Transcript AICU-CV-1_Hemostasis - Thomas Jefferson University

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Hemostasis Problems in
Critical Illness
Per Thorborg, MD, PhD, FCCM
Director, Adult Critical Care Medicine @ OHSU
Professor of Anesthesiology/CCM
Dept. of Anesthesiology and Perioperative Medicine
Lynn Boshkov, MD
Assoc Director, Transfusion Medicine and Director, Hemostasis & Thrombosis
Associate Professor of Pathology, Medicine and Pediatrics
Oregon Health & Science University
Portland, Oregon
Introduction
• While coagulation-associated problems in critical care medicine include
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both hyper- and hypocoagulable states, venous thromboembolism (VTE) is
addressed in another module.
In the ICU, acquired hypocoagulable states are much more common than
congenital states [such as vWD (types I, II, III); hemophilia A, B, C; BernardSoulier and Glanzmann’s thrombasthenias; inborn platelet abnormalities;
isolated coagulation factor deficiencies; dysfibrinogenemias; alpha2antiplasmin deficiency, other rare disorders]. Of these disorders, vWD is by
far the most common. (1%)
In the following teaching module, due to space restrictions, only some of the
most common acquired coagulation problems seen in the ICU patient are
addressed. It is recommended to involve hematology and blood bank early
in the management course of a severely bleeding patient.
The order in which the material will be presented is 1. An updated view of
the coagulation cascade; 2.Critical illness coagulopathies and treatment;
3.Uncontrolled bleeding and massive transfusion; 4. Anticoagulationassociated problems; 5.Case scenarios; and 6. References.
Slide 3
The Three Stages of Hemostasis
• In primary hemostasis, a platelet plug is formed within 5 minutes to
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seal the site of injury.
In secondary hemostasis, fibrin is formed (coagulation) and a fibrin
mesh reinforces the frail platelet plug (timescale hours).
The third part is (secondary) fibrinolysis, which dissolves the clot but
takes place first after tissue repair (timescale days).
The coagulation cascade for fibrin formation, described in the early
1960s by Davie, Ratnoff, and MacFarlane, was based on in vitro
data. While its extrinsic and intrinsic pathways setup explained
many PT and APTT abnormalities, it failed to explain other clinical
observations.
Newer data from the 1990s have replaced this older model with a
cell-based model where interactions among endothelial cells,
platelets, and thrombin have taken center stage.
Slide 4
The Platelet Plug Formation
• Primary hemostasis is initiated by endothelial
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damage exposing subendothelial collagen. Platelets
adhere to collagen via their GPIb receptor using
vWF as a bridging ligand. Platelets activate
changing from discoid (2 μm) to irregular shape with
pseudopods.
Granular contents are released (which include
bridging molecules and platelet agonists such as
vWF, fibrinogen, FV, FVIII, Ca2+, 5-HT, ADP, TxA2).
Activation also changes the conformation of the
GPIIb/IIIa receptor promoting fibrinogen binding and
platelet aggregation.
The activated platelet exposes a phospholipid
surface domain, PF3, which will become the
catalytic center for the next part, the secondary
hemostasis
Slide 5
Platelet Plug: Schematic
Schematic of platelet
adhesion, activation and
granule release,
aggregation, and expression
of pro-coagulant activity
showing major platelet GP
receptors and bridging
ligands.
Slide 6
Cell-Based Coagulation 2005
• With injury, tissue factor (TF) becomes exposed to blood and
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combines with free-circulating FVII initiating fibrin clot formation.
This complex activates FX, which, with FV, can form small amounts
of thrombin, enough to activate local platelets (see next slide).
The surface of the activated platelet becomes the catalytic center for
a larger amount of thrombin production, which produces enough
fibrin to stabilize the platelet clot.
Thrombin has both pro-coagulatory and pro-modulatory, as well as
antifibrinolytic, activities.
Three major modulating systems act to inhibit coagulation activation:
– Tissue factor pathway inhibitor (TFPI) rapidly inhibits the
TF/FVIIa pathway once activated;
– The protein C and S system will inactivate FVa and FVIIIa; and
– Antithrombin will inactivate thrombin (FIIa), as well as FXa, FIXa,
FXIa, FXIIa.
Slide 7
Normal Hemostasis
II
X
TF VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF VIIa
IXa
V
IX
X
Va
Platelet
II
Xa
IXa VIIIa
Va
Activated Platelet
VIIa
Va
IXa VIIIa
Xa
IX
X
II
Slide 8
IIa
IIa
Reproduced with permission from:
Hoffman M et al. Blood Coagul
Fibrinolysis. 1998;9(suppl 1):S61-S65.
Fibrinolysis
• Secondary (normal physiological) fibrinolysis occurs by activation of
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plasminogen to plasmin by tPA. This happens normally within the
clot.
Plasmin degrades fibrin (and fibrinogen) to fibrin degradation
products (FDP); its activity is controlled by alpha2-antiplasmin.
When fibrin has been cross-linked (by FXIII), small segments,
known as D-dimers, can be measured.
Plasminogen activator inhibitor (PAI-1) inactivates tPA, thereby
controlling fibrinolysis.
Abnormally activated (primary) fibrinolysis can cause or contribute to
bleeding. It is most commonly seen after therapy with tPA,
streptokinase, and urokinase and can also complicate liver disease,
prostate and neurosurgery, CPB, and burns.
Laboratory clues to possible abnormal fibrinolysis are unexpectedly
low fibrinogen and a shortened euglobulin clot lysis time.
Slide 9
Thrombocytopathy
Thrombocytopathy denotes abnormal platelet function; number may be normal.
Historically, increased bleeding time was used to diagnose thrombocytopathy;
prolonged closure times on the platelet function analyzer (PFA-100) are now most
commonly used. Standard thromboelastography (TEG) is relatively insensitive to
thrombocytopathy. Bleeding is usually not severe unless combined with other
bleeding problems.
• Drug induced (antiplatelet therapy, COX inhibitors, TXA2 inhibitors, calcium channel
blockers, H2 receptor antagonists, dextran, starch, NTP, NTG, PCN, cephalosporins)
• Uremia
• Hypothermia (<35°C)
• After cardiopulmonary bypass (CPB)
• Malignant paraproteinemia (multiple myeloma, Waldenstrom)
• Treatment: If patient has a clinical bleeding problem, correct underlying problem (stop
drug, perform dialysis if uremia, warm patient if cold). DDAVP may be temporarily
helpful, as may cryoprecipitate (which contains concentrated vWF and fibrinogen).
Depending on drug half-life, platelet transfusion may be an option. See also CPBassociated bleeding. Plasmapheresis is an option in bleeding malignant
paraproteinemia patients.
Slide 10
Thrombocytopenia
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In pure thrombocytopenia, the risk for bleeding depends on the platelet count. In ICU
patients, thrombocytopenia is seen in 20%-45%, usually defined as platelet count
<100,000/mm3. Bleeding is rare if platelets functional and >50,000/mm3.
Symptoms include petechial bleeding, spontaneous or easy bruising, mucosal
bleeding, gingival bleeding, and purpura. In some states (*), there is increased
thrombotic risk.
Increased destruction and/or decreased production may be etiological. Sequestration
alone rarely causes counts <60,000. Causes include:
– Sepsis/procoagulant drive/disseminated intravascular coagulation (DIC)*
– ITP; antiphospholipid syndrome (APLS)*; post-transfusion purpura (PTP, rare)
– Drug-induced thrombocytopenia; post-chemotherapy
– Heparin-induced thrombocytopenia (HIT)*, with thrombosis (HITT)*
– TTP/HUS syndromes*
– Pregnancy-related: HELLP, AFLP, amniotic fluid embolism, abruptio placentae
– Cardiopulmonary bypass
– [Pseudo-thrombocytopenia if using EDTA tubes]
Slide 11
Degree of Thrombocytopenia
• Moderate thrombocytopenia (50,000-100,000/mm3) most commonly
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seen in DIC, sepsis, HIT/HITT, and TTP/HUS.
Severe thrombocytopenia (<20,000/mm3) more commonly seen in
drug-induced thrombocytopenia, ITP, PTP, and occasionally severe
HITT.
Thrombocytopenia usually appears in conjunction with other clinical
problems (see list on previous slide) that may dominate the
symptomatology. One of the first places to check for petechial
bleeding is under the blood pressure cuff.
Trigger point for platelet transfusion depends on the patient’s state
and clinical situation. Generally “trigger” <10,000/mm3
prophylactically; 50-100/mm3 for invasive procedures; ~100/mm3
for major surgery.
Avoid platelet transfusion in patients with TTP, HIT (thrombotic risk)
or if platelet antibodies (ITP) unless life-threatening bleeding (very
rapid destruction—15 mins).
Slide 12
Disseminated Intravascular
Coagulation (DIC)
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DIC is a complication to an underlying disorder, not a disease in itself. When
occurring in sepsis and trauma, DIC doubles the risk of death.
Pathophysiology: usually tissue factor exposure leading to a prothrombotic state with
activation of coagulation and consumption of platelets and coagulation products, as
well as its modulators. Fibrinolysis increases to lyse the increasing clot load. Initially,
bone marrow (platelets) and liver (coagulation factors) may be able to keep
production on par with consumption but, if speed of consumption increases, the
patient becomes hypocoagulable.
Variable speed consumption of platelets and coagulation factors will vary the clinical
presentation from asymptomatic or thrombosis (chronic low grade) to generalized
bleeding or even purpura fulminans.
Acute DIC etiologies include sepsis, trauma, delayed shock resuscitation, certain
cancers, obstetric complications, immunologic disorders, burns, vasculitis, certain
activated blood products, liver failure, conditions that lead to SIRS, newborn purpura
fulminans, toxins, and rare drug-induced hemolytic DIC.
Chronic low-grade DIC etiologies include cancer, vascular aneurysms and giant
hemangiomas, and dead fetus in utero. In chronic DIC, the platelet count and
fibrinogen may be well-preserved or even normal.
Slide 13
Systemic Inflammatory Response
Syndrome (SIRS)
• In inflammatory states, including sepsis, release of proinflammatory cytokines IL-6 and TNF- leading to DIC by
several pathways
– IL-6 stimulate mononuclear and endothelial cells to
express tissue factor, which leads to coagulation
activation and fibrin formation.
– TNF- inhibits normal anticoagulant PC/PS modulator
pathway plus promotes release of Plasminogen
Activator Inhibitor (PAI-1) that depresses fibrinolysis
and leads to increased fibrin deposition.
Slide 14
DIC Is Common in the ICU
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Sepsis: 30% develop DIC, depending on definition
Delayed shock resuscitation: time dependent
Head or crush injury, fat embolism: 50%-70%
Acute leukemias (particularly acute promyelocytic
leukemia), metastatic prostate cancer: 15%
• Abruptio placentae, abortion, amniotic fluid embolism,
hemorrhage, shock: 50% [while pre-eclamptic patients:
7%]
• Immunologic disorders: variable
Slide 15
DIC: Thrombosis vs. Bleeding
Signs of Thrombosis
• Neuro: multifocal, delirium,
coma
• Skin: ischemia
• Renal: oliguria, azotemia,
cortical necrosis
• Pulm: ARDS
• GI: ulceration
Signs of Bleeding
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Neuro: bleeding
Skin: petechiae, ecchymosis
Renal: hematuria
Muc. Mb: epistaxis, gingival
bleeding
• GI: massive bleeding
Slide 16
DIC Lab Tests and Scoring System
• There is no single lab test to conclusively prove the presence of
DIC.
• The International Society on Thrombosis and Haemostasis
proposed, in 2001, a 5-step diagnostic algorithm to calculate a DIC
score. Repeat scoring every 1-2 days.
– Risk assessment – if yes proceed to
– Order plt count, PT, fibrinogen, FDP, or soluble fibrin monomer.
– Scoring: If plt count >100=0, <100=1, <50=2; FDP no increase
=0, moderate increase=1, strong increase=2; PT prolongation
<3 s=0, >3-6 s=1, >6 s=2; fibrinogen level >1g/L=0, <1g/L=1.
– Calculate (add) scores (0-7).
– A score of 5 or more is compatible with overt DIC, whereas a
score of <5 may be indicative of non-overt DIC.
• This DIC score has a 93% sensitivity and 98% specificity. The score
also directly correlates to mortality.
Slide 17
DIC Lab Tests/Scoring
• INR vs. PT in secs: Many hospital laboratories currently report only
the PT INR (international normalized ratio) rather than the PT in
seconds. The PT in seconds in these cases can normally be
obtained by calling the hospital laboratory.
• D-dimer and DIC: Similarly, many hospital laboratories currently do
not do FDPs but only do D-dimer testing (D-dimer is a specialized
type of FDP generated by plasmin degradation of cross-linked
fibrin). In diagnosing DIC, sensitive quantitative D-dimer tests can
be helpful. Weakly positive D-dimers are common in sick
hospitalized patients but levels >4.0 μg/mL are usual in established
DIC (although not pathognomonic). Levels >8.2 μg/mL are said to be
both sensitive and specific for DIC (Am J Clin Pathol. 2004;122:178184), but most labs report only “>4.”
• Other scoring systems for DIC may possibly be more sensitive for
early DIC in the critical care setting (Crit Care Med. 2006;34:625631)
Slide 18
Treatment of Acute Severe DIC
• ICU: always first restore blood volume, cardiac output, gas exchange, and
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electrolytes.
Identify and address the cause of DIC. Many causes for DIC are self-limited
(sepsis, obstetric complications, etc.). Treat the underlying cause.
Transfuse blood products to restore hemostatic potential: plt (>50) and
fibrinogen (>100), possibly FFP (high INR/APTT). If low hct, consider
transfusion of PRBC, trigger depending on patient.
Possibly use antithrombotic agents (only if signs of tissue ischemia):
heparin or LMWH (by hematology).
DO NOT give antifibrinolytics; it may lead to widespread thrombosis.
For DIC that does not respond to above, consider recombinant human
activated protein C (rhAPC) if protein C levels low. APC use (only tested for
sepsis-associated DIC) is associated with increased risk for bleeding,
particularly in the least sick patients, and only reduces mortality in the sicker
patients with an APACHE II score >24. Attention should be paid to
maintaining platelets, fibrinogen, and INR at hemostatic levels if rhAPC is
used in the DIC setting.
Slide 19
Sepsis-Associated Coagulopathy
• Thrombocytopenia is commonly seen in sepsis by several different
mechanisms: consumption of activated platelets,
hemophagocytosis, or adhesion to endothelium. Degree of
thrombocytopenia correlates with sepsis severity.
• Coagulation activation manifests as increased D-dimers in almost all
septic patients and consumption of protein C with low PC levels in
90%, low antithrombin (AT) levels in 50%. Hypercoagulability is
believed to be due to cytokine release with tissue factor expression
on several cell lines, activated platelets and endothelial cells, and
reduced natural anticoagulant modulators.
• LMWH anticoagulation at prophylactic doses is recommended
unless contraindicated.
• Treatment of sepsis-associated coagulopathy with platelets and
FFP, tight blood glucose control, and rhAPC (in the sickest patients
only and if patient fulfills enrollment criteria). Do not forget to treat
underlying sepsis aggressively.
Slide 20
Heparin-Induced Thrombocytopenia
(HIT)
• Of patients receiving unfractionated heparin (UFH) for >7 days, 1%-2%
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develop HIT; of these 30%-80% go on to develop venous or arterial
thrombosis (HITT). HITT is most common in cardiovascular surgery
patients. The frequency of HIT for LMWH is <1%.
Pathophysiology: HIT is caused by platelet-activating IgG antibodies to the
heparin-platelet factor 4 complex. Bleeding is not a feature of HIT except in
areas of infarct (adrenals).
Presentation: Progressive thrombocytopenia develops after 5-10 days
heparin therapy but can develop earlier if prior heparin exposure. HIT
should be suspected if platelets drop at least 50% or to <100,000/mm3.
Test for HIT antibody (SRA or other washed platelet functional assays) more
specific then PF4 ELISA (~50% of re-op CV surgery patients will have pos
PF4 ELISAs).
• Treatment: Stop all heparin, including heparin-coated catheters. Since high
risk for thrombosis, start direct thrombin inhibitor (argatroban or lepirudin),
not warfarin, not LMWH. Avoid platelet transfusions.
Slide 21
ITP and TTP/HUS Syndromes
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In immune thrombocytopenic purpura (ITP) autoantibodies bind to platelet GPs (about 2/3 are to
the GPIIb/IIIa receptor and about 10% to GPIb), and the opsonized platelets are ingested by
macrophages. Patient afebrile, diagnosis by exclusion. Treatment is splenectomy if severe
refractory thrombocytopenia. Steroids (pulse or daily) or high-dose IVIG or anti-D immune globulin
(if the patient is Rh-positive) can often elevate the platelet count within hours to days.
Hematological consultation should be sought.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are
syndromes of unknown etiology, although low to absent vWF cleaving protease (ADAMTS13)
appears to be involved in many cases of primary idiopathic TTP. In the absence of protease
activity, ultra-large vWF mutimers are thought to agglutinate platelets forming platelet thrombi.
TTP/HUS is characterized by thrombocytopenia, anemia with schistocytes in smear, renal
insufficiency, neurologic abnormalities, and fever. The full pentad need not be present for
diagnosis. LDH is used as marker of disease activity. Familial forms of TTP exist (often
associated with low to absent ADAMTS13 activity). TTP/HUS accompanied by bloody diarrhea
may be due primarily to endothelial injury and is characteristic of enterotoxigenic E. coli and other
gut pathogens (undercooked hamburger and contaminated spinach have been associated with
outbreaks). Secondary TTP tends to be more refractory and can complicate cyclosporin,
tacrolimus, cis-platinum, mitomycin C, ticlodipine, clopidogrel therapy; it can complicate bone
marrow transplant, CMV infections, pregnancy, autoimmune diseases as SLE.
Treatment is by plasma exchange (plasma infusion may be used as a temporizing measure) and
steroid therapy that has significantly reduced mortality. Early intervention is advised.
Hematological consultation should be sought.
Slide 22
Pregnancy-Related Thrombocytopenias
• Abruptio placentae: most frequent obstetric
coagulopathy with extent of coagulation abnormalities
proportional to placental separation. Support is PRN with
red cells, cryoprecipitate (if fibrinogen <1.0 g/L), rarely
platelets.
• Amniotic fluid embolus: 1:8,000-1:80,000. Presents
with sudden catastrophic respiratory and CV collapse.
80% mortality; 50% of survivors develop DIC in 24 hrs.
Support cardiorespiratory system and treat DIC PRN.
• Retained dead fetus: Coagulopathy occurs 3-4 weeks
post-fetal death. 80% deliver spontaneously in 2-3
weeks. Treat DIC PRN.
Slide 23
Microangiopathies
• HELLP (hemolysis elevated liver tests low platelets) syndrome occurs
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mostly in the 3rd trimester (~40% after week 28) or postpartum (~1/3) and
complicates ~5% of preeclampsia cases. Decreased platelet count is
followed by liver failure and hemolysis, fetus thrombocytopenic in ~30%.
DIC found in ~20%, renal failure ~8%, pulmonary edema ~6%. Delivery
usually results in rapid improvement.
Acute fatty liver of pregnancy (AFLP) usually develops end of 3rd trimester.
Increased risk with primiparas, twins. Develop thrombocytopenia first,
followed by liver failure and severe coagulopathy. Maternal mortality rare;
fetal mortality is ~10%-15%. Low blood glucose, high ammonia typical.
Delivery results in improvement; coagulation abnormalities may persist for
up to a week postpartum.
TTP/HUS can occur with pregnancy, fetus not involved. HUS (with
associated renal failure) usually develops postpartum. TTP mostly presents
in second trimester but can occur earlier. TTP resolves with termination of
pregnancy. Plasma exchange may be required during pregnancy.
Preeclampsia (PET) is characterized by hypertension and proteinuria,
mostly in the 3rd trimester. Antiphospholipid syndrome (APL) may be
associated with early onset severe PET, thrombosis, and fetal loss.
Slide 24
CPB-Associated Coagulopathy
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Cytokine activation leads to TF expression on endothelial cells and platelet activation.
Platelet dysfunction due to degranulation, loss of GPIIb/IIIa receptors, hypothermia,
heparin-related, protamine-related.
Thrombocytopenia can be caused by dilution and consumption.
Coagulation activation (despite heparin) leads to consumptive dysfunction (DIC) and
decrease in physiologic modulators (AT, PC/PS).
Increased fibrinolysis (from release of tPA), as well as decreased levels of physiologic
fibrinolysis inhibitors (2-antiplasmin).
Heparin anticoagulation contributes both directly and indirectly to platelet dysfunction.
Treatment problematic but platelet transfusions and aprotinin (serine protease
inhibitor inhibits plasmin, TF, FXII and kallikrein) have been used successfully to
reduce blood loss in CPB.
Note: Aprotinin distribution was suspended (late 2007) due to safety concerns (renal
failure and others). Other antifibrinolytic agents (tranexamic acid, ε-aminocaproic
acid) have also been used to reduce blood loss in CPB. Risk/benefit of these agents
currently unclear.
Slide 25
Drug-Induced Coagulopathies
• Warfarin-treated patients may see increased warfarin activity from
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amiodarone, aspirin, cimetidine, fluconazole, metronidazole, and
erythromycin and decreased activity from barbiturates and
phenytoin.
PT/INR increases commonly with cefotetan.
TTP/HUS can be induced by cyclosporin, tacrolimus, cis-platinum,
ticlodipine, clopidogrel.
Hemolytic DIC syndrome induced by quinine, 2nd and 3rd
generation cephalosporins (often life-threatening).
Thrombocytopenia can be caused by GPIIb/IIa receptor antagonists,
vancomycin, amphotericin B, amiodarone, digoxin, procainamide,
quinine, cimetidine, ranitidine, heparin, NSAIDs, phenytoin, HCTZ.
Treatment: Examine patient’s list of drugs and stop culprit drug.
Transfuse PRN. Consider therapeutic plasma exchange for
cephalosporin DIC hemolysis.
Slide 26
Vitamin K Deficiency
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Vitamin K deficiency: intake (food, gut flora) under 40-80 μg/d can lead to functional
deficiency of factors II, VII, IX, and X, as well as protein C and S. Seen in patients
with longstanding malnutrition, with biliary obstruction, or who have been on
prolonged antibiotic treatment, which kills the gut flora that produces vitamin K.
Patients on warfarin who develop any of the above complications are very susceptible
to developing marked coagulopathy.
Can present with dramatic bleeding.
PT/INR is early monitor due to short ½T of FVII; with severe deficiency both PT/INR
and aPTT prolonged; fibrinogen normal.
Treatment: depends on urgency.
Non-urgent: Give Vit K PO or IV alone (Do NOT give vitamin K IM—erratic
absorption); earliest effect IV 4-6 hrs, ~12 hr to correction INR, ~ 2-3 days full effect).
For INR 2-4.5: give 2.5 mg; for INR 4.5-10: give 5 mg; for INR >10:
give 5-10 mg
Urgent: Add FFP at least 15 mL/kg (4-5 U/adult) — give rapidly
Extreme urgency: rVIIa 20-40 μg/kg or FEIBA (factor VIII inhibitor bypass activity) 50
U/kg (prothrombin complex concentrates, if available, are also very useful)
Slide 27
Coagulopathy in Liver Failure
• Liver failure is an important reason for coagulopathy in the ICU in
that the liver synthesizes all coagulation products (except vWF) and
modulators, as well as several fibrinolytic proteins. It also clears
activated clotting products, proteolytic modulator/coagulation factor
complexes, and FDP. In end-stage liver failure, the clinical picture
includes impaired clotting, excessive fibrinolysis, DIC,
thrombocytopenia, and platelet dysfunction. The first abnormal
laboratory value is often increased PT/INR.
• Treatment of the bleeding patient is based on laboratory
assessment. Use blood products and vitamin K. While rFVIIa has
been used effectively to correct INR, its half-life is short (2-3 hours)
and its efficacy is reduced in the acidotic and hypothermic bleeding
patient. In ESLD, mortality without transplant is close to 100%
regardless of therapy.
Slide 28
Etiology of Perioperative
Coagulation Problems
• Massive transfusion syndrome after trauma or vascular injury or in
major surgery.
• Concurrent liver or renal failure; sepsis/DIC; ischemia/reperfusion
(I/R) injury to vascular endothelium after delayed or insufficient
volume resuscitation.
• Other concurrent acquired coagulation defects, such as
anticoagulants, antiplatelet agents, fibrinolytics; vitamin K deficiency;
CPB; head trauma (TF release); immune- or pregnancy-related
thrombocytopenia; factor inhibitors (FVIII—often autoimmune, very
rarely FV—post-bovine thrombin).
• Rarely underlying congenital coagulation defect: vWD, hemophilia
A/B/C, platelet disorders.
Slide 29
Failure to Resuscitate Leads to
Out-of-Control Coagulation
• Prolonged tissue hypoperfusion (several hours) causes I/R injury
with post-reperfusion vascular dysfunction leading to coagulation
activation, microthrombosis and DIC. In trauma patients, persistent
acidosis (pH<7.1), hypothermia (<34C), high injury score, and
persistent hypotension (syst BP <70) correlate with life-threatening
coagulopathy or death. 47% coagulopathic. Prospective torso
trauma study [Cosgriff N et al. J Trauma. 1997; 42:857-861].
• Treatment: prompt fluid resuscitation in hypovolemia mitigates or
prevents endothelial injury that otherwise leads to DIC.
• Volume deficit is first treated with fluid resuscitation, not with
vasopressor agents (possible exception severe CAD).
• Most commonly used resuscitation fluid is lactated Ringer and
isotonic saline with blood products. Colloids restore capillary flow
better but may induce coagulopathy if given in too large volume.
Downside to aggressive volume resuscitation is possible dilution of
coagulation products and fluid overload.
Slide 30
Massive Transfusion (MT)
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Survival after MT (10 U blood/24 h) for trauma patients (8-year Detroit study) was
only 6.6% 35 years ago. In 1990s, survival after MT (10 U/24 h) for all patients had
improved to 60%, around 50% for 20 U (trauma), around 40% for 40 U (trauma), and
the most recent study (2002), 43% for 50 U/24 h (trauma).
The reasons for improved survival are probably multifactorial with more aggressive
volume resuscitation, active rewarming of patient, altered blood banking and
transfusion practices (component therapy), surgical damage control technique, and
evolving trauma systems.
Practical issues in MT scenario include close monitoring of BP via arterial line,
volume status through CVP or better SvO2. Monitor coagulation labs frequently (see
transfusion trigger tables); thromboelastograph clot strength monitoring in OR may be
helpful. Effective communication with blood bank and hematology necessary. Keep
patient warm, fluids through blood warmers only. Hypocalcemia common by patient
inability to rapidly metabolize citrate in blood products.
Some emerging evidence that in the most critically injured trauma patients with
severe coagulopathy on presentation, transfusion of 1:1 RBCs to plasma with
aggressive platelet and cryoprecipitate use may improve outcome (J Trauma.
2007;62:307-310).
Infectious complications in MT of little concern: infection HIV ≤1:2.3 million, HCV
≤1:1.8 million; lethal transfusion reaction 1/100,000 cases.
Slide 31
Slide 32
Slide 33
Anticoagulation-Associated
Bleeding Problems
• Antiplatelet agents: aspirin irreversibly blocks the platelet cyclooxygenase,
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replaced by new platelets in 7days. In bleeding patient, can transfuse
platelets or give DDAVP. Bleeding ticlodipine-, clopidogrel-, or GP IIb/IIIa
antagonist-treated patients can be given platelet transfusion.
Warfarin-treated patients with bleeding should be treated with vitamin K IV
plus 4 U FFP. INR 2.0-4.5 should receive 1 mg vitamin K; INR 4.5-10, 2.5-5
mg; and INR >10, 5-10 mg. FFP has transient but immediate effect. rFVIIa
is effective (but expensive) in low dose 20-40 μg/kg.
Heparin short (30-60 m) half-life makes reversal with protamine rarely
necessary. Protamine only reverses the LMWH antithrombin effect and, due
to longer half-life (12 h), a second protamine dose may be required.
Direct thrombin inhibitors have no specific antidotes, but rFVIIa have been
anecdotally reported to reverse life-threatening bleeding in these patients.
Fibrinolytic agents are associated with a 5% bleeding rate but, due to their
short half-life, antifibrinolytic agents are rarely required. Depending on
laboratory results, patients may require cryoprecipitate and FFP. For
intracranial bleeding complication, platelets are also recommended.
Slide 34
Case Studies
The following are case studies that can be used for review
for this presentation.
Review Cases
End
Case I: Postoperative Bleeding
• 46-year-old woman with stage III rectal cancer resected
6 years ago, followed by chemotherapy
• Admitted 3/3/04 for left liver resection and RFA
(radiofrequency ablation) of metastatic lesion in right
liver lobe
Slide 36
Case I: Postoperative Course
• On 3rd postoperative day,
•
•
•
•
respiratory problems: CT scan to
R/O PE
Oxygenation deteriorated
successively, moved to the ICU
3/8/04. CXR bilateral infiltrates
type ALI/ARDS. ET intubated,
placed on ventilator support
Also developed adrenocortical
insufficiency requiring steroids
Labs: Hct 31.9 drops to 26.2, Plt
53 to 36, INR 1.31 to 1.93, APTT
32.8 to 37.0, D-dimer >4.0,
fibrinogen 221 to 270
Bleeding from suture lines,
hematuria, petechiae under the
BP cuff
Slide 37
Case I: Presentation Points
• RFA cooks liver tissue, causes release of cellular content (such as
tissue factor) into blood. Interestingly, her DIC started gradually and
first manifested on the 4th postoperative day.
• TF release is known to induce both DIC and ARDS.
• Moderate liver dysfunction after hepatic reduction surgery will affect
the need for blood products. In this case, the patient responded well
to blood products alone. AT and PC levels were borderline low, but
she was clinically doing well enough. Save big guns (rhAPC) for
more severe cases.
• Ultimately, her DIC subsided after 2 weeks and she left the hospital
in good condition.
Slide 38
Case II: Heart Patient with Problems
• 49-year-old man s/p CABG in cardiogenic shock with 4vessel graft occlusion, transferred for heart transplant.
Allergic to ASA and ?HITT.
• Plan: biventricular assist device. HIT test negative but plt
drop 30%. Started on argatroban (direct thrombin
inhibitor), low dose, for elevated LFTs. Argatroban
monitoring by APTT, no specific antidote.
• Concerns with HLA immunization with transfusion of
PRBC or platelets for the planned heart transplant.
Planned use of Cell Saver in ORs and, if need for
additional RBCs, to use only leuko-reduced red blood
cells.
Slide 39
Case II: Heart Patient with Problems
• Patient bleeding on argatroban; preoperative labs show INR 2.6,
APTT 117, Hct 29.4, Plt 168, D-dimers 0.53. 2 FFP given
• New labs show INR >15, PTT 193, ACT 501, Fib 239, plt 109, hct
27.3. Cell Saver (470 mL) given, 14 U FFP, PRBC 14 U,
cryoprecipitate to optimize plt function; argatroban stopped
• Postoperative labs: INR 12.05, PTT 165, Fib 371, ACT 461;
postoperative bleeding not responding to blood products: 1 dose
rFVIIa given, bleeding stopped
• Transitioned to Coumadin in postoperative phase
• All further HIT tests negative, including SRA
Slide 40
Case II: Heart Patient with Problems
• Sternal wound debridement 3 weeks later performed under
fondaparinux (direct FXa inhibitor, safe in HIT) anticoagulation.
Surprisingly little blood loss, no blood products given.
• Heart transplant performed few months later under heparin
anticoagulation due to repeated negative HIT tests. Bleeding
problems with high INR 3.68. Received Cell Saver 2000 mL, 12 U
PRBC, 12 U FFP, 2 apheresis units of platelet. Bleeding stopped
after 1 dose rFVIIa 90 μg/kg. Patient now doing well at home on
Plavix.
• Presentation points: HIT tests can be negative early in course,
convert once titers increase. In clinically suspected acute HIT,
switching from heparin may be the safest thing to do. Underlying
poor liver function was possibly responsible for bleeding on
argatroban, Coumadin, and later heparin. While blood products are
the first line of treatment for bleeding, rFVIIa may be effective as a
backup, although optimum dose unclear. In vasculopaths, it may be
most prudent to start with 20-40 μg/kg.
Slide 41
Self Assessment
The following are review questions that can be used for
review for this presentation.
Review Quiz
End
Slide 42
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References
• Hoffman M. A cell-based model of hemostasis. Thromb Haemost.
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2001;85:958-965.
Warkentin TE. Heparin-induced thrombocytopenia and its treatment.
J Thromb Thrombolysis. 2000;9 Suppl 1: S29-S35.
Aird WC. Vascular bed-specific hemostasis: role of endothelium in
sepsis pathogenesis. Crit Care Med. 2001;29: S28-S34.
Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl
J Med. 1999;341: 586-592.
DeLoughery TG. Critical care clotting catastrophes. Crit Care Clin.
2005;21:531-562.
Enomoto MT, Thorborg P. Emerging off-label uses for recombinant
activated FVII: grading the evidence. Crit Care Clin. 2005;21:611632.
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