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  • Hemostasis

    1. 1. Hemostasis Problems in Critical Illness Per Thorborg, MD, PhD, FCCM Director, Critical Care Medicine Dept.of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
    2. 2. Introduction <ul><li>While coagulation-associated problems in critical care medicine include both hyper- and hypocoagulable states, venous thromboembolism (VTE) is addressed in another module. </li></ul><ul><li>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’s, 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%). </li></ul><ul><li>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. </li></ul><ul><li>The order in which they 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, 6. references. </li></ul>
    3. 3. <ul><li>In the primary hemostasis a platelet plug is formed within 5 minutes to seal the site of injury. </li></ul><ul><li>In the secondary hemostasis fibrin is formed (coagulation) and a fibrin mesh reinforces the frail platelet plug (timescale hours). </li></ul><ul><li>The third part is (secondary) fibrinolysis which dissolves the clot but takes place first after tissue repair (timescale days). </li></ul><ul><li>The coagulation cascade for fibrin formation described in the early 1960s by Davie, Ratnoff, and MacFarlane was based on vitro data. While its extrinsic and intrinsic pathways setup explained many PT and APTT abnormalities, it failed to explain other clinical observations. </li></ul><ul><li>Newer data from the 1990s have replaced this older model with a cell-based model where interactions between endothelial cells, platelets, and thrombin have taken center stage. </li></ul>The Three Stages of Hemostasis
    4. 4. The Platelet Plug Formation <ul><li>Primary hemostasis is initiated by platelet activation in which the platelet changes from discoid (2 um) to irregular shape with pseudopods, releases its granular content (FV, FVIII, Ca 2+ , 5-HT, fibrinogen, ADP, TxA 2 ), and extrudes several domains with glycoprotein receptors, such as the GP1b receptor for vWF and the GP IIb/IIIa receptor for fibrinogen. </li></ul><ul><li>The vWF molecule allows the platelet to bind to exposed collagen at the site of injury while the GP IIb/IIIa receptor allows the platelet to form a three-dimensional plus using fibrinogen molecules. </li></ul><ul><li>The activated platelet exposes a phospholipid surface domain, PF3, which will become the catalytic center for the next part, the secondary hemostasis. </li></ul>
    5. 5. Cell-based Coagulation 2005 <ul><li>After injury, Tissue Factor (TF) becomes exposed to blood and combines with free circulating FVII. </li></ul><ul><li>This complex activates FX, which with FV can form small amounts of thrombin, enough to activate local platelets (see next slide). </li></ul><ul><li>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. </li></ul><ul><li>Thrombin has both pro-coagulatory and pro-modulatory as well as antifibrinolytic activities. </li></ul><ul><li>Three major modulating systems act to inhibit coagulation activation: </li></ul><ul><li>1. Tissue factor pathway inhibitor (TFPI) rapidly inhibits the TF/FVIIa pathway once activated. </li></ul><ul><li>2. The Protein C and S system will inactivate FVa and FVIIIa. </li></ul><ul><li>3. Antithrombin will inactivate thrombin (FIIa) as well as FXa, FIXa, FXIa, FXIIa. </li></ul>
    6. 6. Normal Hemostasis TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa X IX V Va II VIII/vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa Reproduced with permission from: Hoffman M, et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. Xa II IIa
    7. 7. Fibrinolysis <ul><li>Secondary (normal) fibrinolysis occurs by activation of plasminogen to plasmin by tPA. </li></ul><ul><li>Plasmin degrades fibrin (and fibrinogen) to fibrin degradation products (FDP), and its activity is controlled by alpha 2 -antiplasmin. When fibrin has been cross-linked (by FXIII) small segments known as D-dimers can be measured. </li></ul><ul><li>Plasminogen activator inhibitor (PAI-1) inactivates tPA and thereby controls fibrinolysis. </li></ul><ul><li>Abnormally activated (primary) fibrinolysis may appear after burns, prostate and neurosurgery, CPB, and after streptokinase or urokinase therapy. </li></ul>
    8. 8. Thrombocytopathy <ul><li>Thrombocytopathy denotes abnormal platelet function (number may be normal). Bleeding time is often increased but better evaluated with platelet function analysis or thromboelastography (TEG). Bleeding is usually not severe unless combined with other bleeding problems. </li></ul><ul><ul><li>Drug induced (antiplatelet therapy, COX inhibitors, TXA 2 inhibitors, calcium channel blockers, H 2 receptor antagonists, dextran, starch, NTP, NTG, PCN, cephalosporins) </li></ul></ul><ul><ul><li>Uremia </li></ul></ul><ul><ul><li>Hypothermia (< 35 ° C) </li></ul></ul><ul><ul><li>After cardiopulmonary bypass (CPB) </li></ul></ul><ul><ul><li>Malignant paraproteinemia (multiple myeloma, waldenstrom) </li></ul></ul><ul><ul><li>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. Depending on drug half-life, platelet transfusion may be an option. See also CPB-associated bleeding. Plasmaferesis is an option in bleeding malignant paraproteinemia patients. </li></ul></ul>
    9. 9. Thrombocytopenia <ul><ul><li>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/mm 3 . Bleeding rare if platelets functional and > 50.000/mm 3 . The most common causes are: </li></ul></ul><ul><ul><ul><li>- Disseminated Intravascular Coagulation (DIC) </li></ul></ul></ul><ul><ul><ul><li>- Sepsis </li></ul></ul></ul><ul><ul><ul><li>- Heparin-induced thrombocytopenia (HIT), with thrombosis (HITT) </li></ul></ul></ul><ul><ul><ul><li>- ITP and TTP/HUS syndromes </li></ul></ul></ul><ul><ul><ul><li>- Pregnancy related: HELLP, AFLP </li></ul></ul></ul><ul><ul><ul><li>- Antiphospoholipid syndrome (APLS) </li></ul></ul></ul><ul><ul><ul><li>- Cardiopulmonary bypass </li></ul></ul></ul><ul><ul><ul><li>- Drug-induced or in transfusion reaction </li></ul></ul></ul><ul><ul><ul><li>- (Pseudo-thrombocytopenia if using EDTA tubes) </li></ul></ul></ul><ul><ul><li>Symptoms include petechial bleeding, spontaneous or easy bruising, mucosal membrane bleeding, gingival bleeding, purpura. Note that several of the above states have also increased risk for thrombosis. </li></ul></ul>
    10. 10. Degree of Thrombocytopenia <ul><li>Moderate thrombocytopenia (50.000 - 100.000/mm 3 ) most commonly seen in TTP, HIT, DIC, sepsis </li></ul><ul><li>Severe thrombocytopenia (< 20.000/mm 3 ) more commonly seen in drug-induced thrombocytopenia, ITP, in transfusion reaction, and occasionally in severe HIT/HITT </li></ul><ul><li>Thrombocytopenia is usually appearing in conjunction with other clinical problems (see list on previous slide) which may dominate the symptomatology. One of the first places to check for petechial bleeding is under the blood pressure cuff. </li></ul><ul><li>Trigger point for platelet transfusion depends on the patient’s state and clinical situation. Avoid platelet transfusion in patients with TTP, HIT, or if platelet antibodies. </li></ul>
    11. 11. Disseminated Intravascular Coagulation (DIC) <ul><li>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. </li></ul><ul><li>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 lyze the increasing clot load. Initially bone marrow (platelets) and liver (coag. factors) may be able to keep production at par with consumption, but if speed of consumption increases the patient becomes hypocoagulable. </li></ul><ul><li>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. </li></ul><ul><li>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, rare drug-induced hemolytic DIC. </li></ul><ul><li>Chronic low grade DIC etiologies include cancer, vascular aneurysms, and giant hemangiomas, dead fetus in utero. </li></ul>
    12. 12. DIC in Systemic Inflammatory Response Syndrome (SIRS) <ul><li>In inflammatory states, including sepsis, release of pro-inflammatory cytokines IL-6 and TNF-  leading to DIC by several pathways: </li></ul><ul><ul><ul><li>IL-6 stimulate mononuclear and endothelial cells to express tissue factor, which leads to coagulation activation and fibrin formation. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul>
    13. 13. DIC Common in the ICU <ul><li>Sepsis: 30% develop DIC, depending on definition </li></ul><ul><li>Delayed shock resuscitation: time dependent </li></ul><ul><li>Head or crush injury; fat embolism: 50 - 70% </li></ul><ul><li>Acute leukemias (particularly Acute Promyeolocytic Leukemia), metastatic prostate cancer: 15% </li></ul><ul><li>Abruptio placenta, abortion, amniotic fluid embolism, hemorrhage, shock: 50% (while pre-eclamptic patients: 7%) </li></ul><ul><li>Immunologic disorders: variable </li></ul>
    14. 14. Presentation of DIC: Thrombosis versus Bleeding <ul><li>Signs of Thrombosis: </li></ul><ul><li>Neuro: multifocal, delirium, coma </li></ul><ul><li>Skin: ischemia </li></ul><ul><li>Renal: oliguria, azotemia, cortical necrosis </li></ul><ul><li>Pulm: ARDS </li></ul><ul><li>GI: ulceration </li></ul><ul><li>Signs of Bleeding </li></ul><ul><li>Neuro: bleeding </li></ul><ul><li>Skin: petechiae, ecchymosis </li></ul><ul><li>Renal: hematuria </li></ul><ul><li>Muc. Mb: epistaxis, gingval bleeding </li></ul><ul><li>GI: massive bleeding </li></ul>
    15. 15. DIC Lab Tests and Scoring System <ul><li>There is no single lab test to conclusively prove the presence of DIC. </li></ul><ul><li>The International Society on Thrombosis and Haemostasis proposed in 2001 a 5-step diagnostic algorithm to calculate a DIC score. Repeat scoring every 1 - 2d. </li></ul><ul><li>1. risk assessment – if yes proceed to: </li></ul><ul><li>2. order plt count, PT, fibrinogen, FDP or soluble fibrin monomer. </li></ul><ul><li>3. Scoring: If plt count > 100 = 0, < 100 = 1, < 50 = 2; FDP no increase = 0, moderate increase = 1, strong increase = 2; PT prolongation < 3s = 0, > 3 - 6s = 1, > 6s = 2; fibrinogen level > 1g/L = 0, < 1g/L=1. </li></ul><ul><li>4. Calculate (add) scores (0-7) </li></ul><ul><li>5. A score of 5 or more is compatible with overt DIC, whereas a score of < 5 may be indicative of non-overt DIC. </li></ul><ul><li>This DIC score has a 93% sensitivity and 98% specificity. The score also directly correlates to mortality. </li></ul>
    16. 16. Treatment of Acute Severe DIC <ul><li>ICU: always first restore blood volume, cardiac output, gas exchange, electrolytes </li></ul><ul><li>Identify and address the cause of DIC. Many causes for DIC are self limited (sepsis, obstetric complications, etc.). Treat underlying cause </li></ul><ul><li>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 </li></ul><ul><li>Possibly use anti-thrombotic agents (only if signs of tissue ischemia): Heparin or LMWH (by hematology) </li></ul><ul><li>DO NOT give antifibrinolytics, it may lead to widespread thrombosis. </li></ul><ul><li>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 > 25. </li></ul>
    17. 17. Sepsis-associated Coagulopathy <ul><li>Thrombocytopenia is commonly seen in sepsis by several different mechanisms: consumption of activated platelets, hemophagocytosis, and adhesion to endothelium. Degree of thrombocytopenia correlates with sepsis severity. </li></ul><ul><li>Coagulation activation manifests as increased D-dimers in almost all septic patients, and consumption of protein C with low PC levels in 90%, low AT levels in 50%. Hypercoagulability believed due to cytokine release with tissue factor expression on several cell lines, activated platelets and endothelial cells, and reduced natural anticoagulant modulators. </li></ul><ul><li>LMWH anticoagulation recommended unless contraindicated </li></ul><ul><li>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. </li></ul>
    18. 18. Heparin-induced Thrombocytopenia (HIT) <ul><li>Of patients receiving unfractionated heparin (UFH), 3% develop HIT; of these one-third go on to develop venous or arterial thrombosis (HITT). The frequency of HIT for LMWH is only 1%. </li></ul><ul><li>Pathophysiology: HIT is caused by IgG antibodies to the heparin-platelet factor 4 combination. </li></ul><ul><li>Presentation: Progressive thrombocytopenia develops after 5 - 10d heparin therapy, but can develop earlier if prior heparin exposure. HIT should be suspected if platelets drop at least 50% or to < 100.000/mm 3 . </li></ul><ul><li>Test for HIT antibody (SRA more specific then ELISA) </li></ul><ul><li>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. </li></ul>
    19. 19. ITP and TTP/HUS Syndromes <ul><li>In Immune Thrombocytopenic Purpura (ITP) antibodies bind to the GPIIb/IIIa receptor, and this complex is ingested by macrophages. Patient afebrile, diagnosis by exclusion. Splenectomy if severe thrombocytopenia, steroid treatment controversial </li></ul><ul><li>Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) is a syndrome of unknown etiology, although the vWF cleaving protease ADAMS13 appears to be involved. It is characterized by thrombocytopenia, anemia with schistocytes in smear, renal insufficiency, neurologic abnormalities, and fever. LDH is used as marker of disease activity. </li></ul><ul><li>Treatment is by plasma exchange and steroid therapy which has significantly reduced mortality. It can complicate cyclosporin, tacrolimus, cisplatinum, mitomycin C, ticlodipine, clopidogrel therapy; it can complicate bone marrow transplant, CMV infections, pregnancy, and autoimmune diseases as SLE. </li></ul>
    20. 20. Pregnancy-related Thrombocytopenias <ul><li>The HELLP (Hemolysis Elevated Liver tests Low Platelets) syndrome occurs after week 28 in pre-eclampsia. Decreased platelet count is followed by liver failure and hemolysis, fetus trombocytopenic in 30%. DIC can follow. Child delivery usually results in rapid improvement </li></ul><ul><li>Acute Fatty Liver of Pregnancy (AFLP) patients also develop thrombocytopenia early, followed by liver failure. Low blood glucose, high ammonia typical. Child delivery results in improvement </li></ul><ul><li>TTP/HUS can occur during pregnancy, fetus not involved. State resolves with termination of pregnancy, but plasma exchange may be required. Sometimes renal failure develops postpartum. </li></ul><ul><li>Treatment: hematological support, child delivery </li></ul>
    21. 21. CPB-associated Coagulopathy <ul><li>Cytokine activation leads to TF expression on endothelial cells and platelet activation. </li></ul><ul><li>Platelet dysfunction due to degranulation, loss of GPIIb/IIIa receptors, hypothermia, heparin-related, protamine-related </li></ul><ul><li>Thrombocytopenia can be caused by dilution and consumption. </li></ul><ul><li>Coagulation activation (despite heparin) leads to consumptive dysfunction (DIC) and decrease in physiologic modulators (AT, PC/PS). </li></ul><ul><li>Increased fibrinolysis (from release of tPA) as well as decreased levels of physiologic fibrinolysis inhibitors (  2 antiplasmin) </li></ul><ul><li>Heparin anticoagulation contributes both directly and indirectly to platelet dysfunction. </li></ul><ul><li>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. </li></ul>
    22. 22. Drug-induced Coagulopathies <ul><li>Warfarin-treated patients may see increased warfarin activity from amiodarone, aspirin, cimetidine, fluconazole, metronidazole, erythromycin, and decreased activity from barbiturates and phenytoin. </li></ul><ul><li>PT/INR increases commonly by cefotetan. </li></ul><ul><li>TTP/HUS can be induced by cyclosporin, tacrolimus, cis-platinum, ticlodipine, clopidogrel. </li></ul><ul><li>Hemolytic DIC syndrome induced by quinine, 2 nd and 3 rd generation cephalosporins </li></ul><ul><li>Thrombocytopenia can be caused by GPIIb/IIa receptor antagonists, amphotericin B, vancomycin, amiodarone, digoxin, procainamide, quinine, cimetidine, ranitidine, heparin, NSAIDs, phenytoin, HCTZ. </li></ul><ul><li>Treatment: examine patients list of drugs, and stop culprit drug. </li></ul>
    23. 23. Vitamin K Deficiency <ul><li>Vitamin K deficiency: intake (food, gut flora) under 40 - 80 mcg/d can lead to functional deficiency of Factors II, VII, IX, X as well as protein C and S. Seen in patients with longstanding malnutrition, with biliary obstruction, or that have been on prolonged antibiotic treatment which kills the gut flora that produces vitamin K </li></ul><ul><li>Can present with dramatic bleeding </li></ul><ul><li>PT /INR is early monitor due to short ½T of FVII </li></ul><ul><li>Treatment urgency: moderate 10 mg oral vitamin K will take effect within 12h; or give 5 - 10 mg iv over 30 - 60 min for effect with 6 - 8h. For urgent need, use 4U FFP until vitamin K takes effect . </li></ul>
    24. 24. Coagulopathy in Liver Failure <ul><li>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. </li></ul><ul><li>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 (2h) and its efficacy is reduced in the acidotic and hypothermic bleeding patient. In ESLD mortality without transplant is close to 100 % regardless of therapy. </li></ul>
    25. 25. Etiology of Perioperative Coagulation Problems <ul><li>Massive transfusion syndrome after trauma, vascular injury, or in major surgery </li></ul><ul><li>Concurrent liver or renal failure; sepsis/DIC; Ischemia/Reperfusion (I/R) injury to vascular endothelium after delayed or insufficient volume resuscitation </li></ul><ul><li>Other concurrent acquired coagulation defects such as anticoagulants or fibrinolytics, vitamin K deficiency, CPB, head trauma (TF release), immune- or pregnancy-elated thrombocytopenia, factor inhibitors (FVIII, FX, FV) </li></ul><ul><li>Rarely underlying congenital coagulation defect: vWD, hemophilia A/B/C, platelet disorders </li></ul>
    26. 26. Failure to Resuscitate Leads to Out-of-control Coagulation <ul><li>Prolonged tissue hypoperfusion (several hours) causes I/R injury with post-reperfusion vascular dysfunction leading to coagulation activation, micro-thrombosis, 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 et al. J Trauma. 1997;42(5):857-61.) </li></ul><ul><li>Treatment: Prompt fluid resuscitation in hypovolemia mitigates or prevents endothelial injury that otherwise leads to DIC. </li></ul><ul><li>Volume deficit is first treated with fluid resuscitation, not with vasopressor agents (possible exception severe CAD). </li></ul><ul><li>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. </li></ul>
    27. 27. Massive Transfusion (MT) <ul><li>Survival after MT (10U blood/24h) for trauma patients (8y Detroit study) was only 6.6% 35 years ago. In the 1990s, survival after MT (10U/24h) for all patients had improved to 60%, around 50% for 20U (trauma), around 40% for 40U (trauma), and the most recent study (2002) 43% for 50U/24h (trauma). </li></ul><ul><li>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. </li></ul><ul><li>Practical issues in MT scenario include close monitoring of BP via arterial line, volume status through CVP or better SvO 2 . 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. </li></ul><ul><li>Infectious complications in MT of little concern: infection 1/100.000 cases; lethal transfusion reaction 1/100.000 cases. </li></ul>
    28. 30. Anticoagulation-associated Bleeding Problems <ul><li>Antiplatelet agents : Aspirin irreversibly blocks the platelet cyclooxygenase, replaced by new platelets in 7d. In bleeding patient, can transfuse platelets or give DDAVP. Bleeding ticlodipine, clopidogrel, or GP IIb/IIIa antagonist treated patients can be given platelet transfusion. </li></ul><ul><li>Warfarin treated patients with bleeding should be treated with vitamin K iv plus 4U FFP. INR 2 - 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 mcg/kg. </li></ul><ul><li>Heparin’s short (30 - 60m) half-life makes reversal with protamine rarely necessary. Protamine only reverses the LMWH anti-thrombin effect, and due to longer half-life (12h), a second protamine dose may be required. </li></ul><ul><li>Direct thrombin inhibitors have no specific antidotes, but rFVIIa have been anecdotally reported to reverse life-threatening bleeding in these patients. </li></ul><ul><li>Fibrinolytic agents are associated with a 5% bleeding rate, but due to their short half-life, antifibinolytic agents are rarely required. Depending on laboratory results, patients may require cryoprecipitate and FFP. For intracranial bleeding complication, platelets are also recommended. </li></ul>
    29. 31. Case I: Postoperative Bleeding <ul><li>46-year-old female with stage III rectal cancer resected 6-years ago, followed by chemotherapy </li></ul><ul><li>Admitted 3/3/04 for L liver resection and RFA( Radio-FrequencyAblation) of metastatic lesion in R liver lobe </li></ul>
    30. 32. Case I: Postoperative Course <ul><li>On third postoperative day resp. problems: CT scan to R/O PE </li></ul><ul><li>Oxygenation deteriorated successively, moved to the ICU 3/8/04. CXR bilateral infiltrates type ALI/ARDS. ET intubated, placed on ventilator support </li></ul><ul><li>Also develops adrenocortical insufficiency requiring steroids </li></ul><ul><li>In 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 </li></ul><ul><li>Bleeding from suture lines, hematuria, petechia under the BP cuff </li></ul>
    31. 33. Case I: Presentation Points <ul><li>RFA cooks liver tissue, causes release of cellular content (such as tissue factor) into blood. Interestingly, her DIC started gradually and was first manifest the fourth postoperative day. </li></ul><ul><li>TF release is known to induce both DIC and ARDS. </li></ul><ul><li>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. </li></ul><ul><li>Ultimately her DIC subsided after 2 weeks and she left the hospital in good condition. </li></ul>
    32. 34. Case II: Heart Patient with Problems <ul><li>49-year-old man s/p CABG in cardiogenic shock with 4 vessel graft occlusion, transferred for heart transplant. Allergic to ASA and ?HITT </li></ul><ul><li>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 </li></ul><ul><li>Furthermore concerns with HLA immunization with transfusion of PRBC or platelets, for the planned heart transplant. Planned use of cellsaver in ORs, and if need for additional RBCs to use only leukoreduced red blood cells. </li></ul>
    33. 35. Case II: Heart Patient with Problems <ul><li>Patient bleeding on argatroban; preoperative labs show INR 2.6, APTT 117, Hct 29.4, Plt 168, D-dimers 0.53. 2 FFP given </li></ul><ul><li>New labs show INR >15, PTT 193, ACT 501, Fib 239, plt 109, hct 27.3. Cellsaver (470ml) given, 14U FFP, PRBC 14U, cryoprecipitate to optimize plt function Argatroban stopped </li></ul><ul><li>Postoperative labs INR 12.05, PTT 165, Fib 371 ACT 461. Postoperative bleeding not responding to blood products: 1 dose rFVIIa given, bleeding stopped </li></ul><ul><li>Transited to coumadine in postoperative phase </li></ul><ul><li>All further HIT tests negative, including SRA </li></ul>
    34. 36. Case II: Heart Patient with Problems <ul><li>Sternal wound debridement 3 weeks later performed under fondaparinux (direct FXa inhibitor, safe in HIT) anticoagulation. Surprisingly little blood loss, no blood products given. </li></ul><ul><li>Heart transplant performed under heparin anticoagulation due to repeated negative HIT tests. Bleeding problems with high INR 3.68. Received cellsaver 2000 ml, 12U PRBC, 12 U FFP, 2 leukopheresed units of platelet. Bleeding stopped after 1 dose rFVIIa 90 mcg/kg. Patient now doing well, at home, on Plavix. </li></ul><ul><li>Presentation points: HIT tests can be negative early in course convert once titers increase. In this scenario, switching from heparin maybe the safest thing to do. Underlying poor liver function was possibly responsible for bleeding on argatroban, coumadine and heparin. While blood products are the first line of treatment for bleeding, rFVIIa may be effective as a backup. </li></ul>
    35. 37. References <ul><li>Hoffman M. A cell-based model of hemostasis . Thromb Haemost. 2001;85(6):958-965. </li></ul><ul><li>Warkentin TE. Heparin-induced thrombocytopenia and its treatment. J Thrombosis and Thrombolysis. 2000;(9):S29-S35. </li></ul><ul><li>Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med. 2001;(29):S28-S34. </li></ul><ul><li>Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;(341):586-592. </li></ul><ul><li>DeLoughery TG. Critical care clotting catastrophes. Crit Care Clin. 2005;21(3):531-562. </li></ul><ul><li>Enomoto MT, Thorborg P. Emerging off-label uses for recombinant activated FVII: grading the evidence. Crit Care Clin. 2005;21(3):611-632. </li></ul>