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Hemorrhage And Thrombosis

Hemorrhage and Thrombosis

COAGULATION BASICS

1. Overview

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

2. Platelet Function

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

PHARMACOLOGY

3. Anticoagulants

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

4. Alternatives to heparin (future)

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

5. Warfarin

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

6. Antiplatelet Agents

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

7. Hemostatic Agents

A. Protamine
1) Basic protein, binds heparin
2) 1 mg protamine = 100 U heparin
3) Adverse reactions
a) Transient systemic hypotension
(1) Related to infusion rate, total dose
b) Anaphylaxis - pulmonary hypertension, systemic hypotension, bradycardia
(1) (Risk factors - prior exposure, DM's/NPH)

8. Aprotinin

A. Mechanism: proteolytic enzyme inhibitor
1) Inhibits fibrinolysis, kinin activation, platelet activation
B. Benefits
1) Decreased blood loss, decreased systemic response to CPB
C. Risks
1) Prothrombotic effects, renal failure (?)
2) Anaphylaxis with re-exposure (cutaneous testing, predose)
D. Usage guidelines
1) Patient risk should influence use - high risk patients (reoperations, long procedures, coagulopathy, need to avoid transfusions)
2) ACT monitoring
E. Other agents
1) Amicar (Epsilon-amino caproic acid)
2) Desmopressin (DDAVP)

ANTICOAGULATION FOR CPB

9. Heparin

A. Standard initial dose = 300 U/kg
B. Maintain ACT > 300-350 (>300?)
C. Monitor with ACT
1) (or direct Heparin concentrations)
D. Redose to maintain therapeutic level
1) 100 U/kg every 60 - 90 minutes (approx.)
2) Use dose-response curve
E. Protamine for heparin reversal
1) Estimate heparin present (dose response curve)
2) Give 1.1 - 1.5 mg protamine : 100 U heparin
3) Confirm reversal to baseline

HEMOSTASIS WITH CPB

10. Basic Considerations with Cardiopulmonary Bypass (CPB)

A. Cardiopulmonary bypass leads to:
1) Activation of clotting cascades
2) Activation of fibrinolytic system
3) Platelet activation and removal
4) Kinin system activation
5) Complement activation
B. Results in hemostatic derangement
C. Results in systemic inflammatory responses

11. Blood Conservation Options

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

HEMORRHAGE

12. Post-CPB

A. Consider
1) Surgical bleeding
2) Heparin excess
a) Incomplete neutralization; reinfusion of anticoagulated blood; heparin rebound
3) Clotting cascade procoagulant deficiency
5) Platelet dysfunction or thrombocytopenia
4) DIC, depleted fibrinogen (preop thrombolytics)
B. Exploration (< 3 - 5%)
1) >500/h x1 hr; >400/hr x 2 hrs; >300/hr x 3 hrs;
2) >1000 total in 4 hrs; >1200 total in 5 hrs

THROMBOSIS

13. CABG Graft Patency

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

14. Prosthetic Valves

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

15. CAD

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

THROMBOSIS - DVT

16. General

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

17. Therapy

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

PULMONARY EMBOLISM

18. Incidence

A. 630,000/year with 200,000 deaths/year
B. Origin
1) DVT (above calf), tumor, foreign body
C. Pathophysiology
!) Combination of mechanical and reflex effects
2) Cardiodynamic effects, cyanosis, pulmonary vasoconstriction
D. Pathologic sequelae
1) Most resolve spontaneously
2) May lead to pulmonary infarction

19. Diagnosis of Pulmonary Embolism

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

20. Management

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

PULMONARY EMBOLECTOMY

21. Indication for operation

A. Hypotension, hypoxia, despite medical therapy (O2, anticoagulation, inotropes)
B. Operation
1) Median sternotomy, cardiopulmonary bypass, bicaval cannulation, pulmonary artery exploration, lung compression
C. Results
1) 25% mortality (major cause - cardiac complications)

EXTENDED OUTLINE

Hemorrhagic and Thrombotic Complications of Cardiac Surgery

1. 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 frequent bleeding diatheses

2. 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

3. 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 damage to formed elements in blood, net blood loss, improve capillary perfusion
6) Frothing, high shear rates, and turbulence in pump damage formed elements hemolysis, 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) excessive hemorrhage

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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