TRANSFUSION MEDICINE—HEMATOLOGY {S1}

BY RANJEET RAMAN

Almost all hemolytic transfusion reactions are caused by mislabeling and misadmini- stering blood samples into the wrong patient!

Components, not whole blood, are transfused. This avoids volume overload, concentrates the required component, and maximizes blood use.

RBC lose their 2,3DPG during storage, and accumulate metabolites.

Platelets are collected by aphaeresis and administered for abnormal bleeding time, thrombocytopenia, and after invasive procedures or trauma.

HLA antibodies will destroy incompatible platelets, so platelets have to be matched like other tissues.

Irradiation is used to prevent graft-versus-host disease by destroying WBC.

Immunohematology – ABO, Rh factor ABO group is a molecular extension from

the membrane. They are genetic polymorphisms.

Antibodies to ABO antigens are T-cell independent and occur spontaneously. They do not require an immune response.

ABO antigens are in very high concentration on RBC. ABO incompatibility is the most common cause of hemolytic transfusion reactions.

Reciprocal arrangement: People who are Group A have anti-B antibodies!! These antibodies are high titer IgM antibodies and will cause hemolysis. They are formed because blood group antigens mimic antigens found in foods and bacteria.

O is the universal RBC donor, but AB is the universal plasma donor!!

Rh is integral to the RBC membrane. Rh is also called the “D antigen.”

Rh+ babies born to mothers with anti-Rh antibodies will die of hemolysis. Rh antigen is extremely immunogenic. Incompatibility causes hemolytic transfusions reactions.

85% of people are Rh+.

Adverse effects of transfusion 1. Acute hemolytic transfusion reactions.

Usually caused by IgM, which will activate complement and bind foreign antigens. Can cause shock, DIC, but especially acute renal failure. Signs include free hemoglobin in urine/plasma, and a positive Coombs test.

2. Delayed hemolytic transfusion reactions. Slower destruction of transfused cells by alloantibodies. Usually involves extravascular RBC destruction in the RES.

3. Allergic reactions. Often happens in patients with IgA deficiency, and may cause anaphylaxis. Can be prevented by using washed blood or IgA deficient blood.

4. Transfusion transmitted diseases. HIV. Current risk is less than one per two

million. HepC. Current risk is less than one per

two million. CMV. Bacteria. Current risk is one per two

thousand. Major problem in platelet transfusions.

HepA is NOT TRANSMITTED by infusions since there is no asymptomatic chronic stage.

Alternatives to Transfusion 1. Predeposit autologous blood. 2. Hematopoietic growth factors

(erythropoietin for RBC, G-CSF for neutropenia, DDAVP for vWD)

PHARMACOLOGY OF BLOOD –TARGETING

PLATELETS

All inhibitors of platelet function are used prophylactically and don’t affect formed thrombi.

Aspirin ASA is an excellent drug that inhibits COX,

and thus thromboxane A2 synthesis. Thromboxane is a potent inducer of platelet aggregation and a vasoconstrictor, so ASA is potent against platelet activation.

It permanently and covalently inhibits COX, so effect lasts until new platelets are formed.

Dipyridamole Increases cAMP inside platelets. This

inhibits platelet aggregation. Dipyridamole inhibits adenosine uptake

(which normally activates adenylate cyclase), so this raises cAMP and platelets fail to aggregate.

Only works in combination with aspirin or warfarin.

ADP antagonists – Thienopyridine, Ticlopidine, Clopidogrel Since ADP induces platelet aggregation, these drugs prevent thrombus formation.

ADP antagonists include Thienopyridine, Ticlopidine, and Clopidogrel.

These permanently and irreversibly bind the ADP receptor on platelets, which blocks release of alpha and dense granules. They also inhibit fibrinogen binding.

These drugs are actually prodrugs that are metabolized to active metabolites.

Toxicities include severe neutropenia, bleeding, and thrombocytopenia.

Platelet GPIIb/IIIa antagonists (note: will not cause intracranial bleeding!!) 1. Abciximab is an antibody against GPIIb/IIIa, so fibrinogen can’t crosslink platelets.

Abciximab is cleared within minutes from the body.

2. Ebtifibatide is a peptide against GPIIb/IIIa. It mimics the AA sequence of fibrinogen that binds to IIb/IIIa, as well as the AA sequence that VWF uses to bind platelets.

Ebtifibatide blocks fibrinogen and vWF-mediated aggregation of platelets.

Unlike ASA and the ADP antagonists, Ebtifibatide has a short and reversible effect.

3. Tirofiban is a small molecule against GPIIb/IIIa. It reversibly blocks fibrinogen binding and like Ebtifibatide is rapidly cleared.

Erythropoietin Erythropoietin binds the EPO receptor of RBC

precursors, activating a Jak/Stat pathway. Stat5 becomes phosphorylated and acts as a nuclear transcription factor for RBC maturation genes.

This blocks apoptosis of erythroid precursor cells.

Erythropoietin actually increases the risk of thrombosis.