What additive is used in blood to prevent clotting during transfusion?

Anticoagulant Additives in Blood Products for Transfusion

Citrate-based anticoagulants are the standard additives used in blood products to prevent clotting during transfusion, with citrate-phosphate-dextrose (CPD), citrate-phosphate-dextrose-adenine (CPDA-1), and sodium citrate being the most commonly used formulations in clinical practice. 1, 2, 3

Mechanism of Action

Citrate functions as an anticoagulant by chelating (binding to) ionized calcium in the blood, thereby preventing the calcium-dependent steps in the coagulation cascade that are essential for clot formation. 2, 3 Calcium ions are required cofactors for the activation of multiple coagulation factors including factors II, VII, IX, and X, as well as for fibrin polymerization and platelet adhesion. 3 By removing available calcium through chelation, citrate effectively blocks these critical coagulation pathways. 3

Standard Citrate-Based Anticoagulants

Red Blood Cell Products

• CPD (Citrate-Phosphate-Dextrose) and CPDA-1 (CPD-Adenine) are the primary anticoagulants used for whole blood collection in the United States, typically in a 1:8 ratio of anticoagulant to blood. 4, 5, 6
• Red cells are stored in optimal additive solutions containing virtually no plasma, platelets, or leucocytes, with all UK blood components now leucodepleted. 1
• CPDA-1 extended red cell shelf life from 21 to 35 days compared to earlier CPD formulations. 5

Plasma and Platelet Products

• Sodium citrate (4%) is used in a 1:10 ratio for manual plasmapheresis. 6
• ACD-A or ACD-B (Acid-Citrate-Dextrose) and sodium citrate are commonly used in 1:12 or 1:15 ratios during automated plasmapheresis. 6
• A standard unit of red blood cells (300-400 mL) typically contains up to 3 grams of citrate. 2
• Fresh frozen plasma (FFP) and platelet products contain particularly high citrate concentrations. 2

Clinical Significance of Citrate Load

Hypocalcemia Risk

The citrate in transfused blood products can cause significant hypocalcemia in recipients through calcium chelation, particularly during massive transfusion protocols. 2, 3 This occurs because:

• Citrate directly binds to and inactivates circulating calcium ions in the recipient's bloodstream. 2
• Hypocalcemia occurs in approximately 70% of patients receiving large volume transfusions. 2
• Renal insufficiency, hypothermia, and hypoperfusion impair citrate metabolism, worsening the calcium-binding effect. 2

Clinical Consequences

Critical hypocalcemia (<0.8 mmol/L) can cause:

• Coagulopathy with platelet dysfunction and decreased clot strength. 2
• Cardiovascular dysfunction including impaired myocardial contractility and dysrhythmias. 2
• Neuromuscular excitability and seizures in severe cases. 2

Management During Transfusion

Ionized calcium should be monitored at baseline and every 1-4 hours during massive transfusion, with a target of maintaining ionized calcium >0.9 mmol/L (normal range: 1.1-1.3 mmol/L). 2 The American College of Critical Care recommends administering 1 gram of calcium chloride per liter of citrated blood products transfused. 2 Calcium chloride 10% is preferred over calcium gluconate as it contains 270 mg elemental calcium per 10 mL compared to only 90 mg in calcium gluconate. 2

Alternative Anticoagulants in Specific Contexts

Heparin

While heparin is an anticoagulant used therapeutically, it is not the standard additive in stored blood products for transfusion. 7 Heparin works through a different mechanism—it interacts with antithrombin III to inhibit activated coagulation factors, particularly Factor Xa and thrombin (Factor IIa). 7 Low-dose heparin may be added to cell therapy products (such as mesenchymal stromal cells) to minimize procoagulant activity, but this is distinct from standard blood component storage. 1

EDTA

EDTA is another calcium chelator that may be used as an anticoagulant in specific research or clinical contexts, particularly when RNA analysis is required, but it is not the standard for transfusion products. 1

Important Caveats

• Standard coagulation laboratory tests may not reflect the true impact of hypocalcemia on coagulation, as blood samples are citrated then recalcified before analysis. 2
• The choice of anticoagulant affects not only storage but also downstream laboratory testing—for example, heparin interferes with polymerase chain reaction (PCR). 1
• Different citrate formulations have varying pH values and citrate concentrations that can affect plasma constituent recovery, including Factor VIII levels. 6