Protein S is a vitamin K-dependent protein that is synthesized in the liver and is a co-factor for protein C, helps to suppress factor Va activity. When deficient, there is excessive factor Va leading to thrombophilia. This autosomal dominant hereditary deficiency is found in 0.5% of the general population.(3) Both heterozygotic and homozygotic mutations may produce hypercoagulability.

Protein C deficiency is another vitamin K-dependent protein synthesized in the liver. It is activated by endothelial cell surface thrombin-thrombomodulin complex and, along with its co-factor protein S, inhibits the prothrombotic factors V and VIII. Protein C especially suppresses activity of factor Va and when it is diminished there is increased procoagulant activity. This autosomal dominant hereditary deficiency is found in 0.3% of the general population.(4) Both heterozygotic and homozygotic mutations may produce hypercoagulability but the latter defect usually produces more severe disease.

Antithrombin (antithrombin III, AT-III) is a potent inhibitor of the coagulation cascade. It is a non-vitamin K-dependent protease that inhibits the action of thrombin as well as other procoagulant factors (eg, factor Xa). Congenital AT-III deficiency is an autosomal dominant disorder that leads to increased risk of venous and arterial thrombosis, with onset of clinical manifestations typically presenting in young adulthood.(5)

Mutant Factor V gene (Leiden mutation) produces activated protein C resistance (APCR). A defect in the procoagulant protein, Factor V, does not allow binding by activated protein C, leading to unopposed procoagulant activity and increased risk of clot formation. It is caused by an autosomal dominant mutation, which blocks binding of activated protein C to the prothrombotic Factor V. APCR is the most common heritable thrombophilic factor, found in 3-7% of the population.(4) APCR is found in 11-64% of persons with hypercoagulability.(4)

Prothrombin is the precursor of the serine protease thrombin. A mutation in the prothrombin gene results in high levels of prothrombin and subsequently a thrombotic predisposition. A review of 13 studies found a cumulative prothrombin mutation prevalence of 4.5% at all ages and 5.7% among those less than 50 years of age.(6)

The CBS enzyme converts homocysteine to cystathionine. Mutation allows a build-up of homocysteine in the blood, i.e. hyperhomocysteinemia. Methylene tetrahydrofolate reductase MTHFR mutation/polymorphism controls serum levels of homocysteine, a major thrombophilic risk factor. Homozygous persons have a 70% reduction in MTHFR activity and twice the normal level of homocysteine in their blood (i.e. hyperhomocysteinemia), resulting in thrombophilia.(7) Usually, it is inherited as an autosomal dominant mutation but it can be acquired by a deficiency of vitamin B12 or folate, or renal insufficiency.

Numerous mechanisms for homocysteinemia-induced ischemia have been proposed. These include an increase in adhesiveness of platelets, activation of the coagulation cascade, conversion of LDL cholesterol into proatherogenic forms, and endothelial damage with increased tissue factor expression.(8)

Evidence from studies has validated the relationship between elevated homocysteine and accelerated atherosclerosis.(9) Patients with increased homocysteine have more severe endothelial disease than those with normal levels.(8) Elevated homocysteine increases the odds of intimal thickening of blood vessels more than three-fold.(8) It is this intimal thickening and inhibition of nitric oxide mediated cavernosal smooth muscle relaxation that can lead to resistant endothelium in the penis and resultant ED.(10)

The majority of patients with dysfibrinogenemia are asymptomatic, about one-third have a bleeding tendency, and a much smaller proportion are predisposed to thrombosis. (11) Acquired dysfibrinogenemia occurs in patients with severe liver disease or malignancy. The resulting coagulopathy is due to a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin. This leads to local reactions and inflammation leading to scarring and thickening of blood vessel walls.

Plasminogen deficiency is a rare autosomal recessive disorder that may lead to decreased activity of the fibrinolytic pathway and present in 1-3% of families with inherited thrombosis versus 0.4% in general population.(12) The deficiency can be determined via immunologic and functional assays for plasminogen. The loss of plasminogen greatly accelerates the formation of intimal lesions that lead to atherosclerosis in mice.(13)

Autoimmune or chronic “connective tissue” diseases, especially lupus erythematosus, chronic fatigue syndrome and myofascial pain syndrome, can develop antibodies directed against protective proteins in the walls of endothelial cells. These patients have increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). SFM dimerizes easily, increasing blood viscosity and precipitating out on the surface of endothelial cells as fibrin deposits, creating local ischemia by blocking nutrient and oxygen delivery in the capillary beds.(14) Initially, endothelial coating is all that is seen, but long-standing cases typically show complete blockage of vessels.

Anticardiolipin antibodies and lupus anticoagulant (ACLA) are antiphospholipid autoantibodies which are directed against negatively charged phospholipid antigens. They are prothrombotic via several mechanisms, including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, action as anti-endothelial cell antibodies, or interaction with platelet membrane phospholipids.

Decreased antithrombin, antithrombin III deficiency (found in 0.1% of the general population and in 0.5-4.9% of persons with hypercoagulability), Factor II gene mutation, decreased thrombomodulin, decreased heparin co-factor II, increased Factors II, VIII, IX, X, XI, XII are all inheritable cofactors for hypercoagulability. One significant abnormality may contribute to a hypercoagulable state. Thrombophilia may be caused by more than one genetic abnormality in any of the proteins mentioned here.

Tissue plasminogen activator is the major stimulator of fibrinolysis. When it is not stimulated or is diminished the homeostatic process of thrombus lysis cannot begin or is considerably slowed, resulting in a hypercoagulable state. Poorly stimulated tissue plasminogen activator is often accompanied by high plasminogen activator inhibitor activity, the major inhibitor of fibrinolysis. High plasma triglycerides and/or hyperinsulinemia can increase inhibitor activity and thereby reduce fibrinolysis.

Lp-a is a lipoprotein particle with a structure very similar to an LDL particle linked to a plasminogen molecule. The function of Lp(a) is unknown. Lp-a is a marker for the development of atherosclerotic vascular disease. Individuals with elevated Lp-a are at an increased risk of developing endothelial dysfunction. It is not clear in the literature, whether Lp-a is directly involved in the atherogenic process. High levels of Lp(a) appear to reduce fibrinolysis, especially in the presence of corticosteroid therapy. In one study, it was demonstrated that Lp-a was not an independent risk factor for ED.(15)

Two or more hypofibrinolysis factors can interrelate and contribute to a hypercoagulable state. These include decreased levels of plasminogen, decreased urokinase, increased homocysteine, and increased Factor XI. Antibody inhibitors may be seen as IgA or IgM, or both. These acquired factors may also lead to hypercoagulability; which include increased anticardiolipin antibody, lupus anticoagulant, antiphosphatidyl serine, B-2 glycoprotein I antibodies, and annexin V antibodies.