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Coagulation
Coagulation
Preoperative scenarios:
1. Patient is on chronic aspirin therapy:
When should the aspirin be stopped?
When is a bleeding time indicated?
How does aspirin affect the PT, aPTT, ACT?
When is regional anesthesia contraindicated?
Any difference in the risk of epidural versus single-shot spinal?
How much variation exists between hemostatic responses to aspirin therapy?
If the patient is on an NSAID other than aspirin, when should it be stopped?
What drugs reverse the effects of aspirin?
Intraoperative Scenarios:
1. A hypotensive trauma patient is brought in with a blunt injury to the abdomen. The
peritoneal tap in the E.R. is positive for blood. Patient is rushed to the O.R., where a
ruptured spleen is removed, and the patient is found to also be bleeding from a pelvic
fracture. You have administered 10 units of blood, and the blood pressure has stabilized.
What is your a priori expectation that this patient now has a coagulation defect?
What clinical observations are relevant to the patients coagulation status?
What will an ACT tell you?
How does the ACT differ from the aPTT?
What additional information will you get from a PT, fibrinogen, fibrin splits,
clotting time, etc.?
2. The same patient receives another 10 units of blood over 4 hours. The surgeons are
having difficulty obtaining hemostasis.
What is your a priori expectation that this patient now has a coagulation defect?
What blood products are you going to administer?
Who is responsible for the decision of what blood products to give?
3. The patient receives another 15 units of blood over the next 4 hours. The field is very
wet. Your catheter sites are oozing. You are now administering every coagulation
product known to man.
Data Base:
Coagulation Factors:
Platelets:
Thrombocytopenia is the most commonly identified coagulation defect.
Maintain platelet count above 50K. Transfuse platelets if platelet count is between 50
and 100K and abnormal bleeding is observed
It is difficult to decrease the platelet count to less than 50k with a normal bone marrow.
Preoperative platelet count correlates with the amount of blood which can be lost prior to
developing thrombocytopenia.
Platelets will probably be needed after 1.5 blood volumes. If medical bleeding develops,
platelets are the first choice in the absence of laboratory identification of the cause of
bleeding.
3-6 units of platelets have about 1 unit of plasma, which contains 50% of usual V, VIII
and 80% of other factors.
October 9, 1995 Coagulopathy Page 4
Pre-existing disorders:
Assuming normal platelets, below 100K, Bleeding time (min) = 30.5 - Platelet
count/3850
Hemophilia
Factor VIII deficiency
Prevalence: 1/10,000 to 1/25,000
Sex-linked inheritance
October 9, 1995 Coagulopathy Page 5
Factor VIII
Level Symptoms
<1% Spontaneous bleeding
3-5% Rare spontaneous bleeding
10-15% Probably asymptomatic until
surgery or dental procedures
Lab:
Bleeding time: normal
PT: normal
PTT: increased
Clotting time: increased
Therapy
By definition, each ml of FFP contains 1 factor VIII
activity unit. Each activity unit transfused raises the activity in the blood
by roughly 2%/kg of body weight. So, in a 70 kg patient, each ml of FFP
(1 factor VIII activity unit) would raise the activity level by 2%/70 kg = .
03%. For surgery we want to have 50% factor VIII activity. We can
compute the number of mls as 50% divided by 0.03% bump in factor VIII
activity per ml, which equals 1750 mls of FFP (about 9 units).
An even easier rule of thumb is that there are about 15 units of FFP in an
adult. To get 50% activity requires about 7.5 units of FFP.
Christmas Disease
Also known as Hemophilia B
Factor IX deficiency
Clinically indistinguishable from hemophilia
Prevalence: 1/10,000
Sex-linked inheritance
Lab:
Bleeding time: normal
PT: normal
PTT: increased
Clotting time: increased
Therapy:
Proplex, Konnyne
Risk of hepatitis has been greatly reduced over past 10 years
through heat sterilization, treatment with detergents, filtering, and
treatment with specific antibodies to remove residual viral
particles.
BeneFIX
Recombinant Factor IX
Approved April, 1997
See www.genetics.com for details
Uremia
Causes platelet dysfunction
Bleeding time may increase 3 to 4 fold
May be reversible with DDAVP or cryoprecipitate.
Liver failure
In complete failure, patients may require 2 units of FFP every 2 hours to maintain
adequate hemostasis.
Warfarin
Factor 7 is the first factor depleted, which is why the PT is affected before the
aPTT.
Warfarin has a half-life of 40 hours.
Warfarin-like effect from broad-spectrum antibiotics, probably from interference
with bacterial flora.
Vitamin K usually corrects a Vitamin K dependent coagulopathy in 6 - 12 hours.
If PT is less than twice normal, it may be safer to operate than to risk the
thrombosis that the patient has been placed on coumarin to prevent.
For emergency surgery, or when vitamin K is contraindicated (e.g. artificial
valvular prosthesis), use 2 units of FFP, then check PT.
Aspirin
Aspirin is in many combination medications, e.g. cold remedies. Patient's may
not realize they have been taking aspirin.
As high as 50% of patients undergoing unexpected surgery have a history of
recent aspirin ingestion.
If patient is otherwise normal, aspirin usually prolongs the bleeding time by 1.5 -
2 minutes. If patient has an undiagnosed, otherwise asymptomatic, disorder (e.g.
heterozygous von Willebrand disease), a single aspirin can increase the bleeding
time to > 30 minutes.
Stop aspirin 3-4 days prior to surgery.
DDAVP is effective in normalizing the prolonged bleeding time caused by
aspirin.
If urgent surgery, transfuse platelets at least 90' after the last dose of aspirin to
allow it to clear from the circulation.
Heparin
Binds antithrombin III with thrombin, inactivating thrombin.
Blocks activation of factor X, XI, IX.
Small doses initially inhibit factor IX, which is why the aPTT is prolonged before
October 9, 1995 Coagulopathy Page 9
the PT is affected.
Can cause thrombocytopenia, which is sometimes profound.
Epidural:
Only 1 case in which an epidural hematoma followed an epidural anesthetic when
coagulation status was normal.
100 cases of spontaneous epidural hematomas in anticoagulated patients with no
history of instrumentation of the epidural space.
Two studies, with 4164 patients receiving heparin during and after (but not
before) surgery found no incidence of epidural hematomas (Oberg & Thoren,
Acta Physiol Scand 85:164, 1972; Rao & El-Etr, Anesthesiology 55:616, 1981).
The catheter was placed the night prior to surgery.
Avoid epidurals if platelet count is less than 100,000, or if the bleeding time is
greater than 8 minutes.
If a patient brought to the O.R. is on heparin, "epidural block is not used in any
form."
Key is to look for evidence of neurologic sequelae, and than rapidly
evaluate it and decompress the spinal cord should sequelae develop.
Spinal:
Gross abnormality in blood clotting mechanisms is considered to be an absolute
contraindication to spinal anesthesia. Minor abnormalities (e.g. mini-dose
heparin prior to surgery) is a relative contraindication to spinal anesthesia.
Tests of hemostasis:
factor XII. Citrated plasma is mixed with diatomaceous earth, which converts
XII into active XIIa. After mixing everything together (plasma, phospholipid
micelles, diatomaceous earth), the clot is timed from the addition of CaCl2 to the
formation of clot.
Rapaport Scale:
Level 1: Negative history, minor operation. No tests necessary.
Level 2: Negative history, major operation. aPTT and platelet count.
Level 3: Suspicious history, or operation which requires unusually good
hemostatic function (e.g. open prostatectomy, bypass): platelet
count, aPTT, PT, Bleeding time.
Level 4: Known coagulation defect: specific factor assays.
Blood products:
Whole blood
If less than 5 days old, contains some clotting factors and active platelets
Factors V and VIII start to degrade after 24 hours
Packed red blood cells
Hct: 57-88% (mean: 73%)
Stored at 4 degrees centigrade.
One third of the amount of fibrinogen in whole blood.
Otherwise, contains no significant amounts of clotting factors or platelets.
Platelets
Stored at room temperature.
Platelet levels start to fall after 4 hours of cold storage.
Nearly normal factor levels.
Indications for platelet transfusion:
Platelet count less than 20,000 (except in ITP patients undergoing
splenectomy)
Platelet count less than 60,000-70,000 in patients scheduled for surgery
Patients with a bleeding time greater than 12-15 minutes, regardless of
platelet count.
Patients whose transfused blood volume exceeds about 1.5 blood volumes.
October 9, 1995 Coagulopathy Page 11
Factor IX Concentrates
Contain factor II, VII, IX, X (the vitamin-K dependent factors).
May also contain activated factors, and can cause thrombotic
complications with intense use.
Use only for documented factor IX deficiency, or for bleeding
unresponsive to other measures, as infusion itself can lead to DIC!
Might be useful as a specific antidote to warfarin, except that the risk of hepatitis
approaches 100%, and FFP works well for restoring vitamin-K dependent factors.
Trade names: Proplex, Konyne
Recently approved recombinant factor IX: BeneFIX
Indications per Stanford QA Program:
Documented factor II, VII, IX, X deficiency in bleeding or surgical
patient
Documented high Factor VIII inhibitor in bleeding or surgical patient
PT > 1.5 times normal
DDAVP (vasopressin)
Yes, I know it is not a blood product, but I didn't know where else to put it.
Increases factor VIII and von Willebrand's factor by releasing them from
endothelial cells.
Factor VIII levels may peak 2-3 times higher than baseline.
Second dose within 48 hours of first dose will have reduced response
because intercellular stores must be replenished.
May normalize Taspirin induced coagulopathy.
May correct uremic coagulopathy.
Reduces postoperative blood loss following cardiac surgery
Buy stock today.
Fibrinolytics
Aprotinin
Nonspecific serine protease inhibitor extracted from bovine lung.
Discovered in 1930
October 9, 1995 Coagulopathy Page 13
Mathematically, 30% of the original blood elements are still present after 1 blood volume
of hemorrhage and replacement. Clinically, the percentage is closer to 40%.
"Routine replacement of clotting factors and platelets based on the volume of blood
transfused is difficult to justify" - John Collins (Former Chairman, Stanford Department
of Surgery), World J. Surg. 11:75-81, 1987
"Clearly red cell transfusions should be freely supplemented with platelet and/or
concentrated coagulation components for the correction of underlying hemostatic
deficiencies if such are considered contributory to hemorrhage." V. Lovric, Anaesth
Intens Care 12:246-251, 1984.
"The mathematics of exchange transfusion would support the contention that specific
hematologic derangements attributable to massive transfusion per se should not become
critical until a patient has received a transfusion volume of approximately twice his
estimated blood volume." T Phillips, J Trauma 27:903-910
"Important principles include ... the administration of platelets to trauma patients ...
receiving 12 or more units of rapid transfusion, especially those who have been truly
massively transfused with volumes of 20 units or more; and the administration of FFP to
those receiving large volumes of factor free fluids." T Phillips, J Trauma 27:903-910
"Where the wound is large .... or where there is head injury, [we recommend]
administration of FFP ... on a one-to-one ratio with pRBC to avoid dilutional
coagulopathy." J Hewson, et al, Crit Care Med 13:387-391, 1985
"Pending controlled studies in man, the routine use of plasma supplementation in the
resuscitation regimen for hemorrhagic shock should be abandoned." D. Martin, et al, Ann
Surg 202:505-511, 1985
"Although the concentrations of factor V and particularly factor VIII are reduced in
stored whole blood, concentrations in massively transfused patients do not correlate with
the number of transfusions and remain sufficiently high to support the coagulation
cascade. Concentrations of other soluble coagulation factors are not affected by massive
transfusions of stored whole blood." in "Massive Transfusion" (chapter 56), from
Hemostasis and Thrombosis, 1987.
I was unable to find any studies which justify a cookbook approach to platelet and FFP
administration. As the above quotations indicate, there is controversy within the surgical
and anesthetic literature regarding routine administration of these products. However,
the clinical reality is that, in the massively transfused patient, relevant laboratory data
may not be available when the decision is made to treat what appears to be medical
bleeding.
Rational therapy involves a trade off between an intellectually satisfying approach
(administer dangerous drugs only for clear indications) and the time constraints of
resuscitating a patient who is bleeding to death. Rational therapy is also an explicit
admission that in situations in which there are no useful therapeutic options for the
patient, treating ourselves may still be in the patient's best interest. Also, the O.R. is not
a rational place to debate transfusion policy with the surgeons.
Rough Guidelines:
Monitor the surgical field for evidence of medical bleeding
If that is observed and is causing you or the surgeons concern, in the
absence of other data, administer platelets.
After 1 blood volume:
Check whole blood clotting time
Check ACT
October 9, 1995 Coagulopathy Page 15
Specific situations:
Massive transfusion
Dilutional thrombocytopenia is the most likely cause of medical bleeding.
Rarely, bleeding may be caused by a deficiency in factors V of VIII.
Very rarely, bleeding from dilution of other factors.
If fibrinogen is low, it is probably because of DIC and not from dilution.
brought under control, our data clearly revealed a very close correlation between
coagulation and ... antecedent shock" J. Hewson, et al, Crit Care Med 13:387-391,
1985
Hypothermia
Inhibits platelet function.
Platelet counts decrease.
Decreases enzyme activity leading to clot formation.
Fibrinolytic activity increases.
Acid-base imbalance
Enzymes are sensitive to pH. Anybody have any references to specific acid-base
effects on hemostasis? I couldn't find any references.
Citrate toxicity
Calcium is an essential cofactor for coagulation. However, I could find no
documentation that the serum calcium ever drops so low as to contribute to a
coagulopathy. Any data or references would be appreciated.
Autotransfusion
No associated coagulopathy from recycled blood as long as it is washed.
Extracorporeal circulation:
The pump eats platelets.
Small amounts of fibrin form in the perfusion circuit despite adequate
heparinization.
Neutralize heparin with protamine, 1.0 mg for every 100U of heparin.
Heparin rebound 2-3 hours after protamine, possible from different rates of
elimination of the drugs.
Factors V and VIII are depleted during bypass, but usually not enough to require
FFP.
FFP Contents:
Take contents in plasma (table 1) and adjust for 200 cc!