Coagulation and TEG


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Physiology of coagulation.
Coagulation disorders, evaluation, treatment and anaesthetic implications.
Thromboelastography and its relevance to Liver transplant and anaesthetic management of the same. Complete with TEG images of liver transplant patients at various phases of the surgery

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Coagulation and TEG

  2. 2.  0.36 ml of celite-activated whole blood  A special cylindrical cuvette or cup, which is pre heated to a temperature of 37 degC  cuvette oscillates through an angle of 45deg and each rotation lasts for 10 seconds.  pin suspended by a torsion wire is lowered into the blood.  Development of fibrin strands “couple” motion of cup to pin  “Coupling” directly proportional to clot strength
  3. 3.  Electrical signal amplified to create TEG trace  Result displayed graphically on pen & ink printer or computer screen  Deflection of trace increases as clot strength increases & decreases as clot strength decreases
  4. 4. TEG analyzer measures major parameters of  clot formation and lysis - R, K, α Angle, MA and LY 30  measures TMA and amplitude at a specific time.  G (shear elastic modulus strength SEMS)  coagulation index (CI)
  5. 5. •r’ time - represents period of time of latency from start of test to initial fibrin formation •normal range 15 - 23 mins (native blood), 5 - 7 mins (kaolin-activated) r time ↑ by • Factor deficiency • Anti-coagulation • Severe hypofibrinogenaemia • Severe thrombocytopenia r time ↓ by • Hypercoagulability syndromes
  6. 6. ‘k’ time - time from the end of R until a fixed level of clot strength is reached i.e. amplitude of the trace is 20 mm. Normal range 5 - 10 mins (native blood) 1 - 3 mins (kaolin- activated) k time ↑ by • Factor deficiency • Thrombocytopenia • Thrombocytopathy • Hypofibrinogenaemia k time ↓ by • Hypercoagulability state
  7. 7. “α” angle - Measures rapidity of fibrin build-up & cross-linking (clot strengthening) assesses rate of clot formation normal range • 22 - 38 (native blood) • 53 - 67(kaolin-activated) α Angle ↑ by • Hypercoagulable state α Angle ↓ by • Hypofibrinogenemia • Thrombocytopenia
  8. 8. MA is a direct function of the maximum dynamic properties of fibrin and platelet bonding via GPIIb/IIIa and represents the ultimate strength of the fibrin clot Correlates to platelet function 80% platelets 20% fibrinogen. Normal range 47 – 58 mm (native blood), 59 - 68 mm (kaolin-activated). MA ↑ by • Hypercoagulable state MA ↓ by • Thrombocytopenia • Thrombocytopathy • Hypofibrinogenemia
  9. 9. G (SEMS – Shear Elastic Modulus Strength)  measured in dyne/cm.2  It is a measure of clot strength or clot firmness. 5000 A G = –––––––––– 100 -A (when A = 50 mm, which is normal value of whole blood, G = 5000 dyne/cm2). CI (Coagulation Index)  patient’s overall coagulation is calculated from R, K, MA and a Angle.  Normal values are from –3.0 to +3.0,  < –3.0 represent hypocoagulable state  > +3.0 represent hypercoagulable state.
  10. 10. A30 – Amplitude 30 min after MA is reached. A60 – Amplitude 60 min after MA is reached LY30 – measures % lysis 30 min after MA is reached. LY60 – measures % lysis 60 min after MA is reached gives measure of degree of fibrinolysis normal range • < 7.5% (native blood) • < 7.5% (celite-activated)
  11. 11. Clot formation  Clotting factors - r, k time  Clot kinetics  Clotting factors - r, k times  Platelets - MA  Clot strength / stability  Platelets - MA Clot resolution  Fibrinolysis - LY30/60; A30/60
  12. 12. Parameters Significance /deficiency Correction Prolonged R coagulation proteins, anticoagulants ffp ↓d α -angle or prolonged K fibrinogen cryoprecipitate ↓d MA platelets platelet concentrate LY30 more than 7.5% increased fibrinolysis Antifibrinolytic agents-EACA tranexamic acid
  13. 13. Advantages of TEG  differential diagnosis of coagulopathy  Differentiates surgical from non surgical bleeding  Guides use of blood components  Guides use of pharmacological agents Limitations of TEG TEG cannot identify- • The individual coagulation factors e.g. VIII, IX, X • Inhibitors e.g. antithrombin, protein-C, protein S etc. • Activators e.g. thromboxane A - 2, AD
  15. 15.  Hereditary
  16. 16.  Acquired
  17. 17.  Hereditary deficiency of factor VII rare autosomal recessive disease with highly variable clinical severity.  Only homozygous deficient patients have factor VII levels generally low enough (<15%) to have symptomatic bleeding.  Easily recognized from their unique laboratory pattern of a prolonged PT but normal PTT. ANAESTHEIC CONSIDERATIONS  Rx of single-factor deficiency state depends on severity.  Most patients with mild to moderate factor VII deficiency can be treated with infusions of FFP.
  18. 18.  Patients with factor VII levels <1% generally require treatment with a more concentrated source of factor VII.  Preferred product for prophylaxis is Proplex T (factor IX complex) because of its high level of factor VII. Treatment of factor VII deficiency with active bleeding  Proplex T or the activated form,  Recombinant factor VIIa (NovoSeven), usually beginning with dose of 20-30 μg/kg, with redosing according to PT results.
  19. 19.  Congenital deficiencies in factors X, V & prothrombin are inherited as autosomal recessive traits & severe deficiencies are quite rare, on the order of one in one million live births.  Pts with severe deficiencies in any of these factors demonstrate prolongations of PT & PTT.  Congenital factor V deficiency - prolonged bleeding time because of relationship btwn factor V & platelet function in supporting clot formation.
  20. 20. ANAESTEHTIC CONSIDERATIONS  Can be corrected with FFP.  Conc of vit K–dependent factors in FFP is approx. same as normal plasma in vivo. (to obtain significant increase in level of any factor, considerable volume infused)  At least 4-6 units of FFP needed to attain 20-30% increase in any missing factor level.  This level represents considerable volume of plasma (800–1200 mL) - significant CVS challenge.  Duration of effectiveness of replacement depends on turnover of each factor, dictating how often repeated infusions of FFP needed for maintenance.
  21. 21.  Factor V is stored in platelet granules. (particularly in bleeding patient, platelet transfusion ideal)  Severe deficiency in pt facing surgery with significant risk of blood loss, several prothrombin complex concentrates (PCCs) available.  Adv - factor levels of 50% or higher can be achieved without risk of volume overload.  Disadv - PCCs are risk induction of widespread thrombosis, thromboembolism & DIC.  Important to recognize variation in factor levels in different products.
  22. 22.  Defects in propagation phase of coagulation convey a significant bleeding tendency, ass. with isolated prolongation of activated partial thromboplastin time (aPTT).  X-linked recessive disorders hemophilia A & B principal eg. of this type.  Marked reduction in either factor VIII or IX associated with spontaneous & excessive hemorrhage, especially hemarthroses & muscle hematomas.  Deficiency in factor XI (gene on chromosome 4), prolongs aPTT but less severe bleeding tendency.  Not all deficiencies with prolongation of aPTT associated with bleeding.
  23. 23.  Initial activation stimulus surface contact activation of factor XII (Hageman factor) to produce XIIa, facilitated by HMW kininogen & conversion of prekallikrein to active protease kallikrein.  Deficiency in any of these 3 factors causes prolongation of aPTT.  These factors play no role in initiation / propagation phase of clotting in vivo - deficiencies of factor XII, HMW kininogen & prekallikrein not associated with clinical bleeding.  Deficiencies in these factors - no special management except alteration of coagulation testing to allow accurate measurement of physiologic factors critical to in vivo hemostasis.
  24. 24.  Factor VIII gene is very large gene on X chromosome.  Most severe hemophiliacs generally have inversion/deletion of major portions of X chromosome genome or missense mutation, resulting in factor VIII activity < 1% of normal.  Point mutations & minor deletions - milder disease with factor VIII levels > 1%.  In some patients, functionally abn protein is produced - causes discrepancy btwn immunologic measurement of factor VIII antigen (protein) & coagulation assay of factor VIII activity.  Clinical severity of hemophilia A best correlated with factor VIII activity level.
  25. 25.  Severe hemophiliacs (activity <1%, <0.01 U/mL) usually diagnosed during childhood - frequent, spontaneous hges into joints, muscles, & vital organs.  Frequent Rx with factor VIII replacement, risk of developing progressive, deforming arthropathy.  Factor VIII levels 1-5% of normal enough to reduce severity of disease - increased risk of hge with surgery/trauma, much less spontaneous hemarthroses/hematomas.  Factor levels 6-30% only mildly affected, may go undiagnosed well into adult life - at risk for excessive bleeding with a major surgical procedure.
  26. 26.  Female carriers also at risk with surgery.  Severe hemophilia A patients prolonged PTT, whereas milder disease PTT may be only few sec > normal.  Since TF VII–dependent (extrinsic) pathway of laboratory clotting is intact, PT is normal. ANAESTHETIC CONSIDERATIONS  If major surgery necessary, factor VIII level must be brought to near normal (100%).  Initial inf of 50-60 U/kg (3500–4000 units in 70kg pt).  T1/2 approx. 12hrs in adults, repeated infusions of 25-30 U/kg every 8-12 hrs needed to keep level > 50%.  For each unit/kg infused, plasma VIII level will increase approx 2%.
  27. 27.  In children, t1/2 factor VIII as less as 6hrs -more frequent inf & lab assays to confirm efficacy.  Peak & trough factor VIII levels measured to confirm dosing level & interval.  Rx continued upto 2 wks to avoid postoperative bleeding (disrupts wound healing).  Longer periods required in patients who undergo bone or joint surgery (4-6 wks of replacement therapy).  Up to 30% of severe hemophilia A patients exposed to factor VIII concentrate or recombinant product develop inhibitor Abs.  Newer recombinant preparations not resulted in reduction in incidence of inhibitor formation.
  28. 28.  Hemophilia B pts similar spectrum of disease as A.  Factor IX levels <1% - severe bleeding, moderate disease seen with levels of 1-5%.  Pts with factor IX levels of between 5-40% generally have very mild disease.  Milder hemophiliacs (>5% activity) may not be detected until Sx performed / dental extraction.  Similar to lab findings with hemophilia A - prolonged PTT & normal PT.
  29. 29. ANAESTHETIC CONSIDERATIONS  General guidelines do not differ significantly from hemophilia A patients.  Recombinant/purified product or factor IX–PCC used to treat mild bleeding episodes/prophylaxis with minor procedures.  In amounts sufficient to increase factor IX levels to 50%+ increased risk of TE complications, especially in orthopedic procedures.  Essential to use only recombinant IX Rx pts undergoing major orthopedic Sx / severe traumatic injuries / liver disease.  Purified factor IX conc/recombinant IX over several days to treat bleeding in hemophilia B.
  30. 30.  Recovery of factor IX is approx. half of factor VIII - dosing approximately double that for factor VIII concentrates.  To achieve 100% plasma level in severe hemophilia B patient, 100 U/kg (7000 units in a 70-kg patient) needs to be administered.  Factor IX has a half-life of 18-24 hrs - repeated infusions at 50% of original dose every 12-24 hrs usually sufficient to keep plasma level >50%.  Like factor VIII recommendations, doses of 30-50 U/kg will give mean factor IX levels of 20%-40%, adequate for less severe bleeds.
  31. 31.  Hemophilia A patients Significant risk of developing circulating inhibitors to factor VIII, incidence of 30%-40% in patients severely deficient in factor VIII.  Hemophilia B patients are less likely. (3%-5%)  Severe hemophilia-like syndrome can occur in genetically normal individuals 2ndary to appearance of acquired autoAb to factor VIII or IX.  Patients usually middle-aged or older with no personal or family history of abnormal bleeding with sudden onset of severe, spontaneous hemorrhage.  Mixing study - presence of inhibitor. By mixing pt plasma & normal plasma 1:1 ratio to determine whether prolonged PTT shortens. Hemophilia A (deficiency in factor VIII but no inhibitor) - shortening of PTT to < 4 s of normal PTT control.
  32. 32.  In contrast, patient with factor VIII inhibitor will not correct PTT to that extent, if at all. Also important to quantitate factor VIII activity level, & using modification of PTT called Bethesda assay to measure inhibitor titer.  In general, factor VIII inhibitor patients fall into one of two groups according to the level of inhibitor.  High responders (>10 U/mL) demonstrate marked inhibitor response after any factor infusion (cannot be neutralized by high-dose replacement Rx). Typical of induction of an alloantibody, & pt constantly at risk of anamnestic response when re-exposed to factor.  In contrast, low responders develop & maintain low levels of inhibitor, constant despite repeated exposure to factor VIII replacement.
  33. 33. ANAESTHETIC CONSIDERATIONS  Mx of Hemophilia A with inhibitor varies according to whether high/low responder.  Low responders (titers <5-10 Bethesda U/mL) – no anamnestic response to factor VIII conc, whereas high responders (titers of several 1000units) dramatic anamnestic responses.  Low-responder category managed with factor VIII concentrates.  Larger initial & maintenance doses of factor VIII required & frequent assays of factor VIII levels essential to guide therapy.  When titer of the factor VIII inhibitor >5-10 U/mL (high responder category), Rx with factor VIII conc is not feasible.
  34. 34.  Major life-threatening bleeds treated with products such as activated PCCs/recombinant factor VIIa.  Rx with activated PCCs - risk of initiating DIC or widespread thromboembolism - recombinant factor VIIa becoming treatment of choice for acquired inhibitors.  Hemophiliacs can generate Xa via factor VIIa binding to tissue factor in initiation phase, but in propagation phase unable to generate Xa & thrombin burst on platelet surface without factor VIII or IX.  Recombinant factor VIIa in high concentrations replaces VIIIa/IXa Xase complex requirement by binding to platelet surface & increasing both Xa generation & thrombin burst.  Active bleeding – 90-120 μg/kg IV every 2-3 hrs until hemostasis achieved.
  35. 35.  Only other defect causing isolated prolongation of PTT & bleeding tendency - Rosenthal's disease.  Autosomal recessive trait, affects males & females equally.  Much rarer than hemophilia A or B, affects up to 5% of Jews of Ashkenazi descent from Eastern Europe.  Generally, bleeding tendency, if at all, quite mild & may only be apparent following Sx.  Hematomas & hemarthroses very unusual, even in patients with factor XI levels <5%.  Homozygous for type II mutation - very low levels of factor XI & develop a factor XI inhibitor when exposed to plasma therapy.
  36. 36. ANAESTHETIC CONSIDERATIONS  Treatment depends on severity of deficiency & bleeding h/o.  Most patients' factor XI deficiency treated with infusions of FFP.  Treatment of active bleeding is either PCCs/recombinant factor, usually beginning with a dose of 20-30 μg/kg, with redosing according to prothrombin time results.  Management of factor XI inhibitors is comparable to that of hemophilia A & B inhibitors.
  37. 37.  Interferes with final step in generation of fibrin clot.  Hypo/afibrinogenemia, relatively rare conditions, autosomal recessive traits.  Afibrinogenemia - severe bleeding diathesis with spontaneous & posttraumatic bleeding.  Since bleeding can begin during first few days of life, may be initially confused with hemophilia.  Hypofibrinogenemic pts usually no spontaneous bleeding, but difficulty with Sx.  Severe bleeding anticipated in patients with plasma fibrinogen levels <50-100 mg/dL.
  38. 38.  Fibrinogen is synthesized in liver under control of 3 genes on chromosome 4. >300 mutations producing dysfunctional & reduced amounts of fibrinogen reported – autosomal dominant traits.  Hypodysfibrinogenemia exhibit excessive bleeding.  Heterozygous pts although have abnormal coagulation tests do not have bleeding tendency.  Approx. 60% clinically silent, while remainder present with bleeding diathesis / paradoxically thrombotic tendency.  Lab evaluation of fibrinogen - measurements of fibrinogen concentration & function.
  39. 39.  Most accurate quantitative measurement by immunoassay/protein precipitation technique.  Other screening tests for fibrinogen dysfunction - thrombin time (TT), CT using retiplase.  Definitive diagnosis & subclassification - fibrinopeptide chain analysis by Na dodecyl sulfate–polyacrylamide gel electrophoresis & amino acid sequencing. ANAESTHETIC CONSIDERATIONS  Cryoppt Rx - to increase fibrinogen level by at least 100 mg/dL in average-size adult, 10-12 units of cryoprecipitate infused, followed by 2-3 units/day. (fibrinogen catabolized at rate of 25%/day).  Dysfibrinogenemia pts with a thrombotic tendency require long-term anticoagulation.
  40. 40.  Factor XIII (fibrin-stabilizing factor) deficiency rare autosomal recessive disorder (prevalence of 1 in five million).  At birth persistent umbilical / circumcision bleeding.  Adults - severe bleeding diathesis - recurrent soft-tissue bleeding, poor wound healing, high incidence of intracranial hge.  Blood clots form but weak & unable to maintain hemostasis.  Fetal loss in women with factor XIII deficiency approachES 100%, suggesting a critical role in maintaining pregnancy.  Factor XIII deficiency considered in severe bleeding diathesis with normal screening tests (PT, PTT, fibrinogen, platelet count, BT).
  41. 41.  Clot dissolution in 5M urea used as a screen.  Definitive diagnosis after abnormal screen accomplished by enzyme-linked immunosorbent assay.  Severe hemorrhage at levels of 1% of normal. Heterozygotes (factor XIII levels of approximately 50%) usually no bleeding tendency. ANAESTHETIC CONSIDERATIONS  Rx with FFP/cryoprecipitate/plasma-derived factor XIII concentrate/Fibrogammin P.  Preop prophylaxis - IV inj 10-20 U/kg at 4-6wk intervals (depending on preinfusion level).  Acute hge - infusion of 50-75 U/kg.  Factor XIII long circulating half-life of 7-12 days, adequate hemostasis achieved with even low plasma concentrations (1%–3%).
  42. 42.  Production disorders may be caused by megakaryocyte aplasia or hypoplasia in bone marrow.  Congenital hypoplastic thrombocytopenia with absent radii (TAR syndrome) usually inherited in autosomal recessive manner.  Thrombocytopenia develops in 3rd trimester/early after birth, often initially severe (<30,000/μL), slowly improves over time nearing normal range by age 2.  Patients often have obvious bilateral radial anomalies & abnormalities of other bones may also occur.
  43. 43. Fanconi Syndrome  Hematologic manifestations do not usually appear until approx. 7 yrs of age, although thrombocytopenia reported in neonates.  Bone marrow - reduced cellularity & reduced numbers of megakaryocytes.  Treatment rarely necessary in neonatal period & stem cell transplantation curative once severe bone marrow failure has developed. May-Hegglin Anomaly  Giant platelets in circulation & Döhle bodies (basophilic inclusions) in WBCs.  Platelet production variably ineffective; 1/3rd significantly thrombocytopenic & at risk of bleeding.
  44. 44. Wiskott-Aldrich Syndrome  X-linked disorder that presents with a combination of eczema, immunodeficiency, and thrombocytopenia.  Circulating platelets smaller than normal, function poorly because of granule defects & have a reduced survival. The latter, however, is not enough to explain the severity of the thrombocytopenia; ineffective thrombopoiesis is the principal abnormality. Autosomal Dominant Thrombocytopenia  Increased megakaryocyte mass with ineffective production & in some cases, release of macrocytic platelets into circulation.  Many have nerve deafness & nephritis (Alport's syndrome).
  45. 45.  Failure in platelet production from marrow damage where all aspects of normal hematopoiesis are depressed even to the point of marrow aplasia (aplastic anemia).  Reductions megakaryocyte mass seen in pts receiving radiationRx/ Ca chemoRx, due to exposure to benzene & insecticides, common drugs such as thiazide diuretics, alcohol, & estrogens, or complication of viral hepatitis.  Infiltration of marrow by malignant process will also disrupt thrombopoiesis.
  46. 46.  Hematopoietic malignancies - multiple myeloma, acute leukemias, lymphoma, & myeloproliferative disorders produce platelet production defect; metastatic Ca & Gaucher's disease (rarer).  Ineffective thrombopoiesis seen in pts with vit B12 or folate deficiency, including patients with alcoholism & defective folate metabolism.  Identical to maturation defect in RBC & WBC lines. Marrow megakaryocyte mass is increased, but effective platelet production is reduced.  Rapidly reversed by appropriate vit therapy.
  47. 47. ANAESTHETIC CONSIDERATIONS  Platelet transfusions mainstay.  Patients with ineffective thrombopoiesis 2ndary to intrinsic abnormality of megakaryocytes treated similarly to those with production disorder when need for urgent surgery of a bleeding episode.  Ineffective thrombopoiesis associated with either vit B12 or folate deficiency immediately treated with appropriate vit therapy.  Recovery of platelet count to normal occurs within a matter of days, making platelet transfusion unnecessary in all but acute situations.
  48. 48. Drug-induced Autoimmune Thrombocytopenic Purpura  Quinine, quinidine & sedormid are best known & studied extensively.  Pts present with severe thrombocytopenia, with platelet counts <20,000/μL.  Drugs act as haptens to trigger Ab formation & serve as obligate molecules for Ab binding to platelet surface.  Can also occur within hrs of 1st exposure to drug due to preformed antibodies - varying frequency (0%–13%) with abciximab (ReoPro) & other glycosylphosphatidyl glycan Ib/IIIa inhibitors.  α-methyldopa, sulfonamides, gold salts, also stimulate autoAb .
  49. 49. Heparin-induced Thrombocytopenia  Modest decrease in platelet count, HIT type I (nonimmune) observed in majority of patients within 1st day of full-dose unfractionated heparin (UH) therapy.  Relates to passive heparin binding to platelets - modest shortening of platelet life span, transient & clinically insignificant.  HIT type II (immune-mediated) - In patients receiving heparin for >5 days, Ab to hep-platelet factor 4 complex - capable of binding to platelet Fc receptors - platelet activation & aggregation.  Results in further release of hep-platelet factor 4 & appearance of platelet microparticles in circulation - magnify procoagulant state.
  50. 50.  Hep-platelet factor 4 complex binding to endothelial cells stimulates thrombin production - leads to increased clearance of platelets with venous &/or arterial thrombus formation - loss of limbs/stroke/ MI/ unusual sites of thrombosis (adrenal, portal vein, skin).  Incidence of HIT type II varies with type & dose of heparin used & duration of Rx.  10-15% of pts receiving bovine UH develop Ab, <6% of patients receiving porcine heparin.  <10% who develop Ab to hep–platelet factor 4 complex will exhibit thrombotic event.  Risk varies (40%+ in postop setting when high circulating levels of both activated platelets & thrombin are present, eg.orthopedic surgery).
  51. 51.  HIT antibody +ve pts undergoing CABG/hep therapy for unstable angina reported to have significant increase in adverse events .  Pts on full-dose UH for >5 days/previously received heparin should be monitored with every other day platelet counts.  >50% decrease in platelet count, even if absolute count within normal range - appearance of HIT type II Ab & mandates stopping hep & substituting direct thrombin inhibitor (lepirudin/argatroban).  If heparin continued, (even LD SC hep/LMWH), significant risk of major thromboembolic event.  Acute form of HIT type II can occur in patients restarted on heparin within 20 days of a previous exposure - sudden onset of dyspnea, shaking chills, diaphoresis, hypertension, tachycardia.
  52. 52.  Platelet transfusions appropriate if pt experiencing life- threatening hge or bleeding into a closed space.  In autoimmune thrombocytopenia 2ndary to drug ingestion, most imp management step is to discontinue drug.  Corticosteroid therapy may speed recovery in patients with ITP–like picture, as seen in pts reacting to sulfamethoxazole.  Rate of recovery depends on clearance rate of drug & ability of marrow megakaryocytes to proliferate & increase platelet production.
  53. 53.  Approx. 60% pts show response, upto 50% have long-lasting improvement in counts, effect not immediate.  Splenectomy can help in >85% if done early in disease.  Substitution of LMWH not an option (significant cross- reactivity.)  In thrombotic event/when continued anticoagulation is required, HIT patients should be started on direct thrombin inhibitor.  After baseline PTT, lepirudin given as IV bolus of 0.4 mg/kg, followed by infusion at rate of approx. 0.15 mg/kg/hr, to keep PTT 1.5-2.5 times normal.  Argatroban given as infusion of approx.2.0 μg/kg/min, titrated to keep PTT between 1.5-3 times normal.
  54. 54. Myeloproliferative Disease  PV, myeloid metaplasia, idiopathic myelofibrosis, essential thrombocythemia & CML - abnormal platelet function.  High platelet counts - abnormal bleeding/tendency for arterial or venous thrombosis/both.  In PV, expansion of TBV, increase in blood viscosity -> thrombotic risk. (splenic, hepatic, portal, & mesenteric BVs)  BT may be prolonged - poor predictor of abnormal bleeding.  Defects in epinephrine-induced aggregation, dense & α- granule function.  Bleeding due to an acquired form of vWD may also be observed in these disorders.
  55. 55. Dysproteinemia  AbN platelet function, defects in adhesion, aggregation & procoagulant activity.  1/3 pts with Waldenström macroglobulinemia, IgA myeloma -demonstrable defect; IgG multiple myeloma pts less affected.  Conc. of monoclonal protein spike correlates with abn. in platelet function.  Functional defect in pts with DIC & fibrin/fibrinogen breakdown - Fibrin fragments impair polymerization & platelet aggregation.  Failure of platelet thrombus formation in DIC multifactorial – 1. Thrombocytopenia 2. Hypofibrinogenemia 3. Loss of dense & α-granule function 2ndary to platelet activation.
  56. 56. Uremia  Untreated pts defect in platelet function correlating with severity of uremia & anemia.  Uncleared metabolic product guanidinosuccinic acid - inhibitor of platelet function by inducing endothelial cell NO release.  Platelet adhesion, activation & aggregation are abnormal, TXA2 decreased.  Prolonged BT >30 min - corrected by HD. (may also relate to anemia since BT shortens with transfusion/erythropoietin)  Acute bleeding – DDAVP can improve platelet function transiently. Infusion of conjugated estrogens (0.6 mg/kg per day) for 5 days shortens BT (normalization of plasma levels of nitric oxide metabolites.)  Improvement several days to appear, lasting for upto 2 wks.
  57. 57. Liver Disease  Usually hge due to discrete defect - bleeding varices/ gastric/duodenal ulcer.  If widespread bleeding – ecchymoses, oozing from IV, coagulopathy considered.  Multifaceted defect in coagulation.  Thrombocytopenia due to hypersplenism, failed thrombopoietin response.  Platelet dysfunction 2ndary to high levels of circulating fibrin degradation products.  Reduced production of factor VII (principal cause of prolonged PT) low-grade, chronic DIC with increased fibrinolysis.
  58. 58. Nephrotic Syndrome Patients  Risk of TE disease including renal vein thrombosis.  Explanation for this is unclear.  Attributed to 1. < normal levels of ATIII or PC, 2ndary to renal loss of coagulation protein 2. factor XII deficiency 3. platelet hyperactivity 4. abnormal fibrinolytic activity 5. >normal levels of other coagulation factors.  Hyperlipidemia & hypoalbuminemia also been proposed as etiologic factors.
  59. 59.  Can be divided into 2 major classes: 1. Congenital predisposition caused by one or more genetic abn. (thrombophilia) 2. Acquired/environmental hypercoagulability.  Hereditary conditions predisposing to venous thromboembolism (VTE) conceptually be divided into 1. Conditions that decrease endogenous antithrombotic proteins 2. Increase prothrombotic proteins
  60. 60. Hereditary Antithrombin Deficiency  AT III most imp of body's defenses against clot formation in healthy BVs/perimeter of active bleeding.  AT III deficiency autosomal dominant trait, 1/1000-5000 individuals.  Homozygous AT deficiency is generally not compatible with life.  Heterozygote AT III level 40-70% of normal, 20 times more likely to develop VTE at some point – usually with some triggering event that further increases their hypercoagulability.
  61. 61. Hereditary Protein C and Protein S Deficiency  Adversely affect thrombin regulation.  Hampers ability to limit rates of thrombin generation.  Heterozygous deficiencies - relative surplus of factors Va & VIIIa from defective inactivation ensures & prothrombinase complexes act with enhanced kinetics - overabundance of thrombin.  Synthesis of PC & PS vit K dependent, PC shorter t1/2.  PC deficient particular risk of thrombosis if warfarin therapy initiated in absence of protective previous anticoagulation by heparin.  Specifically, 1st days of warfarin Rx, before inhibition of vit K has decreased factors VII, IX, & XI to provide anticoagulation - paradoxically hypercoagulability.
  62. 62. Factor VLeiden  Factor VLeiden gene, differs from normal gene by single nucleotide, producing AA substitution at 1 site where APC normally cleaves factor Va - rendering it refractory to inactivation.  VaLeiden stays active in circulation > normal - increased thrombin generation.  Low - intermediate procoagulant risk.  Heterozygous 5-7fold increased risk of VTE, homozygous carriers 80-fold.  Approx. 5% of northern European descent, rarely in African or Asian descent.
  63. 63. Antiphospholipid Antibodies  Tendency for venous & arterial thrombosis in circulating LAC Abs (antiphospholipid/ACL Abs).  APL Abs mix of several IgG, IgM, IgA directed at phospholipid- associated proteins, esp. prothrombin & β2-glycoprotein I.  LAC Abs detected by prolongation of PTT & PT, while ACL Abs measured directly by immunoassay.  ACL Ab defined by its reactivity to cardiolipin, β2-glycoprotein I.  Increases binding of WBCs & platelets to endothelial surface - thrombus formation. Other MOAs - interference with PC activation, reduction in PS levels, development of a HIT-like platelet defect.
  64. 64.  Isolated VT/TE 2/3 of cases; cerebral thrombosis accounts for 1/3.  Coronary, renal, retinal, subclavian, & pedal artery occlusions less common.  Along with factor VLeiden & prothrombin gene mutation, APL Ab considered 1 of top causes of TE in young.  Can also present with catastrophic APL syndrome characterized by multiorgan failure 2ndary to 1. widespread small vessel thrombosis 2. Thrombocytopenia 3. ARDS 4. DIC 5. Autoimmune hemolytic anemia.  Clinical picture is indistinguishable from of TTP (Bacterial infections triggering events)
  65. 65.  Current strategies range from simple management approaches (early ambulation) to combination of SC heparin with elastic stockings followed by conversion to warfarin with ass. lab monitoring.  VTE risk factors must be considered when balancing degree of thrombotic risk costs (monetary & bleeding risk) of aggressive perioperative anticoagulation.  Prophylaxis strategies may take form of pharmacologic or physical methods.  Drugs proven to suitable for VTE prophylaxis include UH, LMWH, oral anticoagulant warfarin, direct thrombin inhibitors (hirudin), factor Xa inhibitors (fondaparinux).
  66. 66.  Physical methods of prophylaxis - graded compression elastic stockings 40-45% risk reduction, intermittent pneumatic compression risk reduction approaches that of UH.  Inv late 70s & 80s presented convincing evidence that RA (usually neuraxial blockade) - decreased incidence of postoperative VTE, esp for lower extremity jt replacement.  RA thus preferred technique for this Sx & procedures with high VTE risk.  Postop prophylactic anticoagulation with warfarin & SC heparin std for high-risk operations.  With advent of routine antithrombotic prophylaxis, adv of RA over GA less clear.
  67. 67.  In conclusion, no particular anesthetic technique is mandated for antithrombotic prophylaxis, & except in special circumstances, LMWH not be withheld in postop period to allow continued use of epidural.  In absolute CI to anticoagulation / major bleeding, placement of VC filter used to prevent recurrent PE.  Available filters - Greenfield, bird's nest, Simon nitinol, Vena Tech, Gunther Tulip Retrievable Vena Caval Filter.  Filters reduce incidence of PE to <4%, but not more effective than long-term anticoagulation.  Complications - insertion site (20-40%) & IVC thrombosis, tilting / migration of filter, damage to wall IVC, filter fracture.
  68. 68. Anesthetic Considerations for Patients on Long-Term Anticoagulation  Periop Mx of pts receiving long-term anticoagulation requires special consideration.  Risk of thrombosis when preop pt not effectively anticoagulated weighed against risk of bleeding during & after surgery if anticoagulation continued periop.  Risks of recurrence of thrombosis greatest if inciting thrombus arterial, esp if associated with AF (recurrent embolism 40% mortality).  In contrast, recurrent lower-extremity VTE risk of associated sudden death of 6%.
  69. 69.  Time elapsed since inciting thrombus also critical (for arterial & venous thrombi).  Most anticoagulated pts managed on warfarin, anticoagulation gradually abates after stopping drug.  INR does not fall for approx 29hrs, then decreases with t1/2 approx 22hrs. (If high risk without anticoagulation, bridging in form of therapeutic doses of UH / LMWH considered approx 60hrs after last dose of warfarin).  In IV UH, window of 6drug-free hrs allowed prior to surgery.  For LMWH, SC, doses given once / twice daily for 3 days before Sx, with last dose no <18hrs preop for twice-daily dose (i.e., 100 U/kg of LMWH) 30hrs for once-daily regimen (i.e., 150–200 U/kg of LMWH). Add. 6-hr drug- free interval if RA planned.
  70. 70.  Postop resumption of anticoagulation requires evaluation of risk of recurrent thrombosis & degree to which Sx increases patient's hypercoagulability (e.g., minor vs major orthopedic Sx).  Since delay of approx 24 hrs after warfarin administration before the INR increases, warfarin resumed asap except in high bleeding risk.  Consideration for bridging therapy with IV or SC anticoagulation until the INR becomes therapeutic.