So I Get This Transfer: Coagulopathy of liver disease

The Case:  (due to HIPAA all facts in this case have been changed)

Middle aged Male, currently being treated for malignancy (with mets to liver/kidney/chest) presents with SOB from recurrent pleural effusions and is found to have a DVT.  Other pmhx includes chronic liver disease and htn.

The patient is transferred to you for admission.

This is easy – admit.  EKG/CXR/labs are all done.  A CTPA is negative for PE.  Slam dunk …. but if all we are is admitting/discharging machines, where is the learning?

So you do a thoracentesis, and it goes so well, in fact, that the patient feels completely better and wishes to go home.

Keeping in mind that we typically discharge people with DVTs, can you safely discharge this patient?

To do so, give lovenox if the  creatinine is fine and warfarin 5mg in the ED, with 5 days prescription for both and urgent follow-up.  You can involve Care Manager if you like.   Then byebye.

(Random fact: Reason for bridging Warfarin with lovenox?  Warfarin depletes protein C and S faster due to their shorter half live making the patient briefly hypercoagulable, which is bad if you already have a clot.)

In preparation for discharge you go over his labs one more time.  INR is 1.4 likely from chronic liver disease.
Now it gets interesting.  With an INR of 1.4, do you need to anti-coagulate him?  With what?  Can you still discharge?  For the sake of argument let’s disregard her potential need for pleurodesis for her recurrent effusion.

Coagulability in Liver Disease

Old dogma relates that patients with liver disease are hypocoagulable.  This is clearly evidenced by their elevated PT/INR/aPTT. And we’ve all seen variceal bleeds in CCT pour out blood.  Obviously they can’t clot right?

An interesting counterpoint is that there is no platelet, PT/INR, or aPTT that contraindicates a paracentesis.  Study after study has shown no increase in complications no matter what the number says.  How come these people aren’t pouring out blood from a paracentesis?  Perhabs those laboratory values aren’t quite what they seem.

New evidence actually argues against the old dogma that liver disease equals hypocoagulable.  To review:

Factors

The liver makes all factors except F VIII and von Willebrand.  In end stage liver disease, all liver-made factors are decreased, which leads to an increase in PT/INR and aPTT.  Interestingly, levels of anti-coagulants (thrombomodulin/protein C/protein S anti-thrombin) are decreased as well, and Factor VIII and VWF are increased.

In the lab PT is actually measured without incorporating host levels of these anti-coagulants – it only measures the prothrombotic factors ability to clot.  BUT recent in vitro studies have shown that cirrhotics and non cirrhotics plasma are equal at forming thrombin (a marker used to measure factor induced clot formation).  The decreased anti-thrombotic factor levels will actually increase the blood’s ability to clot!  The new theory is that chronic liver disase patients are short anti and pro thrombotic factors leading to a balanced thrombotic state.

Platelets

Platelets are needed for two purposes: adhering to damaged endothelial wall, and interacting with clotting factors leading to thrombin activation.

Patients with liver failure frequently have thrombocytopenia BUT studies have shown increased levels of von willebrand factor AND decrease in levels of ADMTS 13.  Combined, this excess and deficiency lead to increased ability of platelet’s to adhere.  Once again in vitro experiments show increased platelet adherence at sites of vascular injury in cirrhotics compared to non-cirrhotics.

Another paper tested platelets ability to activate thrombin in cirrhotics vs healthy people.  Interestingly, per platelet, cirrhotics and healthy people released the same amount of thrombin/were equally able to form clots.  Unfortunately, cirrhotics were more likely to have thrombocytopenia.  According to this in vitro study, counts of 60,000 platelets in cirrhotics generates  thrombin equivalent  to the lower limit of normal in healthy subjects.   Lower than that, the in vitro studies, show a significant decrease in thrombin activation.  It is logical to assume that platelet transfusion in cirrhotics with platelet’s < 60k would completely restore their ability to activate normal levels of thrombin.

Fibrinolysis

Tpa dissolves clots.  Plasminogen Activator inhibitor and thrombin-activatable fibrinolysis inhibitor stops Tpa.  Unfortunately, there are no good laboratory assays to test functional capacity of these factors.  In liver failure, the above factor levels are decreased. The literature has so far been inconclusive about whether liver failure patients have hyperfibrinolysis or hypofibrinolysis.

Conclusion

There is a balance between pro and anti thrombotic forces leading to a normal coagulopathy in chronic liver disease.  Current theory holds that this balance seems to be more fragile/less self stabilizing than normal clotting systems and that patients with chronic liver disease are more susceptible to hypocoagulability and hypercoagulability.

But why do they bleed so much?  Have they been pushed by infection or other cause into hypocoagulability when we see them in the ED?  Another theory is that variceal bleeds are actually bad not because of decreased ability to form clot, but because the tissue so friable and the pressure so high that no amount of clotting factors/platelets could possibly stop the bleed.

DVT/PE/Portal Vein Thrombosis in Liver Failure  

Despite the old theory that chronic liver disease makes people hypocoagulable, studies are split as to the prevalence of VTE in chronic liver failure.   Different studies have shown that people with chronic liver disease have a higher prevalence of VTE, and others have shown a lower prevalence.

The largest study I reviewed- involving almost 100,000 people – showed increase risk of VTE with chronic liver disease.   Though I’m sure factors such as increased hospitalization and cancer may be related, I think it is clear that these patients are not as hypocoagulable as we once thought.

The chief culprit in liver failure patients’ DVT/portal vein thrombosis is thought to be decreased levels of protein C .  Hence, warfarin may not be the best choice.  Dabigatran/rivaroxaban/apixaban do not effect protein C levels…but they are irreversible, so if the patient starts bleeding from varices…good luck.

There are no RCTs or even good papers in general about this.  Only expert opinion, which pretty much recommends endoscopy and possible banding for all chronic liver disease patients with VTE.   Some say no anti-coagulants if the patient has varices, others say you can anti-coagulate after banding.   They all also recommend investigating if the patient has a common pro-thrombotic disorder (factor V leiden/protein C or S deficiency) and favoring anti-coagulation if one of these is found.

But This Patient Also Had Cancer

There have been many studies on the best way to anti-coagulate people with VTE and cancer.  Unfortunately, many of them were small and found no significant difference between LMW heparin and warfarin.  Previous studies have shown a “trend” towards increased repeat VTE’s and increased bleeding with warfarin.

The most significant study of this came in 2003 and showed that LMW heparin had a statistically decreased incidence of repeat, symptomatic VTE compared to warfarin controls.  Though there was no change in mortality (many of the patients died of cancer and not from their PE/DVT).

Back to Our Patient/Lessons

Concerns about this case:

Concern 1: This patient has known liver disease (possible varices) with an INR of 1.4.  Who would anti-coagulate this patient (and don’t chicken out and say admit and let them decide)?

Concern 2:  The INR is 1.4, the patient is already anti-coagulated, do we even need to bridge?  Do we even need to start warfarin?

Concern 3:  Is Lovenox bridge to warfarin best for this patient?

Answer to Concerns

1. The INR of 1.4 does not mean the pt is hypocoagulable.  According to expert opinion, the patient would benefit from anti-coagulation to prevent PE, but an endoscopy should be done prior to starting anti-coagulation.
2. If you want to start the patient on warfarin he 100% needs to be bridged. Protein C levels are already low in liver disease patients
3. Data has shown an advantage of LMW Heparin over warfarin in preventing recurrent, symptomatic VTE.  

Can this happen as an outpatient?  Probably not.  But isn’t fun to have learned all this anyway?

References

1      Lee et al. Low Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. NEJM 349:2, July 2003

2      Armando Tripodi, Ph.D., and Pier Mannuccio Mannucci, M.D., The Coagulopathy of Chronic Liver Disease N Engl J Med 2011; 365:147-156July 14, 2011DOI: 10.1056/NEJMra101117

3      Ewe K. Bleeding after Aliver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981;26:388-93

4      Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005;45:1413-25.

5      Tripodi A, Salerno F, Chantarangkul

6      V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005;41:553-8.

7       Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology 2006;44:440-5.

8      Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA. Factor VIII expression in liver disease. Thromb Haemost 2004;91:267-75.

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