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 1. Overview 

  Primary hemostasis 
   Platelet (a) adhesion, (b) activation, (c) aggregation
  Secondary hemostasis 
   Activation of plasma coagulation (form fibrin) 
    Extrinsic pathway (via tissue factor) 
    Intrinsic pathway (subendothelium or foreign contact) 
    Common pathway
   Inhibition of systemic clotting 
    Natural anticoagulants (AT III, Protein C & S) 
    Fibrinolytic system, i.e. Plasmin (degrades fibrin(ogen))
  Other reactions 
   Complement activation (increased permeability, cell lysis) 
   Kinin generation (vascular dilation, increased permeability)

  Contact 
   With subendothelium after endothelial injury 
   With proteins adsorbed onto synthetic surfaces
  Adhesion 
   Via attachment mechanisms i.e. Glycoprotein Ib/IX 
   (GP Ib/IX) receptor
  Activation 
   Begins as platelets spread with a conformational change 
   Release TxA2, ADP, serotonin, (PF4, BTG)
  Aggregation 
   ADP induced change in GpIIb/IIIa receptor permits binding of adhesive proteins, like fibrinogen, between platelets

3. Anticoagulants 

  Heparin 
   Glycosaminoglycan, MW 3K - 100K 
   Acts by binding enzyme AT III 
    (AT III inhib's IIa,Xa,IXa,XIa,XIIa)
   Half life is 60-90 minutes 
   Monitored with aPTT or ACT 
   Complications: bleeding; HIT => thrombosis, "white clot" 
   (Ab versus Hep-PF4 complex); osteoporosis

   Hirudin (Hirulog, synthetic analog) 
    From leeches, direct inhibitor of thrombin 
    Does not require ATIII 
    Prolongs TT, aPTT, PT, and ACT
   Ancrod 
    From venom of Malayan pit viper
   Others

   Acts as Vitamin K antagonist 
    (Vitamin K required for Fx II, VI, IX, X; Prot C,S)
   Half-life is 36 to 42 hours 
   Monitored w/ INR = Pt. PT / Control PT 
   Reversed w/FFP (immediate); Vit K (8-24 hrs) 
   Complications 
    Bleeding, skin necrosis (Protein C & S deficiency), fetal abnormalities

  Aspirin 
 Inhibits cyclo oxygenase (rate-limiting enzyme for PG's) 
    Reduces TxA2 from platelets (causes aggregation) 
    (Low dose inhibits Plt cyclo oxygenase but not endothelium) 
   Irreversible inhibition for Plt lifetime (7-10 days) 
  Ticlopidine (ASA substitute) 
   Blocks fibrin-GpIIb/IIIa interaction 
   Onset slow, 2-3 days 
  Dipyridamole 
   Inhibits Plt adhesion 
  IV Dextran (40 - MW 40,000 daltons) 
   Decreases Plt-vascular endothelial interaction 
   Decreases von Willebrand factor

  Protamine 
   Basic protein, binds heparin 
   1 mg protamine = 100 U heparin 
   Adverse reactions 
    Transient systemic hypotension 
     Related to infusion rate, total dose 
    Anaphylaxis - pulmonary hypertension, systemic hypotension, bradycardia 
     (Risk factors - prior exposure, DM's/NPH)
8.  Aprotinin 
   Mechanism: proteolytic enzyme inhibitor 
    Inhibits fibrinolysis, kinin activation, platelet activation 
   Benefits 
    Decreased blood loss, decreased systemic response to CPB 
   Risks 
    Prothrombotic effects, renal failure (?) 
    Anaphylaxis with re-exposure (cutaneous testing, predose) 
   Usage guidelines 
    Patient risk should influence use - high risk patients (reoperations, long procedures, coagulopathy, need to avoid transfusions) 
    ACT monitoring 
  Other agents 
   Amicar (Epsilon-amino caproic acid) 
   Desmopressin (DDAVP) 

9. Heparin 

  Standard initial dose = 300 U/kg 
  Maintain ACT > 300-350 (>300?) 
  Monitor with ACT
   (or direct Heparin concentrations) 
  Redose to maintain therapeutic level 
   100 U/kg every 60 - 90 minutes (approx.) 
   Use dose-response curve 

  Estimate heparin present (dose response curve) 
  Give 1.1 - 1.5 mg protamine : 100 U heparin 
  Confirm reversal to baseline 

10. Basic Considerations with Cardiopulmonary Bypass (CPB) 

  Cardiopulmonary bypass leads to: 
   Activation of clotting cascades 
   Activation of fibrinolytic system 
   Platelet activation and removal 
   Kinin system activation 
   Complement activation 
  Results in hemostatic derangement 
  Results in systemic inflammatory responses 

  Cell saver recycling 
  Hemoconcentration of excess CPB blood 
  Reinfusion of shed blood from chest tubes 
   (Consider time, volume, infection hazard) 
  Prevention/reversal of bleeding diathesis 
   Optimization of heparin/protamine use 
   Autologous plasma, fresh whole blood 
   Aprotinin (Trasylol) 
   Epsilon-amino caproic acid (Amicar) 
  Heparinzed CPB circuits 
   More biocompatable, more thrombo resistant 
  Autologous blood donations (with erythropoietin) 

12. Post-CPB 

  Consider 
   Surgical bleeding 
   Heparin excess 
Incomplete neutralization; reinfusion of anticoagulated blood; heparin rebound 
   Clotting cascade procoagulant deficiency 
   Platelet dysfunction or thrombocytopenia 
   DIC, depleted fibrinogen (preop thrombolytics) 
  Exploration (< 3 - 5%) 
   >500/h x1 hr; >400/hr x 2 hrs; >300/hr x 3 hrs; 
   >1000 total in 4 hrs; >1200 total in 5 hrs 

13. CABG Graft Patency 

  Vein patency rate = 75-90% at 1 year 
  Technique is important 
   Avoid endothelial injury 
  Antiplatelet therapy 
   ASA, before or within POD 1 to > 1 year 
   Ticlopidine if allergic to ASA, or with coronary endarterectomy 
   Persantine, likely adds nothing 

  Mechanical valves 
   T-E rate = 2 - 4% per patient-year 
   Coumadin, INR=2.5-3.5, any position 
(ACCP/NHLBI consensus opinion) 
Bleeding complication rate = 2-3% per patient-year 
   Adding anti-platelet drug => decreased T-E, increased bleeding 
Reserved for T-E despite therapeutic coumadin 
  Bioprosthetic valves 
 T-E: greatest 6-12 wks post-op then 2% per patient-year 
 Coumadin, INR=2-3 x 3 months (Opt for AVR) 
 With large, LA, LA clot, prior CVA - extend x 3-12 mos 
  Valve thrombosis 
 Thrombolytics emerging as front-line therapy 

  Acute MI 
   Heparin => decreased LV thrombus/embolism 
    Especially large (anterior) MI's, LV dysfunction 
   Coumadin - possibly beneficial 
  Unstable angina 
   Heparin + ASA 

16. General 

  Risk factors (Virchow's triad) 
   Stasis - immobility, surgery, CHF/atrial fibrillation, obesity 
   Hypercoagulable states, BCP's, malignancy 
   Vein injury 
  48% incidence after CABG 
  Prophylaxis 
   Mechanical, SQ Heparin 
   (ASA, Persantine - ineffective) 

  Distal DVT - low risk for pulmonary embolism 
  Proximal DVT - Anticoagulate 
   Heparin => Warfarin (INR 2-3) x 3-6 mos 
   IVC filter if anticoagulation contraindicated or ineffective 

18. Incidence 

  630,000/year with 200,000 deaths/year 

  DVT (above calf), tumor, foreign body 

  Combination of mechanical and reflex effects 
  Cardiodynamic effects, cyanosis, pulmonary vasoconstriction

  Most resolve spontaneously 
  May lead to pulmonary infarction 

  Clinical 
   SOB, tachycardia, increased P2 
   Classic hemoptysis, pleural rub, S3/4, cyanosis - 1/4 of patients 
   Signs & symptoms of DVT - 1/3 of patients 
  Examinations 
   CxR: normal +/- decreased vascularity (Westermark's sign) 
   ECG: dysrhythmia, ST depression, T-inversion (III,AVF,V1,V4-5) 
   V:Q scanning 
   Pulmonary arteriography 

  Anticoagulation 
   Heparin x 8-10 days (until DVT adherent) 
   Coumadin x 6 weeks-6 months 
  Thrombolytic therapy 
  Percutaneous extraction 
  Surgical management 
   IVC Interruption 
Anticoag contraindicated, recurrent pulmonary emboli on anticoagulation, multiple small pulmonary emboli, pulmonary hypertension, after pulmonary embolectomy 
   Pulmonary embolectomy 
    Indications: persistent hypotension, hypoxia despite medical Rx 

21. Indication for operation 

  Hypotension, hypoxia, despite medical therapy (O₂, anticoagulation, inotropes) 

  Median sternotomy, cardiopulmonary bypass, bicaval cannulation, pulmonary artery exploration, lung compression 

  25% mortality (major cause - cardiac complications)

I. History 
A. 1953 - Gibbon - -first use of CPB for open heart surgery in a human - screen oxygenator 

B. Early screen, bubble, and disc oxygenators were traumatic to blood à frequent bleeding diatheses 

II. Pre-op hemotsatic disorders 
A. Personal/family history and PE are most important tools for identifying a bleeding diathesis 

B. Hereditary bleeding disorders 
1. Hemophilia 
a) X-linked recessive 
b) A = Factor VIII deficiency - tx= factor VIII concentrates 
c) B = Factor IX deficiency - tx=prothrombin complex or FIX 
d) Factor XI -  less common 
e) aPTT prolonged, PT, platelet (plt) fxn, bleeding time (BT) are normal 
2. von Willebrand’s Disease 
a) Most common inherited bleeding disorder 
b) von Willebrand’s factor stabilizes FVII essential for plt fxn 
c) Mucocutaneous bleeding and bruising 
d) Prolonged bleeding time, impaired plt aggregation to ristocetin 
e) Frequently a prolonged aPTT 
3. Treatment 
a) A (FVIII deficiency )-FVIII concentrates 
b) B (FIX deficiency) - prothrombin complex or FIX 
c) Emergency - FFP or cryoprecipitate (for FVIII or vWf deficiency) 
4. “Acquired hemophilia” - autoantibodies to FVIII 

C. Acquired bleeding disorders 
1. Plt dysfunction 2° to abnormal heart valves or assist devices 
a) BT helpful 
b) Plt transfusions will only be transiently helpful 
c) Plt transfusion after discontinuation of CPB 
2. Congenital cyanotic ht dz 
a) Impaired plt aggregation in 14% in acyanotic CHD, 38% cyanotic 
b) More profound with ­ hypoxemia and hemoconcentration 
c) Hepatic synthesis of clotting factors may be impaired 
d) Phlebotomy and hemodilution to Hct 50-60% improves plt number and fxn 
3. Drugs 
a) Most common cause of impaired hemostasis in cardiac surgery 
b) Anticoagulants 
(1) Coumadin - hold for 1-2d pre-op, give Vit K or FFP 
(2) Heparin - response may vary after pre-op heparin 
c) Drugs that affect plts 
(1) ASA 
(a) Increases post-op blood loss 
(b) D/C 5-7days pre-op 
(c) Prolonged BT - correct w/8-12U plts 
d) Fibrinolytics 
(1) tPA, urokinase, streptokinase 
(2) Can reduce fibrinogen levels below safe (100mg/dl) 
(3) FDP’s interfere w/plt fxn 
(4) Heparin can compound the effect 
4. Renal, hepatic failure and disseminated intravascular coagulopathy (DIC) 
a) Uremia 
(1) Defect in plt fxn due to plasma factors and anemia 
(2) vWf-plt interacions impaired 
(3) Plt transfusions ineffective due to uremic plasma 
(4) Tx= correct  anemia, dialysis, cryo (for vWf), DDAVP 
b) Hepatic insufficiency 
(1) Impaired synthesis of clotting factors (esp. vit K dependent - II,VII,IX,X) 
(2) Tx= vit K if PT prolonged, plts if thrombocytopenic 

III. Effects of cardiopulmonary bypass on hemostasis 
A. Initial events of blood-surface interactions 
1. Adsorption of fibrinogen and other plasma proteins to foreign surface is initial event 
2. Contact activation of factor XII (intrinsic pathway) 
3. Platelet adherence, release of cytoplasmic granules, thromboxane A-2 
4. Contact activation initiates complement  cascade and kallikrein/kinin system 
5. Decreased velocity from hemodilution may ß damage to formed elements in blood, ß net blood loss, improve capillary perfusion 
6. Frothing, high shear rates, and turbulence in pump damage formed elements àhemolysis, plt activation 
7. Bubble oxygenator (blood-gas)contributes significantly to impaired hemostasis after 2-3 h. total bypass time 
8. Intracardiac suction, “pump sucker” 

B. Dynamics of plasma coagulation during CPB 
1. Significant amounts of plasma proteins are not lost in extracorporeal circuit 
2.  Though diluted (£50%),  clotting factor levels remain adequate 
3. Prolonged clotting times post-op correlate poorly w/bleeding 
4. Fibrinolysis 
a) ??responsible for derangements of clotting tests early post-op 
b) Activated plasmin degrades fibrin and fibrinigen 
c) FDP’s act as anticoagulants 
d) Aprotinin (see below) 

C. Platelet dynamics during CPB 
1. Number 
a) ¯ to 40-50% baseline in 1st 10-15 min, then stabilizes 
(1) “Passivation” of foreign surfaces after initial exposure 
(2) Reduced plt adhesiveness 
b) Rarely < 75,000/mL 
c) Plt ct returns to normal 3-5d post-op (?sequestration in liver) 
d) Microembolus formation contributes to platelet consumption 
2. Function - substantially altered 
a) Plasma levels of Tx A2, plt-specific proteins rise at onset of CPB 
b) Plt stores of ADP & ATP depleted 
c) Fxn returns to normal 3-5d post-op 
d) Clot retraction impaired by heparin 
(1) High concentrations of heparin impair vWf-platelet binding 
(2) Reduction in clot retraction correlates w/post-op bleeding 
e) Hypothermia, plasmin, other proteases 
f) Neutrophil activation by surface glycoprotein  (GMP-140 or P-selectin) 
g) Attempts to inhibit plt activation during  CPB (ASA, dextran) à excessive hemorrhage 

IV. Conduct of cardiopulmonary bypass 
A. Heparin 
1. Heterogenous family of glycosaminoglycans, not protein (6,000-20,000 dalton) 
2. Accelerates by 2,500-fold the neutralization of thrombin by antithrombin III (ATIII) 
3. Affects factors IX, X, XI, XII, activation of heparin Cofactor II, inhibition of smooth muscle proliferation, cytoprotective 
4. Source of heparin (porcine gut mucosa or bovine lung) has little effect on anticoagulation,   but long-term bovine lung heparin more frequently associated w/HIT 
5. Platelet factor 4 is an anti-heparin compound 
6. Monitoring 
a) ACT or equivalent whole-blood clotting time at least q1h - maintain 300-350 sec 
7. Heparin rebound - coagulopathy and increased clotting times 
a) Pathogenesis not understood - ?protein-bound heparin unavailable to protamine 
b) Tx=protamine 
c) FFP will not reverse effects of residual heparin 

B. Protamine- the sole effective heparin antidote 
1. Small, highly positively charged protein, binds heparin 
2. Derived from fish sperm 
3. 1mg protamine /100U heparin (0.6-0.7 per Dr. Hurst) 
4. Toxicity 
a) Excess can have anticoagulant effect - overrated 
b) Myocardial depression 
c) Vasodilitation 
5. Heparin-protamine complexes - mediators of inflammation and anaphylaxis -    granulocytopenia, pulm sequestration of leukocytes, vasodilitation 
6. Allergic reaction (rare) - pulm edema, hypoxia, hypotension more common in DM exposed to NPH 

V. Perioperative adjuncts to hemostasis and blood conservation 
A. Intra-op (topical agents) 
1. Bovine thrombin - platelet activation and direct fibrinogen clotting-neutral pH 
2. Oxidized cellulose(Surgicell) - contact activation of coagulation cascade - surface for fibrin polymerization 
3. Microcrystalline bovine collagen (Avitene, Instat)-plt activation and adhesion 
4. Hemostatic glues 
a) Cyanoacrylate 
b) Fibrin glue=cryo (for fibrinogen)+bovine thrombin 

B. Autotransfusion 
1. Pre-op phlebotomy and reinfusion post-bypass 
2. Cellsaver - washes red cells (no plts or clotting factors) 
3. Shed mediastinal blood - no study has shown reduction in use of banked, homologous blood 

C. DDAVP 
1. Vasopressin analog 
2. Transiently increases vWf and FVIII 
3. Probably only useful w/impaired vWf-dependent hemostasis (low vWf, drugs, plt receptor) 

D. Aprotinin 
1. Protease inhibitor from bovine lung 
2. Inhibits kallikrein activity, and in turn, contact activation of coag cascade 
3. Inhibits conversion of plasminogen to plasmin 
4. ?secondary preservation of plt fxn 
5. Most effective in preventing initial contact activation of blood and plts 

VI. Evaluation of post-op bleeding 
A. <3% require early re-exploration 

B. 1-3 u PRBC in uncomplicated cases 

C. How much is acceptable? - author >100ml/hr for several hours; see chart from Kirklin 

D. Transfusion: indications and risks 
1. Hct 24%, Hb 8g/dl may be acceptable - individualize 
2. Hepatitis in 7% (mostly hepatitis C) 
3. HIV - 0.25% of donor pool is HTLV-III antibody + 

E. Differential diagnosis of excessive bleeding 
1. Plt ct, PT, PTT in all pts post-op 
2. Heparin excess, integrity of coagulation cascade, plts 

F. Excess anticoagulants 
1. Heparin or FDP 
2. Protamine trial - aPTT or ACT will normalize if heparin-related 
3. Thrombin time +/- protamine - protamine will not correct FDP-related coagulopathy 

G. Thrombocytopenia and plt dysfunction 
1. Plt ct <75,000 + bleeding - tx w/8-12U plts 
2. Normal plt count, normal coags + bleeding - DDAVP, plts 
3. Bleeding time inaccurate post-op 

H. Pathologic fibrinolysis 
1. All clotting times abnormal, thrombocytopenia, hypofibrinogenemia - tx = transfusions + antifibrinolytics (amicar, aprotinin) 
2. Cryoprecipitate (supra normal finbrinogen, vWf, FVIII concentrations) - for fibrinogen <100mg/dL 

I. Massive transfusion 
1. Plasma protein dilution (1-1.5 blood volume transfusion) 
2. Thrombocytopenia most frequent derangement 

VII. Special hemostatic challenges 
A. Jehovah’s Witnesses 
1. Tx pre-op w/vitamins, iron, erythropoietin 
2. 7% mortality 

B. Heparin-induced thrombocytopenia (5% receiving continuous heparin) 
1. Autoantibody to heparin-plt factor 4 complexes 
2. Thrombocytopenia (<100,000) resolves within days of heparin withdrawl 
3. Dx by plt aggregate testing 
4. Strategy: elective - in vitro testing and postpone surgery - ab’s go away 
5. Heparin-like substances, LMW heparin have high cross-reactivity 
6. Org 10172 - rarely induces aggregation 
7. Post-op - D/C all heparin 

VIII. Future trends 
A. Specific indications for DDAVP, aprotinin 

B. Novel heparins - chemically modified 
1. Hirudin - family of direct thrombin inhibitors 

C. Anti-plt drugs 
1. Ab’s to glycoprotein Iib/IIIa) 
2. Synthetic peptides mimic fibrinogen 

IX. Thromboembolic complications of prosthetic valves 
A. INR 
1. DVT - 2.0-3.0 
2. Prosthetic valves - 2.5-3.5 

B. Mechanical valves 
1. Thromboembolic rate 
a) 0.5-3%/PT-yr - overall 
b) MVR = 1-3 
c) AVR = 0.5-2 
2. Addition of an antiplatelet agent further reduces risk (ASA 160mgQD or dipyridamole 400mgQD) 
3. Bleeding complications 0.7-6.3%/pt-yr 

C. Bioprosthetic valves 
1. Thromboembolism - 2%/pt-yr 
2. More common in first 6-12 wks after operation 
3. Recommendation - INR 2.0-3.0 for 3 months 
4. ? Benefit from long-term ASA 

D. Complicating 
1. Child-bearing 
a) Warfarin is teratogenic, crosses placenta - bad for fetus 
b) Self-administration of SC heparin to PTT 1.5-2 x control 
c) Antiplt tx alone? 
2. Vascular and prosthetic grafts 
a) SVG - 75-90% 1-yr patency 
b) ASA + dipyridamole helps - ASA early post-op, dipyridamole pre-op 
c) ASA alone may be effective