One of the principle long-term complications after acute deep vein thrombosis (DVT) is chronic thrombotic venous disease (CTVD), which increases the chance of recurrence and post-phlebitic syndrome. CTVD is characterized by remodeling of thrombotic material within the deep veins into intravascular scars that obstruct blood flow. Why some patients suffer this complication, while others lyse their thrombi is unknown. We have, however, discovered fibrinolytic abnormalities in a similar disease, chronic thrombo-embolic pulmonary hypertension (CTEPH), in which acute pulmonary thrombo-emboli are remodeled into scars within the pulmonary arteries. Our previous studies disclosed that fibrinogen purified from CTEPH patients is somewhat resistant to lysis by exogenous plasmin. Furthermore, we have identified specific fibrinogen mutations among CTEPH patients that may affect the structure of clots. Specifically, their fibrin tends to form less turbid clots, composed of thinner fibers that may enhance the accessibility of epitopes that are stimulatory to endothelial cells and other repair cells.
We aim to determine whether similar genetic variants or post-translational modifications of fibrinogen are present in CTVD patients, which could confer enhancement and/or persistence of fibrin epitopes that stimulate vascular scar formation within acute thrombi. To address this hypothesis, we aim to (1) identify clinical and laboratory variables that may be associated with CTVD after an acute DVT;(2) characterize the fibrin-clot turbidity and the fibrinolytic resistance in a large group of patients with CTVD;(3) characterize structural variants in fibrinogen from patients with CTVD;and (4) determine if resistance to fibrinolysis or variant fibrinogen structure is an important determinant of incomplete recovery after acute DVT. Public Health Relevance: Chronic thrombotic venous disease (CTVD) occurs when blood clots in the leg vein (deep vein thrombi) do not dissolve entirely, and are remodeled into scars that obstruct blood flow. If left untreated, this condition can cause chronic leg pain and disfigurement. Our goal is to understand the mechanisms responsible for the development of CTVD in some patients after acute deep vein thrombosis.

Public Health Relevance

Chronic thrombotic venous disease (CTVD) occurs when blood clots in the leg vein (deep vein thrombi) do not dissolve entirely, and are remodeled into scars that obstruct blood flow. If left untreated, this condition can cause chronic leg pain and disfigurement. Our goal is to understand the mechanisms responsible for the development of CTVD in some patients after acute deep vein thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095089-05
Application #
8307476
Study Section
Special Emphasis Panel (ZHL1-CSR-W (S1))
Program Officer
Link, Rebecca P
Project Start
2008-09-26
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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