BLOOD ISSUES
From the University of Kansas Medical Center’s 55th Annual Postgraduate Symposium on Anesthesiology
| WHAT’S NEW IN TRANSFUSION THERAPY — James D. Kindscher, MD, Professor and Vice Chair, Department of
Anesthesiology, University of Kansas Medical Center, Kansas City, Kansas
|
| Risks of transfusion: for general population, transfusion rate 0.89% yearly (increased rate with age); 95% of intensive
care unit (ICU) patients anemic by day 3; >50% of ICU patients transfused by day 3, with average transfusion
of 5 units of red blood cells (RBCs); over 15-yr period, Food and Drug Administration (FDA) reported 694 transfusion-related
deaths (34 deaths yearly); primary cause acute hemolytic reactions, followed by bacterial contamination
and transfusion-related acute lung injury (TRALI); viral disease “way down on the list”
|
 | Acute hemolytic reactions: most minor antigens cause delayed hemolytic reaction, not acute hemolysis; disseminated
intravascular coagulation (DIC) and hypotension seen with ABO blood group system incompatibility (accounts for
>50% of transfusion deaths); in United States, rate ≈1 in 12,000 to 1 in 19,000 transfusions; fatality rate 1 in
800,000 patients transfused; ≈50% occur in clinical area (misidentify recipient; phlebotomy errors); one third of errors
occur in laboratory
|
| Bacterial contamination: caused 77 of 694 deaths in review of transfusion-related deaths 1985 to 1999; risk primarily
with platelets; also cause by occult donor bacteremia, inadequate skin preparation, and contaminated collection
system; RBCs not major source of contamination (stored at 4°C; not much grows at this temperature, except
Yersinia enterocolitica, Serratia, Pseudomonas); greater risk after 21 days storage; rate ≈1 in 1 million units of
RBCs transfused
|
| Platelets: room temperature storage; preservative solution contains dextrose and nutrients for bacterial growth; rate 1 in
1000 to 1 in 3000 units of platelets; pooled platelets higher risk than apheresis units; accounts for 20% of transfusion-
related deaths; universal bacterial culturing; day 2 assay by sterile culturing system done before release
|
| Viral diseases: in 1950s and 1960s, one third of patients developed serum hepatitis; in 1980s, 20% of blood contaminated
with non-A, non-B hepatitis (hepatitis C virus [HCV]); HIV scare of 1980s (risk 1 in 100 units transfused in 1983; declined
with donor screening and antibody testing; now ≈1 in 2 million units transfused); nucleic acid testing (NAT)
using polymerase chain reaction to assay small DNA sequence reduces window for infection to ≈10 days; NAT recently
instituted for hepatitis B virus (HBV); cost $2 million per quality-adjusted life year (QALY); expected rate
with NAT <1 in 1 million units transfused; 2002 data show 23 million components transfused, 11 HIV cases, 12 HCV
cases, and 112 HBV cases; other viral entities include new variant Creutzfeldt-Jakob disease (nvCJD; same infectious
agent as bovine spongiform encephalopathy) and West Nile virus
|
| West Nile virus: first identified in United States in New York City (1999); in 2002, >4000 human cases and 284 deaths;
from August, 2002 to January, 2003, 23 transfusion-related or organ transplant-related cases; NAT begun in 2003
|
| nvCJD: no reported cases in humans; blood banks in United States use referral questions to reduce risk
|
| Chagas disease: caused by Trypanosoma cruzi; causes “mega” disorder (eg, megacolon, cardiomegaly); endemic in
Central and South America; estimated 100,000 carriers in United States; transfusion-documented cases; NAT begun
in 2005
|
| Future plans: pathogen reduction strategies; mortality rates after receiving transfusions 24% after 1 yr and >50% after
10 yr; risk for death within 10 yr increased 4.1% per unit of RBCs, 1.2% per unit of platelets, and even higher
per unit of fresh-frozen plasma (FFP)
|
| TRALI: first identified ≈20 yr ago; noncardiogenic pulmonary edema occurring within 6 hr of transfusion; characterized
by dyspnea, hypoxia, bilateral fluffy infiltrates on chest x-ray; rule out sepsis, volume overload, and cardiogenic
causes; incidence may be as high as 1 in 1120 transfusions (0.04%-0.16% per unit transfused);
underrecognized and underreported; appears similar to acute respiratory distress syndrome (ARDS); traced to
plasma-containing components; platelets highest-risk group, followed by RBCs, FFP, and cryoprecipitate; mortality
5% to 10%; most cases occur in operating room (OR) or ICU; no absolute clinical or laboratory tests; supportive
treatment (eg, O2 , mechanical ventilation, fluids); self-limited disease (resolves in 48 hr); 2-hit theory (first, predisposing
inflammatory condition; second, passive transfer of neutrophils or human leukocyte antigen [HLA] antibodies);
results in neutrophil sequestration in lungs, with compliment activation and pulmonary leak; may also be
activated lipid complex; donor issues include antibodies to recipient white blood cells (WBCs); risk factors include
increased parity, recipient who is close relative of donor, and increased age of blood product
|
| Immunomodulation: leukocytes may live for long time in host; alters recipient’s WBC activity; suppresses T cells;
reactivates viral disease; increases infection; cancer recurrence; alters immune system; data more convincing in animals
than humans; since 1980, many studies have examined immunomodulation, mostly observational cohort design;
cancer and infection risks unclear
|
| Alternatives to banked blood
|
| Autologous predonation: in 1997, represented only 5% of donated blood in United States; donate ≥3 days before surgery;
erythropoietin therapy helpful; >50% of units wasted; coronary artery bypass graft (CABG) study showed cost
$500,000 per QALY
|
| Acute normovolemic hemodilution: blood drawn at time of surgery; requires high preoperative hemoglobin (Hb) and
low Hb (5-6 g/dL) at end of harvest; impractical in most situations
|
| Intraoperative blood salvage: not recommended with infectious pathology or cancer; rapid return of matched blood cells
|
| Surgical case data at University of Kansas: reviewed transfusions in surgical patients for 3 mo (≈3100 patients);
analyzed discharge Hb levels in all patients receiving transfusion; 28% discharged with Hb >11 g/dL; in this group,
only 4% controlled by anesthesiologist in OR
|
| Cell saver: used in 3.1% of surgical group (eg, heart, vascular, liver transplants, orthopedic cases); 230 units collected
and reinfused; 95 patients (average 2.5 units per patient); cost-effectiveness determined if ≈2 units processed per patient;
394 units of banked blood transfused in OR; 230 units of cell saver in OR; cell saver provided 37% of blood transfused;
first unit $188, each subsequent unit $13; banked blood $163 per unit; total cell saver cost avoidance $450,000 per
year; blood costs
|
| HITS, CLOTS, AND BLEEDS — Michael S. Avidan, MB, BCh, Assistant Professor of Anesthesiology and Intensive
Care Medicine, Washington University School of Medicine, Saint Louis
|
| Physiology of clotting and bleeding
|
| New concepts: no distinct intrinsic and extrinsic pathways; clotting factors have important interactions with cells;
thrombin key coordinator in clotting network; thrombin generated via initial loop, then explosive generation; headquarters
for clotting tissue factor-bearing cells and activated platelets
|
| Key clotting agents: initiators include cell-bearing tissue factor that binds to factor VII; messengers include factor XI,
factor IX, and factor X; thrombin then immediately activated; amplifiers (factors V and VIII) initiate major upregulation
loop and generate additional thrombin; clot stabilized via factor XIII; bound to platelets by fibrin; various
platelet activators
|
| Key anticlotting agents: endothelium headquarters for anticlotting agents; deficiency of anticlotting agent (eg, factor
V Leiden, hyperfibrinogenemia, antithrombin III deficiency) far more common than deficiency of clotting agent
(eg, hemophilia, von Willebrand disease); ≈50% of patients with eg, deep venous thrombosis (DVT) or unexplained
pulmonary emboli have inherited thrombophilia or tendency to clot; anticlotting agents include tissue factor pathway
inhibitor, antithrombin III, glycosaminoglycans (similar to heparin), thrombomodulin, protein C and protein S,
nitric oxide and prostacyclin (intrinsic antiplatelet agents), and plasmin (allows clot to break down)
|
| Normal clotting and anticlotting mechanisms: endothelium breached; tissue factor-bearing cell couples with factor
VII; activates factor X; factor X enlists factor V and brings thrombin into play; thrombin sends out array of activating
signals to many factors and to thrombomodulin (activates anticlotting mechanisms where endothelium intact);
clotting would proceed unopposed without tissue factor pathway inhibitor; initial clotting loop requires few
clotting elements, but stopped by tissue factor pathway inhibitor and by antithrombin; subsequent addition of activated
factors (with platelet activation containing factor XI, and complex of factors IX and VIII) and factors X
and V on platelets results in explosive generation of thrombin; anticlotting mechanisms occur wherever endothelium
intact; clotting danger occurs when tissue factor-bearing cell circulates in blood vessel or with atypical production;
drotrecogin alfa (recombinant human activated protein C) may be beneficial in sepsis to prevent
unregulated clotting
|
| Platelet inhibition: many patients coming to OR receive antiplatelet agents; American Society of Regional Anesthesia
suggests regional anesthesia remains safe in patient taking aspirin; may not be true of other more potent antiplatelet
agents; similarly, those taking glycoprotein IIb/IIIa receptor blockers have virtually no clotting (difficult
to reverse)
|
| Recombinant activated human factor VII (rVIIa): off-label use expanding; original use for hemophilia with inhibitors;
study published in 2002 showed 170,000 uses of rVIIa for variety of indications; only 13 episodes of thrombosis;
should be effective only where tissue factor expressed; with intact endothelium, there should be no cells presenting
tissue factor, and rVIIa should not cause clotting; with denuded endothelium, rVIIa should complex with endothelium,
resulting in factors X and V, initial thrombin generation, and platelet aggregation and clotting; administration to patient
with DIC may cause massive intravascular clotting; patient with diffuse atherosclerotic disease and diseased endothelium
may have regions in blood vessels where tissue factor expressed; administration of rVIIa may cause clotting; strokes and
myocardial infarctions described in those receiving rVIIa; dosing regimen includes beginning with 90 to 120 µg/kg (in
repeated doses); criteria for use of rescue therapy in perioperative setting include severe bleeding with no identifiable surgical
source and bleeding that has not responded to conventional intervention; mortality decreased in patient with intracranial
bleeding receiving rVIIa; use judiciously in patient with ventricular-assist device or extracorporeal circulation; if
risk for thrombosis high, consider starting with small dose (eg, 30 µg/kg)
|
| Thrombosis: Virchow’s triad includes 1) constituents of blood, 2) blood flow, and 3) vessel wall; >10% of ICU patients
have venous thromboses; incidence in hospital unknown; acquired risk factors for thrombosis include malignancy,
surgery, bed rest, obesity, and orthopedic and pelvic surgery; anticoagulant agents include recombinant tissue
factor pathway inhibitor, platelet inhibitor, glycoprotein IIb/IIIa antagonist, tissue plasminogen activator, streptokinase,
and activated protein C
|
| Heparin-induced thrombocytopenia (HIT): heparin depends on antithrombin for efficacy; in cardiac surgery, nutritional
disorder, or ICU patient deficient in antithrombin; FFP replenishes clotting and anticlotting factors; heparin resistance
common eg, with thrombocytosis (other causes include antibodies to heparin); immune-mediated reaction to
heparin-platelet factor 4 (PF4) complex (IgG forms antibodies to heparin-platelet factor 4 complex); antibody complex
then binds to receptor on platelet, causing release of procoagulant microparticles from platelet; platelet count <100,000/
µL or 50% drop from baseline during heparin exposure; antibodies typically occur 5 to 14 days after initiating heparin (if
patient not exposed to heparin within last 100 days); with or without thrombotic complications; diagnosis clinical; can
occur with any type of heparin and any route of administration; mechanisms of hypercoagulability include platelet activation,
procoagulant microparticles, expression of tissue factor on endothelial cells, expression of tissue factor by monocytes
and macrophages activated by HIT antibodies, and neutralization of anticoagulant effects of heparin by PF4
released from activated platelets; arterial and venous clots tend to occur in large vessels, but may occur anywhere; diagnostic
criteria include thrombocytopenia, no other cause, sepsis, thrombosis, and time course; beware of symptoms with
heparin; after cardiac surgery, 35% to 65% of patients have HIT antibodies; limit use of heparin in postoperative period; laboratory
tests include enzyme-linked immunosorbent assay (ELISA) antibody screening test and serotonin-release assay (as
confirmatory test); alternatives to heparin include low molecular weight heparin, warfarin, hirudin, lepirudin, argatroban,
and bivalirudin; advantages of direct thrombin inhibitors include not being neutralized by PF4, more predictability, inhibition
of clot-bound thrombin, and greater attenuation of thrombus growth; disadvantages include no antiplatelet action,
irreversibility, long half-life, and specific action (may require supplementation with antiplatelet agent); DIC may occur
with HIT (do not give warfarin until platelet count rebounds)
|
Educational Objectives
| The goal of this program is to educate the listener about transfusion therapy and provide an overview of clotting and
bleeding. After hearing and assimilating this program, the participant will be better able to:
|
| 1. Describe the risks associated with blood transfusion.
|
| 2. Discuss the risks of immunomodulation.
|
| 3. Summarize the alternatives to banked blood.
|
| 4. Review the physiology of clotting and bleeding.
|
| 5. Explain the cause of heparin-induced thrombocytopenia
|
Discussed on This Program
Abciximab [ReoPro]
Argatroban
Aspirin (acetylsalicylic acid; ASA) [many trade names]
Bivalirudin [Angiomax]
Clopidogrel bisulfate [Plavix]
Drotrecogin alfa (activated protein C) [Xigris]
Heparin sodium injection
Hirudin (investigational)
Lepirudin [Refludan]
Low molecular weight heparins (LMWHs) – dalteparin [Fragmin], enoxaparin [Lovenox], tinzaparin [Innohep]
Tirofiban HCl [Aggrastat]
Warfarin sodium [Coumadin]
Suggested Reading
Avidan MS et al: A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human
antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass.
Anesthesiology 102:276, 2005; Avidan MS et al: Recombinant human antithrombin III restores heparin
responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J
Thorac Cardiovasc Surg 130:107, 2005; Blajchman MA: Immunomodulation and blood transfusion. Am J Ther
9:389, 2002; Francis JL et al: Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy
24:108S, 2004; Goodnough LT: Risks of blood transfusion. Crit Care Med 31:S678, 2003; Hedner U et al:
Potential role for rFVIIa in transfusion medicine. Transfusion 42:114, 2002; Kleinman S et al: Toward an understanding
of transfusion-related acute lung injury: statement of a consensus panel. Transfusion 44:1774, 2004; Looney
MR et al: Transfusion-related acute lung injury: a review. Chest 126:249, 2004; Mayer SA et al: Recombinant activated
factor VII for acute intracerebral hemorrhage. N Engl J Med 352:777, 2005; Napolitano LM: Current status of
blood component therapy in surgical critical care. Curr Opin Crit Care 10:311, 2004; Palavecino E et al: Risk and
prevention of transfusion-related sepsis. Curr Opin Hematol 10:434, 2003; Pomper GJ et al: Risks of transfusion-
transmitted infections: 2003. Curr Opin Hematol 10:412, 2003; Popma JJ et al: Antithrombotic therapy during percutaneous
coronary intervention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
126:576S, 2004; Sullivan MT et al: Blood collection and transfusion in the United States in 1997. Transfusion
42:1253, 2002; Veldman A et al: New insights into the coagulation system and implications for new therapeutic options
with recombinant factor VIIa. Curr Med Chem 10:797, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the
faculty reported nothing to disclose.
Drs. Kindscher and Avidan were recorded at the 55th Annual Postgraduate Symposium on Anesthesiology, presented
April 1-3, 2005, by the University of Kansas Medical Center, Department of Anesthesiology and the University of Kansas
Continuing Education, and held in Kansas City, Missouri. The Audio-Digest Foundation thanks the speakers and the
sponsor for their cooperation in the production of this program.
|
