Point of view

Heparin resistance

SPEAKER – Dr. Sameer goyal

MODERATOR – Dr. S.K. Mathur
Dr. R.K Dubey
Heparin resistance

Inadequate response to the large dose of heparin required

for the safe initiation or maintenance of cardiopulmonary
by-pass (CPB) and defined as the failure to achieve the
desired activated clotting time (i.e ACT > 480 sec)
following a standard dose of heparin (300–400 U/kg).
 What is Heparin ?

 1916 Discovered accidentally by Jay Mclean

 1939 Polysaccharide –various chain lengths
Source : porcine intestinal mucosa, beef lung
Peak effect : after 2 min
Distribution : 95% plasma bound
Elimination: ½ life dose dependent (60-150
min)
 What does Heparin do?

 inhibition of fibrin formation

 Increases the thrombin inhibitory potency of ATIII by
> 1000X
 85% effect on thrombin
 15% effect on anti-factor Xa activity
 Heparin-antithrombin complex inactivates thrombin,
activated FXa and other clotting factors
 ATIII also inhibits factors IXa, Xa, XIa, XIIa,
kallikrein & plasmin
 Limitation of heparin is from the binding of heparin
to other plasma proteins hence the variability of its
clinical effectiveness
 Heparin binds avidly with platelets
 Acute effects of heparin on
platelets

 Increased platelet factor 4 release

 GPIIb /IIIa activation
 P-selectin expression
 Serotonin release
 Decreased platelet count
 Heparin induced thrombocytopaenia

 Chronically stimulated platelets release PF4 -tight

binding to heparin and HIT antibodies

 Detectable up to 4 –6 weeks post heparin

 Risk 1 –3% after 1 week post-op heparin therapy

= Procoagulant microparticles &
platelet aggregation
 Antithrombin III
 Glycoprotein produced by the liver

 Inhibits thrombin and factor Xa

 Serine protease inhibitor

 Target proteases: activated forms of X, IX, XI, XII, II, VII

 Rate of activity enhanced by heparin

 ½ life in blood plasma = 3 days

 Normal concentration approx 0.12mg/ml

 Diagnosis of HR

1. ACT < 480 s after bolus of 300 IU /kg

2. Heparin sensitivity index < 1.0 = ACT

after heparin – ACT baseline / heparin
loading dose (IU/kg)
 Factors associated to a decreased heparin
responsiveness
1. Decreased AT availability

• Congenital or acquired AT deficiency strongly

reduce heparin responsiveness

• The main determinant of decreased AT levels

is the preoperative use of heparin

• Intraoperative factors determining AT consumption are

age, CPB duration, open heart procedures, diabetes.
2. Increased Thrombin formation

• Age (increased factor VIII and von Willebrand

activity)
• Diabetes (increased factor VII, VIII, XI, XII, von
Willebrand activity)
 Pregnancy
3. Decreased heparin availability

• Heparin responsiveness is of a function of how

many heparin molecules (about 1/3) are active; how
many are inactivated by proteins, endothelial cells,
plateletes, leukocytes…

• Thrombocytosis: one of the major determinants of a

decreased heparin responsiveness (increased PF4
heparin scavenging)

• Heparin pre-treatment may decrease heparin

responsiveness by depleting the endothelial cells of TFPI
(tissue factor pathway inhibitor)
Heparin alternatives
 LMWH
 Half life twice that of UFH.
 Problems in protamine neutalization: it reverses only factor iia
inhibition and leaves factor Xa inhibition intact.
 Not recommended for use in HIT.
 BIVALIRUDIN

 Synthetic polypeptide.
 Direct thrombin inhibitor.
 Half life 24 min
 Elimination: primarily by proteolysis and,
 to some extent renal
 Dose: 1mg/kg bolus, then

2.5 mg/kg/hr infusion.

 ARGATROBAN

 Direct thrombin inhibitor

 Half life 39 - 51 min
 Hepatic metabolism
 Not yet approved for use in CPB
 HIRUDIN

 Thrombin inhibitor independent of ATIII.

 Inhibits clot bound thrombin.
 Eliminated by kidneys.
 Half life : 40 min.
 Management

ATIII
Supplementation
rh ATIII
75 U / kg

Extra heparin Thrombin inhibitors

HR

Fresh frozen plasma Gabexate mesilate

 Conclusion

 No standard approach
 Studies show that ATIII concentrate is more effective than
additional heparin to obtain a therapeutic ACT
 In presence of a low heparin sensitivity there is not a single
therapeutic options. Some patients need more heparin, some
more AT, some both the approaches.