What are the Alternatives to Plasma? A Comprehensive Guide to Replacements and Substitutes

October 9, 2025 •

4 min read

Despite its vital role in treating various conditions, the use of donor plasma carries logistical challenges and risks like disease transmission, prompting a long-standing search for safe and reliable alternatives to plasma. These alternatives range from simple saline solutions for volume expansion to highly specific recombinant proteins for correcting clotting factor deficiencies.

Quick Summary

Medications and synthetic products offer alternatives for patients requiring volume expansion or specific coagulation factors. Options range from readily available electrolyte solutions to human-derived proteins and specific factor concentrates, each with distinct advantages and risks depending on the clinical need.

Key Points

Crystalloids: Inexpensive, first-line volume expanders, such as saline and Ringer's lactate, but they redistribute quickly from the bloodstream.
Human Albumin: A natural colloid derived from human plasma, suitable for sustained volume expansion, but it is expensive and has limited availability.
Synthetic Colloids (HES, Dextrans): Largely restricted or disfavored due to significant safety concerns, including kidney injury and bleeding complications.
Specific Factor Concentrates: Recombinant therapies like Factor VIII are targeted, effective, and safer alternatives for treating specific coagulation deficiencies like hemophilia.
Targeted Therapies for Bleeding: Medications such as antifibrinolytic agents (e.g., tranexamic acid) and novel therapies (e.g., Emicizumab) offer precise treatments for specific bleeding disorders.
Evolving Alternatives: Research continues into novel 'blood substitutes' and oxygen carriers, aiming for future universal, safe, and available products.

The Need for Alternatives to Plasma

Fresh Frozen Plasma (FFP) is a blood product used to restore plasma volume and replace deficient coagulation factors. However, FFP is not without its limitations. It requires time-consuming thawing, must be blood-type compatible, and carries the inherent risk of transmitting bloodborne pathogens. Its use is also limited in certain emergency situations and can lead to allergic reactions. These factors have led the medical community to develop and utilize a range of medications and pharmacological alternatives tailored to specific clinical needs, moving beyond a one-size-fits-all approach to fluid therapy.

Pharmacological Alternatives for Volume Expansion

For patients requiring general fluid replacement and volume expansion, two primary categories of pharmacological agents are used: crystalloids and colloids.

Crystalloids: First-Line Fluid Therapy

Crystalloid solutions are a mainstay of fluid therapy and are often the first-line treatment for hypovolemia (low blood volume) and dehydration. They are aqueous solutions of mineral salts or other small, water-soluble molecules that can move freely between the intravascular space and the interstitial space.

Common crystalloids include:

0.9% Sodium Chloride (Normal Saline): A simple solution used for volume replacement.
Lactated Ringer's Solution: Contains a balanced electrolyte profile and lactate, which is metabolized into bicarbonate to help buffer metabolic acidosis.
Plasma-Lyte: A balanced crystalloid solution designed to more closely resemble plasma.

Crystalloids are significantly cheaper than colloids and generally safe, but require larger volumes to achieve the same intravascular volume expansion due to their rapid redistribution into the interstitial spaces. Concerns exist regarding potential side effects with excessive administration, such as hyperchloremia with large volumes of saline.

Colloids: Prolonged Intravascular Expansion

Colloids are intravenous solutions containing large molecular weight substances that do not easily cross cell membranes. They are designed to remain in the intravascular space for a longer period than crystalloids, increasing the colloid osmotic pressure and drawing fluid from the interstitial space into the circulation. Colloids are further categorized into natural and synthetic options.

Natural Colloids

Human Serum Albumin: Prepared from the plasma of healthy donors and pasteurized for safety. It is available in various concentrations (e.g., 5%, 20%, 25%) and is a physiological plasma expander. Albumin is used in conditions like severe liver disease and therapeutic plasma exchange, but its high cost and limited availability restrict its use.
Cryoprecipitate: A blood product that is a concentrated source of specific clotting factors, such as fibrinogen and Factor VIII. It is not a broad volume expander but a targeted treatment for specific bleeding disorders.

Synthetic Colloids

Hydroxyethyl Starches (HES): Once a widely used synthetic colloid, HES solutions have faced significant scrutiny due to safety concerns. In 2021, the FDA issued warnings requiring updated safety labels to highlight the risk of mortality, acute kidney injury, and excess bleeding associated with HES products, especially in critically ill patients. Their use is now highly restricted.
Dextrans: Polysaccharide-based solutions that can also serve as volume expanders. They can have antithrombotic properties but are associated with a risk of anaphylactic reactions and interference with coagulation.
Gelatins: Collagen-derived colloids used in some regions for volume replacement. However, their use is not approved everywhere, partly due to a higher risk of anaphylaxis.

Targeted Alternatives for Coagulation Disorders

For patients with specific deficiencies, particularly those with hemophilia or other bleeding disorders, targeted therapies offer more effective and safer alternatives than broad plasma replacement.

Factor Concentrates and Recombinant Therapies

Factor VIII and Factor IX Concentrates: Highly purified or recombinant forms of specific clotting factors are the standard of care for hemophilia A and B, respectively. These products offer targeted and reliable treatment, avoiding the risks associated with donor-derived plasma.
Novel Rebalancing Agents: Newer therapies, like Emicizumab for hemophilia A, mimic the function of Factor VIII, promoting clot formation via a different mechanism. Other emerging therapies target anticoagulants like antithrombin to restore hemostatic balance.

Antifibrinolytic Agents

Tranexamic Acid and Aminocaproic Acid: These medications prevent the breakdown of blood clots and are used to manage or prevent bleeding, especially for mucosal bleeding or before certain procedures.

Emerging Alternatives and Future Prospects

Significant research continues in developing safe and effective blood substitutes that can carry oxygen, such as hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based solutions. While challenges remain, especially regarding toxicity and side effects, this field offers long-term promise for universal, readily available blood substitutes.

Comparison Table of Alternatives


Feature	Crystalloids	Albumin	Synthetic Colloids (e.g., HES)	Specific Factor Concentrates
Cost	Low	High	Moderate (historically)	High
Source	Synthetic (salts, water)	Human Plasma	Synthetic (e.g., starch)	Human Plasma / Recombinant
Primary Use	Volume expansion, dehydration	Severe hypovolemia, plasma exchange, liver disease	Historically, volume expansion	Specific coagulation deficiencies
Effect on Volume	Short-lived, redistributes quickly	More sustained intravascular expansion	More sustained intravascular expansion	No significant volume effect
Safety Profile	Generally safe; risk of electrolyte imbalance or fluid overload with high volumes	Pasteurized, low risk of viral transmission	Significant risks including kidney injury, coagulopathy, and mortality	Highly specific; minimal risk of systemic side effects
Availability	Readily available	Limited, high demand	Limited or restricted due to safety issues	Excellent, especially recombinant products
Logistics	Simple storage	Refrigerated storage, longer shelf life than FFP	Not applicable	Varies by product; often stable at room temperature

Conclusion

While fresh frozen plasma remains a crucial treatment for specific indications, the field of medications and pharmacology has developed a robust array of alternatives. From the cost-effective and readily available crystalloids for general volume expansion to sophisticated recombinant factor therapies for specific coagulation disorders, clinicians have more options than ever before. The move away from older, less safe synthetic colloids like HES in favor of more targeted and evidence-based treatments represents a significant advancement. As research into next-generation blood substitutes continues, the landscape of plasma alternatives will likely evolve further, improving patient safety and efficacy in critical care and bleeding management.

Learn More

For authoritative information on bleeding disorders and their treatments, visit the National Bleeding Disorders Foundation.

Frequently Asked Questions

The main difference lies in their molecule size. Crystalloids have small molecules that pass through capillary membranes, expanding both the intravascular and interstitial fluid spaces. Colloids contain larger molecules that primarily remain within the intravascular space, providing a more sustained volume expansion.

No, the use of HES is highly restricted in many countries, including the US. In 2021, the FDA issued strong warnings due to evidence of increased mortality, acute kidney injury, and bleeding in critically ill patients, prompting a shift away from these products.

Albumin is often reserved for specific conditions where its higher cost and limited supply are justified, such as large-volume plasma exchanges or certain cases of severe liver disease. While some studies have explored its use in critical illness, evidence does not always show superior outcomes compared to crystalloids for general fluid resuscitation.

For hemophilia, specific factor concentrates, particularly recombinant Factor VIII and Factor IX products, are the standard of care. Other options include novel therapies like Emicizumab, which mimics Factor VIII function, and antifibrinolytic drugs like tranexamic acid to stabilize clots.

Currently, there is no commercially approved product that fully replaces blood for oxygen transport. While Hemoglobin-Based Oxygen Carriers (HBOCs) and perfluorocarbons have been researched as 'blood substitutes', they face significant safety and efficacy challenges, and research is ongoing.

Donor plasma has several drawbacks, including the potential for allergic reactions, the need for blood type compatibility, and the small but present risk of transmitting bloodborne pathogens. Additionally, it requires thawing, adding logistical challenges in emergency situations.

Risks vary by product. Synthetic colloids like HES carry significant risks of kidney injury and bleeding. Crystalloids can cause fluid overload or electrolyte imbalances with excessive use. While albumin is generally safe, it is expensive and has limitations. All donated products carry a low risk of transfusion reactions.