

<span class="mw-page-title-main">Cross-matching</span> Testing before a blood transfusion

Cross-matching or crossmatching is a test performed before a blood transfusion as part of blood compatibility testing. Normally, this involves adding the recipient's blood plasma to a sample of the donor's red blood cells. If the blood is incompatible, the antibodies in the recipient's plasma will bind to antigens on the donor red blood cells. This antibody-antigen reaction can be detected through visible clumping or destruction of the red blood cells, or by reaction with anti-human globulin. Along with blood typing of the donor and recipient and screening for unexpected blood group antibodies, cross-matching is one of a series of steps in pre-transfusion testing. In some circumstances, an electronic cross-match can be performed by comparing records of the recipient's ABO and Rh blood type against that of the donor sample. In emergencies, blood may be issued before cross-matching is complete. Cross-matching is also used to determine compatibility between a donor and recipient in organ transplantation.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.

In ABO hemolytic disease of the newborn maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

Hemolytic disease of the newborn (anti-Kell1) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell1 is becoming relatively more important as prevention of Rh disease is also becoming more effective.

Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.

The Kidd antigen system are proteins found in the Kidd's blood group, which act as antigens, i.e., they have the ability to produce antibodies under certain circumstances. The Jk antigen is found on a protein responsible for urea transport in the red blood cells and the kidney. They are important in transfusion medicine. People with two Jk(a) antigens, for instance, may form antibodies against donated blood containing two Jk(b) antigens. This can lead to hemolytic anemia, in which the body destroys the transfused blood, leading to low red blood cell counts. Another disease associated with the Jk antigen is 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. Hemolytic disease of the newborn associated with Jk antibodies is typically mild, though fatal cases have been reported.

<span class="mw-page-title-main">Neonatal isoerythrolysis</span> Blood disorder in newborn kittens and foals

Neonatal isoerythrolysis (NI), also known as hemolytic icterus or hemolytic anemia, is a disease most commonly seen in kittens and foals, but has also been reported in puppies. It occurs when the mother has antibodies against the blood type of the newborn.

Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.

Type II hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells or extracellular material. This subsequently leads to cell lysis, tissue damage or loss of function through mechanisms such as

  1. complement activation via the classical complement pathway
  2. Antibody-dependent cellular cytotoxicity or
  3. anti-receptor activity.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

<span class="mw-page-title-main">Drug-induced autoimmune hemolytic anemia</span> Medical condition

Drug-induced autoimmune hemolytic anemia also known as Drug-induced immune hemolytic anemia (DIIHA) is a rare cause of hemolytic anemia. It is difficult to differentiate from other forms of anemia which can lead to delays in diagnosis and treatment. Many different types of antibiotics can cause DIIHA and discontinuing the offending medication is the first line of treatment. DIIHA has is estimated to affect one to two people per million worldwide.

An acute hemolytic transfusion reaction (AHTR), also called immediate hemolytic transfusion reaction, is a life-threatening reaction to receiving a blood transfusion. AHTRs occur within 24 hours of the transfusion and can be triggered by a few milliliters of blood. The reaction is triggered by host antibodies destroying donor red blood cells. AHTR typically occurs when there is an ABO blood group incompatibility, and is most severe when type A donor blood is given to a type O recipient.

<span class="mw-page-title-main">Blood compatibility testing</span> Testing to identify incompatibilities between blood types

Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pregnancy that can occur when the baby has a different blood group from the mother. Blood compatibility testing includes blood typing, which detects the antigens on red blood cells that determine a person's blood type; testing for unexpected antibodies against blood group antigens ; and, in the case of blood transfusions, mixing the recipient's plasma with the donor's red blood cells to detect incompatibilities (crossmatching). Routine blood typing involves determining the ABO and RhD type, and involves both identification of ABO antigens on red blood cells and identification of ABO antibodies in the plasma. Other blood group antigens may be tested for in specific clinical situations.

<span class="mw-page-title-main">Monocyte monolayer assay</span> Laboratory test for clinically significant alloantibodies

The monocyte monolayer assay (MMA) is used to determine the clinical significance of alloantibodies produced by blood transfusion recipients. The assay is used to assess the potential for intravascular hemolysis when incompatible cellular blood products are transfused to the anemic patient. When donor cells possess substances that are not produced by the recipient, the recipient's immune system produces antibodies against the substance; these are called alloantibodies. Specific white blood cells, called monocytes, are tasked with ingesting foreign material and become activated during certain inflammatory events. These activated monocytes come in contact with antibody-sensitized red blood cells (RBC) and may or may not exhibit phagocytosis (ingestion) and destroy the donor red blood cells. If monocytes destroy the RBC, the antibody attached to those RBC is considered clinically significant.

<span class="mw-page-title-main">Antibody elution</span> Laboratory procedure

An antibody elution is a clinical laboratory diagnostic procedure which removes sensitized antibodies from red blood cells, in order to determine the blood group system antigen the antibody targets. An antibody elution is deemed necessary when antibodies of the immunoglobulin class G (IgG) are found sensitized (bound) to peripheral red cells collected from a blood product transfusion recipient. IgG antibodies are detected using an assay known as the direct antiglobulin test.

References

  1. 1 2 Harewood, Janine; Ramsey, Adam; Master, Samip R. (2023), "Hemolytic Transfusion Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   28846280 , retrieved 2023-04-29
  2. ↑ Noizat-Pirenne F, Bachir D, Chadebech P, et al. (December 2007). "Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease". Haematologica. 92 (12): e132–5. doi: 10.3324/haematol.12074 . PMID   18055978.
  3. ↑ Talano JA, Hillery CA, Gottschall JL, Baylerian DM, Scott JP (June 2003). "Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease". Pediatrics. 111 (6 Pt 1): e661–5. doi: 10.1542/peds.111.6.e661 . PMID   12777582.
  4. ↑ Elenga N, Mialou V, Kebaïli K, Galambrun C, Bertrand Y, Pondarre C (December 2008). "Severe neurologic complication after delayed hemolytic transfusion reaction in 2 children with sickle cell anemia: significant diagnosis and therapeutic challenges". J. Pediatr. Hematol. Oncol. 30 (12): 928–30. doi:10.1097/MPH.0b013e31818c9172. PMID   19131783.
  5. ↑ Daniels, Geoff (2013-02-20). Human Blood Groups (1 ed.). Wiley. doi:10.1002/9781118493595. ISBN   978-1-4443-3324-4.
  6. 1 2 3 4 Vassiliki Kazakou, MD; Alexandra Kousoulakou, MD; Euthemia Melissari, MD (May 2007). "Delayed hemolytic transfusion reaction by a Kidd antibody after heart surgery: Case report and review of the literature". The Journal of Thoracic and Cardiovascular Surgery. 133 (5): 1364–5. doi: 10.1016/j.jtcvs.2006.11.022 . PMID   17467459.
  7. ↑ "Annual SHOT Report 2021" (PDF). July 2022. pp. 190–191.
  8. ↑ George H. Roberts (2006). "Elution Techniques in Blood Bank" (PDF). American Medical Technologists (AMT). Archived from the original (PDF) on 2019-07-11. Retrieved 2020-07-22.
  9. ↑ Brian Nagao, Shan Yuan, Qun Lu (2011). "Drug-induced Immune Hemolytic Anemia and Thrombocytopenia" (PDF). Transfusion Medicine. 54 (4).{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ "Annual SHOT Report 2021" (PDF). July 2022. p. 185.
  11. ↑ Patel, Amit (2023-04-29). "Beware of transfusions and hyperhaemolysis". British Medical Journal.
  12. ↑ "The 2011 National Blood Collection and Utilization Survey Report" (PDF). Department of Health and Human Services. Archived from the original (PDF) on 19 March 2016. Retrieved 21 January 2016.
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