Assessing Coagulation
Clinical Applications

(Perioperative and ICU Concerns)


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List of Abbreviations
ATIII Antithrombin III
GIT Gastrointestinal Tract
aPTT activated Partial Thromboplastin Time
ACT Activated Clotting Time
PIVKA Proteins Induced by Vitamin K Absence
INR International Normalised Ratio
LMWH Low Molecular Weight Heparin
UFH Unfractionated Heparin
DVT Venous Thromboembolism

Full warfarin anticoagulation

Management of patients presenting for surgery on full warfarin anticoagulation is controversial.  The warfarin will be for three basic reasons, deep vein thrombosis prevention, prevention of atrial thrombosis in atrial fibrillation and the prevention of thrombosis on a mechanical valve. 

A coagulation profile that is as near to normal as possible is needed to prevent excess bleeding from any type of surgery.  This must be balanced against removing the anticoagulation which increases the risk of thrombosis.  The inherent risk of venous thrombosis present with all surgery will be increased in patients who have had a previous deep vein thrombosis.  The risk of arterial thrombosis will revert back to that seen in a non anticoagulated setting.

The indication for the anticoagulation, the pre-operative risk for thrombosis (venous and arterial) and the risks of postoperative bleeding must be weighed carefully in all patients.  Essentially we should decide between two different management strategies.

  1. High Risk of Pre-operative Thrombosis

  2. A protocol driven, perioperative Heparin infusion will prevent a significant number of fatal and serious complications that would arise in a non-anticoagulated patient.

  3. Low risk of peri-operative thrombosis


Other controversies in anticoagulation

Patients who are on low dose subcutaneous heparin or low molecular weight heparin for deep vein thrombosis prophylaxis and patients who are on low dose aspirin therapy are not considered to be at an increased risk of epidural or subarachnoid haematoma formation.

Patients on full heparin anticoagulation or who will be placed on full heparin anticoagulation intra-operatively may have a rachidial block provided the following criteria are adhered to.


"Heparin"

Action

Enhancement of the action of the serine protease inhibitors AT III and heparin co factor II.

A specific 5 sequence sugar is responsible for the binding of heparin to AT III and an exponential increase in its antifactor Xa activity, a further 13 sugars are needed to cross link the AT III and thrombin in order to increase ATIII's antithrombin action

Heparin does not inhibit thrombin bound to fibrin or Xa bound to platelets.

Unfractioned heparin has a Xa:Thrombin inhibiting effect of 1:1. 
The low molecular weight heparins have varying Xa:Thrombin inhibiting effects
    Dalteparin - Fragmin 2.7:1
    Enoxaparin - Clexane 3.8:1

Heparin causes the release of extrinsic pathway inhibitor

Unfractionated and low molecular weight heparins release extrinsic pathway inhibitor from the endothelium and enhance its inhibitory activity against factor Xa and VIIIa.

Biokinetics

Chemistry

Heparins are strongly negativly charged, acidic glycoaminoglycans (mucopolysaccharides) consisting of chains of alternating residues of D-glucosamine and uronic acid, either glucuronic acid or iduronic acid..   Unfractionated heparin consists of chain lengths which vary from 3000 to 30 000 Daltons. 

The low molecular weight preparation consists of chain lengths which vary from 3000 to 9000 Daltons.  They are manufactured from unfractionated porcine heparin by controlled depolymerisation

Dose

Indication

Fixed Dose Unfractionated  Heparin

Adjusted Dose Unfractionated Heparin

Fixed Dose
Low molecular weight heparin

DVT PROPHYLAXIS
General Surgery
Medical conditions

5 000U sc 8-12 hourly

Adjusted sc to aPTT upper range of normal

Dalteparin 2 500U sc daily
Enoxaparin 2 000U sc daily
DVT PROPHYLAXIS
Orthopaedic Surgery
Acute Spinal Injury
Multiple Trauma

Considered inadequate

Adjusted sc to aPTT upper range of normal

Dalteparin 5 000U sc daily
Enoxaparin 3 000U sc daily

DVT TREATMENT

Considered inadequate

Infusion to
aPTT 1.5-2.0 normal
= heparin level of 0.2-0.4U/ml

Dalteparin 100U/kg twice daily
Enoxaparin 100U/kg twice daily
antiXa levels of 0.1-0.2 U/ml

Acute myocardial ischamia
Acute vascular insufficiency
Haemodialysis

Considered inadequate

Infusion to
aPTT 1.5-2.0 normal

Dalteparin 100U/kg twice daily
Enoxaparin 100U/kg twice daily
Cardiopulmonary bypass Considered inadequate

Infusion to
aPTT 2.0-3.0 normal

No data available

Effects

Formulation

Heparin is currently obtained from the lung or gut mucosa of cattle and pigs.   It is available as either a sodium or a calcium salt.

Inadequate heparin response

Reversal

  1. Allowing spontaneous dissipation of heparin effects
  2. Protamine sulphate - acid/base, anionic/cationic reaction forms a harmless precipitate. Protamine has intrinsic anticoagulation properties of its own and must be titrated. 1.3mg/Kg/100 units unfractionated  heparin still predicted to be circulating. Protamine is available as 10mg per 5ml
  3. Alternative cationic alkaline agent
    1. Recombinant platelet factor 4 (2.5 to 5mg/kg)
    2. Hexadimethrine - hypotension, pulmonary hypertension and anticoagulation in excess
      - not a popular drug!
    3. Toludine blue

Heparin Protocol

(This protocol is only a guideline. Many other protocols have been proposed.
It is essential that it is applied in the context of sound clinical judgement!)

  1. Stop Warfarin 3 days prior to surgery
  2. Start Heparin infusion and adjust according to the aPTT or ACT
  3. Stop the heparin infusion 3 hours prior to surgery
  4. Meticulous intra-operative haemostasis is required
  5. Restart the heparin infusion 12 hours after the surgery
  6. Restart the warfarin as soon as oral medication is possible
  7. Stop the heparin when the INR is adequate

Heparin Infusion

  1. Baseline full blood count, platelet count, INR and aPTT/ACT
  2. Bolus with 80 Units/Kg of heparin
  3. Start heparin infusion at 18 Units/Kg/hr
  4. Check coagulation profile regularly
ACT aPTT Response
> or = Pt's Normal < 35 Bolus with 80 Units/Kg
Increase Infusion by 4 Units/Kg/hr
< 1.5x Pt's Normal 36-45 Bolus with 40 Units/Kg
Increase Infusion by 2 Units/Kg/hr
1.5-1.9 x Pt's Normal 46-70 No Change
2-2.5 x Pt's Normal 71-90 Decrease Infusion by 2 Units/Kg/hr
>2.5x Pt's Normal >90 Stop Infusion for 1 hour
Restart Infusion at a rate reduced by 3 Units/Kg/hr

 


Warfarin

Action

Blockage of vitamin K reductase and vitamin K epoxide reductase:

vitkcyc.gif (2744 bytes)

The inhibition of the gamma carboxylase leads to an accumulation of the inactive precursors of the clotting factors - also known as protein induced by vitamin K absence - PIVKA. This affects factors II, VII, IX, X, Protein C, Protein S - the serine protease enzymes

Biokinetics

Chemistry
Derivative of 4-hydroxycoumarin.

Dose

Initial bolus dose 0.2mg/kg to a maximum of 10mg, given daily for 2 days
Adjusted daily dose titrated against factor activity, measured by the prothrombin time / INR for factor VII activity. 

  1. The American College of Chest Physicians Guidelines
    1. Chronic Atrial fibrillation: INR 2.0 to 3.0
    2. Prevention of deep vein thrombosis propagation: INR2.0 to 3.0
    3. Prevention of thrombosis on mechanical heart valves: INR 2.5 to 3.5
  2. Recent European investigations14 - Select a target INR within the range
    1. Prevention of thrombosis on mechanical heart valves:
      • Caged ball and tilting disk valves : INR 4.0 to 5.0
      • Bileaflet valves INR 2.5 to 3.0

Warfarin Guidelines

INR Action
1.1-1.4 Increase dose by 20%
1.5-1.9 Increase dose by 10%
2.0-3.0 Hold dosage
3.1-4.0 Decrease dose by 10%
4.1-4.5 Decrease dose by 20%
4.6-5.0 Omit one dose
Restart dose at 20% less
>5.0 Omit until INR <4.5
Restart dose at 20% less

Effects

  1. Inhibition of the formation of active factors II, VII, IX and X
    1. Anticoagulation
      • Deep vein thrombosis prophylaxis
      • Thromboembolic prevention in mitral valvular lesions and dilated cardiomyopathy
      • Prosthetic valvular anticoagulation
      • Atrial fibrillation associated thromboemboli prophylaxis
      • Reduction in the thromboembolic events in acute myocardial infarction
    2. Haemorrhage
      • Cranial, ears, nose, urinary tract, skin, adrenals, gastrointestinal tract
  2. Inhibition of the active forms of Protein C and its cofactor Protein S
  3. Transfer across the placenta
    1. Embryopathy
    2. Teratogenicity - nasal hypoplasia, stippled epiphyses, blindness and frontal bossing
      {like the Conradi-Hunnerman type of chondrodysplasia punctata!}

Formulation

Coumadin 5mg tablets, Warfarin 3 and 5mg tablets

Interactions

  1. Protein binding displacement
  2. Depletion of intestinal vitamin K sources
  3. Enzyme induction with increased metabolism
  4. Increases in factors VII, VIII, IX and X

Venous Thromboembolism

Clinical risk factors - European Consensus Group Summary

Diagnosis

Prevention

Deep Vein Thrombosis
Prevention and treatment

Abbreviations: LMWH = Low Molecular Weight Heparin, UFH = Unfractionated heparin.
CONDITION Fixed Dose
UFH
Adjusted Dose
UFH
Fixed Dose
LMWH
Warfarin
 
DVT PROPHYLAXIS
General Surgery
Medical conditions

5 000U sc 8-12 hourly

Adjusted sc to aPTT upper range of normal

Dalteparin 2 500U sc daily
Enoxaparin 2 000U sc daily

Considered unneccessary

DVT PROPHYLAXIS
Orthopaedic Surgery
Acute Spinal Injury
Multiple Trauma

Considered inadequate

Adjusted sc to aPTT upper range of normal

Dalteparin 5 000U sc daily
Enoxaparin 3 000U sc daily

Adjusted oral dose to INR 1.5-2.0

DVT TREATMENT

Considered inadequate

Infusion to
aPTT 1.5-2.0 normal
= heparin level of 0.2-0.4U/ml

Dalteparin 100U/kg twice daily
Enoxaparin 100U/kg twice daily
antiXa levels of 0.1-0.2 U/ml

Adjusted oral dose to INR 2.0-3.0

Acute myocardial ischamia
Acute vascular insufficiency
Haemodialysis

Considered inadequate

Infusion to
aPTT 1.5-2.0 normal

Dalteparin 100U/kg twice daily
Enoxaparin 100U/kg twice daily

Adjusted oral dose to INR 2.0-3.0

Cardiopulmonary bypass Considered inadequate

Infusion to
aPTT 2.0-3.0 normal

No data available

To long onset and neutralisation

Surgical specialities


Disseminated Intravascular Coagulation

The most pronounced disorder of coagulation and fibrinolysis is disseminated intravascular coagulation.  The initial common factor in all of the precipitating conditions is an uncontrolled circulation of phospholipid in the blood, disrupting the normal localisation of the clotting process. 

Treatment


Platelet Transfusion

The role of platelet transfusions, especially those given prophylactically to forestall bleeding remains controversial.  The currently accepted threshold for platelet transfusion was derived from a 1962 study by Gaydos.  In this study patients with leukaemia who had a platelet count of less than 20x109, had an increased frequency of gross haemorrhage.  The study did not try to establish a threshold value that prevented all bleeding.  There are a number of problems with giving a platelet transfusion that must be considered prior to the indiscriminate usage of this blood product.

  1. Collection
  2. Storage
  3. Compatibility
  4. Transfusion "triggers"
  5. Transfusion "failures"

Bibliography


Web Page Author: hopley@anaesthetist.com