HDCN Ask the Professor: Calciphylaxis and Protein C deficiency
I am presently involved in the care of our a patient with calciphylaxis.
The patient is suffering severe and difficult to control
pain, related to necrotic leg ulcers. Protein C and S deficiencies have been
desrcibed in calciphylaxis and protein C concentrate has been used in
treating warfarin-induced skin necrosis, which bears some pathologic
resemblence to calciphylaxis.
I would appreciate your expert comment on the potential for
using protein C concentrate in the treatment of calciphylaxis. By the way, the
serum parathyroid levels are normal and the calcium phosphorus product is not
Paul S. Sohi MD (Dalhousie University, Saint John, NB CANADA)
Dr. David J. Leehey (Associate Professor of Medicine, Loyola University at
Chicago School of Medicine)
Calciphylaxis is a rare but probably underreported clinical entity
characterized by arterial calcifications and tissue ischemia. It
is seen most commonly in dialysis and transplant patients. Its
incidence is probably increased in diabetic patients and patients
with severe secondary hyperparathyroidism (although
hyperparathyroidism may not be present in all patients).
Clinically it presents with areas of ischemic necrosis that develop
in the skin, fat, and occasionally muscle, resulting in purplish
skin nodules that evolve into black eschars. The lesions are most
often found on the distal extremities and especially the digits.
Its pathogenesis is poorly understood. A role for PTH is suggested
by frequent clinical improvement after parathyroidectomy.
Because of the similarity of the lesions of calciphylaxis to the
lesions seen in warfarin-induced skin necrosis, it has been
suggested that alterations in the natural anticoagulants protein C
and S may be involved in its pathogenesis. Protein C is a vitamin
K-dependent protein that selectively inactivates factors Va and
VIIIa; this action is facilitated by the presence of the cofactor
protein S, which is also vitamin K-dependent. Protein S forms
complexes with protein C on phospholipid membranes, enhancing
protein C binding and accelerating the inactivation of factor Va.
A syndrome of skin necrosis due to vitamin K deficiency in a
patient with ESRD not taking warfarin has been described,
indicating the critical role of vitamin K deficiency in the
development of skin lesions (Soundararajan et al. Am J Med 1992;
93:467-70). Renal failure causes a disproportionate reduction in
functional protein C activity compared to antigen levels (Vaziri et
al. Arch Phys Med Rehab 1987; 68:791-3). Possible causes include
an unidentified dialyzable inhibitor in uremic plasma (accounting
for the increased activity seen after dialysis), and either
increased formation or reduced clearance of complexes formed by
protein C and its protein inhibitors.
Mehta et al (Am J Med 1990; 88:252-7) described 5 patients with
ESRD and calciphylaxis and compared them to 12 ESRD patients
without evidence of calciphylaxis, 8 patients with nephrotic
syndrome, and 8 healthy volunteers. Protein C antigen levels were
measured by rocket immunoelectrophoresis and functional activity
quantitated by a chromogenic assay. Skin biopsy specimens of 3
involved patients showed thrombotic occlusion of venules identical
to that seen in warfarin-induced skin necrosis. Protein C activity
(but not antigen) levels were significantly reduced in patients
with calciphylaxis compared to the other 3 groups. Further
unpublished studies by this group indicated that patients with
calciphylaxis had an excess of two naturally occuring inhibitors of
activated protein C, alpha-1-antitrypsin inhibitor and plasminogen
activator inhibitor. Recently, Rostaing et al. (Am J Nephrol 1995:
15:524-7) described a dialysis patient with hyperparathyroidism and
calciphylaxis who had low functional protein S levels (protein C
activity was normal). Parathyroidectomy was without benefit.
This question was also posted on NEPHROL, where the following response from
Ravi L. Mehta, MD, (University of California at San Diego Medical Center) was
We had initially explored the idea of a possible
relationship as the lesions seen in calciphylaxis are
strikingly similar to those described in Coumarin necrosis.
We studied 5 patients with typical and extensive lesions of
calciphylaxis seen at the University of Rochester in NY and
found the following:
1) there appeared to be no decrease in the level of protein
C antigen in comparison to other dialysis patients, healthy
volunteers and patients with nephrotic syndrome.
2) When protein C activity is measured however, it is low
and if expressed as a specific activity (activity/antigen)
patients with calciphylaxis have the lowest activity
although it is also reduced in other dialysis patients and
3) We hypothesized that one of the factors in calciphylaxis
may be a failure of the natural anticoagulant pathway to
prevent microvascular clotting thereby setting up localized
ischemia. We found that skin biopsies in three patients
showed thrombotic occlusion of venules similar to that seen
in warfarin induced skin necrosis.
4) Following these initial studies reported in Am J Med
1990, 88:252-258, we asked the question what was resulting
in the decreased functional activity of activated protein C
(APC). With the collaboration of Dr Mary Jo Heeb at the
Scripps clinic here we evaluated the possibility of
inhibitors of APC. Our results (unpublished) showed that
patients with calciphylaxis had an excess of the APC alpha 1
antitrypsin inhibitor complexes and also the APC plasminogen
activator inhibitor. Both of these inhibitors are natural
inhibitors of APC. Unfortunately we did not have enough
stored samples from calciphylaxis patients to pursue these
studies further and have not seen too many new patients in
I believe there have been further publications on this
subject in hemodialysis patients and also recent
descriptions of APC resistance however we have not
investigated this further. I do believe that this is an
intriguing area for further research as APC is now available
as a research tool and it may be interesting to use it in
patients with calciphylaxis. I know that the Scripps clinic
team were trying it as an anticoagulant in experimental
models of hemodialysis but I am not sure if the results were
published. It may be helpful for other subscribers who are
more familiar with the basic advances in the natural
anticoagulant pathway to comment on this topic. I see it
being relevant not only for calciphylaxis but the broader
question of access thrombosis in hemodialysis patients.
For slides of calciphylaxis-associated skin lesions, click here.
Actually, Dr. Sohi's question has not really been answered. Is anyone aware of use of
protein C concentrate to treat calciphylaxis in dialysis patients?