Bleeding and Thrombosis in the Surgical Patient Bronx

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Bleeding and Thrombosis in the Surgical
PatientBronx Veterans Affairs Medical
CenterSurgery and Gastroenterology Grand
RoundsOctober 30, 2003

• Donald Baril
• Department of Surgery
• Mount Sinai School of Medicine

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Hemostasis

• Hemostatic response consists of three primary
  elements
• 1) Vasoconstriction
• 2) Platelet aggregation
• 3) Clotting cascade

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Hemostasis

• Vasoconstriction
• ? occurs as a result of vessel injury
• ? limits flow of blood to the area of injury
• ? enhanced by vasoconstricting elements
  released from platelets (primarily thromboxane
  A2)
• ? reflex sympathetic vasoconstriction may
  result from pain

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Hemostasis

• Platelet aggregation
• ? platelets are activated by thrombin and
  aggregate at the site of injury to form a
  temporary platelet plug
• ? platelets adhere to damaged endothelium via
  von Willebrand factor
• ? bridges GPIb/IX and collagen fibrils
• ? aggregating platelets release ADP, TXA2
  adenosine- 5-diphosphate, serotonin,
  phospholipids and other proteins necessary for
  the coagulation cascade

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Hemostasis

• Clotting cascade
• ? consists of two semi-independent pathways
• ? intrinsic pathway initiated when contact is
  made between blood and exposed endothelial
  tissues (relatively slow approximately 2-6
  minutes)
• ? extrinsic pathway is triggered by vessel or
  tissue damage which leads to the exposure of
  tissue factor (fast approximately 15 seconds)
• ? both pathways lead to the activation of
  prothrombin (factor II)
• ? final common pathway converts fibrinogen to
  fibrin

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Clotting cascade
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Natural inhibitors of the coagulation cascade

• ? Thrombomodulin
• ? Antithrombin III
• ? Tissue factor pathway inhibitor
• ? Protein C
• ? Protein S

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Natural inhibitors of the coagulation cascade
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Natural inhibitors of the coagulation cascade

• Thrombomodulin is a potent inhibitor of thrombin
• Binds thrombin and inhibits its ability to cleave
  fibrinogen or active factors V and VII
• Enhances thrombins ability to activate protein
  C, which degrades factors V and VIII

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Natural inhibitors of the coagulation cascade

• Antithrombin III is a large protease inhibitor
  that inhibits thrombin and factors IXa, Xa, XIa,
  and XIIa but does not inhibit thrombin within
  clots
• ? Heparin accelerates the reaction time of
• antithrombin III 1000 fold

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Natural inhibitors of the coagulation cascade

• ? Tissue factor pathway inhibitor (TFPI)
• ? Protein with three tandem protease inhibitory
  domains
• ? Inhibits Factor Xa and the Factor VIIa-Tissue
  Factor
• Complex
• ? Bound to lipoproteins (LDL, HDL, lipoprotein
  A)
• ? Platelets carry about 10 of the TFPI
• ? Heparin enhances the function of TFPI 2-4
  fold.

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Natural inhibitors of the coagulation cascade

• ? Protein C and Protein S
• ? Vitamin K-dependent serine proteases
  synthesized
• in the liver
• ? Circulate as inactive forms (zymogens)
• ? Protein C
• ? inhibits the activity of factors Va and
  VIIIa
• ? Protein S
• ? cofactor that potentiates the action of
  Protein C

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Preoperative screening for bleeding risk

• ? Complete history and physical

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Preoperative screening for bleeding risk

• ? Incidence of a significant hereditary
  deficiency of a coagulation factor is low (1 per
  10,000-40,000)
• ? approximately 1/3 of these are asymptomatic
• ? Acquired deficiencies of factors should be
  suspected in the presence of advance hepatic
  disease, malabsorption, or malnutrition

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Clinical testing and preoperative screening

• ? Prothrombin time (PT)
• ? measure extrinsic and common pathways
• ? affected by low concentrations of fibrinogen,
  prothrombin and factors II, V, VII, X
• ? Activated partial thomboplastin time (aPTT)
• ? measures intrinsic and common pathways
• ? deficiencies in all clotting factors except
  factors VII and XIII may prolong the aPTT

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Clinical testing and preoperative screening

• ? PT and aPTT testing involves adding activators,
• phospholipids, and calcium to plasma and
  determining
• the time to clot formation
• ? Abnormalities result from
• ? factor deficiencies in the coagulation
  cascade
• ? excess of calcium
• ? inadequately filled collection tubes
• ? excessive tourniquet time
• ? hemolyzed or clotted samples
• ? prolonged time from sample collection to
  testing

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Assessment of platelet function

• ? Platelet count
• ? reproducible, but fails to assess platelet
  function
• ? Bleeding time
• ? highly technician-dependent
• ? poor screening test for preoperative
  hemorrhage
• ? fails to discriminate between those taking ASA
  and those who are not
• ? Platelet function analyzer
• ? quantitative test of platelet function at high
  sheer rates
• ? sensitive to impairment of vWF, inhibition of
  glycoprotein Ib or IIb/IIIa receptors and
  ASA-induced dysfunction

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Is preoperative testing useful?

• ? Houry et al. American Journal of Surgery July
  1995
• ? Multicenter prospective study of 3242
  patients undergoing general surgery procedures
• ? High-risk patients defined as those with
• ? easy/excessive bruising
• ? heavy or prolonged menstrual periods
• ? epistaxis
• ? GI/GU bleeding
• ? prolonged bleeding after cuts/previous
  surgery
• ? hemophilia or other inherited hemorrhagic
  disorder
• ? renal failure, liver disease, hypersplenism,
  collagen vascular disease
• ? purpura, hematomas, jaudince, signs of liver
  failure on physical exam

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Is preoperative testing useful?

• Low-risk patients with normal test results (PT,
  aPTT, platelet count, and bleeding time)
• 0.15 of 1951 pts died of bleeding
• 4.6 had bruising
• 3.0 had hematomas
• 0.46 required reoperation to control
  hemorrhage
• Low-risk patients with abnormal test results
• 0 of 340 pts died of bleeding
• 5.9 had bruising
• 2.9 had hematomas
• 0.59 required reoperation to control
  hemorrhage
• Houry et al. Am J Surg July 1995

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Is preoperative testing useful?

• High-risk patients with normal test results (PT,
  aPTT, platelet count, and bleeding time)
• 0 of 779 pts died of bleeding
• 8.3 had bruising
• 3.5 had hematomas
• 1.16 required reoperation to control
  hemorrhage
• High-risk patients with abnormal test results
• 1.16 of 340 pts died of bleeding
• 10.5 had bruising
• 6.4 had hematomas
• 1.16 required reoperation to control
  hemorrhage
• Houry et al. Am J Surg July 1995

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Preoperative screening to assess risk of
thrombosis

• ? Acquired causes of thrombophilia
• ? cancer
• ? antiphospholipid antibodies
• ? nephrotic syndrome
• ? hyperhomocystinemia
• ? Heritable causes of thrombophilia
• ? factor V Leiden mutation
• ? protein C deficiency
• ? protein S deficiency
• ? antithrombin III deficiency

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Factor V Leiden mutation (activated protein C
resistance)

• ? Inactivation of normal Factor Va occurs through
  an
• ordered series of cleavages at arginine
  residues
• ? In APC resistance, the arginine at position 506
  is substituted
• with glutamine rendering the Factor Va
  molecule resistant to
• cleavage by APC
• ? Thrombosis occurs because this altered Factor
  Va still has the same procoagulant activity as
  normal Factor Va
• ? Present in 1.25-6 of the U.S. population
• ? 25-40 of patients with this mutation have a
  family history of thrombosis
• ? 7.9 fold increased risk for thrombosis

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Protein C deficiency

• ? Congenital deficiency of Protein C
• ? Causes of acquired deficiency of protein C
• ? DVT, PE ? Acute DIC
• ? Post-operative State ? Severe liver
  disease
• ? Malignancy ? Infection
• ? ARDS
• ? Hemolytic-uremic syndrome
• ? Vitamin K Deficiency and/or Warfarin use

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Protein S deficiency

• ? Congenital deficiency of protein S
• ? Type I - Decreased free Protein S, but
  adequate bound levels.
• ? Type II - Decreased free and bound Protein S
• ? 50 will have first thrombotic event before
  age 25
• ? Causes of acquired deficiency of protein C
• ? DVT/PE.
• ? warfarin use
• ? pregnancy, both free and bound Protein S is
  decreased.

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Antithrombin III deficiency

• ? Results from a defect in the synthesis of AT
• ? May also result from increases consumption of
  AT DIC, DVT, PE
• ? Thrombotic events occur with AT activity at
  40-60 of normal

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Preoperative screening to assess risk of
thrombosis

• Testing for thrombophilia should be performed in
  patients
• who have a history of
• ? thombotic event before the age of 50
• ? recurrent thrombosis
• ? first-degree relative with thrombotic event
  before the
• age of 50

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Antiplatelet therapy and surgery - Aspirin

• ? No reported increase in bleeding complications
  in patients taking aspirin preoperatively
  undergoing emergent general surgery procedures
  (Ferraris et al. Surgery, Gynecology, and
  Obstetircs 1983)
• ? Cardiac surgery patients on aspirin therapy
  have been noted to have increased transfusion
  requirements and higher rates of reoperation for
  bleeding but with no difference in mortality
  (Sethi et al. JACC 1990, Goldman et al.
  Circulation 1998)
• ? No consensus recommendations for patients
  undergoing general surgery procedures
• ? stopping therapy in all patients 7-10 days
  prior vs. only those with abnormal bleeding
  times vs. continuing through the
  perioperative period

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Antiplatelet therapy and surgery - Clopidogrel

• ? Known additive effect when clopidogrel is used
  concurrently with aspirin resulting in greater
  increase in bleeding time
• ? Cardiac surgery patients on clopidogrel therapy
  have been noted to have increased transfusion
  requirements and higher rates of reoperation for
  bleeding (Yende et al. Crit Care Med 2001)
• ? No published data on clopidogrel use in
  patients undergoing general surgery procedures

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Chronic anticoagulation and surgery

• ? Factors to consider
• ? risk of thromboembolism in the absence of
  anticoagulation
• ? bleeding risk (patient-risk and
  procedure-risk)
• ? consequences of intra-op and post-op
  bleeding
• ? ability to control bleeding
• ? duration of post-op bleeding risk
• ? urgency of surgery

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Chronic anticoagulation and surgery

• ? Indications for chronic anticoagulation
• ? Mechanical prosthetic heart valves
• ? greatest risk for thromboembolic event with
  mitral valve, caged-ball valves
• ? Atrial fibrillation
• ? greatest risk for thromboembolic event with
  history of TIA/stroke, hypertension,
  impaired LV function, diabetes
• ? Venous thromboembolism
• ? highest risk for recurrent disease within
  the first 1 to 3 months following the
  initial event

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Chronic anticoagulation and surgery - Reversing
therapy

• ? Warfarin inhibits vitamin K-dependent
  ?carboxylation of factors II, VII, IX, X and
  proteins C and S
• ? Procoagulant factors are restored in a pattern
  proportional to their half-lives and require
  activity levels of 40 for near normal
  hemostasis
• ? Factor VII has a half-life of 4-6 hours
• ? Factor II has a half-life of 48-96 hours
• ? approximately 4-5 days are required to reach
  an INR of 1.4 or less

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Chronic anticoagulation and surgery - Reversing
therapy

• ? Vitamin K1 (phytonadione)
• ? fat-soluble vitamin that requires normal
  pancreatic and small bowel function for
  absorption of oral form
• ? 1.5 mg intravenous dose will reverse
  therapeutic levels of oral anticoagulation
  within 24-36 hours1,2
• ? larger doses associated with anaphylactoid
  reactions
• ? 2.5 mg oral dose will have the same effect2
• ? Intramuscular injection should be avoided
  due to risk of hematoma
• ? Subcutaneous injection should be avoided due
  to erratic absorption
• 1. Whitling et al. Arch Intern Med 1998
• 2. Shields et al. Mayo Clinic Proc 1995

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Chronic anticoagulation and surgery - Reversing
therapy

• ? Fresh frozen plasma
• ? required volume is 15-16 ml/kg in a patient
  who is therapeutic on warfarin
• ? prothrombin time will begin to prolong in
  several hours following the administration
  of FFP due to the short half-life of Factor
  VII
• ? major limitation is intravascular volume
  overload

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Chronic anticoagulation and surgery -
Recommendations

• ? Minor procedures with low risk of bleeding and
  easy access to control bleeding need to reduce
  the anticoagulation dosing to achieve the lower
  limit of therapeutic range (INR 2.0-2.5)

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Chronic anticoagulation and surgery -
Recommendations

• ? Patients on oral anticoagulation for aortic
  valve prostheses or low-risk atrial fibrillation
• ? stop oral anticoagulants 3-5 days before
  surgery
• ? resume as soon as possible without loading
  dose

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Chronic anticoagulation and surgery -
Recommendations

• ? Patients on oral anticoagulation for mitral
  valve prostheses, high-risk atrial fibrillation,
  or recent venous thromboembolism (traditional
  approach)
• ? cessation of oral anticoagulation
• ? concurrent anticoagulation with heparin ?
  cessation of heparin 4-6 hours prior to surgery
  ? resumption of heparin as soon as possible
  following surgery

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Chronic anticoagulation and surgery -
Recommendations

• ? Patients on oral anticoagulation for mitral
  valve prostheses, high risk atrial fibrillation,
  or recent venous thromboembolism using bridging
  therapy with low molecular weight heparin
• ? initiate therapy once INR below lower limit
  of therapeutic
• ? last dose given morning of day prior to
  procedure
• ? resume LMWH therapy within 48 hours
• ? restart oral anticoagulation day following
  surgery
• ? options include dalteparin (Fragmin) 100
  IU/kg sc bid or enoxaparin (Lovenox) 1 mg/mg
  sc bid or 1/5 mg/kg sc qd