A 35-year-old woman (gravida 2, para 1), 34 weeks pregnant, has been admitted to your ICU with pre-eclampsia. Her blood pressure is 160/100, she has moderate proteinuria, normal liver function and a platelet count of 120 x 109 /L. There is no evidence of foetal distress. Her significant past history includes a Factor V Leiden mutation and a history of proximal vein thrombosis during her first pregnancy.

a) What pharmacological regimen would you recommend for DVT prophylaxis? Briefly outline your rationale.

b) List three other inherited thrombophilias that may predispose to DVT in pregnancy?

c) Despite appropriate DVT prophylaxis this patient develops clinical features suggestive of a proximal vein DVT. What investigations would you do to help establish the diagnosis and why?

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College Answer


a) What pharmacological regimen would you recommend for DVT prophylaxis? Briefly outline your rationale.

Subcutaneous heparin – unfractionated previously standard of care but recommendation now for low molecular weight heparins eg enoxaparin or dalteparin:

  • Weight based dosing without the need for monitoring
  • ?Reduced risk of bleeding compared to UF heparin
  • Reduced risk of HITS
  • Reduced risk of heparin induced osteoporotic fractures

PROTECT study concluded that in critically ill patients dalteparin was not superior to UF heparin in decreasing incidence of proximal vein thrombosis but proportion of patients with PE and incidence of HITS was lower in dalteparin group.

Heparin does not cross placenta unlike warfarin so no risk of foetal haemorrhage.


b) List three other inherited thrombophilias that may predispose to DVT in pregnancy?

  • Prothrombin gene mutation
  • Antithrombin deficiency
  • Protein S deficiency
  • Protein C deficiency

c) Despite appropriate DVT prophylaxis this patient develops clinical features suggestive of a proximal vein DVT. What investigations would you do to help establish the diagnosis and why?

  • Compression ultrasonography (sensitivity 97% and specificity 94%).
    • Non-invasive, safe and test of choice in pregnancy.
  • D-dimer – levels increase with progression of normal pregnancy so need to interpret in combination
    with other tests. Negative test has predictive value of 100%. Positive test has sensitivity of 100% and specificity of 60%.


If iliac vein thrombosis suspected, consider:

  • MRI – good specificity and sensitivity and no harm to foetus
  • Pulsed Doppler study
  • CT scan of iliac veins – NB radiation exposure to foetus

Discussion

This question interrogates the candidate's ability to recall anticoagulation guidelines in pregnancy, and tests their knowledge of the sensitivity and specificity of routine investigations for deep vein thrombosis.

The pharmacological management of DVT in pregnancy has previously rested on unfractionated heparin. The college answer lists the known benefits of LMW heparin dosing, and then refers to the PROTECT study.

This study did not find much difference in the rate of DVT (still around 5.6%), but the LMWH group had fewer PEs and there was a trend towards less HITS.

Then, the candidate is invited to produce a list of inherited thrombophilias. There is a good UpToDate article on this, available to the paying public. There is a point-form list in it, which essentially mirrors the college answer:

  • Factor V Leiden deficiency
  • Prothrombin gene mutation
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin III deficiency

I will move on to the question about the investigations of DVT, because this is where the candidate is expected to produce numbers to prove their knowledge of the literature.

The D-dimer is certainly useful in ruling out a DVT; a systematic review by Stein et al has show that a negative quantitative D-dimer is "as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding for excluding VTE". But a positive D-dimer does nothing to improve your decisionmaking, given that in pregnancy it will almost certainly be elevated.

Compression ultrasonography, then, is the ideal investigation. It has been shown to have excellent sensitivity and specificity. The exact numbers from the college answer (sensitivity 97% and specificity 94%) don't come from this study; they probably found them in the Zierler paper, which quotes the same statistics but does not mention their origin.

Iliac vein MRI is also mentioned, as well as pulsed doppler.

There is not much MRI information in pregnancy; one study from 1995 is waved around, but it dates back to 1995, and was performed on only 10 patients. Those results were encouraging. A much later systematic review also applauds the sensitivity and specificity of MRI venography in the pelvis, but laments that the studies are few, and that the MRI techniques are wildly heterogeneous in a comparison-defeating sort of way.

References

References

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

Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed.Clin Chem. 2005 May;51(5):825-9. Epub 2005 Mar 11.

Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. .Ann Intern Med. 2004 Apr 20;140(8):589-602.

Polak JF, Wilkinson DL. Ultrasonographic diagnosis of symptomatic deep venous thrombosis in pregnancy. Am J Obstet Gynecol. 1991 Sep;165(3):625-9.

Zierler, Brenda K. "Ultrasonography and diagnosis of venous thromboembolism." Circulation 109.12 suppl 1 (2004): I-9.

Spritzer CE, Evans AC, Kay HH. Magnetic resonance imaging of deep venous thrombosis in pregnant women with lower extremity edema. Obstet Gynecol. 1995 Apr;85(4):603-7.

Fiona C. Sampson, Steve W. Goodacre, Steven M. Thomas, Edwin J. R. van Beek The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis European Radiology January 2007, Volume 17, Issue 1, pp 175-181