Lecture 9 - Transfusion Therapy

Three types of blood donation

Allogeneic donation- routine community blood donation
Directed donation- intended recipient selects specific donors
Autologous donation-donating for oneself

Every unit of donated blood is subjected to these tests:

-ABO blood typing
-Infectious disease testing

What are the 5 different blood components available for transfusion?

-whole blood
-RBC's
-Platelets
-Frozen plasma
-cryoprecipitate

Leukoreduction

Filtration technique designed to remove 99.99% of WBC's from RBC or platelet products

What population of patients are at most risk of cytomegalovirus?

Immunocompromised patients (e.g. neonates)

What is the effect of irradiation of cellular blood products? What patient group is this procedure indicated?

Gamma irradiation renders lymphocytes unable to proliferate

*Important in preventing GvHD in immunocompromised patients

Washing

Removes plasma on RBC and platelet units by repeated saline addition and removal from the unit.

Apheresis

-Blood is collected from the donor and separated into components -Those portions of the blood not required are returned to the donor *Can be used to collect platelets

What coagulation factor concentrates are available?

Factor VIII

What should be done clinically when a patient is in emergent need of transfusion but there is a typing discrepancy?

In emergency situations

Causes of typing discrepancies

-very weakly expressed A or B antigens
-absent blood group antibodies in immunocompromised patients

What individuals have anti-D antibodies?

-Rh negative individuals develop anti-D antibodies only if they are stimulated to produce an antibody by exposure to Rh positive blood -This can occur if Rh- patient gets an Rh+ unit of blood or an Rh- mother is exposed to blood of her Rh+ infant through a fetal-maternal bleed

What isotype are anti-D antibodies?

IgG

Weak "D"

Weakened expression of the "D" antigen in Rh+ individual that can result in mis-typing of patient.

Rh null

-rare individuals who have no Rh antigens on their RBC surface; type as Rh-
-mild, compensated hemolytic anemia, reticulocytosis, stomatocytosis and sometimes elevated bilirubin
-can only be transfused blood from another Rh null individual

What does pre-transfusion testing consist of?

-Performing ABO and Rh testing
-An antibody screen is done to determine if the patient has developed an antibody to a blood group antigen such as anti-K -Antibody screen is done by combining patient serum with carefully selected screening red cells-> if agglutination occurs then the red cell antigen is probably present
-Selection of the same or compatible blood type from an inventory labeled by ABO and Rh type
-Cross-match patient serum with RBCs from donors final check for compatibility

If whole blood is to be transfused, what are the restrictions on type selection?

The blood must be of the same ABO/Rh type--- type-identical

If red blood cells are to be transfused, what are the typing restrictions?

They don't have to be identical, but compatible.

What blood groups are acceptable for platelet transfusion?

All ABO groups are acceptable. However, women of child-bearing age and children who are Rh negative should receive Rh negative blood.

What blood groups restrictions for plasma transfusion?

Must be compatible with recipients RBCs.

What blood groups compatibility concerns are there for cryoprecipitate transfusion?

All ABO groups are acceptable

What blood groups compatibility concerns are there for granulocyte transfusion?

Must be compatible with the recipient's plasma

What are most transfusion errors caused by?

Failure to properly identify the patient at the time of transfusion and failure at the time of initial phlebotomy.

Crossmatch

Mixing donor RBCs with the patient's plasma to determine if agglutination occurs which indicates that an antibody is present in the patient that reacts with antigens on the donor red cells-->INCOMPATIBLE

Direct Anti-globulin Test(DAT)(Coombs)

-not a routine part of transfusion testing
-used to determine if there is IgG antibody or complement(C3d) attached to surface of RBCs

What are the only 4 reasons for a DAT?

1)Hemolytic transfusion reaction(transfusion of incompatible blood)
2)Hemolytic disease of the fetus and newborn(maternal IgG RBC antibody crosses placenta and sensitizes fetal RBCs)
3)Autoimmune hemolysis(IgG or IgM)
4)Drug-induced autoantibodies

What are the 3 types of antiglobulin reagents?

1)Broad-spectrum(contains BOTH IgG and C3d)
2)Anti-IgG
3)Anti-C3d

Why/How is IgG removed from RBCs?

By a technique called elution so that it can be identified and studied.

What are some compensatory mechanisms for anemia?

-Increased cardiac output (HR/SV)
-Redistribution of blood flow
-Increased oxygen extraction
-Increased red cell 2

At what Hgb level is a transfusion indicated?

less than 6 g/dL

At what Hgb level is transfusion generally not indicated?

greater than 10 g/dL

Exchange transfusion

Apheresis procedure to remove patient red cells and replace with normal, non-sickling red cells

What result of chronic transfusion causes increased morbidity and mortality?

Iron overload

What causes Iron Overload?

-Each red cell unit contains ~250 mg of iron with a maximum daily excretion of ~1 mg

-As transfused red cells are destroyed excess iron cannot be adequately eliminated
-Excess iron is stored in the body as hemosiderin and ferritin
-Iron accumulates in RES

What are the treatment for Iron Overload?

Chelation therapy (deferoxamine, deferipone, deferoxamine)

What are the 4 general causes of thrombocytopenia?

-increased destruction
-decreased production
-platelet sequestration
-dilutional thrombocytopenia

Normal platelet count:

150-450,000

What are the indications for transfusing plasma?

-Active bleeding due to MULTIPLE coagulation factor deficiencies
-Patients receiving massive transfusions due to dilution of coagulation factors
-Patients with single factor deficiency when there is no specific factor concentrate available
-Rapid reversal of Warfarin therapy

For an emergency reversal of Warfarin therapy, _______ is used:

Frozen plasma

For a 24-hour reversal of Warfarin therapy _______ is used:

IV Vitamin K

For a 48 hour reversal of Warfarin therapy, _______ is used:

stopping of Warfarin

What are the indications for transfusion of cryoprecipitate?

-Used to treat patients with decreased fibrinogen levels
-Can also be used to treat patients with severe vWD who are deficient in vWF(Type 1 and 2A can be treated with DDAVP)
-Patients with uremic bleeding to improve primary hemostasis

Hemophilia A? Treatment?

deficiency of Factor VIII

Treated with recombinant and high purity plasma-derived Factor VIII

Hemophilia B? Treatment?

deficiency of Factor IX

Treated with recombinant and high purity plasma-derived FactorIX

When is the use of Factor VIIa concentrates indicated?

In patients with hemophilia who have developed an inhibitor(alloantibody)

Off license use in selected cases of refractory bleeding.

When is granulocyte transfusion indicated?

In immunosuppressed patients when:
-profound neutropenia(<500/microL)
-documented sepsis
-failed trial of appropriate antibodies

Hemolytic Disease of the Fetus and Newborn(HDFN)

Anemia and hyperbilirubinemia of the fetus and/or newborn caused by an incompatibility between maternal and fetal red cells

-HDFN is caused by maternal IgG antibodies crossing the placenta; maternal IgM cannot cross and cannot cause HDFN

What percentage of cases of HDFN is due to ABO incompatability? Symptoms?

60%

-generally mild (increased postnatal bilirubin)
-can affect first and subsequent pregnancies

Immune-antibody HDFN

-40% of cases
-most common immune antibody is anti-D
-symptoms can be severe
-generally only affects later pregnancies

Exposure of an Rh- mother to Rh+ blood occurs by:

1)transfusion of Rh+ blood to an Rh- patient
2)fetal-maternal hemorrhage during previous pregnancy

Prenatal presentation of HDFN:

-erythroblastosis fetalis
-anemia
-high-output heart failure
-edema
-polyhydramnios(hydrops fetalis)

Postnatal presentation of HDFN:

-anemia -hyperbilirubinemia
-kernicterus(bilirubin-induced brain dysfunction)
-neonatal demise due to severe neurological complications (~90%)

Rh Immune Globulin

-HDFN prevention
-preparation of antibodies to D-antigen
-prevents development of anti-D in Rh- mothers
-standard dose covers up to a 30 mL bleed
-administer within 72 hours of hemorrhage -28-week dose---No FMH prior to this time

For expected mothers with a positive anti-D antibody screen, what is evaluated?

-Antibody type
-Maternal antibody titre
-Amniocentesis for hemolytic pigment
-Fetal middle cerebral artery systolic blood flow velocity

Critical titer

1:8 to 1:16 (titers of 8 and 16)

At this titer, an amniocentesis to assess the status of the fetus should be done

delta OD450

The abnormal increase in absorbed light at 450 nm caused by the amount of hemolytic pigment in the amniotic fluid.

-compared on a Liley graph to gestational age to determine severity of HDFN

Zone 1: mild
Zone 2: Questionable
Zone 3: Severely affected

Middle Cerebral Artery Peak Systolic Velocity(MCAPSV)

-doppler study -non-invasive
-MCAPSV correlates well with moderate to severe fetal anemia
-useful between 18 and 35 weeks (amniocentesis used after 38 weeks)

Prenatal management of HDFN in a severely affected fetus involves...

Intrauterine transfusion

-18-34 weeks
-Blood:antigen negative, ABO/Rh compatible and irradiated, hematocrit 75-85%

Postnatal treatment for HDFN in mildly affected neonate

-Phototherapy(effective, fluorescent)
-Exchange transfusion(decreases bilirubin, removes antibody-coated red cells, removes maternal antibody, corrects anemia)

What are the indications for exchange transfusion?

-cord Hgb <10 g/dL
-Rapidly rising bilirubin >0.5 mg/dL/hour
-Bilirubin >20 mg/dL in term infant

Transfusion complications fall into these two categories:

1)Infectious disease transmission
2)Non-infectious complications

Noninfectious complications of transfusion can be placed into these 4 categories:

1)Allergic
2)Hemolytic
3)Respiratory
4)Miscellaneous

Symptoms of simple allergic reaction:

-urticaria
-NO additional symptoms

Symptoms of an anaphylactic reaction:

-Urticaria
-Sever hypotension
-Dsypnea(bronchospasm)
-Chills
-Fever

Allergic reactions to transfusion are what type of HSR?

Type I

Pathophysiology of simple allergic reaction

-An allergen(usually some plasma protein) combines with a preformed IgE antibody in the recipient
-Mast cells are then activated by the binding of the allergen to IgE bound to the mast cell
-This results in degranulation and the release of histamine and other mediators

What is the treatment for simple allergic reactions from transfusion?

-Suspend the transfusion -Administer antihistamine prednisone; can be added if the antihistamine alone is insufficient
-Restart transfusion if hives resolve

How can simple allergic reactions to transfusion be prevented?

-Treatment with antihistamine 30 minutes prior to transfusion may reduce risk of recurrent allergic reaction
-For severe recurrent allergic reactions, or reactions unresponsive to antihistamine treatment, red cell and platelet products can be washed to remove residual plasma

Most anaphylactic reactions occur in patients who are______ deficient. Why?

IgA
-Patients who are deficient IgA can be stimulated to produce antibodies to IgA (IgE and anti-IgA) -Patients who are deficient in only one class of IgA(IgA1 or IgA2) can produce allotype specific antibodies which have been implicated in anaphylaxis

What is the treatment for anaphylactic reactions to transfusion?

-Stop transfusion
-Maintain oxygenation(supplemental)
-Stabilize hypotension (Trendelenberg position; crystalloids)
-Epinephrine

crystalloids) -Epinephrine

Symptoms of acute hemolytic reaction:

-Fever/chills -Pain(back, flank, inj. site,chest)
-Naseaa, vomiting
-Dyspnea
-Hypotension
-Hemoglobinemia, -uria

Symptoms of delayed hemolytic reaction:

-Minimal symptoms
-Unexpected anemia
-Jaundice

The majority of hemolytic transfusion reactions are caused by ______ errors.

clerical

Most causes of AHTR are due to.....

The transfusion of ABO-incompatible red cells to patients with preexisting anti-A or anti-B.

Anti-A and anti-B are usually which isotype?

IgM

Intravascular hemolysis is caused by? Results in?

Caused by anti-A/B of IgM type which can efficiently fix complement which can lead to formation of the MAC.

This results in increased levels of bilirubin, hemoglobinemia and hemoglobinuria and the appearance of schistocytes.

Extravascular hemolysis is caused by? Results in?

Caused by anti-A/B of the IgG type that fix complement and also cause intravascular hemolysis, but more often leading to extravascular hemolysis resulting in increased bilirubin.

The most significant threats of AHTR are:

1)Renal Failure(Acute Tubular Necrosis)
2)Disseminated Intravascular Coagulation

What are the roles of Factor XII in the AHTR?

-Factor XII may cause hypotension through the production of bradykinin
-Activated Factor XII can also activate the coagulation cascade, THF-alpha and IL-1 =>ultimately leading to DIC

How is Factor XII activated in AHTR?

Antigen-antibody complexes that precipitate hemolysis activate Factor XII

What is done if AHTR is suspected?

-Stop transfusion immediately
-Maintain venous access infuse normal saline
-Maintain urine output(diuretics may be useful)
-Maintain BP
-Monitor coagulation status

infuse normal saline -Maintain urine output(diuretics may be useful) -Maintain BP -Monitor coagulation status

Most AHTR result from the transfusion of______ .

ABO incompatible blood

What causes delayed hemolytic transfusion reactions?

-In DHTR, red cell antibody is not present or detectable at the time of transfusion
-Red cell antibodies develop in the recipient during the 7-21 days after the transfusion and is caused by exposure to foreign red cell antigens on the transfused red cells
-Development of this antibody results in the destruction of the remaining transfused red cells

Transfusion Related Acute Lung Injury(TRALI) symptoms

-Dyspnea/Hypoxia
-Fever/Chills
-HYPOTENSION
-CVP:normal or low
-CXR:bilat. puls infiltrates

What are the causes of TRALI?

-Single clinical event-infusion of donor antibodies directed against recipient leukocytes
-"Two-hit" mechanism- First "hit" refers to the clinical condition of the patient causing pulmonary endothelial activation and adherence of PMN's second "hit" is the transfusion of biologic response modifiers
-Agents that cause endothelial fenestration in neutropenic patients=> high levels of VEGF or high levels of HLA Class II antibodies

second "hit" is the transfusion of biologic response modifiers -Agents that cause endothelial fenestration in neutropenic patients=> high levels of VEGF or high levels of HLA Class II antibodies

Treatment for TRALI

-Stop transfusion
-Prompt respiratory support
-Intubation and mechanical ventilation, if necessary
-Vasopressors for hypotension
-Diuretics NOT indicated

How is TRALI prevented?

-Minimize the use of donors who have increased chance of having anti-leukocyte antibodies (e.g. multiparous females)

Transfusion Associated Circulatory Overload(TACO) symptoms

-Manifestation of simple volume overload
-Increased CVP
-Congestive Heart Failure

Treatment of TACO

-Stop transfusion
-Manage symptoms
-Diuretics indicated

TACO can be prevented by slowing the infusion rate to _____ .

1.0 mL/kg/hour (usual rate is 2.0-2.5 mL/kg/hour)

Febrile Nonhemolyitc Transfusion Reactions symptoms

-relatively common
-no long-term impact on the patient
-1-2 degree temperature increase during or within 4 hours of transfusion
-chills/rigors

What causes Febrile Nonhemolyitc Transfusion Reactions?

White blood cells and cytokines (IL-1, 6, 8 TNF-a) elaborated in the donor blood product

How is Febrile, Nonhemolyitc Transfusion Reactions treated and prevented?

-Antipyretics
-Leukoreduction of blood products

Graft versus Host Disease(GvHD)

The immunologic manifestation of tissue damage as the result of the proliferation of donor lymphocytes in an immunocompromised host

-Immunocompromised host fails to recognize donor T-cells
-Infusion of viable T-cells
-Proliferation of donor T-cells proliferate in host
-Immunologic damage to liver

GvHD affects only severely immunocompromised patients such as those who have ___________.

-congenital immunodeficiencies
-Hodgkin's disease
-Intrauterine transfusion
-Bone marrow transplants