Coagulation Factors in Controlling Traumatic Bleeds: FFP, PCC, or ...
Coagulation Factors in Controlling Traumatic Bleeds: FFP, PCC, or ...
Coagulation Factors in Controlling Traumatic Bleeds: FFP, PCC, or ...
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<strong>Coagulation</strong> <strong>Fact<strong>or</strong>s</strong> <strong>in</strong> Controll<strong>in</strong>g<br />
<strong>Traumatic</strong> <strong>Bleeds</strong>:<br />
<strong>FFP</strong>, <strong>PCC</strong>, <strong>or</strong> Lucky Sevens?<br />
Rose Sohraby, Pharm.D.<br />
PGY1 Pharmacy Resident<br />
Department of Pharmacy, University Health System, San Antonio, TX<br />
Division of Pharmacotherapy, The University of Texas at Aust<strong>in</strong> College of Pharmacy<br />
Pharmacotherapy Education and Research Center,<br />
University of Texas Health Science Center at San Antonio<br />
March 9, 2012<br />
Learn<strong>in</strong>g Objectives:<br />
1. Expla<strong>in</strong> the pathophysiology of coagulopathies due to traumatic bleed<strong>in</strong>g<br />
2. Describe the role of warfar<strong>in</strong> <strong>in</strong> coagulopathies<br />
3. Expla<strong>in</strong> mechanisms and places <strong>in</strong> therapy of fresh frozen plasma (<strong>FFP</strong>), prothromb<strong>in</strong> complex<br />
concentrate (<strong>PCC</strong>), and recomb<strong>in</strong>ant fact<strong>or</strong> VII (rFVIIa) <strong>in</strong> traumatic bleeds<br />
4. Devise a treatment plan f<strong>or</strong> coagulopathic patients with traumatic bleeds
TRAUMA<br />
I. Trauma 1<br />
a. International endemic affect<strong>in</strong>g persons of all ages<br />
b. Lead<strong>in</strong>g cause of death <strong>in</strong> <strong>in</strong>dividuals aged 1-44 years <strong>in</strong> 2003<br />
II. Hem<strong>or</strong>rhagic shock 2,3 (SEE APPENDIX A)<br />
a. Precipitated by traumatic event, result<strong>in</strong>g <strong>in</strong> acute blood loss<br />
b. Severe impairment of tissue perfusion and oxygenation<br />
c. Standard of care<br />
i Goals: control source of bleed<strong>in</strong>g and resolve shock<br />
ii. Surgical expl<strong>or</strong>ation – direct “hands-on” exam<strong>in</strong>ation (ie. expl<strong>or</strong>at<strong>or</strong>y laparotomy); mechanical<br />
control by direct pressure (ie. ligation of severed blood vessels, excision of damaged solid <strong>or</strong>gans,<br />
surgical pack<strong>in</strong>g)<br />
iii. Initial fluid therapy 2<br />
1. Warmed isotonic electrolyte solutions<br />
2. “3-f<strong>or</strong>-1 rule”: f<strong>or</strong> each 1 mL of blood loss, replace with 3 mL of crystalloid fluid<br />
3. Guided by goal of rest<strong>or</strong><strong>in</strong>g n<strong>or</strong>mal blood pressure<br />
v. Risks of aggressive fluid resuscitation 3<br />
1. Reverse compensat<strong>or</strong>y vasoconstriction<br />
2. Dilute blood’s oxygen-carry<strong>in</strong>g capacity and hemostatic fact<strong>or</strong>s<br />
3. “Wash away” early clots<br />
4. Result: coagulopathy, rebleed<strong>in</strong>g, and recurrent hypotension<br />
provoke further fluid adm<strong>in</strong>istration<br />
COAGULOPAT HY AFT ER T R AUMA<br />
III. Coagulopathy 1,4<br />
a. Def<strong>in</strong>ition: a defect <strong>in</strong> the body’s mechanism f<strong>or</strong> blood clott<strong>in</strong>g<br />
b. Lab<strong>or</strong>at<strong>or</strong>y diagnosis: PT (prothromb<strong>in</strong> time) ≥ 1.5 times n<strong>or</strong>mal, aPTT (activated partial<br />
thromboplast<strong>in</strong> time) ≥ 1.5 times n<strong>or</strong>mal, INR (<strong>in</strong>ternational n<strong>or</strong>malized ratio) > 1.5, platelet count<br />
< 50 x 10 9 L, fibr<strong>in</strong>ogen < 50-100 mg/dL<br />
c. Generalized non-surgical bleed<strong>in</strong>g from wounds, sk<strong>in</strong> edges, vascular access sites<br />
IV. Mechanisms of blood coagulation 1,5<br />
a. Blood coagulation cascade (SEE APPENDIX B)<br />
R. Sohraby 2
i. Several circulat<strong>in</strong>g prote<strong>in</strong>s <strong>in</strong>teract <strong>in</strong> a cascad<strong>in</strong>g series of limited proteolytic reactions<br />
ii. Tissue fact<strong>or</strong> (TF)<br />
1. Transmembrane prote<strong>in</strong> expressed outside the vasculature<br />
2. B<strong>in</strong>ds FVIIa when exposed on damaged endothelium <strong>or</strong> to blood that has extravasated tissue<br />
3. TF-FVIIa complex: ma<strong>in</strong> <strong>in</strong>itiat<strong>or</strong> of blood coagulation – activates FIX and FX<br />
i. Tissue fact<strong>or</strong> pathway <strong>in</strong>hibit<strong>or</strong> (TFPI): <strong>in</strong>hibits catalytic action of TF-FVIIa complex<br />
4. FXa and FVa f<strong>or</strong>m prothromb<strong>in</strong>ase complex on activated cell surfaces<br />
catalyze conversion of prothromb<strong>in</strong> (FII) to thromb<strong>in</strong> (FIIa)<br />
iii. Thromb<strong>in</strong> (FIIa) functions<br />
1. Allows fibr<strong>in</strong>ogen to polymerize and f<strong>or</strong>m a fibr<strong>in</strong> clot, an essential component of a functional<br />
clot<br />
2. Activates upstream clott<strong>in</strong>g fact<strong>or</strong>s (V, VIII, IX)<br />
3. Potent platelet activat<strong>or</strong> and mitogen<br />
4. Activates prote<strong>in</strong> C pathway, lessen<strong>in</strong>g the clott<strong>in</strong>g response<br />
b. Endothelial cell layer 5,6<br />
i. Sett<strong>in</strong>g of vascular <strong>in</strong>jury<br />
1. Series of changes, result<strong>in</strong>g <strong>in</strong> a m<strong>or</strong>e procoagulant phenotype<br />
2. Amplification phase:<br />
Vessel damage extravascular migration of platelets and FVIII-von Willebrand complex<br />
platelet adherence and activation, secretion and synthesis of vasoconstrict<strong>or</strong>s and platelet<br />
recruit<strong>in</strong>g and –activat<strong>in</strong>g molecules<br />
3. Propagation phase:<br />
Large numbers of activated platelets <strong>in</strong>creased rates of thromb<strong>in</strong> generation with<br />
subsequent fibr<strong>in</strong> generation f<strong>or</strong>mation of platelet plug<br />
c. Hemostasis 4<br />
i. Def<strong>in</strong>ition: a complex process that limits blood loss follow<strong>in</strong>g vascular <strong>in</strong>jury<br />
1. Ma<strong>in</strong>ta<strong>in</strong>s blood fluidity<br />
2. Repairs vascular <strong>in</strong>jury<br />
3. Prevents vessel occlusion (thrombosis) and <strong>in</strong>adequate perfusion of vital <strong>or</strong>gans<br />
ii. Both excessive bleed<strong>in</strong>g and thrombosis represent a breakdown of the hemostatic mechanism<br />
d. Dissem<strong>in</strong>ated <strong>in</strong>travascular coagulation (DIC) 1,5<br />
i. <strong>Coagulation</strong> and fibr<strong>in</strong>olytics systems pathologically activated<br />
ii. Hemostatic system “careens out of control”<br />
iii. Leads to generalized <strong>in</strong>travascular clott<strong>in</strong>g and bleed<strong>in</strong>g<br />
iv. May follow massive tissue <strong>in</strong>jury<br />
v. Often fatal when underly<strong>in</strong>g disease process not controlled<br />
R. Sohraby 3
V. “Lethal triad” of coagulopathy 1<br />
a. Aggressive resuscitation result<strong>in</strong>g <strong>in</strong> rebleed<strong>in</strong>g, hypothermia, and dilution<br />
perpetuate coagulopathy and the “lethal triad”<br />
b. Hypothermia 5<br />
i. C<strong>or</strong>e body temperature < 35°C<br />
ii. Reduced heat production<br />
1. Decreased oxygen consumption dur<strong>in</strong>g hem<strong>or</strong>rhagic shock<br />
2. Operative <strong>in</strong>terventions further heat loss from peritoneal and pleural surfaces<br />
3. Fluid resuscitation [heat = mass x specific heat x (T body -T fluid )] 7<br />
iii. Largest effect on platelet activation and adhesion<br />
1. Inhibits <strong>in</strong>teraction between von Willebrand fact<strong>or</strong> (vWF) and platelet glycoprote<strong>in</strong> Ib-IX-V<br />
complex<br />
2. Slows metabolic rate of coagulation fact<strong>or</strong> enzymes<br />
iv. Occurs <strong>in</strong> 80% of trauma non-surviv<strong>or</strong>s and 36% of trauma surviv<strong>or</strong>s 8<br />
v. Effects on specific clott<strong>in</strong>g fact<strong>or</strong> deficiencies 9<br />
1. At 35°C, without dilution, decreased activity <strong>in</strong> all coagulation fact<strong>or</strong>s<br />
2. FXI and FXII only function<strong>in</strong>g at 65% of n<strong>or</strong>mal at 35°C<br />
3. At 32°C, activity of FXI and FXII reduced to 17% and 32%, respectively<br />
c. Acidosis 1,8,10<br />
i. Reduces activity of proteases <strong>in</strong> coagulation system<br />
ii. pH reduction of 7.4 to 7.0<br />
1. Activity level of FVIIa reduced by 90%<br />
2. Activity of TF-FVIIa complex reduced by 55%<br />
3. Rate of prothromb<strong>in</strong> activation by FXa-FVa complex reduced by 70%<br />
d. Hemodilution 1<br />
i. Hem<strong>or</strong>rhage: direct loss of coagulation fact<strong>or</strong>s<br />
ii. Dilutional coagulopathy: losses rest<strong>or</strong>ed with fluids without clott<strong>in</strong>g fact<strong>or</strong>s<br />
1. Reduced plasma and coagulation fact<strong>or</strong>s <strong>in</strong> circulat<strong>in</strong>g blood volume<br />
reduced ability of clot f<strong>or</strong>mation<br />
2. Crystalloids given en route to trauma center<br />
3. Packed red blood cells (pRBCs) given pri<strong>or</strong> to lab<strong>or</strong>at<strong>or</strong>y tests (INR, fibr<strong>in</strong>ogen, hemoglob<strong>in</strong>,<br />
platelets) becom<strong>in</strong>g available<br />
4. Abn<strong>or</strong>mal results trigger request f<strong>or</strong> fresh frozen plasma (<strong>FFP</strong>)<br />
i. Takes 20-30 m<strong>in</strong> to thaw further delay to c<strong>or</strong>rect ongo<strong>in</strong>g coagulopathy<br />
5. Perpetuat<strong>in</strong>g cycle delays diagnosis and treatments and contributes to dysfunctional clott<strong>in</strong>g<br />
capabilities<br />
e. Risk fact<strong>or</strong>s f<strong>or</strong> coagulopathy 1<br />
*>10 units pRBC/24 hrs **Injury Severity Sc<strong>or</strong>e<br />
(SEE APPENDIX C)<br />
R. Sohraby 4
i. Patients with none of these risk fact<strong>or</strong>s had 1% chance of develop<strong>in</strong>g life-threaten<strong>in</strong>g<br />
coagulopathy 11<br />
ii. Patients with coagulopathy on admission had significantly higher m<strong>or</strong>tality rates than those with<br />
n<strong>or</strong>mal clott<strong>in</strong>g on admission (46% vs. 10.9%) 12<br />
iii. Abn<strong>or</strong>mal admission PT <strong>in</strong>creases adjusted odds of dy<strong>in</strong>g by 35%; abn<strong>or</strong>mal aPTT <strong>in</strong>creases<br />
adjusted odds of dy<strong>in</strong>g by 326% 13<br />
1. PT: evaluates adequacy of the extr<strong>in</strong>sic pathway; clott<strong>in</strong>g ability of fact<strong>or</strong>s I, II, V, VII, X 14<br />
2. PTT: measures efficacy of both the <strong>in</strong>tr<strong>in</strong>sic and common coagulation pathways; evaluates<br />
fact<strong>or</strong>s I, II, V, VIII, IX, X, XI, and XII 14<br />
WAR FAR IN<br />
VI. Warfar<strong>in</strong> + Trauma = Bad 4,17<br />
a. Increas<strong>in</strong>g need to manage trauma patients who receive anticoagulation<br />
i. Expand<strong>in</strong>g warfar<strong>in</strong> use due to expand<strong>in</strong>g ag<strong>in</strong>g population<br />
1. Use <strong>in</strong>creased from 2.3% to 4.0% from 2002 to 2006<br />
2. Use <strong>in</strong> patients > 65 years <strong>in</strong>creased from 7.3% to 12.8% from 2002 to 2006<br />
3. 1-10% annual <strong>in</strong>cidence of maj<strong>or</strong> bleed<strong>in</strong>g <strong>in</strong> warfar<strong>in</strong> patients<br />
ii. Increas<strong>in</strong>g trauma rates <strong>in</strong> patients ≥ 65 years<br />
1. 2009: 20.8% trauma cases <strong>in</strong> patients ≥ 65 years – <strong>in</strong>creased from 15.3% <strong>in</strong> 2004<br />
b. <strong>Traumatic</strong>ally <strong>in</strong>jured patients receiv<strong>in</strong>g warfar<strong>in</strong> at higher risk f<strong>or</strong> severe <strong>in</strong>tracranial hem<strong>or</strong>rhage and<br />
uncontrolled bleed<strong>in</strong>g<br />
i. Four- to five-fold <strong>in</strong>creased risk of death <strong>in</strong> anticoagulated trauma patients vs. non-anticoagulated<br />
trauma patients 18<br />
ii. Increased anticoagulation <strong>in</strong>tensity <strong>in</strong>creases risk of hem<strong>or</strong>rhagic events 19<br />
1. 98,900 patient years of observation<br />
2. Evaluated how under- and over-anticoagulation <strong>in</strong>fluence patient outcomes<br />
3. Compared with INR 2.0-3.0, relative risk of hem<strong>or</strong>rhagic events was 2.7 (absolute risk<br />
3.7%/year) at INR 3.0-5.0, and 21.8 (absolute risk 30.1%/year) f<strong>or</strong> INR >5.0<br />
iii. Rapid reversal of anticoagulation <strong>in</strong> trauma patients necessary to prevent <strong>or</strong> m<strong>in</strong>imize<br />
hem<strong>or</strong>rhagic complications<br />
1. Protocol of rapid identification of <strong>in</strong>tracranial bleed<strong>in</strong>g and warfar<strong>in</strong> reversal decreased<br />
<strong>in</strong>tracranial hem<strong>or</strong>rhage progression and reduced m<strong>or</strong>tality 20<br />
VII. Pharmacology 15<br />
a. Vitam<strong>in</strong> K antagonist (VKA)<br />
b. Commonly prescribed f<strong>or</strong> treatment and prevention of thromboembolic events<br />
c. Inhibits enzyme, vitam<strong>in</strong> K epoxide reductase (VKORC1)<br />
blocks f<strong>or</strong>mation of reduced vitam<strong>in</strong> K from vitam<strong>in</strong> K epoxide<br />
i. Reduced f<strong>or</strong>m of vitam<strong>in</strong> K required f<strong>or</strong> biological activity of extr<strong>in</strong>sic coagulation fact<strong>or</strong>s<br />
d. Response to warfar<strong>in</strong> <strong>in</strong>fluenced by several fact<strong>or</strong>s (medications, diet, pharmacogenomics, etc.)<br />
e. PT used <strong>in</strong> cl<strong>in</strong>ical practice as a therapeutic response marker<br />
i. INR used to standardize its rep<strong>or</strong>t<strong>in</strong>g [INR = (patient PT/mean PT) ISI ]<br />
ii. Moderate <strong>in</strong>tensity anticoagulation (INR 2.0-3.0) recommended f<strong>or</strong> most <strong>in</strong>dications<br />
iii. Safety and efficacy depend on ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g INR with<strong>in</strong> therapeutic range<br />
VIII. Questions to answer<br />
a. What treatment strategies should be used <strong>in</strong> traumatic bleed<strong>in</strong>g patients on warfar<strong>in</strong> pre-<strong>in</strong>jury?<br />
b. What treatment strategies should be used <strong>in</strong> traumatic bleed<strong>in</strong>g patients NOT on warfar<strong>in</strong> pre-<strong>in</strong>jury?<br />
R. Sohraby 5
R EVER SAL OF COAGULOP ATHY<br />
IX. Discont<strong>in</strong>ue warfar<strong>in</strong> 15,20<br />
a. Allow natural <strong>in</strong>crease <strong>in</strong> synthesis of associated clott<strong>in</strong>g fact<strong>or</strong>s<br />
b. Long t 1/2 (average 40 hrs); takes several days f<strong>or</strong> reversal, theref<strong>or</strong>e not enough <strong>in</strong> sett<strong>in</strong>g of traumatic<br />
bleed<br />
X. Vitam<strong>in</strong> K (phytonadione) 21<br />
a. Highly effective at revers<strong>in</strong>g effects of warfar<strong>in</strong><br />
i. Ineffective <strong>in</strong> patients with severe liver failure – po<strong>or</strong> synthesis of coagulation fact<strong>or</strong>s<br />
b. Large doses directly converted to reduced vitam<strong>in</strong> K via the enzyme vitam<strong>in</strong> K reductase<br />
c. Subcutaneous <strong>in</strong>feri<strong>or</strong> to <strong>or</strong>al <strong>or</strong> <strong>in</strong>travenous (IV) adm<strong>in</strong>istration – unpredictable and delayed response<br />
d. Under n<strong>or</strong>mal circumstances, no considerable difference <strong>in</strong> how fast <strong>or</strong>al <strong>or</strong> IV adm<strong>in</strong>istration will<br />
w<strong>or</strong>k<br />
i. Guidel<strong>in</strong>es recommend 10 mg IV f<strong>or</strong> urgent reversal of anticoagulation due to high risk of delayed<br />
enteral uptake <strong>in</strong> emergently bleed<strong>in</strong>g patient 21,22<br />
ii. Dilute and adm<strong>in</strong>ister as slow IV <strong>in</strong>fusion, no faster than 1 mg/m<strong>in</strong><br />
e. Increased synthesis of fact<strong>or</strong>s with<strong>in</strong> 1-3 hrs; however, cl<strong>in</strong>ical effect cannot be detected until 4-6 hrs;<br />
maximum effect after 24-36 hrs 21<br />
XI. Resuscitation solution 23<br />
a. Necessary to rest<strong>or</strong>e and supp<strong>or</strong>t tissue oxygenation and perfusion 14<br />
b. 1960s: whole blood used effectively as resuscitation solution 23<br />
i. Conta<strong>in</strong>ed all elements needed f<strong>or</strong> hemostasis<br />
c. Early 1970s: blood suppliers began separat<strong>in</strong>g whole blood <strong>in</strong>to components and supply<strong>in</strong>g blood<br />
products <strong>in</strong> the f<strong>or</strong>m of pRBCs, platelets, plasma, etc.<br />
i. Current standard of practice <strong>in</strong> civilian communities<br />
ii. Whole blood only available f<strong>or</strong> “walk<strong>in</strong>g blood banks” <strong>in</strong> the military<br />
iii. Currently left with pRBCs, crystalloid fluids, replacement of various coagulation fact<strong>or</strong>s piecemeal<br />
us<strong>in</strong>g cryoprecipitate and <strong>FFP</strong><br />
d. Good f<strong>or</strong>: patients with congenital <strong>or</strong> acquired coagulopathy – advantageous to allocate resources<br />
acc<strong>or</strong>d<strong>in</strong>g to the needs of <strong>in</strong>dividual patients 14,23<br />
e. Problem: replacement of lost blood volume with crystalloid and pRBCs alone does not replenish<br />
coagulation fact<strong>or</strong>s <strong>in</strong> acutely hem<strong>or</strong>rhag<strong>in</strong>g trauma patients 23<br />
i. Recent emphasis on hemostasis with replacement of <strong>FFP</strong>, platelets, cryoprecipitate, and rFVIIa<br />
f. Response to discont<strong>in</strong>uation of whole blood and the adoption of component therapy<br />
i. 3 L crystalloid f<strong>or</strong> each 1 L of blood loss 24<br />
1. Problem: massive fluid overload significant edema, acute respirat<strong>or</strong>y distress syndrome,<br />
hepatic failure, renal failure, sepsis<br />
2. Does not conta<strong>in</strong> necessary clott<strong>in</strong>g fact<strong>or</strong>s f<strong>or</strong> complete resuscitation<br />
ii. Fluid replacement as near to whole blood as possible <strong>in</strong> severely <strong>in</strong>jured military patients — 1:1:1<br />
ratio of blood, plasma, and platelets 25<br />
1. M<strong>or</strong>tality improved from ~80% to < 30% <strong>in</strong> severely <strong>in</strong>jured patients who required > 10 units<br />
of blood <strong>in</strong> 8 hrs 26<br />
2. Sh<strong>or</strong>ter length of stay and less blood required f<strong>or</strong> resuscitation<br />
3. Early use of pRBCs, <strong>FFP</strong>, and platelets offers best chance of limit<strong>in</strong>g coagulopathy <strong>in</strong> early<br />
phases of care 14<br />
g. Current approaches as a solution to hem<strong>or</strong>rhage 23<br />
i. 1:1:1 ratio – plasma, platelets, pRBCs (cryoprecipitate PRN)<br />
ii. 1:1 ratio – plasma, pRBCs (cryoprecipitate and platelets PRN)<br />
h. “Ideal” resuscitation fluid 14<br />
i. Efficacious<br />
ii. Safe<br />
iii. Inexpensive<br />
iv. Easy to st<strong>or</strong>e and transp<strong>or</strong>t<br />
v. Assist <strong>in</strong> carry<strong>in</strong>g oxygen and nutrients to cells<br />
R. Sohraby 6
XII. Fresh frozen plasma (<strong>FFP</strong>) 15,21,23<br />
a. Recommended <strong>in</strong> massive bleed<strong>in</strong>g <strong>or</strong> bleed<strong>in</strong>g complicated by coagulopathy<br />
b. Conta<strong>in</strong>s fact<strong>or</strong>s II, VII, IX, X, fibr<strong>in</strong>ogen, vWF, and antithromb<strong>in</strong><br />
i. Blood group specific (requires ABO group test<strong>in</strong>g)<br />
ii. Total <strong>FFP</strong> pack volumes can range between 150-250 mL; <strong>in</strong>stitutionally-dependent<br />
c. Widely available and most common means of replac<strong>in</strong>g depleted coagulation fact<strong>or</strong>s and urgently<br />
revers<strong>in</strong>g coagulopathy<br />
i. Indications: active bleed<strong>in</strong>g and PT <strong>or</strong> PTT > 1.5 times n<strong>or</strong>mal, <strong>or</strong> an INR > 1.5<br />
ii. Many protocols suggest transfus<strong>in</strong>g <strong>FFP</strong> after patient has received 4-6 units pRBCs; however,<br />
becom<strong>in</strong>g m<strong>or</strong>e common to transfuse earlier due to development of post-traumatic coagulopathy 12<br />
d. Drawbacks 15,23<br />
i. Low and variable amounts of coagulation fact<strong>or</strong>s unpredictable reversal of VKA therapy<br />
ii. Recommended dosage of ~15 mL/kg often <strong>in</strong>sufficient to c<strong>or</strong>rect coagulopathy<br />
1. Some recommend 10-30 mL/kg 21<br />
iii. Large volume risk of volume overload<br />
1. Patients on VKA often elderly, may have compromised and vulnerable cardiovascular system<br />
iv. Delay <strong>in</strong> adm<strong>in</strong>istration – thaw<strong>in</strong>g takes ~30 m<strong>in</strong><br />
1. Thawed plasma: <strong>FFP</strong> that has been thawed and kept at 1-6°C f<strong>or</strong> up to 5 days –<br />
except f<strong>or</strong> differences <strong>in</strong> FVII levels, thawed plasma and <strong>FFP</strong> considered equivalent <strong>in</strong> terms of<br />
fact<strong>or</strong> concentrations 27,28<br />
v. Risk of transfusion-related acute lung <strong>in</strong>jury (TRALI) – estimated <strong>in</strong>cidence of 8-25%<br />
1. Most common cause of transfusion-related death <strong>in</strong> the US<br />
vi. Citrate toxicity<br />
vii. Transmission of viral illness (low risk)<br />
XIII. Prothromb<strong>in</strong> complex concentrate (<strong>PCC</strong>) 14,21,23,29<br />
a. FDA labeled <strong>in</strong>dication: prevention and control of bleed<strong>in</strong>g due to fact<strong>or</strong> IX deficiency <strong>in</strong> hemophilia B<br />
i. Produced from pooled human plasma<br />
ii. Conta<strong>in</strong>s standardized, although variable, amount of coagulation fact<strong>or</strong>s<br />
iii. Virus-<strong>in</strong>activated<br />
iv. Not blood-group specific<br />
v. M<strong>in</strong>imal risk of volume overload<br />
1. 10 mL diluent per vial<br />
b. F<strong>or</strong>mulations 30 (SEE APPENDIX D)<br />
i. Conta<strong>in</strong>s fact<strong>or</strong>s II, +/- VII, IX, X, +/- coagulation <strong>in</strong>hibit<strong>or</strong>s prote<strong>in</strong> C and S, +/- hepar<strong>in</strong> (0.2-15<br />
units/mL)<br />
ii. Low levels FVII = 3-fact<strong>or</strong> <strong>PCC</strong> (Profiln<strong>in</strong>e ® SD, Bebul<strong>in</strong> ® VH) – only f<strong>or</strong>mulations available <strong>in</strong> the US<br />
iii. High levels FVII = 4-fact<strong>or</strong> <strong>PCC</strong> (Beriplex ® VH, Octaplex ® )<br />
iv. Dose expressed as units of FIX<br />
v. Considerable differences between <strong>PCC</strong>s <strong>in</strong> quantities of coagulation fact<strong>or</strong>s<br />
vi. 2012 CHEST guidel<strong>in</strong>es 22 recommend 4-fact<strong>or</strong> <strong>PCC</strong> over <strong>FFP</strong> f<strong>or</strong> VKA-associated bleed<strong>in</strong>g<br />
c. 3-fact<strong>or</strong> <strong>PCC</strong> ± thawed plasma <strong>in</strong> supratherapeutic INR reversal 27<br />
i. Retrospective case series<br />
ii. 82 patients with INR > 5.0, excluded <strong>in</strong>tracranial hem<strong>or</strong>rhage<br />
iii. Adm<strong>in</strong>istration of thawed plasma alone OR 3-fact<strong>or</strong> <strong>PCC</strong> (25 units/kg <strong>or</strong> 50 units/kg) alone not<br />
sufficient <strong>in</strong> provid<strong>in</strong>g satisfact<strong>or</strong>y INR c<strong>or</strong>rection (< 3.0) <strong>in</strong> 42-62% patients<br />
iv. Addition of 2.1 units thawed plasma to <strong>PCC</strong> significantly improved prop<strong>or</strong>tion of patients<br />
achiev<strong>in</strong>g adequate INR (89-93%)<br />
d. Optimal dosage f<strong>or</strong> a given situation is unclear 31<br />
i. Influenced by several fact<strong>or</strong>s: urgency of reversal, risks f<strong>or</strong> thrombosis, traumatic <strong>in</strong>jury, and level<br />
of anticoagulation bef<strong>or</strong>e and after adm<strong>in</strong>istration of reversal strategy<br />
ii. Recommended maximum rate of <strong>in</strong>fusion is 3 mL/m<strong>in</strong>; up 10 mL/m<strong>in</strong> has been rep<strong>or</strong>ted without<br />
complications (ie. thrombosis)<br />
iii. Reversal of INR occurs with<strong>in</strong> 10-30 m<strong>in</strong>, duration 6-96 hrs<br />
R. Sohraby 7
e. Maj<strong>or</strong> drawback: risk of thrombotic complications 15,30,32,33<br />
i. Hemophilia B: deep ve<strong>in</strong> thrombosis, DIC, pulmonary embolisms, and acute myocardial <strong>in</strong>farctions<br />
rep<strong>or</strong>ted (1960s-80s) 33<br />
1. Supra-physiological levels of other fact<strong>or</strong>s (besides IX) <strong>in</strong> the preparation<br />
2. Repetitive dos<strong>in</strong>g<br />
ii. Cause may be due to activated fact<strong>or</strong> IX <strong>or</strong> presence of procoagulant phospholipids 33<br />
1. Reduction <strong>in</strong> thromboembolic complications among hemophilia B patients when highlypurified<br />
fact<strong>or</strong> IX began to replace <strong>PCC</strong>s – despite higher levels of fact<strong>or</strong> IX compared with <strong>PCC</strong><br />
2. Prothromb<strong>in</strong> cited to be maj<strong>or</strong> determ<strong>in</strong>ant of excessive thromb<strong>in</strong> generation <strong>in</strong> <strong>PCC</strong><br />
iii. Inclusion of coagulation <strong>in</strong>hibit<strong>or</strong>s – hepar<strong>in</strong>, antithromb<strong>in</strong>, prote<strong>in</strong> C, S, Z – may provide “balance”<br />
to coagulation fact<strong>or</strong>s, avoid<strong>in</strong>g excessive <strong>in</strong>crease <strong>in</strong> thromb<strong>in</strong> generation and reduc<strong>in</strong>g<br />
thrombotic risk 33<br />
iv. Incidence unknown – varies based on <strong>PCC</strong> content, dosage, concurrent use of procoagulants, and<br />
patient-specific risk fact<strong>or</strong>s (age, liver disease, surgery, hist<strong>or</strong>y of thrombosis)<br />
v. No evidence to suggest difference <strong>in</strong> thromboembolic risk between 3- and 4-fact<strong>or</strong> <strong>PCC</strong>s 33<br />
Dickneite G, et al. Prothromb<strong>in</strong> complex concentrate vs. fresh frozen plasma f<strong>or</strong> reversal of dilutional<br />
coagulopathy <strong>in</strong> a p<strong>or</strong>c<strong>in</strong>e trauma model. 2009. 34<br />
Design<br />
Randomized, placebo-controlled trial <strong>in</strong> pigs<br />
Population<br />
47 anaesthetized, mildly hypothermic (36°C) pigs<br />
Interventions<br />
65-70% of total blood volume substituted <strong>in</strong> phases with hydroxyethyl starch and pRBCs<br />
Randomized to receive: 15 mL/kg isotonic sal<strong>in</strong>e, 25 units/kg <strong>PCC</strong>, <strong>or</strong> standard-dose (15<br />
mL/kg) <strong>or</strong> high-dose (40 mL/kg) p<strong>or</strong>c<strong>in</strong>e <strong>FFP</strong><br />
4-fact<strong>or</strong> <strong>PCC</strong> used<br />
Immediately after treatment given, standardized <strong>in</strong>jury <strong>in</strong>flicted<br />
Endpo<strong>in</strong>ts<br />
PT, thromb<strong>in</strong> generation, time to hemostasis, volume of blood loss<br />
Results<br />
<strong>PCC</strong> therapy fully reversed prolonged PT and c<strong>or</strong>rected reduced peak thromb<strong>in</strong> generation<br />
Compared with 15 mL/kg <strong>FFP</strong>, <strong>PCC</strong> sh<strong>or</strong>ted time to hemostasis after either bone <strong>or</strong> spleen<br />
trauma, and reduced volume of blood loss<br />
Take Home Po<strong>in</strong>ts <strong>PCC</strong> 25 units/kg effective <strong>in</strong> c<strong>or</strong>rect<strong>in</strong>g dilutional coagulopathy and controll<strong>in</strong>g bleed<strong>in</strong>g when<br />
adm<strong>in</strong>istered pri<strong>or</strong> to trauma<br />
Grottke O, et al. Increas<strong>in</strong>g concentrations of prothromb<strong>in</strong> complex concentrate <strong>in</strong>duce dissem<strong>in</strong>ated<br />
<strong>in</strong>travascular coagulation <strong>in</strong> a pig model of coagulopathy with blunt liver <strong>in</strong>jury. 2011. 30<br />
Design<br />
Randomized, placebo-controlled trial <strong>in</strong> pigs<br />
Population<br />
27 anaesthetized pigs<br />
Interventions<br />
Coagulopathy <strong>in</strong>duced by replac<strong>in</strong>g ~70% blood volume with hydroxyethyl starch and<br />
R<strong>in</strong>ger’s lactate solution<br />
RBCs collected and re-transfused<br />
10 m<strong>in</strong> after trauma, animals randomly received 4-fact<strong>or</strong> <strong>PCC</strong> (35 <strong>or</strong> 50 units/kg) <strong>or</strong> sal<strong>in</strong>e<br />
Endpo<strong>in</strong>ts<br />
Blood loss; survival; presence of emboli<br />
Results<br />
Total blood loss significantly lower and survival higher <strong>in</strong> low- and high-dose <strong>PCC</strong> groups vs.<br />
sal<strong>in</strong>e group (p
f. The<strong>or</strong>ies beh<strong>in</strong>d mechanism 37<br />
i. Orig<strong>in</strong>al thought: supra-physiological concentrations speed up tissue FVIIa-mediated reaction,<br />
result<strong>in</strong>g <strong>in</strong> m<strong>or</strong>e thromb<strong>in</strong> generation<br />
1. Problem: concentrations of rFVIIa required f<strong>or</strong> hemostatic efficacy were far greater than what<br />
would be required to saturate TF<br />
ii. Cell-based system: rFVIIa can b<strong>in</strong>d to platelets and directly activate FX and FIX without TF<br />
iii. Recent data: when adm<strong>in</strong>istered <strong>in</strong> doses sufficient to bypass need f<strong>or</strong> FVIII <strong>or</strong> FIX, rFVIIa b<strong>in</strong>ds to<br />
surface of activated platelets <strong>in</strong> TF-<strong>in</strong>dependent manner and promotes FX activation and<br />
thromb<strong>in</strong> generation<br />
XV. Summary of available options 21<br />
Characteristic <strong>FFP</strong> <strong>PCC</strong> rFVIIa<br />
FII<br />
FVII<br />
FIX<br />
FX<br />
✓<br />
✓<br />
✓<br />
✓<br />
✓<br />
+/-<br />
✓<br />
✓<br />
✓<br />
Other<br />
Fibr<strong>in</strong>ogen<br />
vWF<br />
Antithromb<strong>in</strong><br />
+/- Prote<strong>in</strong>s C and S<br />
+/- Hepar<strong>in</strong><br />
Time to effect 10 m<strong>in</strong> 10 m<strong>in</strong> 10 m<strong>in</strong><br />
t1/2 1.5-2 days 6-8 hrs < 60 m<strong>in</strong><br />
CLINICAL EVIDENCE : WIT H PR E -INJUR Y WAR F AR IN<br />
Nishijima DK, et al. The efficacy of fact<strong>or</strong> VIIa <strong>in</strong> emergency department patients with warfar<strong>in</strong> use and traumatic<br />
<strong>in</strong>tracranial hem<strong>or</strong>rhage. 2010. 39<br />
Design<br />
Retrospective bef<strong>or</strong>e-and-after study<br />
Population 40 patients with pre-<strong>in</strong>jury warfar<strong>in</strong> use, traumatic <strong>in</strong>tracranial hem<strong>or</strong>rhage, and INR ≥ 1.3<br />
Protocol: adm<strong>in</strong>istration of 1.2 mg rFVIIa <strong>in</strong> the ED and standard treatment (<strong>FFP</strong> + vitam<strong>in</strong> K)<br />
Endpo<strong>in</strong>ts Primary: <strong>in</strong>-hospital m<strong>or</strong>tality<br />
Secondary: m<strong>or</strong>tality at 48 hrs and 30 days; successful reversal of anticoagulation (INR
Chapman SA, et al. Prothromb<strong>in</strong> complex concentrate versus standard therapies f<strong>or</strong> INR reversal <strong>in</strong> trauma<br />
patients receiv<strong>in</strong>g warfar<strong>in</strong>. 2011. 16<br />
Design<br />
Retrospective case series<br />
Population 31 total patients: received warfar<strong>in</strong> pre-<strong>in</strong>jury; INR > 1.5; received vitam<strong>in</strong> K, <strong>FFP</strong>, and/<strong>or</strong> <strong>PCC</strong><br />
Exclusion criteria: received rFVIIa<br />
Endpo<strong>in</strong>ts Achievement of INR ≤ 1.5; time to INR ≤ 1.5; INR change from basel<strong>in</strong>e (%); m<strong>or</strong>tality; LOS<br />
Results<br />
Basel<strong>in</strong>e: <strong>PCC</strong> patients had higher ISS (17.8 vs. 9.1, p < 0.001) and m<strong>or</strong>e required surgical <strong>in</strong>tervention<br />
(7 vs. 2, p=0.017); otherwise, no differences<br />
o Average age ~70 years, mean GCS ~14, ~one-third with “fall”, ~25% with traumatic bra<strong>in</strong> <strong>in</strong>jury<br />
o Mean INR 3.03 <strong>in</strong> <strong>PCC</strong> group, 2.77 <strong>in</strong> no-<strong>PCC</strong> group (p=0.78)<br />
Treatment:<br />
o <strong>PCC</strong> group: 36% received vitam<strong>in</strong> K, 85% received <strong>FFP</strong> (average ~4 units), average dose ~25.6<br />
units/kg<br />
o No-<strong>PCC</strong> group: 61% received vitam<strong>in</strong> K, 89% received <strong>FFP</strong> (average ~5.1 units)<br />
INR outcome:<br />
o Similar prop<strong>or</strong>tion achiev<strong>in</strong>g INR ≤ 1.5 (~90%)<br />
o Sh<strong>or</strong>ter time to INR ≤ 1.5 <strong>in</strong> <strong>PCC</strong> group (17 hrs vs. 30 hrs, p=0.048)<br />
o Similar change from basel<strong>in</strong>e INR between groups<br />
M<strong>or</strong>tality: 3 <strong>in</strong> <strong>PCC</strong> group (23.1%) vs. 0 <strong>in</strong> no-<strong>PCC</strong> group (p=0.06)<br />
LOS: ICU LOS similar between groups (9.1 vs. 6.1 days, p=0.17); hospital LOS similar (11.4 days vs. 9.7<br />
days, p=0.26)<br />
Take Home 3-fact<strong>or</strong> <strong>PCC</strong> ~25 units/kg allows faster achievement to goal INR when used <strong>in</strong> trauma<br />
Po<strong>in</strong>ts<br />
Sicker basel<strong>in</strong>e characteristics <strong>in</strong> 3-fact<strong>or</strong> <strong>PCC</strong> group likely cause of m<strong>or</strong>tality and LOS difference<br />
Sarode R, et al. Rapid warfar<strong>in</strong> reversal: a 3-fact<strong>or</strong> prothromb<strong>in</strong> complex concentrate and recomb<strong>in</strong>ant fact<strong>or</strong><br />
VIIa cocktail f<strong>or</strong> <strong>in</strong>tracerebral hem<strong>or</strong>rhage. 2011. 40<br />
Design Retrospective case series<br />
Population 46 patients admitted f<strong>or</strong> warfar<strong>in</strong>-related <strong>in</strong>tracerebral hem<strong>or</strong>rhage<br />
“Trauma Coumad<strong>in</strong> Protocol” (TCP) group = 3- fact<strong>or</strong> <strong>PCC</strong> 4000 units + rFVIIa 1.0 mg + vitam<strong>in</strong> K 5 mg<br />
IV daily x 3 days<br />
Control group: hist<strong>or</strong>ical, received <strong>FFP</strong> <strong>or</strong> <strong>FFP</strong> + 3-fact<strong>or</strong> <strong>PCC</strong>, unknown amounts of vitam<strong>in</strong> K<br />
Endpo<strong>in</strong>ts Pre/post- TCP INR; INR at 24 hrs; time to INR c<strong>or</strong>rection; thromboembolisms; m<strong>or</strong>tality<br />
Results<br />
Mean<br />
Mean time from blood Mean post<strong>in</strong>fusion<br />
INR<br />
Treatment<br />
basel<strong>in</strong>e INR bank dispense to next INR<br />
Mean INR at 24 hrs<br />
TCP: 3-fact<strong>or</strong><br />
<strong>PCC</strong> + rFVIIa +<br />
3.4 176 m<strong>in</strong> 1.0 1.2<br />
vitam<strong>in</strong> K (n=46)<br />
Take Home<br />
Po<strong>in</strong>ts<br />
<strong>FFP</strong> (n=3) 2.6 406 m<strong>in</strong> 1.6 1.6<br />
<strong>FFP</strong> + <strong>PCC</strong> (n=9) 3.3 217 m<strong>in</strong> 1.4 1.3<br />
p-value NS 0.048* 0.0036*, 0.0019** 0.0056*,0.025**<br />
*TCP vs. <strong>FFP</strong><br />
**TCP vs. <strong>FFP</strong>+<strong>PCC</strong><br />
TCP group: 2 NSTEMIs (1 received 2.4 mg rFVIIa); 4 died with<strong>in</strong> 24 hrs; 3 died with<strong>in</strong> 72 hrs<br />
30 days post-TCP: 10 died, 17 survived, 19 lost to follow-up<br />
Comb<strong>in</strong>ation 3-fact<strong>or</strong> <strong>PCC</strong> + low-dose rFVIIa improved INR c<strong>or</strong>rection <strong>in</strong> <strong>in</strong>tracerebral hem<strong>or</strong>rhage,<br />
despite sh<strong>or</strong>ter time from blood bank dispense to next INR measurement<br />
No comparison group f<strong>or</strong> thrombotic events and m<strong>or</strong>tality<br />
XVI. <strong>PCC</strong> and thrombosis <strong>in</strong> VKA reversal 33<br />
a. Possible underly<strong>in</strong>g thrombotic risk fact<strong>or</strong>s may be unmasked when anticoagulation is reversed<br />
b. Review of 14 studies (460 patients) <strong>in</strong> anticoagulation reversal showed no evidence of DIC<br />
i. Seven thrombotic complications (4/7 not attributable to <strong>PCC</strong> therapy)<br />
ii. Three cases attributed to <strong>PCC</strong> were <strong>in</strong> patients with extensive co-m<strong>or</strong>bidities<br />
c. Possibility that <strong>PCC</strong> therapy <strong>in</strong>creases thrombotic risk, but unlikely that <strong>PCC</strong> alone is the cause<br />
R. Sohraby 10
Kal<strong>in</strong>a M, et al. A protocol f<strong>or</strong> the rapid n<strong>or</strong>malization of INR <strong>in</strong> trauma patients with <strong>in</strong>tracranial hem<strong>or</strong>rhage on prescribed<br />
warfar<strong>in</strong> therapy. 2008. 41<br />
Purpose To evaluate efficacy and safety of a Proplex T protocol f<strong>or</strong> rapid reversal of warfar<strong>in</strong>-<strong>in</strong>duced coagulopathy<br />
Design Study group: prospective<br />
Control group: hist<strong>or</strong>ical<br />
Patient Inclusion<br />
Population Trauma patients<br />
Hist<strong>or</strong>y of prescribed warfar<strong>in</strong> therapy<br />
Intracranial hem<strong>or</strong>rhage on CT scan<br />
INR >1.5<br />
Outcomes ICU length of stay; hospital length of stay; INR; Delta INR; Time to complete reversal of coagulopathy; Time to operate<br />
procedure; Use of <strong>FFP</strong> and vitam<strong>in</strong> K; M<strong>or</strong>tality<br />
Methods<br />
Patients who met <strong>in</strong>clusion criteria received weight-based dose of <strong>PCC</strong>, Proplex T, acc<strong>or</strong>d<strong>in</strong>g to manufacturer<br />
guidel<strong>in</strong>es f<strong>or</strong> n<strong>or</strong>malization of coagulopathy<br />
o 1 unit/kg * body weight <strong>in</strong> kg * % desired <strong>in</strong>crease <strong>in</strong> plasma fact<strong>or</strong> IX<br />
Proplex T: conta<strong>in</strong>s concentrated f<strong>or</strong>ms of fact<strong>or</strong>s II, VII, IX, and X<br />
Control group: hist<strong>or</strong>ical; received <strong>FFP</strong> + vitam<strong>in</strong> K<br />
Statistics<br />
Perf<strong>or</strong>med us<strong>in</strong>g Chi 2 and Fisher’s exact test f<strong>or</strong> nom<strong>in</strong>al variables<br />
Mann Whitney U f<strong>or</strong> non-n<strong>or</strong>mally distributed cont<strong>in</strong>uous variables<br />
Significance denoted by a P ≤0.05<br />
Results Control group (n=65) vs. study/protocol group (n=46):<br />
Patient groups:<br />
111 trauma patients 46 patients <strong>in</strong> the study group, 65 patients <strong>in</strong> the control group<br />
Mean age ~77 years<br />
GCS ~12 <strong>in</strong> both groups<br />
100% of patients were <strong>in</strong>volved <strong>in</strong> blunt trauma – falls and mot<strong>or</strong> vehicle accidents<br />
Similar demographics, ISS, GCS, and head AIS<br />
Increased number of patients receiv<strong>in</strong>g <strong>PCC</strong> (54.3% vs. 35.4%, p=0.047)<br />
Use of <strong>FFP</strong> and vitam<strong>in</strong> K was similar between groups<br />
Parameters of coagulopathy reversal & outcomes:<br />
Improved time to n<strong>or</strong>malization of INR (INR ≤ 1.5) <strong>in</strong> study group (331.3 vs. 737.8 m<strong>in</strong>, p=0.048)<br />
Improved number of patients with a therapeutic reversal of coagulopathy <strong>in</strong> study group (73.2% vs. 50.9%, p=0.026)<br />
Improved time to the operat<strong>in</strong>g room <strong>in</strong> study group (222.6 vs. 351.3 m<strong>in</strong>, p=0.045)<br />
No significant difference <strong>in</strong> ICU length of stay (~6-7 days), hospital length of stay (~10-13 days), <strong>or</strong> m<strong>or</strong>tality (~23%)<br />
between groups<br />
<strong>PCC</strong> use (n=48) vs. no <strong>PCC</strong> use (n=63):<br />
Patient groups:<br />
Patients who received <strong>PCC</strong> had higher head AIS sc<strong>or</strong>es (4 vs. 3, p=0.003); lower GCS sc<strong>or</strong>es (10 vs. 13, p=0.002)<br />
Parameters of coagulopathy reversal & outcomes:<br />
Longer ICU days (7 vs. 5 days, p=0.01), and longer hospital days (14 vs. 9 days, p=0.02) <strong>in</strong> <strong>PCC</strong> group<br />
Improved time to n<strong>or</strong>malization of INR <strong>in</strong> <strong>PCC</strong> group (327 vs. 758 days, p
CLINICAL EVIDENCE : WIT HOUT PR E -INJUR Y WAR F AR IN<br />
XVII. Review of rFVIIa f<strong>or</strong> refract<strong>or</strong>y bleed<strong>in</strong>g <strong>in</strong> non-hemophilic patients 42<br />
a. 26 trauma cases of excessive bleed<strong>in</strong>g (13 blunt, 13 penetrat<strong>in</strong>g)<br />
b. Average adm<strong>in</strong>istered pre-treatment: 38 units pRBC + 24 units <strong>FFP</strong> + 24 units platelets<br />
c. rFVIIa achieved hemostasis <strong>in</strong> 20/26 (77%); 17/20 (85%) with achieved hemostasis survived<br />
i. All 3 who died after achiev<strong>in</strong>g hemostasis died from sepsis and multi-system <strong>or</strong>gan failure<br />
XVIII. Review of rFVIIa <strong>in</strong> life-threaten<strong>in</strong>g hem<strong>or</strong>rhage <strong>in</strong> trauma patients 43<br />
a. 126 different patients with trauma-related bleed<strong>in</strong>g and associated coagulopathy<br />
b. Dos<strong>in</strong>g ranged from 36-240 mcg/kg (s<strong>in</strong>gle <strong>or</strong> multiple doses)<br />
i. Variable nature and severity of refract<strong>or</strong>y bleed<strong>in</strong>g<br />
c. Efficacy results<br />
i. In 100/126 (79%) evaluable patients, rFVIIa adm<strong>in</strong>istration associated with rapid reduction <strong>or</strong><br />
cessation of blood loss, decrease <strong>in</strong> pRBC requirements, and prevention of imm<strong>in</strong>ent death<br />
1. ~21% failed to respond to rFVIIa; all non-responders died from exsangu<strong>in</strong>ation<br />
ii. Long-term survival available f<strong>or</strong> 116/126<br />
1. 59 (51%) survived to recovery <strong>or</strong> rehabilitation<br />
d. Safety results<br />
i. No non-thrombotic adverse events rep<strong>or</strong>ted <strong>in</strong> any publications<br />
ii. Thromboembolic events observed <strong>in</strong> 5/126 (4%) patients<br />
1. Necrotic bowel (n=3), DVT (n=1), cerebral s<strong>in</strong>us thrombosis (n=1)<br />
2. Unclear whether cases of necrotic bowel attributable to rFVIIa; possibility that rFVIIa allowed<br />
survival of patients who would have otherwise exsangu<strong>in</strong>ated bef<strong>or</strong>e traumatic bowel <strong>in</strong>jury<br />
apparent<br />
iii. 11/17 available autopsy results (Dutton), no evidence of <strong>in</strong>appropriate vascular thrombosis<br />
iv. “These f<strong>in</strong>d<strong>in</strong>gs suggest that rFVIIa may not present any immediate safety concerns”<br />
Boffard KD, et al. Recomb<strong>in</strong>ant fact<strong>or</strong> VIIa as adjunctive therapy f<strong>or</strong> bleed<strong>in</strong>g control <strong>in</strong> severely <strong>in</strong>ured trauma patients: two<br />
parallel randomized, placebo-controlled, double-bl<strong>in</strong>d cl<strong>in</strong>ical trials. 2005. 44<br />
Purpose To evaluate efficacy and safety of rFVIIa as adjunctive therapy f<strong>or</strong> control of bleed<strong>in</strong>g <strong>in</strong> patients with severe blunt <strong>or</strong><br />
penetrat<strong>in</strong>g trauma<br />
Design Two parallel randomized, placebo-controlled, double-bl<strong>in</strong>d trials (one <strong>in</strong> blunt trauma, one <strong>in</strong> penetrat<strong>in</strong>g trauma)<br />
conducted simultaneously<br />
Patient Patients with severe blunt and/<strong>or</strong> penetrat<strong>in</strong>g trauma<br />
Population Inclusion:<br />
Severe trauma, def<strong>in</strong>ed as those suffer<strong>in</strong>g physical <strong>in</strong>jury requir<strong>in</strong>g 6 units of RBCs with<strong>in</strong> 4 hrs of admission<br />
Known age 16-64 years<br />
Exclusion:<br />
Cardiac arrest pre-hospital <strong>or</strong> <strong>in</strong> the emergency <strong>or</strong> operat<strong>in</strong>g room bef<strong>or</strong>e trial drug adm<strong>in</strong>istration<br />
Gunshot wound to the head<br />
GCS < 8 unless <strong>in</strong> the presence of a n<strong>or</strong>mal CT scan<br />
Base deficit > 15 mEq/L <strong>or</strong> severe acidosis with pH < 7.0<br />
Transfusion of ≥ 8 units RBCs bef<strong>or</strong>e arrival at the trauma center<br />
Injury susta<strong>in</strong>ed ≥12 hrs bef<strong>or</strong>e randomization<br />
Outcomes<br />
Primary: number of RBC units transfused dur<strong>in</strong>g 48-hr period after first dose of trial product<br />
Secondary: requirement f<strong>or</strong> other transfusion products, m<strong>or</strong>tality, days on the ventilat<strong>or</strong>, days <strong>in</strong> the ICU<br />
Methods<br />
Patients assigned to either blunt <strong>or</strong> penetrat<strong>in</strong>g trauma trial<br />
On receiv<strong>in</strong>g 6 units of RBCs with<strong>in</strong> a 4-hr period, eligible patients with<strong>in</strong> each trial equally randomized to receive<br />
either three IV <strong>in</strong>jections of rFVIIa (200 + 100 + 100 mcg/kg) <strong>or</strong> three placebo <strong>in</strong>jections<br />
First dose of trial product adm<strong>in</strong>istered after transfusion of 8 units RBCs; second and third doses followed 1 and 3 hrs<br />
after the first dose, respectively<br />
Statistics<br />
140 patients required <strong>in</strong> each trauma trial to detect difference with 80% power and 5% type I err<strong>or</strong><br />
One-sided Wilcoxon-Mann-Whitney rank test: total number of RBC units transfused with<strong>in</strong> 48 hrs from the start of<br />
trial product treatment compared between treatment groups<br />
o Hodges-Lehmann estimate: difference <strong>in</strong> RBC transfusions<br />
Fisher’s exact test: number of patients requir<strong>in</strong>g massive transfusion (> 20 units of RBCs – def<strong>in</strong>ed post-hoc) and<br />
number of patients experienc<strong>in</strong>g either MOF, ARDS, <strong>or</strong> death with<strong>in</strong> 30 days<br />
R. Sohraby 12
Statistics<br />
(cont<strong>in</strong>ued)<br />
Results<br />
Chi 2 test<strong>in</strong>g: effects on 48 hr m<strong>or</strong>tality<br />
Wilcoxon-Mann-Whitney rank test: (post-hoc) ventilat<strong>or</strong>-free and ICU-free days with<strong>in</strong> 30 days of trial product use<br />
Patient groups:<br />
143 patients eligible f<strong>or</strong> analysis <strong>in</strong> blunt trauma trial: 74 placebo + 69 rFVIIa<br />
124 patients eligible f<strong>or</strong> analysis <strong>in</strong> penetrat<strong>in</strong>g trauma trial: 64 placebo + 70 rFVIIa<br />
Treatment groups well-matched <strong>in</strong> both trauma populations<br />
Predom<strong>in</strong>antly male patients; characterized by be<strong>in</strong>g coagulopathic, acidotic, and hypothermic<br />
Causes of penetrat<strong>in</strong>g trauma primarily gunshots (68%) and stab wounds (30%); 77% of blunt trauma due to trafficrelated<br />
<strong>in</strong>jury<br />
Transfusion requirements:<br />
Blunt trauma patients: rFVIIa reduced 48-hr requirements by 2.6 units (p=0.02); need f<strong>or</strong> massive transfusion<br />
reduced from 33% of patients <strong>in</strong> placebo group to 14% of patients <strong>in</strong> the rFVIIa group (p=0.03)<br />
Penetrat<strong>in</strong>g trauma patients: no significant effect of rFVIIa <strong>in</strong> 48-hr RBC requirements; need f<strong>or</strong> massive transfusion<br />
reduced from 19% <strong>in</strong> the placebo group to 7% <strong>in</strong> the rFVIIa group (p=0.08)<br />
No statistical difference <strong>in</strong> patients who died to the w<strong>or</strong>st outcome<br />
No significant differences <strong>in</strong> adm<strong>in</strong>istration of fresh frozen plasma, platelets, n<strong>or</strong> cryoprecipitate<br />
Auth<strong>or</strong>s’<br />
Conclusions<br />
Take Home<br />
Po<strong>in</strong>ts<br />
Critique<br />
Cl<strong>in</strong>ical outcome and safety:<br />
Positive trends <strong>in</strong> fav<strong>or</strong> of rFVIIa f<strong>or</strong> death, critical complications (MOF and ARDS)<br />
Overall similar ADR profiles between groups <strong>in</strong> both trials<br />
12 thromboembolic ADRs rep<strong>or</strong>ted dur<strong>in</strong>g both trials: 6 <strong>in</strong> rFVIIa-treated patients, 6 <strong>in</strong> placebo-treated patients<br />
rFVIIa significantly improved bleed<strong>in</strong>g control, as reflected by the decrease <strong>in</strong> RBC transfusion requirements and the<br />
number of patients requir<strong>in</strong>g massive transfusion <strong>in</strong> a population of blunt trauma patients with severe bleed<strong>in</strong>g and<br />
coagulopathy secondary to the traumatic <strong>in</strong>jury<br />
rFVIIa appears to be a promis<strong>in</strong>g adjunct to exist<strong>in</strong>g therapy with<strong>in</strong> trauma<br />
In blunt trauma patients, rFVIIa reduced RBC requirements and need f<strong>or</strong> massive transfusion<br />
No difference between placebo and rFVIIa groups <strong>in</strong> m<strong>or</strong>tality<br />
Similar thromboembolism ADRs rep<strong>or</strong>ted between groups <strong>in</strong> both trials<br />
Power not met on RBC transfusion endpo<strong>in</strong>ts <strong>in</strong> penetrat<strong>in</strong>g trauma population; likely expla<strong>in</strong>ed by higher prop<strong>or</strong>tion<br />
of surgically treatable bleed<strong>in</strong>g<br />
Data on thromboembolic complications collected through adverse event rep<strong>or</strong>t<strong>in</strong>g only – likely underrep<strong>or</strong>t<strong>in</strong>g of<br />
asymptomatic thromboembolic events<br />
Differences <strong>in</strong> patient management across regions and trial centers due to complexity of study population and<br />
diversity of choices faced by trauma teams – despite adherence to trial protocol<br />
o Potential <strong>in</strong>fluence of site-specific effects on RBC reduction assessed by parametric analysis of the ranks<br />
<strong>in</strong>clud<strong>in</strong>g a site effect and a site-treatment <strong>in</strong>teraction – effect of treatment was <strong>in</strong>dependent of site (p=0.24) f<strong>or</strong><br />
the site vs. treatment <strong>in</strong>teraction<br />
Transfusion therapy not standardized care; confound<strong>in</strong>g variable, yet used as primary endpo<strong>in</strong>t<br />
o Placebo group acted as control across census<br />
Upper limit dosage used to assess safety<br />
Per auth<strong>or</strong>, total rFVIIa dose of 400 mcg/kg achieved FVII level of 40 mcg/L <strong>in</strong> the plasma<br />
o <strong>FFP</strong> and cryoprecipitate (unknown dose) approach ~1/3 of this, and contribute to dilutional coagulopathy<br />
XVX. Safety of rFVIIa <strong>in</strong> off-label trials 45<br />
a. Review of 26 studies <strong>in</strong>volv<strong>in</strong>g 4419 patients<br />
b. All rep<strong>or</strong>ted thrombotic <strong>or</strong> embolic were confirmed by means of objectives tests<br />
i. Arterial (c<strong>or</strong>onary, cerebrovascular, other) and venous<br />
c. Rate of thromboembolic events similar between groups (10.2% <strong>in</strong> rFVIIa vs. 8.7% <strong>in</strong> placebo, p=0.16)<br />
e. Higher arterial thromboembolic event rate <strong>in</strong> rFVIIa group vs. placebo group (5.5% vs. 3.2%, p=0.003)<br />
i. No significant difference <strong>in</strong> <strong>in</strong>cidence of venous thromboembolisms<br />
e. Three trauma studies, n=837 (<strong>in</strong>cluded Boffard et al.)<br />
i. 428 placebo + 409 rFVIIa (20% of total population assessed)<br />
ii. Mean age 36.5 years, all <strong>in</strong> rFVIIa group received > 120 mcg/kg<br />
iii. 4.6% <strong>in</strong>cidence arterial thrombosis vs. 3.5% <strong>in</strong> placebo group (p=0.36)<br />
iv. Boffard et al. trial makes up 32% (277/837); likely underrep<strong>or</strong>t<strong>in</strong>g of asymptomatic<br />
thromboembolic events<br />
R. Sohraby 13
XX. NovoSeven ® package <strong>in</strong>sert 35<br />
a. Black Box Warn<strong>in</strong>g: serious thrombotic adverse events associated with the use of NovoSeven ® RT<br />
outside labeled <strong>in</strong>dications<br />
i. Two meta-analyses: <strong>in</strong>creased risk of thrombotic events (10.0% <strong>in</strong> rFVIIa vs. 7.5% <strong>in</strong> placebo)<br />
ii. Arterial thrombosis (ie. myocardial <strong>in</strong>farction, myocardial ischemia, cerebral <strong>in</strong>farction, cerebral<br />
ischemia) statistically <strong>in</strong>creased with rFVIIa use vs. placebo (5.3-5.6% vs. 2.8-3.0%)<br />
iii. Meta-analysis of cl<strong>in</strong>ical trials did not suggest <strong>in</strong>creased risk of venous thromboembolic events<br />
(4.8% <strong>in</strong> rFVIIa vs. 4.7% <strong>in</strong> placebo)<br />
XXI. Cost<br />
<strong>FFP</strong> <strong>PCC</strong> rFVIIa<br />
Cost $69.00 per unit $0.70 per unit $1.38 per mcg<br />
Dosage<br />
15 mL/kg (~250<br />
mL/units)<br />
25 units/kg 90 mcg/kg<br />
Dosage per 80 kg<br />
7.2 mg<br />
1200 mL (4.8 units) 2000 units<br />
patient<br />
(7 mg – nearest whole vial)<br />
Cost per 80 kg<br />
patient<br />
~$330 ~$1400 ~$9660<br />
XXII. Summary<br />
a. What treatment strategies should be used <strong>in</strong> traumatic bleed<strong>in</strong>g patients on warfar<strong>in</strong> pre-<strong>in</strong>jury?<br />
i. YES: Discont<strong>in</strong>ue warfar<strong>in</strong><br />
1. Natural <strong>in</strong>crease <strong>in</strong> synthesis of clott<strong>in</strong>g fact<strong>or</strong>s<br />
ii. YES: Vitam<strong>in</strong> K 10 mg IV over 10 m<strong>in</strong><br />
1. Directly converted to reduced vitam<strong>in</strong> K, <strong>in</strong>creased production of extr<strong>in</strong>sic clott<strong>in</strong>g fact<strong>or</strong>s<br />
iii. YES: <strong>PCC</strong> 25 units/kg – can repeat dose <strong>in</strong> 30 m<strong>in</strong> if <strong>in</strong>adequate effect<br />
1. Improved time to n<strong>or</strong>malized INR and improved number of patients with therapeutic<br />
reversals of coagulopathy <strong>in</strong> blunt trauma patients 41<br />
i. … But, does the INR represent an adequate assessment of level of hemostasis?<br />
2. No difference <strong>in</strong> m<strong>or</strong>tality, LOS, w<strong>or</strong>sen<strong>in</strong>g <strong>in</strong>tracranial hem<strong>or</strong>rhage 41<br />
3. CHEST guidel<strong>in</strong>es 22 recommend 4-fact<strong>or</strong> <strong>PCC</strong> vs. <strong>FFP</strong> f<strong>or</strong> VKA-associated maj<strong>or</strong> bleed<strong>in</strong>g<br />
(grade 2C); however, unavailable <strong>in</strong> the US<br />
4. Benefit of improved INR vs. risk of thromboembolism<br />
i. Indication of anticoagulation – benefits vs. risks<br />
ii. In 460 patient review, 0.65% thrombotic events attributable to <strong>PCC</strong> therapy 33<br />
iv. YES: <strong>FFP</strong> 5-10 mL/kg<br />
1. Provides FVII, which is lack<strong>in</strong>g <strong>in</strong> 3-fact<strong>or</strong> <strong>PCC</strong> – would the<strong>or</strong>etically provide advantage of<br />
promot<strong>in</strong>g clott<strong>in</strong>g cascade 27<br />
2. Increased prop<strong>or</strong>tion of patients achieved reversal of anticoagulation after <strong>FFP</strong> adm<strong>in</strong>istration<br />
(post-<strong>PCC</strong>) 27<br />
v. NO: rFVIIa<br />
1. Improved time to n<strong>or</strong>malized INR and number of patients achiev<strong>in</strong>g c<strong>or</strong>rected INR 39<br />
2. No difference <strong>in</strong> m<strong>or</strong>tality 39<br />
3. Risk of arterial thrombosis – questionable <strong>in</strong> trauma patients 35,45,46<br />
4. Cost ~7x greater than <strong>PCC</strong><br />
b. What treatment strategies should be used <strong>in</strong> traumatic bleed<strong>in</strong>g patients NOT on warfar<strong>in</strong> pre-<strong>in</strong>jury?<br />
i. YES: 1:1:1 ratio <strong>FFP</strong>, pRBCs, platelets (+ fibr<strong>in</strong>ogen PRN < 100 mg/dL) 14<br />
1. Standard of treatment<br />
ii. YES: <strong>PCC</strong> 25 units/kg – can repeat dose <strong>in</strong> 30 m<strong>in</strong> if <strong>in</strong>adequate effect<br />
1. Consider use <strong>in</strong> refract<strong>or</strong>y bleed<strong>in</strong>g as “last eff<strong>or</strong>t” if <strong>in</strong>adequate response to <strong>FFP</strong>, pRBCs,<br />
platelets, and cryoprecipitate<br />
2. Animal studies – improved coagulation and attenuated blood loss 30,34<br />
3. Consider use if volume-sensitive patient<br />
4. No retrospective n<strong>or</strong> prospective trials to supp<strong>or</strong>t n<strong>or</strong> refute<br />
R. Sohraby 14
iii. NO: rFVIIa<br />
1. Decreased pRBCs used and decreased number of required massive transfusions <strong>in</strong> blunt<br />
trauma patients 44<br />
2. Achieved hemostasis <strong>in</strong> 77% trauma patients 42<br />
2. No difference <strong>in</strong> m<strong>or</strong>tality, LOS 42<br />
3. Risk of arterial thrombosis significant <strong>in</strong> off-label usage – although not significant <strong>in</strong> trauma<br />
patients – based 32% of patients from Boffard et al. trial; likely underrep<strong>or</strong>t<strong>in</strong>g of<br />
asymptomatic thromboembolic events 35,45,46<br />
4. Cost ~7x greater than <strong>PCC</strong><br />
XXIII. Conclusion<br />
R. Sohraby 15
REFERENCES<br />
1. Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and treatment <strong>in</strong> the <strong>in</strong>jured patient.<br />
W<strong>or</strong>ld J Surgery 2007; 31(5):1055-64.<br />
2. American College of Surgeons Committee on Trauma. Advanced Trauma Life Supp<strong>or</strong>t ® f<strong>or</strong> Doct<strong>or</strong>s, Student<br />
Course Manuel. 8 th ed. Chicago, IL: American College of Surgeons;63-4.<br />
3. Dutton RP. Goals of therapy <strong>in</strong> common bleed<strong>in</strong>g emergencies. Pharmacother 2007; 27(9.2):85S-92S.<br />
4. Chapman SA, Irw<strong>in</strong> ED, Beal AL, et al. Prothromb<strong>in</strong> complex concentrate versus standard therapies f<strong>or</strong> INR<br />
reversal <strong>in</strong> trauma patients receiv<strong>in</strong>g warfar<strong>in</strong>. Ann Pharmacother 2011; 45(7-8):869-75.<br />
5. Zehnder JL. Drugs Used <strong>in</strong> Dis<strong>or</strong>ders of <strong>Coagulation</strong>. In: Katzung BG, Masters SB, Trev<strong>or</strong> AJ, et al, eds. Basic &<br />
Cl<strong>in</strong>ical Pharmacology. 11th ed. New Y<strong>or</strong>k, NY: McGraw-Hill; 2009.<br />
http://www.accesspharmacy.com/content.aspx?aID=4513528. Accessed February 4, 2012.<br />
6. Pantanwala AE, Acquisto NM, Erstad BL. Prothromb<strong>in</strong> complex concentrate f<strong>or</strong> critical bleed<strong>in</strong>g. Ann<br />
Pharmacother 2011;45(7):990-9.<br />
7. Gentilello LM. Practical Approaches to Hypothermia. In: Maull KI, Cleveland HC, Feliciano DV, et al, eds.<br />
Advances <strong>in</strong> Trauma and Critical Care. vol 9. St. Louis, MO: Mosby, Inc.; 1994:39–79.<br />
8. Ferrara A, MacArthur JD, Wright HK, et al. Hypothermia and acidosis w<strong>or</strong>sen coagulopathy <strong>in</strong> the patient<br />
requir<strong>in</strong>g massive transfusion. Am J Surg 1990; 160(5):515-8.<br />
9. Johnston TD, Chen Y, Reed RL 2 nd . Functional equivalence of hypothermia to specific clott<strong>in</strong>g fact<strong>or</strong> deficiencies.<br />
J Trauma 1994; 37(3):413-7.<br />
10. Meng ZH, Wolberg AS, Monroe DM 3 rd , et al. The effect of temperature and pH on the activity of fact<strong>or</strong> VIIa:<br />
implications f<strong>or</strong> the efficacy of high-dose fact<strong>or</strong> VIIa <strong>in</strong> hypothermic and acidotic patients. J Trauma 2003;<br />
55(5):886-91.<br />
11. Cosgriff N, Mo<strong>or</strong>e EE, Sauaia A, et al. Predict<strong>in</strong>g life-threaten<strong>in</strong>g coagulopathy <strong>in</strong> the massively transfused<br />
trauma patient: hypothermia and acidosis revisited. J Trauma 1997; 42(5):857-61.<br />
12. Brohi K, S<strong>in</strong>gh J, Heron M, et al. Acute traumatic coagulopathy. J Trauma 2003; 54(6):1127-30.<br />
13. MacLeod JB, Lynn M, McKenney MG, et al. Early coagulopathy predicts m<strong>or</strong>tality <strong>in</strong> trauma. J Trauma 2003;<br />
55(1):39-44.<br />
14. Pagana KD, Pagana TJ. Mosby’s Diagnostic and Lab<strong>or</strong>at<strong>or</strong>y Test Reference. 5 th ed. St. Louis, MO: Mosby, Inc.;<br />
2001:706-9.<br />
15. Fraga GP, Bansal V, Coimbra R. Transfusion of blood products <strong>in</strong> trauma: an update. J Emerg Med 2010;<br />
39(2):253-60.<br />
16. Aiyagari V, Testai FD. C<strong>or</strong>rection of coagulopathy <strong>in</strong> warfar<strong>in</strong> associated cerebral hem<strong>or</strong>rhage. Curr Op<strong>in</strong> Crit<br />
Care 2009; 15(2):87-92.<br />
17. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of vitam<strong>in</strong> K antagonists: American College of<br />
Chest Physicians Evidence-Based Cl<strong>in</strong>ical Practice Guidel<strong>in</strong>es (8 th Edition). Chest 2008; 133(6<br />
Suppl):160S-98S.<br />
18. M<strong>in</strong>a AA, Bair HA, Howells GA, et al. Complications of pre<strong>in</strong>jury warfar<strong>in</strong> use <strong>in</strong> the trauma patient. J Trauma<br />
2003; 54(5):842-7.<br />
19. Oake N, Jenn<strong>in</strong>gs A, F<strong>or</strong>ster AJ, et al. Anticoagulation <strong>in</strong>tensity and outcomes among patients prescribed <strong>or</strong>al<br />
anticoagulant therapy: a systematic review and meta-analysis. Can Med Assoc J 2008; 179(3):235-44.<br />
20. Ivascu FA, Janczyk RJ, Junn FS, et al. Treatment of trauma patients with <strong>in</strong>tracranial hem<strong>or</strong>rhage on pre<strong>in</strong>jury<br />
warfar<strong>in</strong>. J Trauma 2006; 61(2):318-21.<br />
21. Vang ML, Hvas AM, Ravn HB. Urgent reversal of vitam<strong>in</strong> K antagonist therapy. Acta Anaesthe Scand 2011;<br />
55(5):507-16.<br />
22. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic<br />
therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based<br />
Cl<strong>in</strong>ical Practice Guidel<strong>in</strong>es. Chest 2012; 141(2 Suppl):e152S-e84S.<br />
23. McSwa<strong>in</strong> N, Barbeau J. Potential use of prothromb<strong>in</strong> complex concentrate <strong>in</strong> trauma resuscitation. J Trauma<br />
2011; 70(5 Suppl):S53-6.<br />
24. Shires GT, Carrico CJ, Baxter CR, et al. Pr<strong>in</strong>ciples <strong>in</strong> treatment of severely <strong>in</strong>jured patients. Adv Surg 1970;<br />
4:255-324.<br />
25. Holcomb JB. Use of recomb<strong>in</strong>ant activated fact<strong>or</strong> VII to treat the acquired coagulopathy of trauma. J Trauma<br />
2005; 58(6):1298-303.<br />
26. Duchesne JC, Hunt J, Wahl G, et al. Review of current blood transfusions strategies <strong>in</strong> a mature level I trauma<br />
center: were we wrong f<strong>or</strong> the last 60 years? J Trauma 2009; 65(2):272-6.<br />
27. Holland L, Warkent<strong>in</strong> TE, Refaai M, et al. Suboptimal effect of a three-fact<strong>or</strong> prothromb<strong>in</strong> complex concentrate<br />
(Profiln<strong>in</strong>e-SD) <strong>in</strong> c<strong>or</strong>rect<strong>in</strong>g supratherapeutic <strong>in</strong>ternational n<strong>or</strong>malized ratio due to warfar<strong>in</strong> overdose.<br />
Transfusion 2009; 49(6):1171-7.<br />
R. Sohraby 16
REFERENCES (cont<strong>in</strong>ued)<br />
28. Downes K, Wilson E, Yomtovian R, et al. Serial measurements of clott<strong>in</strong>g fact<strong>or</strong>s <strong>in</strong> thawed plasma st<strong>or</strong>ed f<strong>or</strong> 5<br />
days. Transfusion 2001; 41(4):570.<br />
29. Samama CM. Prothromb<strong>in</strong> complex concentrates: a brief review. Eur J Anaesthesiol 2008; 25(10):784-9.<br />
30. Grottke O, Braunschweig T, Spronk HM, et al. Increas<strong>in</strong>g concentrations of prothromb<strong>in</strong> complex concentrate<br />
<strong>in</strong>duce dissem<strong>in</strong>ated <strong>in</strong>travascular coagulation <strong>in</strong> a pig model of coagulopathy with blunt liver <strong>in</strong>jury.<br />
Blood 2011; 118(7):1943-51.<br />
31. Dager WE. Us<strong>in</strong>g prothromb<strong>in</strong> complex concentrates to rapidly reverse <strong>or</strong>al anticoagulant effects. Ann<br />
Pharmacother 2011; 45(7):1016-20.<br />
32. Godier A, Susen S, Samama CM. Treatment of massive bleed<strong>in</strong>g with prothromb<strong>in</strong> complex concentrate:<br />
argument aga<strong>in</strong>st. J Thromb Haemost 2010; 8(12):2592-5.<br />
33. Sørensen B, Spahn DR, Innerhofer P, et al. Cl<strong>in</strong>ical review: prothromb<strong>in</strong> complex concentrates – evaluation of<br />
safety and thrombogenicity. Crit Care 2011; 15(1):201 (ePub).<br />
34. Dickneite G, Pragst I. Prothromb<strong>in</strong> complex concentrate vs fresh frozen plasma f<strong>or</strong> reversal of dilutional<br />
coagulopathy <strong>in</strong> a p<strong>or</strong>c<strong>in</strong>e trauma model. Brit J Anaesth 2009; 102(3):345-54.<br />
35. NovoSeven ® RT [package <strong>in</strong>sert]. Novo N<strong>or</strong>disk A/S, Bagsvaerd, Denmark; Revised January 2010. Accessed<br />
February 23, 2012.<br />
36. Rizoli SB, Boffard KD, Riou B, et al. Recomb<strong>in</strong>ant activated fact<strong>or</strong> VII as an adjunctive therapy f<strong>or</strong> bleed<strong>in</strong>g<br />
control <strong>in</strong> severe trauma patients with coagulopathy: subgroup analysis from two randomized trials. Crit<br />
Care 2006; 10(6):R178.<br />
37. DeLoughery TG. Management of bleed<strong>in</strong>g emergencies: when to use recomb<strong>in</strong>ant activated Fact<strong>or</strong> VII. Expert<br />
Op<strong>in</strong> Pharmaco 2006; 7(1):25-34.<br />
38. Kenet G, Walden R, Eldad A, et al. Treatment of traumatic bleed<strong>in</strong>g with recomb<strong>in</strong>ant fact<strong>or</strong> VIIa. Lancet 1999;<br />
354(9193):1879.<br />
39. Nishijima DK, Dager WE, Schrot RJ, et al. The efficacy of fact<strong>or</strong> VIIa <strong>in</strong> emergency department patients with<br />
warfar<strong>in</strong> use and traumatic <strong>in</strong>tracranial hem<strong>or</strong>rhage. Acad Emerg Med 2010; 17(3):244-51.<br />
40. Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfar<strong>in</strong> reversal: a 3-fact<strong>or</strong> prothromb<strong>in</strong> complex concentrate<br />
and recomb<strong>in</strong>ant fact<strong>or</strong> VIIa cocktail f<strong>or</strong> <strong>in</strong>tracerebral hem<strong>or</strong>rhage. J Neurosurg published onl<strong>in</strong>e ahead of<br />
pr<strong>in</strong>t 2011.<br />
41. Kal<strong>in</strong>a M, T<strong>in</strong>koff G, Gbadebo A, et al. A protocol f<strong>or</strong> the rapid n<strong>or</strong>malization of INR <strong>in</strong> trauma patients with<br />
<strong>in</strong>tracranial hem<strong>or</strong>rhage on prescribed warfar<strong>in</strong> therapy. Am Surgeon 2008; 74(9):858-61.<br />
42. Barletta JF, Ahrens CL, Tyburski JG, et al. A review of recomb<strong>in</strong>ant fact<strong>or</strong> VII f<strong>or</strong> refract<strong>or</strong>y bleed<strong>in</strong>g <strong>in</strong><br />
nonhemophilic trauma patients. J Trauma 2005; 58(3):646-51.<br />
43. Pape HC, Erhardtsen E, Meyer C, et al. Recomb<strong>in</strong>ant fact<strong>or</strong> VIIa f<strong>or</strong> life-threaten<strong>in</strong>g hem<strong>or</strong>rhage <strong>in</strong> trauma<br />
patients: review of the literature. Eur J Trauma 2006; 32(5):439-48.<br />
44. Boffard KD, Riou B, Warren B, et al. Recomb<strong>in</strong>ant fact<strong>or</strong> VIIa as adjunctive therapy f<strong>or</strong> bleed<strong>in</strong>g control <strong>in</strong><br />
severely <strong>in</strong>ured trauma patients: two parallel randomized, placebo-controlled, double-bl<strong>in</strong>d cl<strong>in</strong>ical trials.<br />
J Trauma 2005; 59:8-18.<br />
45. Levi M, Levy JH, Anderson HF. Safety of recomb<strong>in</strong>ant activated fact<strong>or</strong> VII <strong>in</strong> randomized cl<strong>in</strong>ical trials. N Eng J<br />
Med 2010; 363(19):1791-800.<br />
46. Ferrari L, Podda GM. Off-label use of recomb<strong>in</strong>ant activated coagulation fact<strong>or</strong> VII f<strong>or</strong> bleed<strong>in</strong>g may raise the<br />
risk of arterial thrombosis. Intern Emerg Med 2011; 6(3):261-2.<br />
47. Poon BB, Witmer C, Pruemer J. <strong>Coagulation</strong> Dis<strong>or</strong>ders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds.<br />
Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New Y<strong>or</strong>k, NY: McGraw-Hill; 2011.<br />
http://www.accesspharmacy.com/content.aspx?aID=8000061. Accessed February 26, 2012.<br />
48. Injury Severity Sc<strong>or</strong><strong>in</strong>g. Surgical Critical Care.<br />
http://www.surgicalcriticalcare.net/Resources/<strong>in</strong>jury_severity_sc<strong>or</strong><strong>in</strong>g.pdf. May 29, 2001. Accessed<br />
February 4, 2012.<br />
49. Profiln<strong>in</strong>e ® SD [package <strong>in</strong>sert]. Grifols Biologicals Inc., Los Angeles, CA: 2004. Accessed February 23, 2012.<br />
50. Bebul<strong>in</strong> ® VH [package <strong>in</strong>sert]. Baxter Healthcare C<strong>or</strong>p<strong>or</strong>ation: Westlake Village, CA: Revised September 2006.<br />
Accessed February 23, 2012.<br />
51. Doherty DE. Glasgow Coma Scale. Medscape Pharmacists. http://www.medscape.com/viewarticle/412341.<br />
March 20, 2011. Accessed February 9, 2012.<br />
52. Maas AI, Hukkelhoven CW, Marshall LF, et al. Prediction of outcome <strong>in</strong> traumatic bra<strong>in</strong> <strong>in</strong>jury with computed<br />
tomographic characteristics: a comparison between the computed tomographic classification and<br />
comb<strong>in</strong>ations of computed tomographic predict<strong>or</strong>s. Neurosurgery 2005; 57(6):1173-82.<br />
R. Sohraby 17
APPENDICES<br />
APPENDIX A 2<br />
Estimated blood loss based on patient’s <strong>in</strong>itial presentation<br />
CLASS I CLASS II CLASS III CLASS IV<br />
Blood loss (mL) Up to 750 750-1500 1500-2000 > 2000<br />
Blood loss (% blood Up to 15% 15-30% 30-40% > 40%<br />
volume)<br />
Pulse rate 140<br />
Blood pressure N<strong>or</strong>mal N<strong>or</strong>mal Decreased Decreased<br />
Pulse pressure N<strong>or</strong>mal <strong>or</strong> <strong>in</strong>creased Decreased Decreased Decreased<br />
(mmHg)<br />
Respirat<strong>or</strong>y rate 14-20 20-30 30-40 > 35<br />
Ur<strong>in</strong>e output (mL/hr) >30 20-30 5-15 Negligible<br />
CNS/mental status Slightly anxious Mildly anxious Anxious, confused Confused, lethargic<br />
Fluid replacement Crystalloid Crystalloid Crystalloid and blood Crystalloid and blood<br />
APPENDIX B 47<br />
Blood <strong>Coagulation</strong> <strong>Fact<strong>or</strong>s</strong><br />
Fact<strong>or</strong> Synonym Biologic Half-Life Blood Product Source<br />
I Fibr<strong>in</strong>ogen 100-150 Cryoprecipitate<br />
II Prothromb<strong>in</strong> 50-80 <strong>FFP</strong>, <strong>PCC</strong><br />
V Proacceler<strong>in</strong> 12-36 <strong>FFP</strong><br />
VII Proconvert<strong>in</strong> 4-6 rFVIIa, <strong>FFP</strong>, <strong>PCC</strong><br />
VIII Antihemophilic fact<strong>or</strong> 12-15 <strong>FFP</strong>, fact<strong>or</strong> concentrates, cryoprecipitate<br />
IX Christmas fact<strong>or</strong> 18-30 <strong>FFP</strong>, <strong>PCC</strong>, fact<strong>or</strong> concentrates<br />
X Stuart-Power fact<strong>or</strong> 25-60 <strong>FFP</strong>, <strong>PCC</strong><br />
XI Plasma thromboplast<strong>in</strong> antecedent 40-80 <strong>FFP</strong><br />
XII Hageman fact<strong>or</strong> 50-70 Not associated with bleed<strong>in</strong>g diathesis<br />
XIII Fibr<strong>in</strong>-stabiliz<strong>in</strong>g fact<strong>or</strong> 150 <strong>FFP</strong>, cryoprecipitate, fact<strong>or</strong> concentrate<br />
vWF von Willebrand fact<strong>or</strong> 8-12 <strong>FFP</strong>, cryoprecipitate, fact<strong>or</strong> concentrate<br />
APPENDIX C 48<br />
Injury severity sc<strong>or</strong>e (ISS): anatomical sc<strong>or</strong><strong>in</strong>g system that provides an overall sc<strong>or</strong>e f<strong>or</strong> patients with<br />
multiple <strong>in</strong>juries. Each <strong>in</strong>jury is assigned an abbreviated <strong>in</strong>jury scale (AIS) and is allocated to one of six body<br />
regions. The three most <strong>in</strong>jured body regions have their sc<strong>or</strong>e squared and added together to produce the ISS<br />
sc<strong>or</strong>e. The ISS sc<strong>or</strong>e takes values from 0-75. If an <strong>in</strong>jury is assigned an AIS of 6, the ISS sc<strong>or</strong>e is automatically<br />
assigned to 75.<br />
Abbreviated <strong>in</strong>jury scale (AIS): Injuries are ranked on a scale of 1 to 6, with 1 be<strong>in</strong>g m<strong>in</strong><strong>or</strong>, 5 severe, and 6 a<br />
non-survivable <strong>in</strong>jury. This represents the “threat to life” associated with an <strong>in</strong>jury and is not meant to<br />
represent a comprehensive measure of severity.<br />
Injury AIS Sc<strong>or</strong>e<br />
1 M<strong>in</strong><strong>or</strong><br />
2 Moderate<br />
3 Serious<br />
4 Severe<br />
5 Critical<br />
6 Unsurvivable<br />
Region Injury Description AIS Square Top Three<br />
Head & Neck<br />
Face<br />
Chest<br />
Abdomen<br />
Extremity<br />
External<br />
Injury Severity Sc<strong>or</strong>e:<br />
R. Sohraby 18
APPENDICES (cont<strong>in</strong>ued)<br />
APPENDIX D 49,50<br />
Comparison of <strong>PCC</strong> Products (available <strong>in</strong> the US)<br />
Characteristic Profiln<strong>in</strong>e ® SD Bebul<strong>in</strong> ® VH<br />
Source material<br />
Pooled human plasma<br />
Microbial<br />
Solvent detergent<br />
Vap<strong>or</strong> heated<br />
reduction<br />
F<strong>or</strong>mulation Lyophilized concentrate <strong>in</strong> s<strong>in</strong>gle-dose vials Lyophilized concentrate <strong>in</strong> s<strong>in</strong>gle dose vials<br />
with ~0.15 units hepar<strong>in</strong> per unit fact<strong>or</strong> IX<br />
Fact<strong>or</strong><br />
composition<br />
Approved<br />
<strong>in</strong>dication<br />
St<strong>or</strong>age/shelf-life<br />
Adverse effects<br />
Potency per 1 unit fact<strong>or</strong> IX<br />
100-150 units/mL fact<strong>or</strong> IX<br />
≤ 1.5 units fact<strong>or</strong> II<br />
≤ 1 unit fact<strong>or</strong> X<br />
≤ 0.35 units fact<strong>or</strong> VII<br />
Refrigeration at 2-8 °C until expiration date<br />
Room temperature (≤30 °C) up to 3 months<br />
After reconstitution, use with<strong>in</strong> 3 hrs<br />
Thrombosis<br />
Infectious disease transmission<br />
Infusion reactions<br />
Potency per 1 unit fact<strong>or</strong> IX<br />
24-37.5 units/mL fact<strong>or</strong> IX<br />
~1 unit/mL fact<strong>or</strong> II<br />
~1 unit/mL fact<strong>or</strong> X<br />
≤ 0.20 units fact<strong>or</strong> VII<br />
Fact<strong>or</strong> IX deficiency due to hemophilia B<br />
Refrigeration at 2-8 °C until expiration date<br />
Room temperature stability not available<br />
After reconstitution, use with<strong>in</strong> 3 hrs<br />
Thrombosis<br />
Infectious disease transmission<br />
Infusion reactions<br />
Hepar<strong>in</strong>-<strong>in</strong>duced thrombocytopenia<br />
APPENDIX E 52<br />
Marshall CT Classification<br />
Categ<strong>or</strong>y<br />
Diffuse <strong>in</strong>jury I<br />
(no visible pathology)<br />
Diffuse <strong>in</strong>jury II<br />
Diffuse <strong>in</strong>jury III<br />
Diffuse <strong>in</strong>jury IV<br />
Evacuated mass lesion<br />
Non-evacuated mass<br />
lesion<br />
Def<strong>in</strong>ition<br />
No visible <strong>in</strong>tra-cranial pathology on CT scan (9.6% m<strong>or</strong>tality)<br />
Cisterns present with midl<strong>in</strong>e shift 0-5 mm and/<strong>or</strong> lesion densities present; no high <strong>or</strong><br />
mixed density lesion > 25 mL (13.5% m<strong>or</strong>tality)<br />
Cisterns compressed <strong>or</strong> absent with midl<strong>in</strong>e shift 0-5 mm; no high- <strong>or</strong> mixed-density<br />
lesion > 25 mL (34% m<strong>or</strong>tality)<br />
Midl<strong>in</strong>e shift > 5 mm; no high- <strong>or</strong> mixed-density lesion > 25 mL (56.2% m<strong>or</strong>tality)<br />
Any lesion surgically evacuated<br />
High <strong>or</strong> mixed density lesion > 25 mL; not surgically evacuated<br />
APPENDIX F 51<br />
Glasgow Coma Scale & Sc<strong>or</strong>e<br />
Feature Scale Response Sc<strong>or</strong>e Notation<br />
Eye open<strong>in</strong>g<br />
Spontaneous<br />
To voice command<br />
To pa<strong>in</strong> stimuli<br />
No response<br />
4<br />
3<br />
2<br />
1<br />
Verbal response<br />
Best mot<strong>or</strong> response<br />
Oriented and converses<br />
Confused<br />
W<strong>or</strong>ds (<strong>in</strong>appropriate)<br />
Sounds (<strong>in</strong>comprehensible)<br />
No sounds<br />
Obeys commands<br />
Localizes to pa<strong>in</strong><br />
Withdrawals from pa<strong>in</strong><br />
Dec<strong>or</strong>ticate postur<strong>in</strong>g<br />
Decerebrate postur<strong>in</strong>g<br />
None<br />
Total Coma Sc<strong>or</strong>e 3/15 – 15/15<br />
5<br />
4<br />
3<br />
2<br />
1<br />
6<br />
5<br />
4<br />
3<br />
2<br />
1<br />
R. Sohraby 19