Coagulopathy
October 22, 1997
Steven L. Shafer, M.D.
October 9, 1995CoagulopathyPage 1
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?
2.Patient is on heparin for DVT, 6 weeks following a small PE:
How risky is it to stop the heparin?
When should the heparin be stopped prior to surgery?
Is regional anesthesia contraindicated?
Would an axillary block be contraindicated?
How would assess residual heparin effect in the O.R.?
Is safe to reverse heparin with protamine prior to a regional anesthetic?
3.Patient takes warfarin for chronic atrial fibrillation:
When should the warfarin be stopped?
How does warfarin affect the bleeding time, PT, aPTT, ACT?
Should vitamin K be administered?
If major surgery (e.g. AAA repair) is planned, should FFP be administered prophylactically? If so, how much?
How about the patient taking warfarin for a mechanical aortic valve?
4.Patient has a history of hemophilia:
What is the clinical spectrum of this disease?
How does factor VIII level relate to clinical disease?
What factor VIII levels are necessary for surgery?
What contains factor VIII?
What does not contain factor VIII?
How does hemophilia affect the bleeding time, PT, aPTT, ACT?
5.Patient has a history of Christmas disease:
What is the clinical spectrum of this disease?
How common is it?
What factor IX level is necessary for surgery?
What contains factor IX? What else is this used for?
How does this disease affect the bleeding time, PT, aPTT, ACT?
6.Patient has a history of Von Willebrand's disease.
What is the clinical spectrum of this disease?
How common is it?
Why is it important to know the subtypes?
How does this disease affect the bleeding time, PT, aPTT, ACT?
What therapy might be helpful preoperatively?
What therapy might be helpful should bleeding develop intraoperatively?
What drugs should they avoid?
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.
What are all of the coagulation products known to man?
What benefits do you expect to get from each of them?
How likely is it that the factors in each blood product will address the coagulopathy?
What interventions, other than blood products, per se, might help resolve the coagulopathy?
Data Base:
Coagulation Factors:
Final Common Pathway: Think of paper money: X -> V -> II -> I
Extrinsic Pathway: Factor X is activated (to Xa) by factor VII.
Intrinsic Pathway: Factor X is activated by factors XII, XI, IX, and VIII (e.g. everything else)
FactorNameNormalRequiredHalf-lifeStability
(mg%)(mg%)at 4 degrees
Ifibrinogen150-35070 (50%)4 daysstable
IIprothrombin70-13020 (30%)2-5 daysstable
IIIthromboplastin
IVcalcium
Vproaccelerin70-1305 (10%)12 hours7 days
VIactivated 5
VIIproconvertin70-15020 (30%)300 minstable
VIIIantihemophilic50-20030 (60%)17 hours7 days
IXChristmas70-13020 (30%)40 hoursstable
XStuart70-13010 (15%)40 hoursstable
XIPTA70-13020 (30%)60 hours7 days
XIIHageman40-1500 (0%)stable
XIIIfibrin stabilizing50-2001 (2%)12 daysstable
1
Vitamin K dependent factors:
II, VII, IX, X
(Not to be confused with the cranial nerves that carry parasympathetic fibers:
III, VII, IX, X)
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.
Platelets lasts 5-7 days at room temperature.
Platelet concentrates contain some RBC's, which is why ABO typing is needed.
Platelet factor III, a phospholipid, activates factor X, using IX and VIII.
Pre-existing disorders:
Idiopathic Thrombocytopenic Purpura
Possibly from antiplatlet antibodies
Can occur acutely, especially in kids following viral illness
Symptoms:
Easy bruising
Epistaxis
Petechiae
G.I. Bleeding
Laboratory:
Platelet count: 5,000 - 20,000
Bleeding time: prolonged
PT: normal
PTT: normal
Clotting time: normal
Treatment:
Steroids
Splenectomy
Usually don't require platelets for splenectomy. If you plan to give platelets, wait until the spleen is out before transfusing them.
Secondary Thrombocytopenic Purpura
Causes include malignancy (bone marrow invasion), sepsis, collagen disorders, allergic reactions, DIC, and poisoning from insecticides and organic dyes.
Laboratory:
Platelet count: <60,000
Bleeding time: prolonged
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
Factor VIII
LevelSymptoms
<1%Spontaneous bleeding
3-5%Rare spontaneous bleeding
10-15%Probably asymptomatic until surgery or dental procedures
2
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).
Alternatively, we can use a simple formula to reach 50% factory VIII activity levels as follows:
PreparationFactor VIII activity VolumeVolume required
activity units/mlmls per unitunits transfused
infusate transfusedper kg body weight
FFP1 200 .12
Cryoprecipitate8 13 .24
1
The transfused units/kg can be calculated as follows:
FFP:50% (target) /2% (bump in activity units/kg) x 1 unit transfused/200 activity units 0.12 transfused units/kg
Cryo:50%/2% (bump/kg) x 1 unit transfused/13 mls x 1 ml/8 units factor VIII activity 0.24 transfused units
Thus, to reach 50% activity levels, a 70 kg adult requires 9 units of FFP (volume = 1800 mls, or 17 units of cryoprecipitate (volume = 221 mls). DDAVP raises factor VIII levels by 2-3 times normal, may be all that is necessary in some mild cases. Danazol (an anabolic steroid) also raises factor VIII levels and has been used, in combination with Amicar, in mild hemophiliacs to avoid transfusions prior to surgery.
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.
Recombinant Factor VIII:
Recombinant human antihemophilic factor is now commercially available. Evidently (according to the WWW site of Genetics Institute, Inc) “recombinant Factor VIII is the largest protein ever produced using genetic engineering technology.” Recombinant Factor VIII is very expensive, but the price will likely drop as more pharmaceutical companies introduce recombinant factor VIII into the market place. Presently there are two products, Kogenate and Recombinate. There is probably no reason to use Factor VIII from donors, now that recombinant Factor VIII is available.
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 for details
von Willebrand's Disease
Clinically: mild form bleeding disorder, associated with nosebleeds, bruising, increased surgical bleeding, and excessive menstruation. Clotting factors are OK but platelet function is not.
Three types:
Type 1: Low levels of von Willebrand’s factor, but the protein is normal. Autosomal dominant, clinically mild
Type 2: von Willebrand’s protein is present but structurally altered. Autosomal dominant.
2A: Large multimers are absent from plasma and platelets
2B: Large multimers have INCREASED affinity for the platelet receptor, resulting in rapid clearance from the plasma
Pseudo von Willebrand’s: looks like 2B, but the problem is not with von Willebrand’s factor, but with the platelet receptor that has INCREASED affinity for the von Willebrand’s factor. End result is the same: rapid clearance of von Willebrand’s factor from plasma.
Type 3: von Willebrand’s protein is absent. Autosomal recessive.
Types 2 and 3 are most severe.
Lab:
Bleeding time: prolonged
PT: normal
PTT: normal
Clotting time: normal or prolonged
Lab results may be normal and repeated testing required to establish diagnosis. Tests such as the ristocetin cofactor, antibody assay to the von Willebrand’s factor, ristocetin-induced platelet for aggregation (RIPA), FVIII assay, and bleeding time are used to separate types I, 2, and 3.
Treatment:
Cryoprecipitate
FFP transfusion has a sustained beneficial effect.
DDAVP 0.3 to 0.4 mcg/kg normalizes bleeding time for Type 1 and 2A von Willebrand’s
Contraindicated in type 2B and pseudo von Willebrand’s disease because it will cause platelet aggregation and thrombocytopenia.
Amicar and Cyclokapron are useful for 5-7 days after bleeding episodes.
Miscellaneous Factor Disorders
Factor I deficiency (fibrinogen)
sex-linked inheritance
PT: increased
PTT: increased
Factor VII deficiency
autosomal recessive
Bleeding time: normal
PT: prolonged
PTT: normal
Factor X deficiency (Stuart factor)
Bleeding time: increased
PT: increased
PTT: increased
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.
Preoperative Drug Therapy:
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 the PT is affected.
Can cause thrombocytopenia, which is sometimes profound.
Regional versus General Anesthesia in the anticoagulated patient: (from Cousins)
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:
WATCH FIELD FOR BLEEDING!
Whole blood clotting time
a red top tube in your pocket
should clot in less than 15 minutes
clot dissolution (especially within 20 minutes) suggests DIC
can be done in O.R.
PT
Monitors extrinsic pathway (factor VII)
Used for warfarin monitoring because first factor depleted is factor VII.
aPTT
Measures intrinsic pathway.
Responds to heparin effect first because of heparin's inhibition of factor IX.
Usually just called the PTT, but it is actually a different test.
PTT is not done routinely any more.
Factor XII activation is variable and can skew results dramatically.
Includes contribution of platelets (in the form of platelet factor 3)
Phospholipid micelles mimic the platelet function in the PTT.
"activated" to shorten the time of the test and eliminate the variable activation of 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.
ACT (activated clotting time)
Measures same pathway (intrinsic) as the aPTT.
May be a better measurement of in vivo activity because the whole, uncitrated, blood is used, and the patient's platelets are used are used instead of micelles.
Not used outside of the O.R. because the test must be run immediately after drawing the sample.
Useful to subsequently observe the clot for lysis.
INR: (International Normalized Ratio)
Calculated as . Generally want to have below 1.2
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.
Pump runs greater than 2 hours.
Large tissue injuries may cause a functional defect in platelets, independent of dilutional and consumptive thrombocytopenia.
Each unit contributes 5000 platelets/ul at 1 hour.
Indications per Stanford QA Program:
Platelet count less than 20,000/mm3
Platelet count less than 50,000/mm3 with active bleeding
Platelet count less than 100,000/mm3, + high risk bleeding (e.g. CNS, eye)
Platelet dysfunction (e.g. uremia) and active bleeding or surgery
Acute massive bleeding
Splenectomy, may give 20 units preoperatively
For ECMO or CPB within 24 hours of procedure.
Fresh Frozen Plasma
Major justification is to give factor VIII.
Factor VIII rapidly synthesized in response to injury.
Maintain PT between 12 and 15.
Consider FFP after 1.5 - 2 blood volumes.
Not indicated for:
Volume expansion
To reconstitute pRBCs.
Routine administration of FFP is increasingly controversial.
Your body contains about 12 units of FFP. Thus, 12 units of FFP should fully restore normal coagulation.
Indications per Stanford QA Program:
Congenital coagulation disorders, liver disease, Coumadin overdose
DIC, nephrotic syndrome, newborn hemorrhagic diathesis, septic shock,
protein losing enteropathy, plasmapheresis, newborn exchange transfusion, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome
"Suspected coagulopathy due to deficiency of soluble coagulation factors in a patient who is bleeding where coagulation studies are pending at the time of infusion."
During surgery or active bleeding if PT 18, PTT 45
"Active bleeding with blood loss > 20%"
During CPB or ECMO with TT 17
"Other indications."