The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.
BACKGROUND
Platelet-mediated arterial occlusion is a well-recognized cause of limb loss in patients with heparin-induced thrombocytopenia. However, the syndrome of distal ischemic necrosis complicating the deep venous thrombosis (venous limb gangrene) sometimes associated with heparin-induced thrombocytopenia has not been well characterized.


OBJECTIVE
To study the pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.


METHODS
Characterization (based on descriptive and case-control studies) of a novel syndrome of limb loss and hypothesis testing by analysis of plasma samples.


METHODS
Five university-associated hospitals in one medical community.


METHODS
Clinical and laboratory records of 158 patients with heparin-induced thrombocytopenia were reviewed to identify patients with venous limb gangrene (n = 8), limb arterial thrombosis (n = 10), and uncomplicated deep venous thrombosis (n = 58).


METHODS
Clinical and laboratory factors associated with venous limb gangrene, including thrombin-antithrombin complexes and vitamin K-dependent procoagulant and anticoagulant factors.


RESULTS
Warfarin treatment was more frequently associated with venous limb gangrene than with limb arterial thrombosis (8 of 8 patients compared with 3 of 10 patients; P = 0.004). The anticoagulant effect of warfarin seemed greater in the 8 patients with venous limb gangrene than in the 58 patients who did not develop gangrene (median International normalized ratio, 5.8 compared with 3.1; P < 0.001). Compared with plasma from controls, plasma from patients with venous limb gangrene had a higher ratio of thrombin-antithrombin complex to protein C activity during warfarin treatment. No hereditable abnormalities of the protein C anticoagulant pathway were seen in any patient.


CONCLUSIONS
Warfarin treatment of deep venous thrombosis associated with heparin-induced thrombocytopenia is a possible cause of venous limb gangrene, perhaps because of acquired failure of the protein C anticoagulant pathway to regulate thrombin generation.
Warkentin
T E
TE
McMaster University, Hamilton Health Sciences Corporation, Ontario, Canada.
Elavathil
L J
LJ
Hayward
C P
CP
Johnston
M A
MA
Russett
J I
JI
Kelton
J G
JG
D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D005734:Gangrene / Q000139:chemically induced*; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*; D013924:Thrombophlebitis / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy; D014859:Warfarin / Q000009:adverse effects*
D000925:Anticoagulants; D011486:Protein C; D014859:Warfarin; D006493:Heparin; D013917:Thrombin