A 40 year old previously well male presents with a ruptured appendix and associated   peritonitis   (Day  0).  He  returns   to  theatre   3  days  later  with ischaemic  colitis  and requires  a right  hemicolectomy.  At laparotomy,  he is noted to have extensive thrombosis in his superior mesenteric vein and portal vein. Attempts to anticoagulate him postoperatively (day 5 onwards) with intravenous heparin have been unsuccessful.

His post op haematology results are as follows:

Day 0

Day 1

Day 3

Day 5

Day 7

Day 9

Range

INR

1.2

1.7

1.8

1.6

0.8 – 1.3 seconds

APTT

36

38

36

28*

31*

37*

24 – 35 seconds

Fibrinogen

5.8

1.8

1.4

1.7

2.0 – 5.0 g/L

INR mix

1.9

0.8 – 1.3 seconds

APTT mix

32.5

30 – 40 seconds

D dimer

>4.0

< 0.5 mg/L

* On I.V. heparin

APTT therapeutic range for I.V. heparin therapy: 60 – 90 seconds

Additional tests performed on Day 7

A. Tests of hypercoagulability (plasma)
Antithrombin (functional) 20% (Reference: 80 – 120%)

B. Factor assays (plasma)
Factor VIII 4.10 IU/ml (Reference: 0.5 – 1.5)

C. Anti-Factor Xa assay (plasma)
Anti-Factor Xa 0 IU/ml            (Reference for IV heparin therapy: 0.3 – 0.7)

a)  What  are  the  possible  factors  preventing  therapeutic  anticoagulation  in this patient?

b)  List 2 strategies to effect anticoagulation with intravenous heparin.

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College Answer

a)  What  are  the  possible  factors  preventing  therapeutic  anticoagulation  in this patient?

•    Disseminated intravascular coagulation
•    High clot burden
•    Antithrombin III deficiency
•    High Factor VIII levels

b)  List 2 strategies to effect anticoagulation with intravenous heparin.

•    Change to low molecular heparin, instead of unfractionated heparin
•    Give  cryoprecipitate  and/or  fresh  frozen  plasma  (if  there  is  confirmed ATIII deficiency )
•    Give antithrombin III concentrate

Discussion

Some discussion of the management of heparin resistance goes on in the end of my brief pharmacological entry on unfractionated heparin. In short, there are several strategies one can employ. The specific choice relies on what exactly is causing the heparin resistance.

•    Change to low molecular heparin, instead of unfractionated heparin
•    Give  cryoprecipitate  and/or  fresh  frozen  plasma  (if  there  is  confirmed ATIII deficiency )
•    Give antithrombin III concentrate

This CICM question asks specifically about increasing the effect of heparin, and candidates who suggested using something else (such as a direct thrombin inhibitor) would probably have earned no marks.

References

References

Anderson, J. A. M., and E. L. Saenko. "Editorial I Heparin resistance." British journal of anaesthesia 88.4 (2002): 467-469.

Young, E., et al. "Heparin binding to plasma proteins, an important mechanism for heparin resistance." Thrombosis and haemostasis 67.6 (1992): 639-643.

Hirsh, J., et al. "Heparin kinetics in venous thrombosis and pulmonary embolism." Circulation 53.4 (1976): 691-695.

Beresford, C. H. "Antithrombin III deficiency." Blood reviews 2.4 (1988): 239-250.

The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group Dalteparin versus Unfractionated Heparin in Critically Ill Patients N Engl J Med 2011; 364:1305-1314April 7, 2011

Koster, Andreas, et al. "Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation." Journal of cardiothoracic and vascular anesthesia 17.2 (2003): 171-175.

Isil, Canan Tulay, et al. "Management of heparin resistance in an emergency cardiac surgical patient." Indian journal of anaesthesia 56.4 (2012): 430.