Blood transfusion reactions and transplant rejection: Pathology review

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Case study0:00–1:00

35 year old Adam is brought to the emergency department by an ambulance after being involved in a motor vehicle crash. Upon examination, you notice that he is significantly bleeding from his thigh, so you decide to give him a blood transfusion.
Five minutes later, he develops shortness of breath, one episode of nonbloody vomiting, and a diffuse rash with erythematous borders starts to appear all over his body.
Also, his blood pressure drops to 60 over 40 millimeters of mercury. Some days later, you see 50 year old Jack, who’s complaining of fever, malaise, and a decreased production of urine for the past two days.
On further questioning, Jack tells you that he underwent a kidney transplantation one month ago. Upon examination, you realize that he has a high blood pressure of 150 over 80 millimeters of mercury.
You decide to perform a biopsy of his transplanted kidney, which reveals a dense lymphocytic infiltrate.Okay, based on the initial presentation, Adam seems to have some form of blood transfusion reaction, which includes any adverse event that occurs following blood transfusion.

Pathology1:00–1:52

Jack, on the other hand, seems to be experiencing some form of transplant rejection, which is when the immune system of the recipient attacks the transplanted organ or graft.
All right, let’s start with blood transfusion reactions. For your tests, there are six blood transfusion reactions that you need to be aware of, including anaphylactic or allergic transfusion reaction, acute hemolytic transfusion reaction, delayed hemolytic transfusion reaction, febrile nonhemolytic transfusion reaction, transfusion-related acute lung injury, and transfusion-associated circulatory overload.

Anaphylactic transfusion reaction1:52–3:37

Let’s begin with the anaphylactic or allergic transfusion reaction. It is a type I hypersensitivity reaction mediated by the recipient’s IgE antibodies against plasma proteins like immunoglobulins found in transfused blood.
Initially, the proteins in the donor’s plasma will be recognized by preformed IgE immunoglobulins present on the surface of mast cells, which in turn release their granules containing inflammatory mediators, such as histamine.
As a result, within seconds or minutes of starting the transfusion, the recipient develops urticaria, which is a raised pale rash with erythematous borders, accompanied by pruritus or itching and fever, as well as wheezing or a whistling sound in the chest, hypotension or low blood pressure, which can potentially progress into respiratory arrest, meaning the individual may stop breathing, as well as anaphylactic shock, which is when the blood pressure is too low to maintain adequate tissue perfusion.
Sometimes though, symptoms start 2 to 3 hours after the transfusion, as more time is needed for the mature plasma cells to be formed and produce IgE antibodies in response to the foreign plasma proteins.

Acute hemolytic transfusion reaction3:37–6:13

What you definitely need to know for your exams is that anaphylactic transfusion reaction commonly occurs in individuals with IgA deficiency, because they have anti-IgA antibodies, and IgA is found in most blood products.
So, bear in mind that individuals with IgA deficiency should receive washed blood products from which IgA immunoglobulins have been removed.Next is acute hemolytic transfusion reaction, which is a type II hypersensitivity reaction where the recipient’s preformed antibodies attack the transfused red blood cells.
This transfusion reaction typically occurs because of an ABO blood type incompatibility. Now, the ABO system refers to the type of glycoproteins found on the surface of red blood cells; so you can have either type A, type B, type AB, or neither, which is called type O blood.
The immune system produces antibodies against the glycoproteins that you don’t have. People with type A blood have antibodies against type B glycoproteins and vice versa, while those with type AB blood don’t have antibodies against any red blood cell glycoprotein, and finally, people with type O blood have antibodies to both A and B glycoproteins.
Now, as an example, if a recipient with type A blood is given a transfusion from a donor with type B blood, the recipient’s immune system will attack the donor blood, leading to intravascular hemolysis or red blood cell destruction within the recipient’s blood vessels.
Symptoms of acute hemolytic transfusion reaction can begin during the transfusion due to the presence of preformed antibodies, or anytime within 24 hours from the transfusion, which is the time it takes plasma cells to form the antibodies.

Delayed hemolytic transfusion reaction6:13–7:53

Individuals who have acute hemolytic transfusion reactions may experience fever, hypotension, tachycardia, and tachypnea.
Now, acute hemolysis results in a massive release of hemoglobin into the blood. Some of this hemoglobin breaks up into heme and globin.
Heme is then converted into bilirubin, leading to hyperbilirubinemia or high bilirubin in blood. As a consequence, individuals may present with jaundice, which is when the excess bilirubin deposits in the skin and eyes, causing them to turn yellow.
On the other hand, some hemoglobin can reach the kidneys to be excreted in the urine, which is known as hemoglobinuria. As a result, individuals with acute hemolytic transfusion reaction may present with red urine associated with flank pain.
In addition, free hemoglobin is toxic to the kidneys and can cause acute renal failure. Now, there’s also delayed hemolytic transfusion reaction, which is when hemolysis starts after 24 hours of transfusion, generally within one to two weeks.
This typically occurs when there are antibodies against minor antigens on the donor blood, such as Rhesus or Rh. Now, people are either Rh positive, meaning they have the Rh protein on their red blood cells, or they are Rh negative, meaning it’s absent.

Febrile nonhemolytic transfusion reaction7:53–9:23

So, if an Rh negative person receives Rh positive blood, they could develop a delayed hemolytic transfusion reaction. Now, keep in mind that this reaction results from an anamnestic response, meaning that to develop a response, the recipient must be previously exposed to these minor antigens, like by a prior transfusion or pregnancy, which led to the development of antibodies without causing a noticeable reaction.
On subsequent exposure, like a later blood transfusion or a second pregnancy, these antibodies will be ready to trigger an intense immune reaction.
Now, in delayed hemolytic transfusion reactions, the antibodies don’t directly destroy the donor’s red blood cells, but rather mark them for destruction by organs of the reticuloendothelial system, meaning the spleen and liver, resulting in extravascular hemolysis.
Individuals with delayed hemolytic transfusion reactions are often asymptomatic, while some may experience self-limited symptoms, such as a mild fever and jaundice.All right, next up is febrile nonhemolytic transfusion reaction, which is more common in children for unclear reasons.

Transfusion-related acute lung injury9:23–11:16

Now, as the name implies, this reaction doesn’t cause red blood cell destruction, and it mainly manifests as a fever following blood transfusion.
This occurs due to the release of inflammatory mediators like cytokines from white blood cells in donor blood. Another proposed mechanism for febrile nonhemolytic transfusion reaction involves a type II hypersensitivity reaction where antibodies in the recipient’s blood target human leukocyte antigens or HLAs on the surface of the donor's white blood cells.
This again causes these cells to break and release their cargo of cytokines into the blood after transfusion. In both cases, the released cytokines put the body in a state of heightened immune response, like when you have a cold.
Symptoms of febrile nonhemolytic transfusion reaction usually start within 1 to 6 hours after transfusion, and include fever, chills, headache, and flushing, which is a sudden reddening that usually involves the face and neck.
Febrile nonhemolytic transfusion reaction can be prevented by a process called leukoreduction, where white blood cells are removed from blood prior to transfusion.
And that’s a high yield fact!Another blood transfusion reaction you should know for your exams is transfusion-related acute lung injury, or TRALI for short, which is the number one cause of death among all transfusion reactions.

Transfusion-associated circulatory overload11:16–12:08

TRALI can start within minutes to 6 hours after blood transfusion. The underlying mechanism of TRALI can be best explained by the “two-hit” model.
The first “hit” occurs before the transfusion process, when any stressor like sepsis, shock, or trauma, causes neutrophils in the blood to be recruited and sequestered in the pulmonary capillaries.
These stressors also cause the neutrophils to be primed, meaning they’re prepared to start an inflammatory response when there's another stressor or a second “hit”.
In TRALI, the second hit is the transfusion itself, where antibodies in the donor’s blood activate the primed neutrophils, giving them the signal to start an inflammatory response in the lungs.

Transplant rejection12:08–12:33

Neutrophils then respond by releasing inflammatory mediators like cytokines, proteases, oxidases and reactive oxygen species.
This in turn will increase pulmonary capillary permeability, leading to fluid accumulation in the lungs’ interstitium. As a result, individuals develop noncardiogenic pulmonary edema, which is when the fluid accumulation is not due to cardiac causes like heart failure.

Hyperacute transplant rejection12:33–13:34

And that’s an extremely high yield fact! In addition, the pulmonary edema is associated with respiratory distress, which is characterized by dyspnea or shortness of breath, and tachypnea or rapid breathing.
Also, individuals with TRALI may experience fever and hypotension or low blood pressure.Now, a similar blood transfusion reaction is transfusion-associated circulatory overload, or TACO for short.
All right, the thing is, all blood products are packed in fluid, and therefore, a potential complication of transfusions is fluid overload.

Acute transplant rejection 13:34–15:25

In a test question, look for an individual who has congestive heart failure or chronic kidney disease, and presents within 6 hours of the transfusion with respiratory distress and cardiogenic pulmonary edema.
The treatment for both reactions is different as well. The main treatment for transfusion-related acute lung injury is respiratory support by delivering supplemental oxygen, while the treatment of TACO includes the use of diuretics in addition to supplemental oxygen.
All right, let’s switch gears and talk about transplant rejection, which is when the recipient’s immune system attacks the transplanted organ.
For your tests, you need to know that there are three types of transplant rejection based on their rapidity of onset. These are hyperacute transplant rejection, acute transplant rejection, and chronic transplant rejection.Okay, let’s start with the hyperacute transplant rejection, where hyperacute indicates that it starts within minutes from introducing the organ into the recipient’s body.
It’s a type II hypersensitivity reaction, meaning it occurs when the recipient’s blood contains preformed antibodies that bind to the transplanted organ or graft.
This leads to the activation of the complement system, which normally helps the immune system destroy foreign bodies like pathogens.

Chronic transplant rejection 15:25–17:44

So, complement activation results in a strong inflammatory response against the graft. In addition, these antibodies also bind to the endothelial cells within the graft’s blood vessels, inducing platelet aggregation.
This results in widespread thrombosis or clotting within the graft, which ultimately becomes ischemic and necrotic. Keep in mind that hyperacute transplant rejection can be life-threatening, and the only treatment involves prompt graft removal.
Next is acute transplant rejection, which usually develops weeks or months after the transplant. This begins when the recipient’s CD4 T helper cells directly recognize the major histocompatibility complexes or MHCs on the graft cells.
The CD4 T helper cells in turn stimulate CD8 cytotoxic T cells to attack and destroy the graft’s cells. So, this is a type IV hypersensitivity reaction.
In addition, T helper cells stimulate B cells to start producing antibodies that bind to antigens on the graft’s cells, initiating a humoral immune response.
So, this is a type II hypersensitivity reaction that’s similar to a hyperacute transplant rejection. However, an acute transplant rejection takes longer to develop because there are no preformed antibodies, so they’re produced after the transplant takes place.
Upon histology, some high yield findings that you could see include dense interstitial lymphocytic infiltrate in the graft’s tissue, as well as vasculitis or inflammation of the graft's blood vessels.
Symptoms of acute transplant rejection include fever and malaise, as well as specific symptoms related to the transplanted organ.
For example, individuals with acute rejection to kidney transplant would also have oliguria or low urine output, as well as peripheral edema or lower leg swelling, and hypertension or high blood pressure.

Graft-versus-host disease17:44–19:38

Treatment and prevention of acute transplant rejection involves the use of immunosuppressive therapy.Now, the last transplant rejection reaction that you need to know for your tests is chronic transplant rejection.
This type of transplant rejection can develop months or even years after the transplant. Now, similarly to acute transplant rejection, chronic transplant rejection is mediated by a combination of type IV and type II hypersensitivity reactions.
However, in chronic transplant rejection, the MHCs and other antigens on the graft cells are first recognized and captured by the recipient’s antigen presenting cells.
The antigen presenting cells then present the graft antigens to the recipient’s CD4 T helper cells. Finally, T helper cells activate CD8 cytotoxic T cells and B cells, triggering a gradual immune response that ultimately damages the transplanted organ.Upon histology, some high yield findings include abnormal thickening of the graft’s blood vessels due to proliferation of the vascular smooth muscle.
In addition, there’s parenchymal atrophy or loss of functional tissue, together with interstitial fibrosis or tissue scarring.
Now, examples of chronic graft rejection include chronic allograft nephropathy, where the function of a transplanted kidney declines over time; as well as bronchiolitis obliterans, which occurs when bronchioles in the transplanted lung obliterate or become progressively damaged due to inflammation, which ultimately results in fibrosis.

Review19:38–22:53

Chronic rejection can also occur in a transplanted heart, which manifests as accelerated atherosclerosis, where fatty deposits or plaques build up inside the coronary blood vessels, and may put the individual at risk for coronary artery disease.
Finally, vanishing bile duct syndrome is an example of chronic rejection in liver transplantation, where the intrahepatic bile ducts in the liver are progressively destroyed and eventually disappear.
Unfortunately, chronic transplant rejection is a progressive process that up until now can’t be prevented or treated. Okay, finally, there’s graft-versus-host disease, or GvHD for short, which is similar to transplant rejection but works the other way around.
In other words, it’s the graft that’s rejecting the recipient or host. Graft-versus-host disease is a type IV hypersensitivity reaction that’s especially common with grafts that are rich in lymphocytes, such as the bone marrow or liver.
What happens is that the T lymphocytes from an immunocompetent donor attack the cells of the immunocompromised host, causing severe organ dysfunction.
Symptoms of graft-versus-host disease can include maculopapular rash with red and raised lesions, and most often involves the palms and soles.
In addition, individuals may often develop hepatosplenomegaly, or enlarged liver and spleen, associated with jaundice or yellow skin.
Graft-versus-host disease may also frequently cause diarrhea and abdominal pain. Less frequently, chronic graft versus host disease can affect the lungs, causing dyspnea or shortness of breath, as well as the muscles, causing muscle cramps and weakness.
The good news is that graft-versus-host disease can be prevented by irradiating blood products to kill the lymphocytes prior to transfusion.
In certain situations though, graft-versus-host disease can be induced on purpose in individuals who have leukemia, where the donor T cells from a bone marrow transplant attack and kill the host’s leukemic cells.
This is called graft-versus-tumor effect.All right as a quick recap… Anaphylactic transfusion reaction is a type I hypersensitivity reaction mediated by the recipient’s IgEs against the donor’s plasma proteins that starts within seconds to minutes from the transfusion, and can manifest as urticaria, pruritus, wheezing, hypotension, and can evolve into respiratory arrest or shock.

Summary22:53–24:02

Acute hemolytic transfusion reaction is a type II hypersensitivity that occurs in cases of ABO incompatibility, leading to intravascular hemolysis within 24 hours due to preformed antibodies.
On the other hand, delayed hemolytic transfusion reaction results from newly formed antibodies against minor antigens on red blood cells like Rh, causing extravascular hemolysis after 24 hours.
Febrile non-hemolytic transfusion reaction can result from the release of cytokines from white blood cells present in donor blood, causing fever, chills, headache, and flushing.
Transfusion-related acute lung injury results from a two-hit inflammatory response in the pulmonary vasculature that results in fluid accumulation in the lungs within minutes to 6 hours, leading to noncardiogenic pulmonary edema.
On the other hand,
Blood transfusion reactions and transplant rejection: Video | Osmosis