Treatment of Hereditary and Acquired Thrombophilic Disorders

Abstract

The treatment of hereditary and acquired thrombophilic disorders is based on an understanding of the disease pathophysiology, prevalence, associated morbidity and mortality, and available therapeutic options. Genetic mutations are identified that result in activated protein C (APC) resistance and hyperhomocyst(e)inemia. The underlying etiologies are less well-defined; however, the disorders of factor XII deficiency, dysfibrinogenemia, Wien-Penzing platelet defect, and sticky platelet syndrome (SPS) are treatable inherited thrombophilias. Antithrombin deficiency, protein C and protein S deficiencies, and plasminogen deficiency are disorders both inherited and acquired. Antiphospholipid antibodies, myeloproliferative syndromes, and Trousseau's syndrome are acquired. Treatment for acute arterial thrombosis or venous thromboembolism is the same or similar for all thrombophilic disorders. Long-term management is based on the risk of a primary or recurrent acute thrombotic event, compared with the risk of the proposed therapy. Few blinded, controlled studies are available to validate treatment recommendations. When long-term anticoagulation is advised, careful consideration should be given to the risk associated with therapy. Bleeding risk, variable efficacy, and the risk of cutaneous necrosis limit the use of warfarin. Fixed low-dose unfractionated porcine heparin and low-molecular-weight heparins (LMWH) offer significant advantages for long-term management. These recommendations are derived from an analysis of the pertinent medical literature and are expected to change with the progress of clinical and laboratory investigation.

Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo

“…4 The importance of APC as a natural anticoagulant is illustrated by the development of severe thrombosis in patients with congenital protein C deficiency. 5 In addition to the anticoagulant effect, APC has been shown to be capable of activating protease activated receptor (PAR)-1 on endothelial cells, 6 thereby activating the mitogen activated protein kinase (MAPK) pathway. The MAPK pathway is activated during mitosis, meiosis, and G0-G1 transition 7 and is implicated in regulation of the cell cycle, mitogen-induced cell growth, and proliferation.…”

Activated Protein C Directly Activates Human Endothelial Gelatinase A

“…APC functions as an anticoagulant by binding to the cofactor, protein S, which inactivates the clotting factors Factor VIIIa and Factor Va. The importance of APC as an anticoagulant is reflected by the findings that deficiencies in this molecule result in familial disorders of thrombosis (7). In addition to its anti-coagulant activity, APC has been reported to have an anti-inflammatory effect (8).…”

Thrombophilia: the dermatological clinical spectrum

“…In recent years, various studies have described the occurrence of thrombophilias in patients with leg ulcers [47,59,60], which can be explained by two distinct mechanisms [1]: (i) indirect form: hypercoagulability provokes a deep venous thrombosis, which in turn leads to a post-thrombotic syndrome, which is the principal known risk factor for the appearance of chronic venous ulcers [60] (ii) direct form: thrombophilia triggers the formation of thrombi within small vessels in the dermis, which leads to the formation of ulceration, which becomes a chronic ulcer [1] The occurrence and exact etiopathogenic role of thrombophilias in the origin of ulcers of the lower limbs remains to be established.…”