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Heparin Pathologies


  • pg 1
									  Presented by: Maggie Savelberg,
          Group Members:
Desiree Bonadonna and Britt McIlwain

 University of Nebraska Medical Center
           Omaha, Nebraska
1   Introduction

Coagulation & Anticoagulation   2

3   Heparin

     Resistance & Rebound       4

5   Allergic Rxn’s & HIT

                      SOP       6

7   World Knowledge

Cardiac surgery requiring cardiopulmonary bypass
  (CPB) places a large burden of activation of the
          hemostatic coagulation system

                     Caused by..

                                              (Speiss et al., 2008)
     Pathophysiological Effects of CPB
             on Hemostasis
• Denaturing of plasma proteins  air-blood interface =
  coagulation factor defects

• Platelets & coagulation factors (esp. fibrinogen) deposit on the
  extracorporeal surface.

• Plasma proteins adhere to solid surface  activation of
  thrombin  thrombin stimulates endothelium  release t-PA
   fibrinolysis  large component of post-op bleeding.

• Consumptive Coagulopathy: Inadequate heparinization 
  active coagulation in extracorporeal circuit  factor
  consumption  secondary fibrinolysis  and finally DIC
     Pathophysiological Effects of CPB
             on Hemostasis
• Vascular endothelium provides a non thrombogenic surface
  due to their synthesis of prostaglandins and peptides; all other
  cells and extracorporeal circuit surfaces initiate coagulation.

• Platelets are destroyed mechanically: mostly in the oxygenator
  (the larger the surface area the greater the platelet loss) and
  through cardiotomy suction (air-blood interface).

• Hypothermia also causes thrombocytopenia by a reversible
  sequestration of platelets in the portal circulation. (Gravlee,

• Temperature also is key in many enzymatic processes which
  determine the sequential activation of coagulation factors.

            Elevated hemostatic activity without
        anticoagulation is associated with CPB may
         induce a systemic inflammatory reaction
                        and lead to:

                        Postoperative                     Organ
                         Thrombosis                     Dysfunction

   Therefore, adequate anticoagulation is a critical component of
     successful management of hemostatic and inflammatory
          responses associated with CPB. (Parekh, 2008)

Understanding current
concepts of coagulation
is important in
determining the
preoperative bleeding
risk of patients and in
managing hemostatic
therapy perioperatively.
(Tanaka KA., 2009)
  Adults vs. Pediatric Coagulation
• At birth, activities of the vitamin K dependent factors
  II, VII, IX, and X and the contact factors XI and XII are
  reduced by 50% of normal adult values. (Pichler,

• The levels of the factors V, VIII, XIII, and fibrinogen
  are similar to adult levels.

• Supporting evidence by Miller et al.,1997 where the
  TEG revealed no defect in coagulation between
  newborn infants and adults, and in fact those under1
  year of age initiate clot faster than adults.

• Plasminogen is reduced by 50%. Platelets are
  normal but are hyporeactive. (Pichler, 2008)

            Coagulation                        Anticoagulation

Although the immature systems of neonates needs further study, according to
Gruenwald et al., 2010 (Sick Kids Hospital Toronto) She can conclude
definitively that individualized heparin and protamine management in
pediatrics has been shown to reduce platelet activation and coagulopathies.
                    Getting on bypass…
     • Heparin is the most commonly administered drug worldwide
       to achieve systemic anticoagulation for ECC.

     • Discovered in 1916 (McLean) : quick onset, easy reversal.

     • Heparin alone has no direct anticoagulant effect without the
       activity of antithrombin (AT, also known as antithrombin III).




                                                                 (Hirsh, 2001)


• AT is an endogenous serine             (Hirsh, 2001)
  protease inhibitor that irreversibly
  binds thrombin and factor Xa, and
  other various coagulant enzymes.

• Heparin enhances AT mediated
  inhibition of coagulant enzymes
  more than 1,000-fold by reducing
  the half-life of the enzymes and by
  promoting their binding with AT
  through induction of a
  conformational change in AT.
           Conformational Change

• Heparin binds to a lysine site on
  the AT molecule.

• This binding causes a
  conformational change in the
  arginine-reactive site

• This conformational change in AT
  converts it from a slow to a FAST
  thrombin and factor Xa inhibitor.

• This is called allosteric activation.
• Heterogeneous molecular size ranging from 3000 to
  30000 d (Johnson 1976, Hirsh 2001).

• Negatively charged repeating sulfated disaccharide units
  referred to as a glycosaminoglycan (Ng 2009)

• High molecular weight moieties cleared faster.

                                                        (Hirsh, 2001)
• Low levels: Binds to multiple plasma
  proteins, platelets, macrophages and
  endothelial cells to eliminate
  saturable phase of heparin through
  depolymerization (Hirsh, 2001).

• At therapeutic levels: Combination of
  the rapid saturable method described
  above and through the slower
  nonsaturable dose dependent
  mechanism of renal clearance.

• At very high levels: Predominantly      (Hirsh, 2001)
  through the slower method of renal

• t1/2 is dose dependent (30 -150 min)
                Actions & Uses
• Amplifies vessel wall permeability, reduces vascular
  smooth muscle cell production, and has an osteopenic
  effect (Clowes 1977, Shaughnessy 1995)

• Many other clinical applications:

                             Venous thromboembolism
                             Prophylaxis of DVT and PE
                                 Treatment of DVT
                               Coronary heart disease
                                  UA and Acute MI
                                                (Hirsh, 2001)
                Heparin Dosing
              SOP: Recommendation

• An evidence-based decision tree can be used to arrive at an
  adequate heparin dosage and guide healthcare providers to a
  consistent and cost-effective use of resources. (McKinney, 2007)

• In our algorithmic approach we concluded that a loading dose of
  300 IU/kg of LBM is an appropriate starting dose.

  • LBM can be used to reduce the amount of heparin and
    protamine administered up to 25% in patients with a BMI >30
    (Baker, 2007)
   Standardization ?
• Despite evidence based
  guidelines for CPB and
  cardiac surgery, no
  standardization exists for
  anticoagulation management
  during bypass. (Lobato, 2010)

• Target ACTs for initiating CPB
  ranged from 300-500 seconds.

• However the majority of
  institutions (78% Americans
  and 69% of Canadians) used
  between 400-480 seconds.         (Lobato, 2010)
• Activated clotting time (ACT) is a commonly used method for
  monitoring heparin levels during CPB.

• Satisfactory anticoagulation is defined as a celite ACT of 400
  seconds or more, and mechanical circulation is not instituted
  until this value is reached. (Leong, 1998)

• When aprotinin was commonly given to pts, ACT > 750
  seconds as aprotinin artificially prolonged the celite ACT as a
  result of the drug’s inhibition of kallikrein and contact activation
  of the intrinsic coagulation pathway.
• No definitive test accurately
  represents the entire picture of
  anticoagulation and is reproducible.

• ACTs have little evidence of their
  accuracy and multiple studies have
  shown significant lack of agreement
  between devices.

• Standard of 480 seconds

• It has been quoted that “target times
  employed stem more from historical
  clinician comfort than outcome
  studies” (Ng 2009)
Anticoagulation Monitoring
           Hepcon /HMS Systems
• While the measurement of heparin concentrations is
  not a new technology it has certainly obtained more
  popularity over the last 5-10 years.

• Heparin concentration of whole blood as measured by
  the HMS has had conflicting reports of efficacy.

                         (Dunning, 2008)
        Anticoagulation Monitoring

• Hardy et al., 1996 found poor
  correlation between plasma heparin
  concentration using a chromogenic
  substrate for factor Xa and did not
  recommended using the Hepcon for
  monitoring heparin concentrations
  during bypass

• In a large study by Slight et al., 2008 the
  HMS was shown to be slightly more
  efficacious than an ACT-based
  heparinization protocol with end-points
  of LOS and blood usage.

• Overall, evaluations by the STS gives
  the HMS system a grade B level of
  evidence and thus its use is
  recommended where available.
            • Useful in detection of coagulation disorders when used in combination with PT
            • Able to differentiate between intrinsic, extrinsic, common and multiple pathway
              deficiencies (Cowell, 2007)

            • Instrumental in detecting Factor VII deficiency

           • Determined by the amount of anti-Xa factor using a chromogenic substrate which
             releases a colored compound detected by a spectrophotometer is the most reliable
Anti-factor form.
    Xa     • Many different tests available, and variability is large.

            • May decrease blood product administration when used with a specific algorithm in
              the post-operative period (Dunning 2008).
            • Superior to ACT, PT, and PTT in predicting bleeding with the need for blood products
   TEG        versus bleeding from surgical sources (Ti 2002)
      Anticoagulation Management
                               SOP: Recommendation
                                       Measure the post-
                                     heparin ACT (& heparin
                                      concentration /HDR if
                                           warranted)                                                 Pre-heparin ACT

               ACT <480 sec                                             ACT >480 sec                  ACT <95 but <145

                                                                                                                  If still low: see
                                                                                                                   history of the
  Heparin Dose            Heparin Dose                                                       Repeat ACT,
                                                                         Initiate CPB                            patient/ laboratory
  > 400 IU/kg?             < 400 IU/kg?                                                    redraw sample.
                                                                                                                   tests for poss

                         Use HDR test if
 AT III Deficient?        available to                                Monitor ACT every   More fequent when
                                                 Monitor ACT every
   Administer               calculate                                    20 mins for       re-warming and
                                                 30 mins for adults
recombinant ATIII       additional heparin                              pediatric pts     with DHCA cases.
 Anticoagulation Management
                    SOP: Recommendation

                                                          Notify anesthesia
                                     Give 1/5 or 20% of
                                        the original
                      ACT <600 sec
                                      heparin loading
    On CPB,                                 dose
monitoring ACT;                                           Repeat ACT in 10
maintain over 600                                              mins
                                        No further
                      ACT >600 sec
          Heparin Resistance

 >600 USP       Inadequate
 units/kg to    response to    Heparin
achieve safe     heparin in
ACT for CPB       22% of      Resistance
  initiation      patients
Heparin Resistance

             Patients at Risk

• Individuals on previous heparin therapy.

• Patients with low heparin dose response
  curves in institutions using HMS/Hepcon®.

                                    (Speiss et al., 2008)
Heparin Resistance

 • Heparin-induced thrombocytopenia (HIT)

 • Heparin-induced decrease in antithrombin III
   (AT III)

 • Enhanced factor VIII activity: Pts on heparin
   who have had DVTs.

 • Acquired or inherited AT III deficiency.
                                          (Leong, et al. 1998)

 • Additionally: Nitroglycerin administration,
   thrombocytosis, hemodilution and immature
   coagulation systems.
Heparin Resistance
           Secondary Causes

 • Secondary or acquired AT III deficiency

  •   Previous heparin use
  •   Pregnancy
  •   Oral contraceptives
  •   IABP
  •   Shock
  •   Streptokinase use
  •   AT deficiency
  •   DIC
  •   Infective endocarditis
  •   Intracardiac thrombus
  •   Elderly patients                 (Leong, et al. 1998)
Heparin Resistance

          Technical Causes

  • Mislabelled syringe

  • Heparin not injected intravasularly
    • Perhaps IV line not running properly
    • Line may be out altogether

  • Heparin at low activity (old or non-
    refrigerated vials)
    • Expiry date?                     (Leong, et al. 1998)
             Heparin Resistance
• Give additional dose of heparin (20% of initial bolus SOP Recommendations
  dose).                                                 for AT III dosing are:
• Switch from porcine to bovine heparin or back and         100 x (weight in kgs) to
  forth – although generally not found to be effective.
                                                             increase AT III levels
                                                               from 0% to 100%.
• Fresh frozen plasma (FFP) 2-3 units, or preferably
  antithrombin (AT) concentrate.                                         (Gravlee, 1993)

 • AT treatment resulted in a; higher success rate in
   achieving ACT>400 seconds; decreased volume
   load on patient by 50 fold; more expensive but no
   thaw time as required by FFP; viral inactivation (AT)
   vs. the under-diagnosed incidence of TRALI (FFP).
                                             (Speiss et al., 2008)
   Heparin Rebound
Heparin rebound phenomenon has been in
    existence for more than 45 years.

Kolff (1956) described heparin rebound as:
"a treacherous hemorrhagic phenomenon”

Sise and colleagues (1961), Wright (1961);
     "rebound hypercoagulable state”

 Ferarris (2007) “Heparin rebound is the
reappearance of anticoagulant activity after
  adequate neutralization with protamine”
     Heparin Rebound
       Why is there rebound?
Heparin is bound in equilibrium to nonspecific
      to plasma proteins, vascular wall
   matrix proteins and endothelial cells.

   Protamine is administered = binding to
   unbound heparin and heparin dissociated
     from tissue and protein binding sites

Heparin/protamine complexes are then cleared
              from the circulation
                                     (Teoh, 2004)
                                     (Subramaniam, 2008)
       Heparin Rebound
         Why is there rebound?
Heparin rebound occurs because not all heparin
    is bound to and cleared by protamine.

  proportion remains bound nonspecifically to
    plasma proteins and vascular cells, which
         provides a reservoir of heparin.

     Dissociates over time and produces an
     anticoagulant effect when it binds to AT
          “Heparin Rebound Effect”
                                            (Teoh, 2004)
Heparin Rebound

    Heparin                         Protein bound
rebinds with AT                     heparin + AT III
      III                           bound heparin

released from

                    Protein bound
                       remains               (Teoh , 2004)
   Heparin Rebound
        Blood Management

• The latest Guidelines on Perioperative
  Blood Transfusion cited reports (in the
  setting of cardiopulmonary bypass
  surgery) that defined heparin rebound
  as the reappearance of anticoagulant
  activity after adequate neutralization with
  protamine that may contribute to
  excessive postoperative bleeding
  after cardiac surgery.          (Ferraris , 2007)
     Heparin Allergy
• Decreased circulating levels of
  coagulation factors.

• Decreased level of inhibitors
  of fibrinolysis

• Reduced numbers and
  function of platelets

• Incomplete neutralization of
  heparin using protamine.

                  (Subramaniam, 2008)
            Heparin Rebound

            SOP: Treatment Recommendation

• Thus, a slow continuous protamine infusion post-
  operatively can significantly reduce heparin rebound
  (Teoh, 2004). However there is no evidence-based
  advice as to how to best avoid heparin rebound

                                            (Subramaniam, 2008)
               Heparin Allergy

                                                            Results can be
                                       side effects exist
                                         and must be
                                         prepared for
                  to unfractionated
                       and low-
                      heparins is
  Heparin is a      common, and
  widely used          while the
anticoagulant for pathogenesis, is
cardiopulmonary      still not fully
     bypass          understood.
                   Heparin Allergy
 Hypersensitivity to Heparin

• Hypersensitivity reactions to heparin consist of:
  • Heparin induced immune thrombocytopenia
    (HIT), allergic vasculitis, hypereosinophilia,
    immediate hypersensitivity as well as delayed-
    type skin reactions.                              Type III Reactions

                                                      (Jappe, 2008)
Heparin Allergy

                  (Jappe, 2008)
                Heparin Allergy
          Type I Reactions
• Case #1: Danaparoid was used as
  an anticoagulant alternative for

• Case #2: Cardiogenic shock
  ensued with heparin bolus for

• Case #3: PVR on 55 year old
  female with history of significant
  heparin allergy
                          Heparin Allergy: HIT
                                                                    HIT 1                                        HIT 2
                   Etiology                             Non-immune mediated                       Immune mediated, aka HAT, HIT/T
                                                     Occurs in 10-20% of patients2.                  and White Clot Syndrome
                                                                                                     Occurs in 1-4% of patients.
                 Onset Time                                       1-4 days                                      5-10 days

                  Prognosis                       Resolves when heparin stopped, not               May have serious consequences
                                                   associated with significant clinical
                Platelet Count                            Mild thombocytopenia                       30-50% reduction in baseline
                                                          (usually >100 x 109/L)                    (usually <<100 x 109/L but not
                                                                                                             exclusive to)
               Complications                             May be associated with                      Thromboembolism (20-40%),
                                                     thromboembolic complications                        myocardial ischemia,
                                                   (TEC) which has high association                   pulmonary emobolus, limb
                                                         with mortality (25-30%).                     amputation, stroke, death.
                  Diagnosis                             Exclusion of other causes                       Detection of antibodies

            Length of Treatment                                  6-14 days                               Minimum of 6 months

(1) Cheng, D.., (2006) Perioperative Care in Cardiac Anesthesia and Surgery. Chp 19: HIT and Alternatives to Heparin Table taken from pg.174,
(2) (Gurbuz, A.T., et al., 2005) European Journal of Cardio-thoracic Surgery 27:138-149
             Heparin Allergy: HIT 2
Caused by heparin-dependent
  immunoglobin G (IgG) antibodies
  (HIT-IgG) binding to a
  conformationally modified epitope
  on platelet factor 4 (PF4) antibodies
  present in 18% of patients exposed
  to UFH (Gurbuz, 2004)

The binding of heparin and other
  glycosaminoglycans to PF4 =
  heparin-PF4 complex, alters its shape
  rendering it immunogenic. Against
  which IgG antibodies are formed.

(Antigenicity of the heparin-PF4
  complex depends on the molecular
  weight and degree of sulfation of the
  heparin molecule.)
Heparin/PF4 Complex

         PF4 Complex

             IgG antibody
HIT: The big picture
                                                  HIT: Diagnosis

   1. Thrombocytopenia during heparin therapy.

        Note: Thrombocytopenia during first 4 post-
        operative days of cardiac surgery due to
        hemodilution and platelet consumption is rarely
        HIT related.

   2. Exclusion of other causes of
       thrombocytopenia i.e. septicemia, MOF
       (multi-organ failure),post-transfusion

   3. Diagnosis confirmed by:
         a) Detection of HIT-IgG antibodies by
             ELISA, for heparin-PF4 complexes
             using goat anti-human antibody                                                        ELISA Plate
             (antigen assay)
         b) Or by a heparin-induced platelet
             aggregation study (HIPAA)

   4. Resolution of thrombocytopenia after
       cessation of heparin.

Gurbuz, et al. (2005) Heparin Induced Thrombocytopenia in the Cardiovascular Patient: Diagnostic and Treatment Guidelines, Eur. J of Card-Thor Surg. 27:138
                    Heparin Allergy
                    SOP: Treatment Recommendation

• History of heparin anaphylaxis and current HIT type II (surgeon
  preference) may warrant an alternative anticoagulation or
  desensitization strategy.

• The preference in such cases will be anticoagulation with bivalirudin.

• A current history of a positive HIT type I, as well as HIT type II patients
  (surgeon preference) will be anticoagulated with heparin and on-bypass
  plasmapheresis, as well as post-operative plasmapheresis will be

• Careful monitoring of condition with frequent platelet counts and
  coagulation profiles will be performed on both patient groups post-
World Knowledge
            World Knowledge
                            R.Britt McILwain BS RRT CCP
                                 UAB Medical Center
                                Birmingham, Alabama

  Group             • Patients <18 y of age: 400 units/kg
                    • Adults: 300 units/kg
                •Target ACT: Adults (480 s)

                •POC testing: iStat

                    • Anesthesia and Perfusion communicate.
                    • Adults: ACTs
                    • Pediatrics: Hepcon (helps account for dilutional
                    effect with low BSAs)

                •Brand: APP Pharmaceuticals

                •Coating: Yes, but no change to target ACTs.
                    •Hemoconcentrate many patients may pull off
                    too much heparin = decreased hep conc.
            World Knowledge
                          Desiree Bonadonna CCP, LP, BSE
                               Duke University Hospital
                                    Durham, NC
Responses       •Dosing:
                    • Patients (Avg wt): 30,000 IU
                    • Smaller and larger: 300 IU/kg calculated

                •Target ACT: Adults (400 s) due to Actalyke
                         reporting lower but more accurate values
                         (Welsby, 2002)

                •POC testing: Actalyke ACT analyzer Model # A2P by
                         Helena Laboratories with the MaxACT tube .

                    • Perfusion and anesthesia: Re-dose at 20% of
                    loading dose when ACT low.

                •Coating: Not heparin coated.
          World Knowledge

                  Heparin protocol?
       100% had a heparin management protocol.

            Initial loading dose of Heparin?

66.6% used 400 IU/kg               33.3% used 300 IU/kg
World Knowledge

Lower ACT    Higher ACT
 threshold    threshold
           World Knowledge


Who decides when to give more heparin during CPB?
            100% - Anesthesia & Perfusion

     What is your ACT threshold during CPB?
                100% - 480 seconds
    World Knowledge
       POC Testing Devices Reported


              World Knowledge

     Does your institution use Heparin-coated circuits?
33% heparin coated    33% bio-coating      33% no coating

   If so, do you follow low dose systemic heparinization?
                         100% no

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