Aprotinin: Uses, Dosage, Side Effects and Interactions

Aprotinin is a fascinating medication with a long history in surgical medicine, particularly in cardiac procedures. Originally derived from bovine lung tissue, aprotinin is a serine protease inhibitor that has revolutionized the management of bleeding during major surgeries. Over time, its uses have expanded and its safety profile has become increasingly well understood. In this comprehensive article, we’ll explore why aprotinin is used, how it is dosed, its side effects, and important interactions clinicians and patients should know.

Uses of Aprotinin

Aprotinin’s medical journey began serendipitously, with its ability to reduce blood loss during surgery being discovered almost by accident. Today, its uses span both research and clinical domains, with a strong focus on bleeding prevention and potential applications in viral infections.

Use Case	Main Benefit	Typical Context	Source(s)
Cardiac Surgery	Reduces blood loss, transfusion needs	CABG, valve replacement, reoperations	1 3 4 6 7 8 10 12 13 15
Vascular/Transplant Surgery	Lessens operative bleeding	Major vascular/transplant procedures	8 10 13
Orthopedic Surgery	Lowers perioperative blood loss	Total hip replacement	11
Research/Other	Tool for protein/protein studies; inhibits viral replication	Biochemical research, SARS-CoV-2	2 5

Table 1: Primary Uses of Aprotinin

Cardiac Surgery and Blood Conservation

Aprotinin is most renowned for its role in cardiac surgery, especially during procedures involving cardiopulmonary bypass (CPB) such as coronary artery bypass grafting (CABG), heart valve replacements, and reoperations. It works by inhibiting serine proteases like plasmin and kallikrein, which play a critical role in breaking down clots (fibrinolysis) and triggering inflammation during surgery. By limiting this breakdown, aprotinin preserves platelet function and reduces bleeding, often cutting transfusion requirements by half or more in high-risk patients 1 3 4 6 8 10 12 13 15.

Both adult and pediatric cardiac cases benefit, though in children, high-dose regimens are most effective for complex congenital heart surgeries 7 9. Its application in procedures using membrane oxygenators also shows significant bleeding reduction 4. Additionally, aprotinin has helped improve outcomes for patients receiving left ventricular assist devices (LVADs) as a bridge to transplantation 3.

Vascular, Transplant, and Orthopedic Surgeries

Beyond the heart, aprotinin’s antifibrinolytic properties have shown value in major vascular and transplant surgeries, where blood conservation is equally critical 8 10 13. It also reduces blood loss in orthopedic settings such as total hip replacement, decreasing both intra- and postoperative transfusion needs 11.

Research and Antiviral Activity

Aprotinin is a powerful tool in molecular biology, used to study protein interactions because of its protease inhibition 2. Notably, recent research demonstrates that aprotinin can inhibit SARS-CoV-2 replication at therapeutic concentrations, suggesting a possible role in managing COVID-19 progression, especially when delivered as an aerosol for early intervention 5.

Dosage of Aprotinin

Dosing aprotinin correctly is essential for maximizing benefit while minimizing risks. Regimens vary depending on the surgery type, patient population, and desired effect.

Regimen Type	Dosage Example	Context/Population	Source(s)
High-Dose	>5 million KIU total (bolus + infusion + pump prime)	Adult cardiac surgery	6 7 8 10 12
Low-Dose	1–2 million KIU (often pump prime only)	Cardiac surgery, lower risk	1 6 9 15
Pediatric High-Dose	3x10⁴ KIU/kg + 5x10⁵ KIU pump prime (not weight adjusted)	Pediatric cardiac surgery	7 9
Orthopedic Surgery	2x10⁴ KIU bolus + 5x10⁵ KIU/h infusion	Total hip replacement	11

Table 2: Common Aprotinin Dosage Regimens

High-Dose vs Low-Dose Strategies

In cardiac surgery, high-dose regimens (often exceeding 5 million KIU total) are the standard for patients at high risk of bleeding. These regimens typically combine:

• A loading bolus before incision
• Addition to the cardiopulmonary bypass pump prime
• Continuous infusion during the procedure

Both high-dose and lower-dose regimens effectively reduce blood loss and transfusion needs, but high doses are preferred for complex or high-risk cases 6 7 8 10 12.

Low-dose or "pump-prime only" regimens (e.g., 2 million KIU added to pump prime) also provide significant benefit, sometimes matching high-dose results, particularly in adult patients not at extreme risk 1 6 9 15. However, pump-prime-only strategies may carry a slight risk of increased myocardial infarction in some populations, so their routine use remains debated 6.

Pediatric Dosing

In pediatric cardiac surgery, dosing is weight-based and higher on a per-kilogram basis. High-dose protocols are especially effective in reducing blood loss among children with complex congenital heart disease (e.g., transposition of the great arteries) 7 9.

Orthopedic and Other Surgeries

In total hip replacement, a typical regimen is a 20,000 KIU bolus followed by a 500,000 KIU/hour infusion until the end of surgery 11.

Special Considerations

• Renal Function: Generally, aprotinin is cleared renally, but dosing adjustments are rarely required unless severe kidney impairment exists 12 14.
• Heparin Interaction: Aprotinin prolongs the activated clotting time (ACT) when used with heparin, necessitating careful monitoring and possible reduction in heparin doses 1 4.

Side Effects of Aprotinin

Like any powerful medication, aprotinin is associated with certain risks and side effects. Most patients tolerate it well, but understanding potential adverse reactions is crucial for safe use.

Adverse Effect	Frequency/Severity	Notes / Populations at Risk	Source(s)
Hypersensitivity	<0.1%–0.6% (first dose); higher with repeat dosing	Anaphylaxis possible; rare	10 13
Renal Dysfunction	Generally rare/transient	Some increased creatinine noted, especially post-cardiac surgery	3 10 12 14
Circulatory Depression	Very rare, mild	Resolved with vasopressors	10
Myocardial Infarction	No significant increase, but possible with pump-prime-only regimen	Monitor in high-risk cardiac cases	6 13
Thrombotic Events	Not significantly prothrombotic	No increase in DVT or graft occlusion in most studies	11 13 16

Table 3: Notable Aprotinin Side Effects

Hypersensitivity and Allergic Reactions

Aprotinin is derived from bovine tissue, so allergic reactions can occur. First-time use carries a very low risk (<0.1%–0.6%) of serious hypersensitivity, but risk is higher with repeat exposures. Anaphylaxis is exceedingly rare but possible, so monitoring during administration is essential 10 13.

Renal Effects

Some studies have observed a transient rise in serum creatinine after aprotinin use, especially in cardiac surgery, but without lasting renal impairment 3 10 12. Large studies and careful monitoring have not shown significant long-term kidney damage. Animal studies suggest that high doses may decrease renal blood flow and glomerular filtration rate, but these effects are less pronounced in humans at therapeutic doses 14.

Cardiovascular and Thrombotic Risks

Initial reports raised concerns that aprotinin might promote thrombosis or early vein graft occlusion, but more recent and larger studies have not confirmed a significant increase in myocardial infarction, stroke, or deep venous thrombosis, except possibly with certain low-dose regimens 6 11 13 16.

Other Side Effects

• Circulatory depression (mild, rare): Some patients may experience low blood pressure, usually resolving quickly with standard therapy 10.
• No significant hepatic dysfunction or other organ toxicity has been linked to routine aprotinin use 11 12.
• No increased inflammatory complications: In fact, aprotinin may reduce some aspects of the inflammatory response 17 19.

Safety in Pediatrics

In children, high-dose aprotinin regimens are generally well tolerated, with no significant increase in adverse events compared to controls 7 9.

Interactions of Aprotinin

Aprotinin’s mechanism of action can influence the effects of other drugs, especially those affecting coagulation and inflammation. Understanding these interactions is vital for safe perioperative care.

Interaction Partner	Effect of Interaction	Clinical Implication	Source(s)
Heparin	Prolongs ACT, reduces heparin dose needed	Adjust heparin dosing during surgery	1 4
Protamine	May lessen need for protamine reversal	Allows continued blood salvage	4
Antifibrinolytics (e.g., tranexamic acid)	Comparable or superior blood conservation	Not typically combined; choose one agent	13
Platelet Function	Inhibits plasmin/thrombin-induced activation	Preserves platelet count/function	1 15 16
Endothelial Modulators	Reduces leukocyte migration, inflammation	May protect against ischemia-reperfusion injury	17 19
Factor VIIa-Tissue Factor	Competitive inhibition	Potential influence on clotting cascade	18

Table 4: Key Drug and Physiological Interactions of Aprotinin

Anticoagulation Interactions

Aprotinin notably prolongs the activated clotting time (ACT) when used with heparin, a standard anticoagulant in cardiac surgery. This allows for lower total heparin doses and may obviate the need for as much protamine (the reversal agent) after surgery, facilitating safer blood salvage and retransfusion 1 4.

Platelet and Coagulation Pathways

Aprotinin inhibits plasmin, which would otherwise degrade platelet receptors and activate platelets inappropriately. It also prevents thrombin-induced activation of platelets by blocking protease-activated receptor 1 (PAR1), reducing the risk of pathological clotting and preserving normal platelet function 15 16.

Interaction with Other Antifibrinolytics

Aprotinin should not be combined with other antifibrinolytic agents such as tranexamic acid or aminocaproic acid, as this could increase the risk of adverse events without proven additional benefit. Comparative studies show aprotinin is at least as effective, if not superior, in high-risk situations 13.

Modulation of Inflammation and Endothelial Effects

By inhibiting select adhesion molecules (e.g., ICAM-1, VCAM-1) and neutrophil transmigration, aprotinin reduces inflammatory cell recruitment in tissues. This effect is particularly valuable in surgeries prone to ischemia-reperfusion injury and systemic inflammation 17 19.

Emerging Interactions

Aprotinin’s inhibition of the factor VIIa-tissue factor complex suggests a possible influence on the extrinsic pathway of coagulation, though clinical relevance is still being explored 18. Its antiviral activity against SARS-CoV-2 is an exciting new area of research, with no known negative interactions in this context 5.

Conclusion

Aprotinin is a versatile and powerful medication for controlling bleeding in high-risk surgeries, especially cardiac and complex pediatric procedures. Its precise dosing regimens, robust safety profile, and unique anti-inflammatory and antiviral properties make it a valuable tool in modern perioperative medicine. Understanding its uses, dosing, side effects, and interactions is crucial for maximizing its benefits while ensuring patient safety.

Key Takeaways:

• Primary Uses: Cardiac, vascular, and orthopedic surgery for blood conservation; research; emerging antiviral role 1 3 4 5 6 7 8 10 11 12 13 15.
• Dosage: High-dose regimens for high-risk adults and complex pediatric cases; low-dose or pump-prime for lower risk 6 7 8 9 10 11 12 15.
• Side Effects: Generally well tolerated; rare hypersensitivity, transient renal effects, very rare circulatory depression 3 10 11 12 13 14.
• Interactions: Adjust heparin dosing, do not combine with other antifibrinolytics; preserves platelet function and dampens inflammation 1 4 13 15 16 17 18 19.
• Emerging Roles: Potential early intervention for COVID-19 via SARS-CoV-2 inhibition 5.

As always, careful patient selection and monitoring are essential, and clinical decisions should be tailored to the individual’s risk profile and procedure complexity.