Hemostasis Problems in Critical Illness Per Thorborg, MD, PhD, FCCM Director, Adult Critical Care...

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Hemostasis Problems inCritical Illness

Per Thorborg, MD, PhD, FCCMDirector, Adult Critical Care Medicine @ OHSU

Professor of Anesthesiology/CCMDept. of Anesthesiology and Perioperative Medicine

Lynn Boshkov, MDAssoc Director, Transfusion Medicine and Director, Hemostasis & Thrombosis

Associate Professor of Pathology, Medicine and PediatricsOregon Health & Science University

Portland, Oregon

Introduction

• While coagulation-associated problems in critical care medicine include 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; Bernard-Soulier and Glanzmann’s thrombasthenias; inborn platelet abnormalities; isolated coagulation factor deficiencies; dysfibrinogenemias; alpha2-antiplasmin 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. Anticoagulation-associated problems; 5.Case scenarios; and 6. References.

The Three Stages of Hemostasis

• In primary hemostasis, a platelet plug is formed within 5 minutes to 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.

• Primary hemostasis is initiated by endothelial 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

The Platelet Plug Formation

Schematic of platelet adhesion, activation and granule release, aggregation, and expression of pro-coagulant activityshowing major platelet GP receptors and bridging ligands.

Platelet Plug: Schematic

Cell-Based Coagulation 2005

• With injury, tissue factor (TF) becomes exposed to blood and 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.

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTF VIIaVIIa

XX

XaXa

IIIIIIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIaXaXa

IIaIIa

IIaIIa

XaXa

Normal Hemostasis

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 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.

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 CPB-associated bleeding. Plasmapheresis is an option in bleeding malignant paraproteinemia patients.

Thrombocytopenia

• 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]

Degree of Thrombocytopenia

• Moderate thrombocytopenia (50,000-100,000/mm3) most commonly 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).

Disseminated Intravascular Coagulation (DIC)

• 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.

Systemic Inflammatory Response Syndrome (SIRS)

• In inflammatory states, including sepsis, release of pro-inflammatory 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.

DIC Is Common in the ICU

• 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

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

• Neuro: bleeding

• Skin: petechiae, ecchymosis

• Renal: hematuria

• Muc. Mb: epistaxis, gingival bleeding

• GI: massive bleeding

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.

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;122:178-184), 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;34:625-631)

Treatment of Acute Severe DIC

• ICU: always first restore blood volume, cardiac output, gas exchange, and 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.

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.

Heparin-Induced Thrombocytopenia (HIT)

• Of patients receiving unfractionated heparin (UFH) for >7 days, 1%-2% 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.

ITP and TTP/HUS Syndromes

• 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.

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.

Microangiopathies

• HELLP (hemolysis elevated liver tests low platelets) syndrome occurs 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.

CPB-Associated Coagulopathy

• 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.

Drug-Induced Coagulopathies

• Warfarin-treated patients may see increased warfarin activity from 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.

Vitamin K Deficiency

• 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)

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.

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.

Failure to Resuscitate Leads toOut-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.

Massive Transfusion (MT)

• 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.

Anticoagulation-Associated Bleeding Problems

• Antiplatelet agents: aspirin irreversibly blocks the platelet cyclooxygenase, 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.

Case Studies

The following are case studies that can be used for review for this presentation.

Review Cases

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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

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

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.

Case II: Heart Patient with Problems

• 49-year-old man s/p CABG in cardiogenic shock with 4-vessel 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.


• 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


• 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.

Self Assessment

The following are review questions that can be used for review for this presentation.

Review Quiz

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References

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