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correspondence

Acute Hepatic Necrosis and Ischemic Limb Necrosis


To the Editor: Thrombosis can complicate the
coagulopathy of chronic liver disease, probably
because of decreased levels of the naturally occurring anticoagulants antithrombin and protein C, with resulting procoagulant imbalance.1
A disturbance of procoagulantanticoagulant balance is a fundamental concept in the pathogenesis of microvascular thrombosis that results in
ischemic limb necrosis despite palpable arterial
pulses. This latter condition has been reported in
patients with heparin-induced thrombocytopenia2 or adenocarcinoma3 two prothrombotic
disorders featuring greatly increased thrombin
generation in whom severe depletion of protein C (a vitamin Kdependent natural anticoagulant) develops during treatment with warfarin
(a vitamin K antagonist).2,3 In theory, acute liver
failure could similarly be prothrombotic,4 especially with rapid, profound depletion of protein C,
which has one of the shortest half-lives (9 hours)
of the hepatically synthesized factors.
Acute ischemic hepatitis (peak alanine aminotransferase level, 2468 U per liter [reference range,
0 to 28]; peak total bilirubin level, 11.3 mg per
deciliter [193 mol per liter]) developed in a
61-year-old woman after cardiac arrest. Emergency coronary-artery bypass surgery restored
hemodynamic stability (with no ongoing requirements for vasopressors), but hepatic ischemia
persisted because of 99% atherosclerotic hepatic-artery stenosis that was detected on angiography. Ischemic limb necrosis (bilateral, acral, and
involving both the hands and feet) began on day
4, when the international normalized ratio increased to 5.1 (reference range, 0.9 to 1.3) and
the fibrinogen level decreased to 70 mg per deciliter (reference range, 160 to 420).
Figure 1 shows the patients clinical course
and platelet counts, the laboratory markers indicating a disturbance of the procoagulantanticoagulant balance, and the correlation between
factor activity levels and the respective factor
half-lives. We found an increase in levels of procoagulant markers (thrombinantithrombin complexes, fibrin monomers, and fibrin d-dimers) to
levels that were approximately 100 to 200 times

as high as normal values, with severe depletion


of protein C and antithrombin (nadir values of
1% and 20% of the normal values, respectively).
Thus, the ratio of procoagulant to anticoagulant
markers was more than 1000 to 10,000 times as
high as the normal ratio.
To examine the role of impaired hepatic synthesis of coagulation factors, we performed a
regression analysis of levels of coagulation factor activity (for factors II, V, VII, IX, X, XI, XII,
and XIII; prekallikrein; high-molecular-weight
kininogen; protein C; protein S; and antithrombin) versus their respective half-lives.5 We found
a highly significant positive association (r2=0.62,
P=0.001), indicating that differing factor halflives could help to explain the observed profile
of reduced levels of coagulation factors, particularly the very low levels of protein C activity.
Testing for heparin-dependent platelet-activating
antibodies was negative. We postulate that a disturbance of procoagulantanticoagulant balance

Figure 1 (following page). Findings in a Patient with


Acute Hepatic Necrosis and Ischemic Limb Necrosis.
Panel A shows the patients clinical course and platelet
counts. Limb necrosis began 4 days after cardiac arrest
and progressed despite heparin therapy. The expanded
figure of days 4.00 to 6.00 shows a disturbance of the
procoagulantanticoagulant balance. Levels of procoagulant markers (fibrin d-dimer, fibrin monomer, and
thrombinantithrombin complexes) were 100 to 200
times as high as the upper limit of the normal range
(dashed line), whereas the nadir levels of the natural
anticoagulants, protein C and antithrombin, were only
1% (0.01 U per milliliter [reference range, 0.70 to 1.80])
and 20% (0.20 U per milliliter [reference range, 0.77 to
1.25]) of the normal values (at day 4.75), respectively,
with subsequent increases in protein C after transfusion of frozen plasma and protein C concentrate. Panel
B shows levels of coagulation factor activity (based on
mean values of two plasma samples obtained approximately 4.75 days after admission and before plasma
administration) versus factor half-lives. The dashed
line indicates the least-squares regression line fitted
through the data points shown. Factor VIII coagulant
levels were approximately four times as high as normal
levels (not shown). These findings are consistent with
the role of factor VIII as an acute-phase reactant.

n engl j med 367;9 nejm.org august 30, 2012

The New England Journal of Medicine


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Copyright 2012 Massachusetts Medical Society. All rights reserved.

879

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

A
Norepinephrine
and dopamine

300,000

Platelet Count/mm3

Heparin

Admission for acute myocardial infarction


Cardiac arrest after heart catheterization
Emergency cardiac surgery
Platelet transfusions

Death

200,000
Continuous renal-replacement therapy
Ischemic limb necrosis

100,000

Heparin

103

Value Relative to Upper Limit


of Normal Range (log10 scale)

102

Procoagulant
Thrombinantithrombin
complex
Fibrin monomer
Fibrin D-dimer

101

Protein C
concentrate

Frozen plasma (2 units each)

Normal

100

101

Anticoagulant
Antithrombin
Protein C

102
4.00

4.25

4.50

4.75

5.00

5.25

5.50

5.75

6.00

Days after Admission

Factor Activity Level


(U/ml)

1.0
0.8

Factor XII

Prekallikrein
Factor IX

Factor XIII

Factor XI

0.4
Factor VII
0.2
0.0

High-molecular-weight
kininogen

Protein S

0.6

Factor II

Protein C
Factor V
0

20

40

r2 =0.62

Antithrombin

Factor X
60

80

100

120

140

160

Factor Half-Life (hr)

arising from the combination of greatly in- tors (protein C and antithrombin) can explain
creased thrombin generation with impaired he- ischemic limb necrosis despite palpable pulses
patic synthesis of key natural anticoagulant fac- in patients with acute hepatic necrosis.
880

n engl j med 367;9 nejm.org august 30, 2012

The New England Journal of Medicine


Downloaded from nejm.org on March 4, 2014. For personal use only. No other uses without permission.
Copyright 2012 Massachusetts Medical Society. All rights reserved.

notices

Deborah M. Siegal, M.D.

corrections

McMaster University
Hamilton, ON, Canada

Richard J. Cook, Ph.D.

Nighttime Intensivist Staffing and Mortality among Critically


Ill Patients (May 31, 2012;366:2093-101). In Table 3 (page
2099), the P value in the last row of the table should have been
0.053, rather than <0.001. The article is correct at NEJM.org.

University of Waterloo
Waterloo, ON, Canada

Theodore E. Warkentin, M.D.


McMaster University
Hamilton, ON, Canada
twarken@mcmaster.ca
Supported by a grant (T6950) from the Heart and Stroke Foundation of Ontario.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Tripodi A, Mannucci PM. The coagulopathy of chronic liver

disease. N Engl J Med 2011;365:147-56.

Transcatheter Aortic-Valve Replacement for Inoperable Severe


Aortic Stenosis (May 3, 2012;366:1696-704). In Figure 2 (page
1700), the y axis should have been labeled Mortality (%),
rather than Survival (%). The article is correct at NEJM.org.
Pregnancy in a Woman with a Leptin-Receptor Mutation
(March 15, 2012;366:1064-5). In the list of authors (page 1065),
the second authors surname should have been Dommergues,
rather than Dommergue. The article is correct at NEJM.org.

2. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA,

Russell JI, Kelton JG. The pathogenesis of venous limb gangrene


associated with heparin-induced thrombocytopenia. Ann Intern
Med 1997;127:804-12.
3. Warkentin TE. Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis. Ann Intern
Med 2001;135:589-93.
4. Idem. Heparin-induced thrombocytopenia in critically ill patients. Crit Care Clin 2011;27:805-23.
5. Harmening DM, Escobar CE, McGlasson DL. Introduction to
hemostasis. In: Harmening DM, ed. Clinical hematology and
fundamentals of hemostasis. 5th ed. Philadelphia: F.A. Davis,
2009:543-76.
DOI: 10.1056/NEJMc1207074
Correspondence Copyright 2012 Massachusetts Medical Society.

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Electronic Health and Medicine: Advances
and Challenges
The seminar will be held in Warsaw, Poland, on Sept. 27. It
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Contact Ms. R. Kuskowska, Polish Academy of Sciences,
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The following courses will be offered in Boston: Forces of
Change: New Strategies for the Evolving Health Care Marketplace (Sept. 1014) and Leadership Strategies for Evolving
Health Care Executives (Oct. 28Nov. 2).
Contact Peter J. Bretton, Center for Continuing Professional
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n engl j med 367;9 nejm.org august 30, 2012

The New England Journal of Medicine


Downloaded from nejm.org on March 4, 2014. For personal use only. No other uses without permission.
Copyright 2012 Massachusetts Medical Society. All rights reserved.

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