Tranexamic Acid and Fibrinolytics
1. We started to use Tranexamic acid for prophylactic use one year ago and it was not ease. The Presentation prepared by Dr. Bruno Furst methodology. We remembering information easer when it is unusual. We doing wordrobe and bilding Pyramid. At first there is some information about general understanding about Homeostasis, tromboembolism and antifibrinolytics in general.
2. Blood loss prevention understanding in Europe coming from time 5000
years ago. People use to wear necklace with some fungus which could prevent
bleeding and avoid quick death from arrow wound. Antifibrinolytics were started
to use in 60-ies.
3. Commonest question. Is there direct balance and direct interaction between
coagulation and antifibrinolytics? Can prophylactic dose of TXA disturb all Coagulation system and
increase risk of DVT, morbidity and mortality? For correct answer we need to understand what does it mean haemostasis
and coagulation .
4. Haemostasis is essentially a balance between thrombus formation and thrombus dissolution
(fibrinolysis). The normal physiological response that prevents significant blood
loos following vascular injury is
called haemostasis.
5. Thrombosis is a pathological condition resulting from inappropriate
activation of haemostatic mechanisms. Venous thrombosis is usually associated with stasis of
blood. Arterial thrombosis is usually associated with
atherosclerosis. A portion of a thrombus may break away, travel as an embolus and block
downstream, causing ischemia and infarction.
6. It looks like we are not in 6th degree of understanding of haemostasis today.
Our understanding starts from observing of nature.
We know that leech introducing with his saliva hundreds of enzymes. We
using only one – hirudine.
People used fungus of every day protection 5000 years ago, we do not
know even action of this fungus now.
Aprotinin is Polypeptide derived from bovine lungs and only after 60
years of use, we realised that it possesses antigenic properties and finally it
was subsequently been withdrawn from the market
We know that TXA not increasing risk of DVT, MI, Stroke, but we do not
know why.
7. Haemostasis system is quite difficult and practically impossible to
remember all parts of that sophisticated mechanism even for
hamatologist.
And it looks like understanding is still in progress. We can compare
understanding of coagulation 5000 year ago in Europe.
Two chunks of birch fungus on leather straps, possibly used to stanch
bleeding and prevent infection, were part of portable first aid kit 5000 year
ago in Europe.
8. There are two main parts of system Coagulation and
Fibrinolysis. Coagulation has three main products Thrombin, Fibrin and thrombus.
Fibrinolysis system is anemy of Coagulation and destroing thrombus by
enzyme plasmin.
Tissue plasminogen activator is esential element of system.
9. Coagulation mechanism is most difficult part and for that reason, for
easer understanding we can divide system in to three main parts:
Factors,
Trombin and
Fibrin formation.
For proper trombus formation we need additionally
platelets.
To pathway theory is not popular in our days. It useful only for
laboratory specialists
10. Easer to remember when you are imaging Traffic Police
car.
Factors, Fibrin, Trombin Platelets.
11. Fibrinolysis system is easer but still has some
components.
In the presence of atheroscerosis, the fibrinolytic properties of the
endothelium are diminished.
12. Easer to remember is imagine Fibrinolysis like Pigy Pepa in Tip Car
13. Usually surgeons aware only about perioperative blood loss and paying
not enough attention to other periods of possible blood loss.
30 % of patients presenting for TKR are in a high-risk group for
requiring transfusion, hemoglobin is 10-13 g/dL.
The use of erythropoietin to stimulate erythropoiesis in the
preoperative period has been studied extensively and has been shown to safely
reduce the need for perioperative allogeneic transfusions.
14. There are tree main types of blody operations:
Cardiopulmonary bypass,
Liver transplantation
And major O&T operation.
Major O&T operations is bloody and do require AFL .
Average transfusion requirement of 1-2 Units of bood.
Total average blood loss is 1500 mL.
15. To quantify blood is not easy.
We have only four objective postoperative bloody
values:
HGB balance,
Transfused blood units
Operating time
Low oxygen saturation .
Other symptoms are subjective and cannot be like indication for blood
transfusion.
16.
There are no specific laboratory tests which can show definite activity
of AFL system.
To get coagulation profile usually takes 20 – 60
minutes.
Tromboelastometry near patient bed enhances get answer per 10 minutes
which could be value befor selective operation or in A&E.
Fibrinogen and D-dimers test takes at least 20 – 60 minutes to do. Some
times it to long. Thromboelastometry is new type of coagulation system testing
and can be done near the bed of patient per 10 minutes.
???? clinical
signs (bleeding) and laboratory parameters (D-dimer, creatine kinase and
troponin I) at baseline, 4 h and 24 h after surgery
????
???? Thrombophilia screening, coagulation parameters, homocysteine
????
Genetic assay showed that both patients carried heterozygosity for
MTHFR C677T, in which cytosine (C) is replaced by thymidine (T) at base position
677. To our knowledge, this is the first report describing the association
between genetic factors and the onset of stroke following antifibrinolytic drugs
intake. These data suggest a synergic effect of plasminogen activator inhibitor
and heterozygosity for MTHFR C677T on the pathogenetic mechanisms leading to
ischaemic stroke in young people.
prolonged clotting times (PT
Activated coagulation time ACT
17.
After prescribing of Tranexamic acid there are only changes in D-Dimer
concentration.
D-Dimers level is lower. Other markers are the same.
Randomized, double blind, placebo-controlled study of 42 patients after
TKR
TXA 15 mg per kg or an equivalent volume of normal saline was given 30
min before surgery and subsequently every 8 h for 3 days.
18.
D-dimer
(normal range: < 300 ng/mL
Black squares represent Tranexamic group white
represents placebo.
Cerebrovascular events included seizure and stroke.
Acute kidney injury was assessed applying RIFLE [15] criteria (>100% creatinine increase, using
preoperative and highest creatinine concentration during the first week after
surgery); renal failure was defined as dysfunction requiring dialysis.
Myocardial infarction was considered as either new Q waves or new,
persistent ST-segment or T-wave changes.
Indication for re-operation was determined by clinical judgment and
blood loss as >200 mL/h in three consecutive hours.
Mortality was defined as death within 30 days of CPB, recorded in
medical history or telephone contact with the surgeon responsible or family.
These adverse effects were included as a composite variable.
19.
Cell Salvage should be prepared for every O&T more
bloody major operation
Blood transfusion is still associated with increased
morbidity and mortality.
Transfusion protocol.
Blood transfusion 1) risks 2)benefits alternatives
Cell Saver (Haemonetics Braintree, Mass)
OrthoPAT (Zimmer Warsaw, Ind)
Removes cellular debris, fat , bone fragments and Methyl Methacrolate
Monomer)
20.
The risk of hepatitis C transmission has been estimated to be
approximately 1:500 after blood transfusion.
Symptoms of mild acute haemolytic transfusion reaction
include:
• Fever
• Urticaria
• Rash
• Prunitis
IF SIGNS AND SYMPTOMS WORSEN WITHIN 15 MINUTES TREAT AS
A
SEVERE REACTION
Indications of Severe acute haemolytic transfusion reaction
include:
• Pain at infusion site
• Increasing anxiety
• Pyrexia
• Hypotension
• Loin/back pain
• Respiratory distress
• Dark urine
• Severe tachycardia
• Unexpected bleeding (DIC)
21.
There are 4 major types of prevention postoperative
anaemia:
Surgical techniques
Anaesthesia tricks
Pharmacological intervention
Politics
Plugging of cannal and Tourniquet increasing fibrinolysis
Modern surgeon thinking
22.
Clinical suspicion and confirmation of diagnosis of DVT is not ease. It
is complicated objectivisation of clotting changes in veins.
It is important to write on Ultrasound request form that we need both
proximal and distal DVT investigation because otherwise Ultrasaund specialist
will test only distal DVT possibility.
Ultrasound is non-invasive, not painful and less complicated test but
sensitivity for proximal DVT is still low. Venography is quite sensitive test
but brings still complications.
Advertised 40 mg of Clexane not all wise enough for some groups of
patients.
Venography is only performed in symptomatic patients.
Most postoperative venous thromboses are asymptomatic, however,
perticularly the proximal ones (Oishi 1994).
Only small number of patients after AFL use has venography. That
invalidates any comparison of the true incidence of thrombotic
complications.
23.
There is no doubt for AFL beneficial PROPHYLACTIC use in
major surgery.
Prosthesis for haemophylics is rear but it could
be.
A)
Profilactic:
Indications:
) Tretment Indications:
For more than 40 years, Fibrinolytics have been used in cardiac and
major orthopaedic surgery with proven afficacy
26.
Aprotinin (Trasilol) is a
polypeptide derived from bovine lungs and possesses antigenic
properties.
Polyvalent reversible inhibitor of serine proteinases. Polypeptide of
58 amino acids.
Aprotinin can cause :
Aprotinin has subsequently been withdrawn from the
market
Aprotinin has recently been linked to higher mortality rates when
compared to TXA and EACA in cardiovascular surgery.
30.
TXA is synthetic analogue of lysine
TXA has been used in surgical situations since the 1960
TXA is cheaper and safer than Aprotinin and much more potent than EACA,
with overall good penetration into major joints.
Cyklokaprone
31.
AFL acts by reversibly blocking lysine binding sites on plasminogen
molecules, thereby counteracting fibrinolytic activity.
TXA inhibits fibrinolysis by blocking the lysine
- binding sites of plasminogen to fibrin.
Dosing 10 – 20 mg/kg
32
Stroke, MRI
1.9%
Sezure
Tranexamic acid has been shown to have an epileptogenic effect in
animals
Acute kidney injury
8.8 %
Renal feilure
4.4 %
Myocardial infartion 1.9
%
Mortality
5 %
33.
Adult trauma patients with significant haemorrhage
(systolic blood pressure < 90 mm Hg or heart rate > 110 beats per
min, or both),
or who were considered to be at risk of significant haemorrhage, and
who were within 8 h of injury, were eligible for the trial.
Patients were included if the responsible doctor was
substantially uncertain about whether or not to treat with tranexamic acid
(ie, entry was governed by
the uncertainty principle) (8).
Patients for whom the responsible doctor considered that there was a
clear indication for tranexamic acid were not randomly assigned.
Similarly, patients for whom there was considered to be a clear
contraindication to tranexamic acid treatment were not randomly assigned.
However, when the responsible doctor was substantially uncertain as to
whether or not to treat with
this agent, these patients were eligible for
randomisation.
Consent procedures at participating hospitals were
37.
There are no scientific evidence when we should start treat patient by
TAXI in every day practical hospital life.
40
Meta-analyses were performed using logarithm of the odds ratio (OR) and
rate difference.
Meta-analysis of use of antifibrinolytic compared with placebo or no
treatment on venous thromboembolism.
The odds ratio for the individual studies is represented as a square
within a bar representing the 95% confidence interval (CI).
Symbol size is proportional to the study weight.
The odds ratio for summaries is represented as diamond.
The width of diamonds corresponds to the 95% CI.
An odds ratio greater than 1 indicates that the antifibrinolytic is at
risc compared with placebo
42.
Clinical suspicion and confirmation of diagnosis of DVT is not ease. It
is complicated objectivisation of clotting changes in veins.
It is important to write on Ultrasound request form that we need both
proximal and distal DVT investigation because otherwise Ultrasaund specialist
will test only distal DVT possibility.
Ultrasound is non-invasive, not painful and less complicated test but
sensitivity for proximal DVT is still low. Venography is quite sensitive test
but brings still complications.
Advertised 40 mg of Clexane not all wise enough for some groups of
patients.
Venography is only performed in symptomatic patients. Most
postoperative venous thromboses are asymptomatic, however, perticularly the
proximal ones (Oishi 1994). The
small number of patients who had venography invaslidates any comparison of the
true incidence of thrombotic complications.
46.
Cochrane evaluation disign.
11 clinical trials
The size of each green square depends on weight of each
study.
Black diamond signifies that the main difference is in favour of TXA.
49
Do not forget about clexane, tromboprophylaxis, aspirin when treating
patients in plaster.
2. Blood loss prevention understanding in Europe coming from time 5000
years ago. People use to wear necklace with some fungus which could prevent
bleeding and avoid quick death from arrow wound. Antifibrinolytics were started
to use in 60-ies.
3. Commonest question. Is there direct balance and direct interaction between
coagulation and antifibrinolytics? Can prophylactic dose of TXA disturb all Coagulation system and
increase risk of DVT, morbidity and mortality? For correct answer we need to understand what does it mean haemostasis
and coagulation .
4. Haemostasis is essentially a balance between thrombus formation and thrombus dissolution
(fibrinolysis). The normal physiological response that prevents significant blood
loos following vascular injury is
called haemostasis.
5. Thrombosis is a pathological condition resulting from inappropriate
activation of haemostatic mechanisms. Venous thrombosis is usually associated with stasis of
blood. Arterial thrombosis is usually associated with
atherosclerosis. A portion of a thrombus may break away, travel as an embolus and block
downstream, causing ischemia and infarction.
6. It looks like we are not in 6th degree of understanding of haemostasis today.
Our understanding starts from observing of nature.
We know that leech introducing with his saliva hundreds of enzymes. We
using only one – hirudine.
People used fungus of every day protection 5000 years ago, we do not
know even action of this fungus now.
Aprotinin is Polypeptide derived from bovine lungs and only after 60
years of use, we realised that it possesses antigenic properties and finally it
was subsequently been withdrawn from the market
We know that TXA not increasing risk of DVT, MI, Stroke, but we do not
know why.
7. Haemostasis system is quite difficult and practically impossible to
remember all parts of that sophisticated mechanism even for
hamatologist.
And it looks like understanding is still in progress. We can compare
understanding of coagulation 5000 year ago in Europe.
Two chunks of birch fungus on leather straps, possibly used to stanch
bleeding and prevent infection, were part of portable first aid kit 5000 year
ago in Europe.
8. There are two main parts of system Coagulation and
Fibrinolysis. Coagulation has three main products Thrombin, Fibrin and thrombus.
Fibrinolysis system is anemy of Coagulation and destroing thrombus by
enzyme plasmin.
Tissue plasminogen activator is esential element of system.
9. Coagulation mechanism is most difficult part and for that reason, for
easer understanding we can divide system in to three main parts:
Factors,
Trombin and
Fibrin formation.
For proper trombus formation we need additionally
platelets.
To pathway theory is not popular in our days. It useful only for
laboratory specialists
10. Easer to remember when you are imaging Traffic Police
car.
Factors, Fibrin, Trombin Platelets.
11. Fibrinolysis system is easer but still has some
components.
In the presence of atheroscerosis, the fibrinolytic properties of the
endothelium are diminished.
12. Easer to remember is imagine Fibrinolysis like Pigy Pepa in Tip Car
13. Usually surgeons aware only about perioperative blood loss and paying
not enough attention to other periods of possible blood loss.
30 % of patients presenting for TKR are in a high-risk group for
requiring transfusion, hemoglobin is 10-13 g/dL.
The use of erythropoietin to stimulate erythropoiesis in the
preoperative period has been studied extensively and has been shown to safely
reduce the need for perioperative allogeneic transfusions.
14. There are tree main types of blody operations:
Cardiopulmonary bypass,
Liver transplantation
And major O&T operation.
Major O&T operations is bloody and do require AFL .
Average transfusion requirement of 1-2 Units of bood.
Total average blood loss is 1500 mL.
15. To quantify blood is not easy.
We have only four objective postoperative bloody
values:
HGB balance,
Transfused blood units
Operating time
Low oxygen saturation .
Other symptoms are subjective and cannot be like indication for blood
transfusion.
16.
There are no specific laboratory tests which can show definite activity
of AFL system.
To get coagulation profile usually takes 20 – 60
minutes.
Tromboelastometry near patient bed enhances get answer per 10 minutes
which could be value befor selective operation or in A&E.
Fibrinogen and D-dimers test takes at least 20 – 60 minutes to do. Some
times it to long. Thromboelastometry is new type of coagulation system testing
and can be done near the bed of patient per 10 minutes.
???? clinical
signs (bleeding) and laboratory parameters (D-dimer, creatine kinase and
troponin I) at baseline, 4 h and 24 h after surgery
????
???? Thrombophilia screening, coagulation parameters, homocysteine
????
Genetic assay showed that both patients carried heterozygosity for
MTHFR C677T, in which cytosine (C) is replaced by thymidine (T) at base position
677. To our knowledge, this is the first report describing the association
between genetic factors and the onset of stroke following antifibrinolytic drugs
intake. These data suggest a synergic effect of plasminogen activator inhibitor
and heterozygosity for MTHFR C677T on the pathogenetic mechanisms leading to
ischaemic stroke in young people.
prolonged clotting times (PT
Activated coagulation time ACT
17.
After prescribing of Tranexamic acid there are only changes in D-Dimer
concentration.
D-Dimers level is lower. Other markers are the same.
Randomized, double blind, placebo-controlled study of 42 patients after
TKR
TXA 15 mg per kg or an equivalent volume of normal saline was given 30
min before surgery and subsequently every 8 h for 3 days.
18.
D-dimer
(normal range: < 300 ng/mL
Black squares represent Tranexamic group white
represents placebo.
Cerebrovascular events included seizure and stroke.
Acute kidney injury was assessed applying RIFLE [15] criteria (>100% creatinine increase, using
preoperative and highest creatinine concentration during the first week after
surgery); renal failure was defined as dysfunction requiring dialysis.
Myocardial infarction was considered as either new Q waves or new,
persistent ST-segment or T-wave changes.
Indication for re-operation was determined by clinical judgment and
blood loss as >200 mL/h in three consecutive hours.
Mortality was defined as death within 30 days of CPB, recorded in
medical history or telephone contact with the surgeon responsible or family.
These adverse effects were included as a composite variable.
19.
Cell Salvage should be prepared for every O&T more
bloody major operation
Blood transfusion is still associated with increased
morbidity and mortality.
Transfusion protocol.
Blood transfusion 1) risks 2)benefits alternatives
Cell Saver (Haemonetics Braintree, Mass)
OrthoPAT (Zimmer Warsaw, Ind)
Removes cellular debris, fat , bone fragments and Methyl Methacrolate
Monomer)
20.
The risk of hepatitis C transmission has been estimated to be
approximately 1:500 after blood transfusion.
Symptoms of mild acute haemolytic transfusion reaction
include:
• Fever
• Urticaria
• Rash
• Prunitis
IF SIGNS AND SYMPTOMS WORSEN WITHIN 15 MINUTES TREAT AS
A
SEVERE REACTION
Indications of Severe acute haemolytic transfusion reaction
include:
• Pain at infusion site
• Increasing anxiety
• Pyrexia
• Hypotension
• Loin/back pain
• Respiratory distress
• Dark urine
• Severe tachycardia
• Unexpected bleeding (DIC)
21.
There are 4 major types of prevention postoperative
anaemia:
Surgical techniques
Anaesthesia tricks
Pharmacological intervention
Politics
Plugging of cannal and Tourniquet increasing fibrinolysis
Modern surgeon thinking
22.
Clinical suspicion and confirmation of diagnosis of DVT is not ease. It
is complicated objectivisation of clotting changes in veins.
It is important to write on Ultrasound request form that we need both
proximal and distal DVT investigation because otherwise Ultrasaund specialist
will test only distal DVT possibility.
Ultrasound is non-invasive, not painful and less complicated test but
sensitivity for proximal DVT is still low. Venography is quite sensitive test
but brings still complications.
Advertised 40 mg of Clexane not all wise enough for some groups of
patients.
Venography is only performed in symptomatic patients.
Most postoperative venous thromboses are asymptomatic, however,
perticularly the proximal ones (Oishi 1994).
Only small number of patients after AFL use has venography. That
invalidates any comparison of the true incidence of thrombotic
complications.
23.
There is no doubt for AFL beneficial PROPHYLACTIC use in
major surgery.
Prosthesis for haemophylics is rear but it could
be.
A)
Profilactic:
Indications:
- cardiac surgery
- O&T Major
Surgery - Other operations with greater
expected blood loss - Coagulation
disorders - Religious issues
- Significant preoperative
anaemia
) Tretment Indications:
- Dental extraction;
- Tonsilectomy;
- Prostate surgery;
- Heavy menstrual
bleeding - In patients with
haemophilia
For more than 40 years, Fibrinolytics have been used in cardiac and
major orthopaedic surgery with proven afficacy
26.
Aprotinin (Trasilol) is a
polypeptide derived from bovine lungs and possesses antigenic
properties.
Polyvalent reversible inhibitor of serine proteinases. Polypeptide of
58 amino acids.
Aprotinin can cause :
- Renal dysfunction and failulure
- Increased risk for
death - Congestive heart
failure - Stroke
Aprotinin has subsequently been withdrawn from the
market
Aprotinin has recently been linked to higher mortality rates when
compared to TXA and EACA in cardiovascular surgery.
30.
TXA is synthetic analogue of lysine
TXA has been used in surgical situations since the 1960
TXA is cheaper and safer than Aprotinin and much more potent than EACA,
with overall good penetration into major joints.
Cyklokaprone
31.
AFL acts by reversibly blocking lysine binding sites on plasminogen
molecules, thereby counteracting fibrinolytic activity.
TXA inhibits fibrinolysis by blocking the lysine
- binding sites of plasminogen to fibrin.
Dosing 10 – 20 mg/kg
32
Stroke, MRI
1.9%
Sezure
Tranexamic acid has been shown to have an epileptogenic effect in
animals
Acute kidney injury
8.8 %
Renal feilure
4.4 %
Myocardial infartion 1.9
%
Mortality
5 %
33.
Adult trauma patients with significant haemorrhage
(systolic blood pressure < 90 mm Hg or heart rate > 110 beats per
min, or both),
or who were considered to be at risk of significant haemorrhage, and
who were within 8 h of injury, were eligible for the trial.
Patients were included if the responsible doctor was
substantially uncertain about whether or not to treat with tranexamic acid
(ie, entry was governed by
the uncertainty principle) (8).
Patients for whom the responsible doctor considered that there was a
clear indication for tranexamic acid were not randomly assigned.
Similarly, patients for whom there was considered to be a clear
contraindication to tranexamic acid treatment were not randomly assigned.
However, when the responsible doctor was substantially uncertain as to
whether or not to treat with
this agent, these patients were eligible for
randomisation.
Consent procedures at participating hospitals were
37.
There are no scientific evidence when we should start treat patient by
TAXI in every day practical hospital life.
40
Meta-analyses were performed using logarithm of the odds ratio (OR) and
rate difference.
Meta-analysis of use of antifibrinolytic compared with placebo or no
treatment on venous thromboembolism.
The odds ratio for the individual studies is represented as a square
within a bar representing the 95% confidence interval (CI).
Symbol size is proportional to the study weight.
The odds ratio for summaries is represented as diamond.
The width of diamonds corresponds to the 95% CI.
An odds ratio greater than 1 indicates that the antifibrinolytic is at
risc compared with placebo
42.
Clinical suspicion and confirmation of diagnosis of DVT is not ease. It
is complicated objectivisation of clotting changes in veins.
It is important to write on Ultrasound request form that we need both
proximal and distal DVT investigation because otherwise Ultrasaund specialist
will test only distal DVT possibility.
Ultrasound is non-invasive, not painful and less complicated test but
sensitivity for proximal DVT is still low. Venography is quite sensitive test
but brings still complications.
Advertised 40 mg of Clexane not all wise enough for some groups of
patients.
Venography is only performed in symptomatic patients. Most
postoperative venous thromboses are asymptomatic, however, perticularly the
proximal ones (Oishi 1994). The
small number of patients who had venography invaslidates any comparison of the
true incidence of thrombotic complications.
46.
Cochrane evaluation disign.
11 clinical trials
The size of each green square depends on weight of each
study.
Black diamond signifies that the main difference is in favour of TXA.
49
Do not forget about clexane, tromboprophylaxis, aspirin when treating
patients in plaster.
