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All patients on warfarin should have an INR performed, and a CT scan should be done in most anticoagulated patients. All supratherapeutically anticoagulated patients, as well as any anticoagulated patient with a traumatic CT abnormality, should be admitted for neurologic observation and consideration given to short term reversal of anticoagulation. Routine repeat CT scanning at 12 to 18 hours or when even subtle signs of neurologic worsening occur is a strong recommendation. A multi-institutional, prospective trial using these guidelines would be a first step toward demonstrating improved outcomes in the anticoagulated patient population after head trauma. Semi-SR (J Trauma 2006;60(3):553)

irreversibly alters platelets but stays in serum for 8 hours, so can not give more PLT

Best Review article of oral anticoag assoc ICH (Stroke 2006;37:256)

Hematoma expansion occurs in ~40% of pts in early hours following onset

Vitamin K
It takes at least 2 to 6 hours, and often more than 24 hours,to achieve an effective response to vitamin K administration, although vitamin K alone is often inadequate to completely normalizethe international normalized ratio in that time frame. Concomitantadministration of coagulation factors is therefore required.Nevertheless, because of the short HLT of transfused coagulationfactors (factor II: 48 to 60 hours; factor VII: 5 to 6 hours;factor IX: 20 to 24 hours; factor X: 24 to 48 hours), the administrationof 5 to 20 mg of vitamin K is necessary to achieve a sustainedreversal of anticoagulation.^42–46 The effect of vitaminK is more rapid when given intravenously. Although there havebeen concerns regarding allergic and anaphylactic reactionsto intravenous vitamin K, the risk of this complication appearsto be quite low,⁴⁷ with an incidence in one study of 3 per 10000 doses (95% CI: 0.04 to 11 per 10 000 doses).⁴⁸ Subcutaneousadministration may be safer but does not correct the INR asrapidly or as reliably as intravenous use.⁴⁹

Fresh Frozen Plasma
FFP contains all coagulation factors in a nonconcentrated form; hence, to achieve effective hemostasis a large volume (up to several liters) is required.^9,50,51 In principle, 1 mL of FFP/kgbody weight increases the levels of coagulation factors by 1to 2 International Units (IU)/dL.⁵² The traditional dose of10 to 15 mL of plasma/kg body weight may have to be exceededin massive bleeding.⁵³ However, the standard of an FFP unitis based on its factor VIII content; the actual levels of vitaminK-dependent coagulation factors are not specified and vary considerably.^50,54Our routine experience, and that of others, suggests that FFPvolumes required to reduce the INR below 1.4 may vary considerably:for example, between 800 and 3500 mL.^39,55

FFP requires compatibility testing and thawing before transfusion.Furthermore, the large volume required and a rapid transfusionrate can lead to circulatory overload. In cases of life-threateningbleeding such as ICH, or in patients with impaired cardiac function,FFP is therefore a less than ideal treatment option. In addition,FFP transfusion is associated with several potential adversereactions, including transfusion-related acute lung injury, blood-borne infection, citrate toxicity, and allergic reactions.^56,57

PCC
PCC contain coagulation factors VII, IX, X, and prothrombinas well as proteins C, S, and Z in a concentrated form, and,unlike FFP, can be given without waiting for compatibility testingand thawing. The potency of PCC is expressed as factor IX contentin IU, varying between preparations,⁵⁸ and a dose consists of ${approx}$ 50 to 150 mL of reconstituted product. Based on data obtainedfrom patients with hemophilia B, a dose of 1 IU of factor IX/kgbody weight increases the level of plasma factor IX by 1 IU/dL.⁵⁹

Studies of small numbers of patients suggest that PCC corrects a prolonged INR more rapidly than FFP.^38,50,60 However, a retrospectivestudy comparing vitamin K, FFP, PCC, and no treatment in 151patients with OAT-ICH, found no difference in 90-day mortality.⁶¹The main concerns with PCC-use focus on the potential to inducethrombosis and disseminated intravascular coagulation.^62–66

^{10 mg of Vit K/50 U/kg of PCC or 15 cc/kg of FFP}

Time Window for Treatment
In SICH, evidence suggests that significant hematoma expansion tends to occur during the first 4 hours after onset, and thisis likely to be the critical time window for a hemostatic treatment.^30,37In OAT-ICH, the natural course of hematoma expansion is probablymore prolonged, perhaps up to 24 or 48 hours,^1,18,79 raisingthe possibility that patients presenting as late as 24 hours(or even later) may benefit from effective hemostatic treatment.

Dose Regimen
Administration of an effective hemostatic agent at an earlystage of SICH appears to accelerate the formation of a fibrinclot, which stops the bleeding.³⁷ In this case, it seems thata single dose is sufficient. However, in OAT-ICH, the underlyingcoagulopathy may require a higher dose or repeated dosing.

Monitoring Hemostasis During the Reversal of Anticoagulant Effect
PT-INR is routinely used for regulating OAT as well as monitoring the reversal of its anticoagulant effect. The test is sensitive to decreased levels of factor VII and factor X, and prothrombin, but not to decreased levels of factor IX.^{50,53,80,51,75} BecauseFFP contains variable amounts of factor IX, the correction ofthe INR with FFP may not be accompanied by a correction of factorIX levels.⁵⁰ For example, Makris et al found that administrationof 800 mL FFP decreased the mean INR from 6.73 to 2.38, whereasthe mean factor IX levels were essentially unchanged (from 26.45IU/dL to 27.36 IU/dL).⁵⁰ Thus, the INR may be normalized butthe patient remains at risk of further bleeding.

The use of the INR for monitoring patients treated with rFVIIa is also problematic. Pharmacological doses of rFVIIa will always lower the INR regardless of the levels of other coagulation factors. Hence, when monitoring the reversal of anticoagulant effect, INR values should be interpreted with caution as they might not reflect the actual status of all vitamin K-dependent coagulation factors.^53,51

Thromboelastography may provide a more meaningful measure of coagulation status. This system records a profile of clot formationin whole blood, providing an overall picture of hemostatic function.^81,76Based on 7 patients with central nervous system bleeding duringOAT who were treated with rFVIIa, Sørensen and colleagues showed that it may be feasible to use thromboelastography to monitor hemostatic status.⁷¹ Nevertheless, more data are neededto prove the clinical utility of the measure.

Br J Surg. 1993 Jun;80(6):723-4. Links
Use of desmopressin to prevent bleeding complications in patients treated with aspirin.
Flordal PA,
Sahlin S.
Department of Surgery, Karolinska Institute, Danderyd Hospital, Sweden.
Aspirin induces a haemorrhagic diathesis that persists for at least 1 week after discontinuation of the drug. The effect of the vasopressin analogue desmopressin was studied in 12 patients treated with aspirin who were undergoing cholecystectomy. Desmopressin was given to six of these patients. There were five postoperative bleeding complications; all occurred in patients who had not received desmopressin (P < 0.05). The bleeding time was prolonged in aspirin-treated patients and normalized by desmopressin (P < 0.05). Desmopressin can be used safely to prevent bleeding induced by aspirin.

Anesth Analg. 1997 Dec;85(6):1258-67. Links
Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators.
Laupacis A,
Fergusson D.
Clinical Epidemiology Unit, Loeb Research Institute, University of Ottawa, Canada. alaupacis@Lri.ca
Concern about the side effects of allogeneic red blood cell transfusion has increased interest in methods of minimizing perioperative transfusion. We performed meta-analyses of randomized trials evaluating the efficacy and safety of aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid in cardiac surgery. All identified randomized trials in cardiac surgery were included in the meta-analyses. The primary outcome was the proportion of patients who received at least one perioperative allogeneic red cell transfusion. Sixty studies were included in the meta-analyses. The largest number of patients (5808) was available for the meta-analysis of aprotinin, which significantly decreased exposure to allogeneic blood (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.25-0.39; P < 0.0001). The efficacy of aprotinin was not significantly different regardless of the type of surgery (primary or reoperation), aspirin use, or reported transfusion threshold. The use of aprotinin was associated with a significant decrease in the need for reoperation because of bleeding (OR 0.44, 95% CI 0.27-0.73; P = 0.001). Desmopressin was not effective, with an OR of 0.98 (95% CI 0.64-1.50; P = 0.92). Tranexamic acid significantly decreased the proportion of patients transfused (OR 0.50, 95% CI 0.34-0.76; P = 0.0009). Epsilon-aminocaproic acid did not have a statistically significant effect on the proportion of patients transfused (OR 0.20, 95% CI 0.04-1.12; P = 0.07). There were not enough patients to exclude a small but clinically important increase in myocardial infarction or other side effects for any of the medications. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the number of patients exposed to perioperative allogeneic transfusions in association with cardiac surgery. Implications: Aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid are used in cardiac surgery in an attempt to decrease the proportion of patients requiring blood transfusion. This meta-analysis of all published randomized trials provides a good estimate of the efficacy of these medications and is useful in guiding clinical practice. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the exposure of patients to allogeneic blood transfusion perioperatively in relationship to cardiac surgery.

Anesth Analg. 2004 Mar;98(3):578-84, table of contents. Links
Prophylactic treatment with desmopressin does not reduce postoperative bleeding after coronary surgery in patients treated with aspirin before surgery.
Pleym H,
Stenseth R,
Wahba A,
Bjella L,
Tromsdal A,
Karevold A,
Dale O.
Departments of Anesthesiology, St Olav University Hospital, Trondheim, Norway. hilde.pleym@stolav.no
The synthetic vasopressin analog desmopressin has hemostatic properties and may reduce postoperative bleeding after coronary artery bypass grafting (CABG). A study on the effects of recent aspirin ingestion on platelet function in cardiac surgery showed a greater impairment of platelet function in patients treated with aspirin <2 days before the operation. We evaluated the effects of desmopressin on postoperative bleeding in CABG patients who were treated with aspirin 75 or 160 mg until the day before surgery. The study was a prospective, randomized, double-blinded, placebo-controlled, parallel group trial. One-hundred patients were included and divided into two groups. One group received desmopressin 0.3 micro g/kg and the other received placebo (0.9% NaCl) after the neutralization of heparin with protamine sulfate. Postoperative blood loss was recorded for 16 h. The mean (SD) bleeding was 606 (237) mL in the desmopressin group and 601 (301) mL in the placebo group (P = 0.93), representing no significant difference (95% confidence interval, -107 to 117 mL). We conclude that desmopressin does not reduce postoperative bleeding in CABG patients treated with aspirin until the day before surgery. IMPLICATIONS: Continuation of aspirin until the day before coronary artery bypass grafting may increase postoperative bleeding. The administration of desmopressin to these patients after the neutralization of heparin with protamine sulfate does not reduce postoperative bleeding.

Blood. 2003 Dec 15;102(13):4594-9. Epub 2003 Aug 14. Links
Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin.
Reiter RA,
Mayr F,
Blazicek H,
Galehr E,
Jilma-Stohlawetz P,
Domanovits H,
Jilma B.
Department of Clinical Pharmacology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
Whereas bleeding is the most frequent adverse event encountered in patients receiving glycoprotein (GP) IIb/IIIa inhibitors, there are currently no recommendations for how to treat such patients. The present study tested the hypothesis that infusion of desmopressin (DDAVP) reverses the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin). Study group 1 (10 healthy volunteers) received a DDAVP infusion to establish dose-response curves for the in vitro inhibition of platelet function by eptifibatide, abciximab, and tirofiban together with l-aspirin before and after DDAVP. In a randomized, double-blind, placebo-controlled, crossover study (group 2) volunteers received l-aspirin and a standard eptifibatide infusion. Thereafter, DDAVP or a physiologic saline infusion was given over 30 minutes. In group 1, all GPIIb/IIIa inhibitors prolonged collagen-epinephrine (CEPI) and collagen-adenosine diphosphate (CADP) closure times (CTs), measured with the platelet function analyzer 100 (PFA-100). DDAVP caused a shift in the concentration response curves to the right of all 3 GPIIb/IIIa inhibitors. In group 2, DDAVP accelerated the normalization of CADP-CT and CEPI-CT after the stop of eptifibatide infusion with a maximum effect at 1.5 hours to 2 hours. In contrast, CEPI-CT remained above normal in the placebo group for more than 4 hours. In conclusion, DDAVP accelerates normalization of the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin).

Transfusion. 2005 Mar;45(3):420-6. Links
Additive effects between platelet concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor eptifibatide.
Reiter R,
Jilma-Stohlawetz P,
Horvath M,
Jilma B.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
BACKGROUND: Platelet (PLT) glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated efficacy in decreasing ischemic complications of percutaneous coronary intervention and/or unstable angina. In case of bleeding, the drug can be stopped and PLT transfusions can be given. STUDY DESIGN AND METHODS: This crossover study tested the additive effects of PLT concentrates (PCs) after desmopressin (DDAVP) infusion in antagonizing the anti-PLT effects of GPIIb/IIIa inhibitors and aspirin. After eptifibatide and aspirin infusion (at standard dosages), 10 healthy volunteers received DDAVP or placebo. Thereafter, increasing amounts of PLTs from fresh single-donor apheresis concentrates were added in vitro to blood samples of all volunteers to increase PLT counts by 30 x 10(9), 60 x 10(9), or 120 x 10(9) per L. RESULTS: Adding platelets in vitro further improved PLT function after DDAVP: it shortened collagen-adenosine diphosphate closure times (p < 0.01), to normal ranges as measured by the PLT function analyzer (PFA-100). In contrast, normal PLT function could not be restored even when PLT counts were increased by 50 percent (120 x 10(9)/L) in the placebo group. CONCLUSION: Combined use of PLTs from fresh apheresis PC and DDAVP additively enhances recovery of normal PLT function after eptifibatide infusion. Such a strategy may help to avoid excessive transfusion of PC.
PMID: 15752161 [PubMed - indexed for MEDLINE]
Go to source: Entrez PubMed

Another review of reversal of anticoag in ICH (Mayo Clinic Proceed 2007;82(1):82)

Vit K takes 6-24 hrs to reverse and IX and X reversal takes longer than 24 hours

Leo / Lou

Its my understanding that you are both about half correct. Plavix

irreversably inactivates the P2Y-12 ADP receptors on platelets,

meaning that any circulating plavix will wreak havoc on any platelets

being transfused. Once the receptor is inactivated theres no

reversing it, nor does there seem to be a way to subvert the blockade

pharmacologically. As far as I am aware, all activators of platelets

independant of P2Y receptor binding (thrombin and TXA2) are locally

relseased mediators, so I can't think of a pharmacologic therapy worth

attempting. Now, if circulating clopidogrel levels are low, some

platelets that are infused may not suffer from total P2Y inativation

and thus promote clotting, but the effectiveness is potentially

limited. The Plavix people claim that 7 days is long enough without

the drug on board to return clotting function and allow platelet

transfusion to be effective, however many of the surgeons and

anesthesiologists I have spoken to claim it is more on the order of

two weeks in many patients.

As far as formal indications and contraindications for the platelets,

I can't speak, but thats the cliffs notes on the physiologic story

behind it, as its been explained to me.

~ Chris

Chris,

This is a very good answer to the question. The real issue is the

presence or absence of residual active drug. The answer can be found

in the pharmacokinetics of clopidrogel. Clopidrogel would be a lot

less demonized and a lot safer it if didn't have such a miserably long

half life. I've pasted in a couple of abstracts below, and as you can

the half life ranges from 275 to 433 hours in chronic dosing! That's

about 11-1/2 days for the shortest half life! The variation in half

life seems to be do to variations in abortion as opposed to variations

in metabolism. The irreversible inactivation of P2Y-12 ADP receptors

isn't as much of a problem as the long circulating time of effective

doses of the drug. Aspirin works by irreversibly acetylating

platelets, however, it is rapidly eliminated which means that you can

give unacetylated donor platelets and rapidly reverse the antiplatelet

effect.

I have no idea why clopidrogel was selected as the prototypical P2Y-12

ADP receptor inhibitor. It would have seemed infinitely wiser to me to

choose a compound which is much more rapidly metabolized. My

prediction (absent anything but a hunch) is that you will see P2Y-12

ADP receptor inhibitors designed to have a much shorter half life

released in the coming years. Clopidrogel will then fade away from

routine use or disappear completely.

I am about the hard businesses of trying to master the mechanics of

hemorheology. I scarcely see this discipline mentioned in CCM, but I

predict that this will be a font of new insights and pharmaceuticals

in the coming decade. Modulating RBC aggregability, as well as WBC and

platelet adhesion and interactions has powerful therapeutic potential.

Hopefully, they'll do better with those drugs than they did with

clopidrogel.

Semin Thromb Hemost. 1999;25 Suppl 2:29-33. Links

Pharmacokinetic profile of 14C-labeled clopidogrel.

Lins R,

Broekhuysen J,

Necciari J,

Deroubaix X.

Biopharma Research, AZ Stuivenberg, Antwerpen, Belgium.

In order to obtain a global assessment of circulating

clopidogrel-related products and of the excretion of the drug, the

pharmacokinetic behavior and the excretion balance of 14C

radioactivity following the administration of a single dose of 75 mg

of 14C-labeled clopidogrel were compared in 6 clopidogrel-free healthy

male subjects (Period I) and after 7 days of once daily therapy with

the unlabeled drug in these subjects (at steady state) (Period II).

The two study periods were separated by a 4-week washout period. For

each administration of 14C-clopidogrel, blood samples were collected

before and at regular intervals over 28 days after administration of

the radiolabeled drug. Expired air samples were collected before and

over 24 hours after the administrations of 14C-clopidogrel. All urine

voided and all stools were collected before and for up to 120 hours

after the administration of 14C-clopidogrel, in consecutive periods of

12 to 24 hours. The mean radiocarbon plasma concentration profiles

after administration of 14C-clopidogrel given as a single dose (Period

I) and during steady state (Period II) were superimposable. There were

no statistically significant differences between the two treatments

for any parameters. A Cmax of 3.9 mg-Eqv/L was reached after a median

time of 1 hour (Tmax). The plasma elimination half-life, t1/2, ranged

from 336 hours to 672 hours in Period I and from 275 to 433 hours in

Period II. The radiocarbon excretion over 10 to 12 hours post-dose

(time to last measurable radioactivity) in expired air represented

0.31 to 0.35% of the administered dose. Mean cumulative urinary

excretion over 120 hours represented 41% of the dose after a

single-dose administration and 46 % after administration at steady

state. The cumulative fecal recovery over 120 hours ranged from 35 to

57% of the dose in Period I and from 39 to 59% of the dose in Period

II. Mean total excretion of radioactivity was 92% of the dose during

Period I and 93% during Period II. These data indicate that, following

multiple-dose administration of clopidogrel, the biodisposition of the

drug remains unaltered compared to a single dose.

PMID: 10440420 [PubMed - indexed for MEDLINE]

Semin Thromb Hemost. 1999;25 Suppl 2:25-8. Links

Pharmacokinetics of clopidogrel.

Caplain H,

Donat F,

Gaud C,

Necciari J.

Institut Aster, Hopital Cognacq-Jay, Paris, France.

Clopidogrel is extensively metabolized, as evidenced by the absence of

detectable amounts of unchanged clopidogrel in plasma samples in most

clinical trials. The major circulating compound is the inactive

carboxylic acid derivative SR26334, and information on the absorption

and elimination of clopidogrel after oral administration is derived

from the pharmacokinetics of this metabolite. Single-dose

pharmacokinetics of SR26334 were investigated in a randomized,

dose-proportionality study comparing single 50, 75, 100, and 150 mg

oral doses of clopidogrel administered to 12 subjects. Multiple-dose

pharmacokinetics of SR26334 were primarily derived from a study

carried out in 18 subjects treated with clopidogrel 75 mg once daily

for 14 days. Further data on multiple-dose pharmacokinetics were

provided by the results of a long-term study carried out in a group of

35 subjects who received clopidogrel 75 mg once daily for 12 weeks.

All subjects were healthy male volunteers and, in all cases,

clopidogrel was taken in the morning after an overnight fast. The mean

Cmax values (+/-SD) for SR26334 following single doses of 50, 75, 100,

and 150 mg were 1.6+/-0.30 mg/L, 2.9+/-0.68 mg/L, 3.1+/-0.94 mg/L, and

4.9+/-1.22 mg/L, respectively. The ANOVA performed on dose-normalized

Cmax showed no statistically significant dose effect, demonstrating a

dose-proportional increase of Cmax in this range of clopidogrel doses.

The urinary excretion of SR26334 was low-2.2 to 2.4% of the dose

administered-and Cl(r-2-24) remained virtually constant at all four

doses. Median T(max)(0.8-1.0 hour) and mean plasma t1/2 (7.2-7.6

hours) values were not significantly different between doses.

Following repeated dosing with clopidogrel 75 mg, mean (+/-SD)

C(trough) values (values before dosing) for SR26334 at steady state

ranged from 0.8+/-0.04 mg/L to 0.11+/-0.07 mg/L. These values are

similar to those observed during the 12-week administration of

clopidogrel indicating that steady-state values are reproducible and

that the esterasic biotransformation of clopidogrel into its

carboxylic acid metabolite remains constant over a number of months of

treatment.

PMID: 10440419 [PubMed - indexed for MEDLINE]

Mike Darwin

Louis M. Aledort, M.D.
Professor, Medicine / Hematology And Medical Oncology

E-mail: louis.aledort@mssm.edu
Tel: (212) 241-7971

I just wanted to clarify that Dr. Aledort also gives some FFP (2 U typically) in bleeding liver disease patients along with the PCC, as PCC does not replace other important factors like V and VIII.

Ultrarapid Rversal of OAT

18 pts on coumadin, some supratherapeutic. All got 20 units/kg of PCC with full reversal within 3 minutes
(inten care med 2007;33:721)

Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the
international normalized ratio more rapidly than subcutaneous vitamin K
in the treatment of warfarin-associated coagulopathy. A randomized,
controlled trial. Ann Intern Med. Aug 20 2002;137(4):251-254.

animal study showing ddavp reverses aspirin induced platelet dysfunction (British Journal of Haematology, 2002, 117, 658–663)

1:	Lethagen S.	Related Articles, Links
	Desmopressin--a haemostatic drug: state-of-the-art review. Eur J Anaesthesiol Suppl. 1997 Mar;14:1-9. Review. PMID: 9088828 [PubMed - indexed for MEDLINE]

3:	Kam PC.	Related Articles, Links
	Use of desmopressin (DDAVP) in controlling aspirin-induced coagulopathy after cardiac surgery. Heart Lung. 1994 Jul-Aug;23(4):333-6. PMID: 7960860 [PubMed - indexed for MEDLINE]

4:	Reiter RA, Mayr F, Blazicek H, Galehr E, Jilma-Stohlawetz P, Domanovits H, Jilma B.	Related Articles, Links
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5:	Chard RB, Kam CA, Nunn GR, Johnson DC, Meldrum-Hanna W.	Related Articles, Links
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Reversal of Anticoagulation or Antiplatelet

Anticoagulated Patients

^{10 mg of Vit K/50 U/kg of PCC or 15 cc/kg of FFP}

Ultrarapid Rversal of OAT

2:	Flordal PA, Sahlin S.	Related Articles, Links
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