This page shows what was measured, who it was measured in, and what that does not settle.
What Protamine sulfate does in the body
Switching off heparin when someone has had too much of it, or when the operation using it has finished
Heparin is one of the most negatively charged molecules the body ever encounters. Protamine is a short peptide that is almost nothing but arginine, an amino acid that carries a positive charge. Put the two in the same bloodstream and they snap together like magnets, forming a stable salt in which neither one works any more. The complex is then cleared, and clotting resumes within about five minutes.
What happened in people
A protamine-to-heparin ratio of 1.3 produced 615 mL of 24-hour blood loss against 470 mL at a ratio of 0.8 (p=0.021), with more plasma and platelet transfusion in the high-dose arm
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
The only licensed heparin antidote anywhere, given at the end of essentially every cardiopulmonary bypass operation performed worldwide
Where it acts
Blood plasma. The drug never enters a cell and has no intracellular target
Kind of result
A number that stands in for health
Supervision
RNAWiki has not recorded a supervision or regulatory status for this substance.
What the registries record it as
The substance registry classes this as structurallydiverse.
FDA substance registry · 0DE9724IHC · read 2026-08-29
It is recorded as coming from BONY FISH WHOLE. The part recorded is sperm.
FDA substance registry · 0DE9724IHC · read 2026-08-29
Where each sentence above came from
No recorded sentence describes the change this makes in a way that stands on its own. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 124 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Co-primary: rate of haemostasis success, and time to haemostasis
✓ The study showed what it set out to show
Who was studied
ACE-PROTAVI (ACTRN12621001261808) — routine protamine after transfemoral TAVI
Haemostasis success 97.9% versus 91.6%, absolute risk difference 6.3% (95% CI 2.0% to 10.6%), p = 0.006; median time to haemostasis 181 s versus 279 s, p = 0.002
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Both primary endpoints are procedural surrogates. The 30-day composite benefit (OR 0.37, 95% CI 0.1 to 0.8) was driven predominantly by minor vascular complications, not by death or major bleeding.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Slow intravenous injection, given by a clinician with resuscitation equipment present
Interval reported. 95% CI 2
Written into the record, not signed off as a reviewed claim.
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. 311 patients were screened to randomise 100, so the enrolled population is a narrow slice of the procedural population. No secondary endpoint reached significance.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Slow intravenous injection, given by a clinician with resuscitation equipment present
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
615 mL (95% CI 500 to 830) on the high ratio versus 470 mL (95% CI 420 to 530) on the low ratio, p = 0.021
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. The endpoint was met in the direction opposite to the one a reader assumes: more antidote produced more bleeding. Post-protamine activated clotting times were similar in both arms, so the monitoring test used in routine practice was blind to the harm.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Slow intravenous injection, given by a clinician with resuscitation equipment present
Interval reported. 95% CI 500 to 830) on the high ratio versus 470 mL (95% CI 420 to 530) on the low ratio, p = 0
Written into the record, not signed off as a reviewed claim.
Difference in mean post-protamine activated clotting time -2.0 s (95% CI -7.2 to 3.3), p = 0.47; 2.1 fewer 50 mg vials per case on fixed dosing (95% CI -2.4 to -1.8), p < 0.0001
Repeated elsewhere
Unreplicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. A comparability trial, not a superiority trial, and its primary endpoint is a laboratory number. Patients already anticoagulated or coagulopathic were excluded, which is a population in which the answer could differ.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Slow intravenous injection, given by a clinician with resuscitation equipment present
Interval reported. 95% CI -7
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 4 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Protamine sulfate
What a person takes: Slow intravenous injection, given by a clinician with resuscitation equipment present.
The measurement behind this step
Supplied as a ready-to-use aqueous solution and given directly into a vein at the end of a procedure using heparin, or after accidental overdose. Onset is within about five minutes. There is no oral, subcutaneous or intramuscular route: the molecule is a polycationic peptide and would be destroyed or sequestered before reaching the plasma by any other path.
Getting in
It is injected slowly into a vein, and slowness is the whole safety strategy
Given straight into the bloodstream at the end of the operation. The rate matters more than almost anything else about it: pushed fast, it can drop the blood pressure to nothing.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The FDA label carries a boxed warning naming severe hypotension, cardiovascular collapse, noncardiogenic pulmonary oedema, catastrophic pulmonary vasoconstriction and pulmonary hypertension, and lists rapid administration and high dose among the risk factors. Complement activation by the heparin-protamine complex, lysosomal enzyme release from neutrophils and thromboxane generation are the mechanisms the label associates with anaphylactoid reactions.
It stays in the bloodstream — there is nothing for it to do inside a cell
Its target is another drug floating in the plasma, so it never has to cross a membrane or enter tissue. Everything happens in the blood.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Protamine is a peptide of about 32 residues carrying roughly twenty arginines, giving it one of the highest positive charge densities in pharmacology. That charge makes membrane crossing energetically prohibitive, which is why the drug has no intracellular pharmacology and why its distribution volume is essentially the plasma space.
Positive meets negative and the two drugs lock together
Heparin is the most negatively charged molecule in the bloodstream. Protamine is almost pure positive charge. They snap together into a stable salt, and inside that salt neither one works.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The label states that protamine has an anticoagulant effect when given alone, but that in the presence of heparin a stable salt is formed and the anticoagulant activity of both drugs is lost. Binding is a cooperative electrostatic interaction along the length of the heparin chain rather than a defined receptor contact, which is why potency is specified as heparin units neutralised per milligram and not as an affinity constant.
Heparin worked by supercharging a natural brake on clotting. Pulled away into the complex, it stops supercharging anything, and the brake returns to its normal slow speed.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Heparin accelerates antithrombin inactivation of thrombin and factor Xa by several orders of magnitude through a template and conformational mechanism. Sequestering the polysaccharide removes that acceleration. The label reports neutralisation within five minutes of an appropriate intravenous dose, and adds that the metabolic fate of the heparin-protamine complex has not been elucidated.
The clotting time comes back — and past that point the drug turns on you
Once all the heparin is bound, any protamine left over is itself a mild blood thinner and a platelet poison. That is not a theoretical concern: the higher-dose arm of a randomised trial bled more.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Free protamine impairs thrombin generation and platelet function. In the Meesters trial the high-ratio arm had maximum post-protamine thrombin generation suppressed to 6 ± 9% of baseline against 38 ± 40% in the low-ratio arm (p=0.001), longer intrinsic clotting times, and 615 mL versus 470 mL of 24-hour blood loss (p=0.021), while activated clotting times were indistinguishable between the groups.
Sometimes the bleeding returns half an hour to eighteen hours after surgery even though the heparin looked fully neutralised at the end. The label says so and does not explain it.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
The FDA label reports hyperheparinaemia or bleeding in experimental animals and in some patients 30 minutes to 18 hours after cardiopulmonary bypass despite complete neutralisation by an adequate protamine dose. The label directs continued observation and repeat coagulation studies. The proposed explanations, including partial metabolism of the complex or attack on it by fibrinolysin, are stated in the label as postulates rather than findings.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 6 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Given in the operating theatre and the catheterisation laboratory by anaesthetists and cardiologists, at the end of cardiopulmonary bypass, after vascular and structural heart procedures, and occasionally on the ward for accidental heparin overdose.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Where the result stopped carrying
PS TAVI, the first randomised placebo-controlled trial of routine protamine, missed its primary bleeding endpoint (OR 0.48, 95% CI 0.2 to 1.2, p=0.11) at 100 patients
Higher protamine dosing increased 24-hour blood loss and transfusion in a randomised trial, reversing the drug’s intended effect
Heparinase I was investigated as a replacement and found unsuitable in the one study identified by the 2008 systematic review
The FDA label reports bleeding returning 30 minutes to 18 hours after bypass despite complete neutralisation, and offers only postulates for why
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Given by a clinician
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Slow intravenous injection, given by a clinician with resuscitation equipment present
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
RNAWiki has not recorded a supervision or regulatory status for this substance.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
No register row and no identity class settled the question.
No source is stored against this line.
What is in the pack
Supplied as a ready-to-use aqueous solution and given directly into a vein at the end of a procedure using heparin, or after accidental overdose. Onset is within about five minutes. There is no oral, subcutaneous or intramuscular route: the molecule is a polycationic peptide and would be destroyed or sequestered before reaching the plasma by any other path.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Carries a boxed warning for severe hypotension, cardiovascular collapse, noncardiogenic pulmonary oedema, catastrophic pulmonary vasoconstriction and pulmonary hypertension. Named risk factors are high dose or overdose, rapid administration, repeated doses, previous protamine exposure and current or previous use of protamine-containing drugs such as NPH insulin; allergy to fish, previous vasectomy, severe left ventricular dysfunction and abnormal preoperative pulmonary haemodynamics may also be risk factors. The label directs that vasopressors and resuscitation equipment be immediately available, and states the drug should not be given when bleeding occurs without prior heparin use. Given alone or in excess it is itself an anticoagulant and impairs platelet function.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Slow intravenous injection, given by a clinician with resuscitation equipment present
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Onset is within about five minutes. There is no oral, subcutaneous or intramuscular route: the molecule is a polycationic peptide and would be destroyed or sequestered before reaching the plasma by any other path.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
9 products list this as an active ingredient in the United States drug directory. 9 of them contain it and nothing else.
FDA National Drug Code directory · 52221-110 · read 2026-08-29
They are sold as injection, solution and powder, taken intravenous.
FDA National Drug Code directory · 52221-110 · read 2026-08-29
The regulator's established pharmacologic class for it is heparin binding activity [moa], heparin reversal agent [epc] and reversed anticoagulation activity [pe].
FDA National Drug Code directory · 52221-110 · read 2026-08-29
5 published labels name it as an active ingredient. 5 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · 8df0a819-9e1a-44ce-97a6-3ea82c867d44 · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · 8df0a819-9e1a-44ce-97a6-3ea82c867d44 · read 2026-08-29
2744 marketed supplement labels list this ingredient, classed as mineral, non-nutrient/non-botanical and other combinations.
Those labels carry all other, nutrient and structure/function claims. A claim of that kind is written by the manufacturer and is not assessed by any regulator, so its presence says nothing about whether it is true.
Protamine Sulfate is intravenous at HOW SUPPLIED: Product Code Unit of Sale Strength Each PRX22905 NDC 63323-229-94 Unit of 25 50 mg per 5 mL (10 mg per mL) NDC 63323-229-41 5 mL Single Dose Flip-top Vial PRX22930 NDC 63323-229-95 Individually Packaged 25…, recorded as fda label in effect 2024-01-18 in the United States.
US prescribing information · 8df0a819-9e1a-44ce-97a6-3ea82c867d44 · read 2026-08-30
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
RNAWiki could not confidently classify this substance, so no self-experiment plan is offered.
Questions worth asking
Which of the trials of Protamine sulfate studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That the licensed indication, treatment of heparin overdosage, rests on a controlled trial — it rests on a 1969 approval and on the drug doing visibly what it says on the vial
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the benefit measured in transcatheter valve patients transfers to the end of cardiopulmonary bypass, where the drug is mostly given and where no placebo-controlled trial exists
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the activated clotting time is an adequate guide to how much to give — two randomised trials now show it is identical across doses that produce very different bleeding
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the haemodynamic collapse seen after protamine causes the associated excess mortality rather than marking sicker patients; the authors of the 6,921-patient cohort say so themselves
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
How much did people take in the studies?
The sources RNAWiki checked hold nothing for this field.
Why it matters. A result belongs to an amount. Without the amount the result floats free.
What would answer it
A stored source that records it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Protamine sulfate are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
The first placebo-controlled trial of protamine was published in 2024
In plain words
In 410 patients having a heart valve replaced through the groin, protamine or a dummy injection was given at the end. Successful haemostasis went from 91.6% on placebo to 97.9% on protamine, and bleeding and vascular complications at 30 days fell.
What was measured
Rate of haemostasis success and time to haemostasis after transfemoral valve implantation
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
ACE-PROTAVI was an investigator-initiated, double-blind, placebo-controlled randomised trial at three Australian hospitals, December 2021 to June 2023, in patients undergoing transfemoral transcatheter aortic valve implantation. Of 410 randomised, 199 received protamine and 211 placebo. Haemostasis success was 188 of 192 (97.9%) against 186 of 203 (91.6%), an absolute risk difference of 6.3% (95% CI 2.0% to 10.6%, p=0.006). Median time to haemostasis was 181 seconds (IQR 120-420) against 279 seconds (IQR 122-600), p=0.002. The major secondary composite of death, bleeding and vascular complications at 30 days occurred in 10 of 192 (5.2%) against 26 of 203 (12.8%), OR 0.37 (95% CI 0.1 to 0.8, p=0.01), predominantly driven by minor vascular complications. The investigators report no adverse events associated with protamine use. This is a percutaneous valve population, not the cardiopulmonary bypass population the drug is mostly used in.
Written into the record, not signed off as a reviewed claim
Nobody has ever randomised protamine against placebo in cardiac surgery
In plain words
The place protamine is used most, and the place it was licensed for, is the end of a heart-lung bypass operation. There is no placebo-controlled trial there, and there never will be, because withholding it is not considered testable.
What was measured
That the haemostatic benefit measured in transcatheter valve patients is the benefit obtained at the end of cardiopulmonary bypass — a transfer between two populations whose bleeding risk, heparin dose and surgical field have almost nothing in common
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The FDA-approved indication is the single sentence "treatment of heparin overdosage", granted to Eli Lilly under NDA 006460 on 13 August 1969, before the 1962 efficacy requirements were applied retrospectively to most older products. The randomised evidence that exists is in percutaneous procedures where the comparator is a short wait rather than an open chest: ACE-PROTAVI and PS TAVI. Within cardiac surgery the randomised literature compares protamine doses against each other, never against nothing. The 2008 systematic review that went looking found only 25 studies conducted in an evidence-based manner across the entire literature, of which three had what the reviewers considered an optimal design.
Written into the record, not signed off as a reviewed claim
Too much of the antidote causes the bleeding it was given to stop
In plain words
Patients randomised to the higher protamine dose bled more, not less: 615 mL over 24 hours against 470 mL on the lower dose. More of them needed plasma and platelets. The clotting time looked the same in both groups, which is exactly the problem.
What was measured
Twenty-four-hour postoperative blood loss, thrombin generation and transfusion rates at two protamine-to-heparin dosing ratios
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Meesters et al. randomised 96 on-pump coronary bypass patients to a protamine-to-heparin dosing ratio of 0.8 (n=49) or 1.3 (n=47) in an open-label, multicentre, single-blinded trial. The low-ratio group received 329 ± 95 mg against 539 ± 117 mg (p<0.001), yet post-protamine activated clotting times were similar between groups. The high-dose group had longer intrinsic clotting times on thromboelastometry (236 ± 74 s versus 196 ± 64 s, p=0.006), and maximum post-protamine thrombin generation was suppressed far more (6 ± 9% of baseline versus 38 ± 40%, p=0.001). Twenty-four-hour blood loss was 615 mL (95% CI 500 to 830) against 470 mL (95% CI 420 to 530), p=0.021. Fresh frozen plasma went to 11% versus 0% (p=0.02) and platelet concentrate to 21% versus 6% (p=0.04). The activated clotting time, which is the number the dose is titrated against in most operating theatres, did not detect any of this.
Written into the record, not signed off as a reviewed claim
The field abandoned the ratio it dosed by for forty years
In plain words
Protamine was traditionally matched milligram-for-milligram against the heparin given. A blinded trial gave one group a flat dose instead and found the clotting time and the bleeding identical, while the matched group received roughly two extra vials each.
What was measured
That neutralising heparin unit-for-unit is the correct target — a dosing convention that survived four decades on arithmetic rather than on a trial, and that both randomised comparisons now contradict
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Jain et al. ran a single-centre, double-blinded randomised trial in 125 elective adult cardiac surgical patients receiving at least 27,500 units of initial heparin, comparing a fixed 250 mg protamine dose (n=62) against a 1 mg per 100 unit ratio-based dose (n=63). The mean post-protamine activated clotting time did not differ (-2.0 s; 95% CI -7.2 to 3.3; p=0.47). The fixed-dose group used 2.1 fewer 50 mg vials per case (95% CI -2.4 to -1.8; p<0.0001). Cumulative 24-hour chest tube output did not differ (-77 mL; 95% CI -220 to 65; p=0.28). Read alongside Meesters, the direction of travel is unambiguous: the ratio-based convention that governed practice for decades delivers more drug than the physiology needs, and the intrinsic anticoagulant effect of the excess is a real harm rather than a textbook footnote. The trial was single-centre and excluded patients already anticoagulated or coagulopathic.
Written into the record, not signed off as a reviewed claim
The trial that tried to show protamine prevents major bleeding did not
In plain words
A Polish trial randomised 100 valve patients to protamine or saline and looked at serious bleeding in the first two days. Bleeding was lower on protamine, but not by enough to rule out chance.
What was measured
Composite of life-threatening and major bleeding by VARC criteria within 48 hours of valve implantation
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
PS TAVI was a single-centre, single-blind, randomised placebo-controlled trial at the Medical University of Warsaw. Of 311 patients screened between December 2016 and July 2020, 100 met the inclusion criteria and 47 were randomised to protamine sulfate. The primary endpoint, a composite of life-threatening and major bleeding by Valve Academic Research Consortium criteria within 48 hours, occurred in 29% of the population overall: 21% on protamine against 36% on placebo, OR 0.48 (95% CI 0.2 to 1.2, p=0.11). No secondary endpoint differed significantly. The authors conclude that routine protamine did not significantly decrease major and life-threatening bleeding and that larger studies are required. The effect estimate points the same way as ACE-PROTAVI; the trial was a quarter of the size.
Written into the record, not signed off as a reviewed claim
Blood pressure changes after protamine track with death, and nobody knows why
In plain words
In nearly 7,000 bypass patients, the bigger the drop in blood pressure and the bigger the rise in lung artery pressure after protamine, the higher the chance of dying in hospital. The link held even for small changes. It is an association, not a demonstrated cause.
What was measured
Degree-duration integrals of systemic hypotension and pulmonary hypertension in the 30 minutes after protamine, against in-hospital mortality
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Welsby et al. analysed 6,921 coronary bypass patients at a single university hospital using automated anaesthesia records. Degree-duration integrals of systemic hypotension below 100 mmHg and pulmonary hypertension above 30 mmHg over the 30 minutes after protamine were tested against in-hospital mortality in logistic models adjusted for risk factors. Overall mortality was 2%. Each 150 mmHg-minute increment carried an odds ratio of 1.28 for systemic hypotension (95% CI 1.14 to 1.43, p<0.001) and 1.27 for pulmonary hypertension (95% CI 1.06 to 1.48, p<0.001). Proximity of the haemodynamic response to the protamine dose strengthened the relation, and it persisted after excluding major disturbances. The authors state explicitly that randomised trials are necessary to address causality, and none has been done. Separately, the systematic review of anaphylaxis found an incidence of 0.69% in prospective studies against 0.19% in retrospective ones, with pronounced heterogeneity.
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A salmon-sperm peptide so densely positively charged that it sticks to heparin and cancels it by pure electrostatics, licensed in 1969 on a clotting-time reading and only randomised against placebo half a century later, in a 410-patient valve trial where it raised the rate of successful haemostasis from 91.6% to 97.9% — while a separate randomised trial showed that giving too much of it makes patients bleed more, not less.
Recorded evidence blocks (6)
Q1
On the Protamine sulfate label: indicated for what?
Which 2 trials of Protamine sulfate posted no result?
Posted no result
2 of 2 completed trials
Registrations
NCT02644785 and NCT02974660
Completion dates
oldest 2016-02; newest 2020-09
Show the evidence
Trial
NCT02644785
2016-02
NCT02974660
2020-09
Q4
At the median, Protamine sulfate's trials enrolled 150 people — anything larger?
Median enrolment
150
Largest enrolment
1000
Registered trials counted
7
Q5
What do 310 spontaneous reports say about Protamine sulfate — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Protamine sulfate appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 310 reaction mentions were counted: hypotension 100; post procedural haemorrhage 42; anaphylactic reaction 41; therapeutic product effect decreased 30. FAERS via Open Targets · CHEMBL1201651 · 2026-06-24
Show the evidence
hypotension
100
post procedural haemorrhage
42
anaphylactic reaction
41
therapeutic product effect decreased
30
blood pressure decreased
21
bradycardia
20
4 more recorded rows
cardiac arrest
18
pulmonary hypertension
14
bronchospasm
12
haemodynamic instability
12
recorded 2026-06-24 · last checked 2026-09-04
Q6
Which 10 reactions does Protamine sulfate's label not list?
ChEMBL 37 — CC BY-SA 3.0 Unported · ChEMBL ATC CC BY-SA · ClinicalTrials.gov — US Government work · Open Targets 26.06 — CC0 · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
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