Coagulopathy - Stanford University



Coagulopathy

October 22, 1997

Steven L. Shafer, M.D.

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)

Factor Name Normal Required Half-life Stability

(mg%) (mg%) at 4 degrees

I fibrinogen 150-350 70 (50%) 4 days stable

II prothrombin 70-130 20 (30%) 2-5 days stable

III thromboplastin

IV calcium

V proaccelerin 70-130 5 (10%) 12 hours 7 days

VI activated 5

VII proconvertin 70-150 20 (30%) 300 min stable

VIII antihemophilic 50-200 30 (60%) 17 hours 7 days

IX Christmas 70-130 20 (30%) 40 hours stable

X Stuart 70-130 10 (15%) 40 hours stable

XI PTA 70-130 20 (30%) 60 hours 7 days

XII Hageman 40-150 0 (0%) stable

XIII fibrin stabilizing 50-200 1 (2%) 12 days stable

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: 17, reptilase clotting time > 14

DIC or Septic Shock

"Other indications."

Recombinant Factor VIII:

Kogenate and Recombinate

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

Contact activation during CPB

mediated by kallikrein system

activation of intrinsic pathway on contact with pump material

causes thrombin formation

impairs platelet adhesive function

High dose blocks contact activation

protects platelet adhesive receptors

preserves platelet aggregation

in synergy with heparin, prevents thrombin formation

Low dose: just blocks fibrinolysis, cheaper drugs may do just as well

Raises ACT as an artifact.

Maintain ACT >750?

Perhaps us a different test of heparin activity.

Reserved for complex cases with long anticipated CPB time. At Stanford often used for “redo” surgery.

Synthetic antifibrinolytic amino acids:

Epsilon-Aminocaproic acid (EACA)

para aminomethylbenzoic acid (PAMBA)

tranexamic acid

Useful to treat excessive bleeding following cardiac surgery

Only action is antifibrinolysis, no protective effect as found with aprotenin

Amicar is often used in routine cardiac surgery to reduce transfusion requirements.

Rational Transfusion Therapy: Does it exist?

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.

"It would be wasteful to administer platelets prophylactically to all patients for a condition that, at most, may affect only one out of 16 (6.25%) of those with massive transfusion, and for a condition that is so readily and effectively treated when it occurs." R. Reed, Ann Surg 203:40-48, 1986

"There appears to be no clear advantage to the prophylactic infusion of platelets in comparable patients ... who receive massive transfusions but do not have medical bleeding." C Harrigan, et al, 98:836-843, 1985

"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

Send off PT, aPTT, platelet count, and fibrinogen level.

Order platelets

After 1.5 blood volumes:

Repeat whole blood clotting time, ACT

Order FFP

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.

Disseminated intravascular coagulation

Refractory coagulopathy is common after massive transfusions and probably caused by prolonged hypotension, hypoperfusion, and vascular damage.

Fibrinogen is rapidly consumed by thrombin, producing fibrin.

Fibrin is rapidly degraded by plasmin, producing fibrin split products.

Fibrin split products interfere with clot formation.

Diagnosis:

Bleeding diathesis

platelet count < 80K

low fibrinogen

elevated fibrin split products

Other lab results:

TT (thrombin time): increased

PT: increased

PTT: increased

Clot time: greater than 10 minutes, shouldn't subsequently lyse.

Marked decrease in factors V, and VIII also.

Treatment:

Treat the underlying disorder

Platelets

FFP

Cryoprecipitate

Concentrated factor I and VIII.

Factors most likely depleted.

Needed in the highest level for adequate hemostasis.

Lost most rapidly from banked whole blood, red cells, and platelets.

Vitamin K

Nothing may be effective.

Amicar is contraindicated.

"From 4 to 6 h, by which time ongoing surgical bleeding has usually been 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!

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