Thrombophilia
Approx. 5-8% of U.S. population has a clotting disorder or Thrombophilia.
Propensity for blood to clot in which an inherited OR acquired defect can generally be found as the cause.
The total incidence of an inherited thrombophilia in subjects with a DVT ranges from 24 to 37% overall compared with about 10 percent in controls (5).
Most develop after an insult.
*In our patient’s case, most likely the arthroscopy.
Thrombophilias have also been linked to both recurrent miscarriage and possibly various complications of pregnancy such as IUGR, stillbirth, severe pre-eclampsia and abruptio placenta.
Inherited Deficiency Types
Factor V Leiden Deficiency
Prothrombin Deficiency
Anti-Thrombin III Deficiency
Hyperhomocystenemia
Protein C Deficiency or Dysfunction
Protein S Deficiency or Dysfunction
Plasminogen Deficiency
Dysfibrinogenemia
Factor V Leiden Deficiency
Factor V Leiden Mutation, also called Activated Protein C resistance. Accounts for 40-50% of VTE cases. Therefore, obtaining the title of Most common Inherited Thrombophilia. There is a
Mutation in the gene that makes the Factor V protein. Factor V is activated normally, but is resistant to degradation by Activated Protein C, which regulates the clotting process.
12-26% Risk of VTE with Factor V Mutation according to multiple studies including Physician’s Health Study which found 12% incidence of Heterozygosity with a 1st confirmed DVT or PE compared with 6% in controls.
Leiden Thrombophilia Study was a study of 471 Pts. all under age 70 with DVT and 474 controls, found 21% incidence of Activated Protein C Resistance with 5% in controls. Relative Risk was increased 7-fold for Heterozygotes and 80-fold for Homozygotes.
Prothrombin Deficiency
Prothrombin mutation (G20210A, 5'UTR) is a mutation that results in an increased amount of thrombin (Activated Factor II) in the circulation, which is associated with an increased risk for venous blood clots.
Prevalence: Wide Variability in Geographic Distribution of the Prothrombin Gene Mutation. Caucasian Population 0.7-6.5%, with highest prevalence of heterozygosity of the gene in Spain.
Europeans 0.7-4.0%, Southern Europe is twice as high as northern.
Very Rare in Non-white, African American and Asian Populations.
Protein C Deficiency or Dysfunction
Protein C is a vitamin K-dependent plasma anticoagulant that is activated by APC to regulate the speed of the coagulation cascade by degrading factors Va and VIIIa.
Inherited protein C deficiency is uncommon and may be either quantitative (type I) or qualitative (type II).
Protein C deficiency or dysfunction is associated with an increased Incidence VTE with relative risk 8-10, whereas no association with arterial thrombotic disease has been found.
Protein C levels are generally Decreased in acute thrombotic states, disseminated intravascular coagulation (DIC), liver disease, malnutrition (vitamin K deficiency) and with warfarin therapy.
Increased protein C levels may be seen in diabetes, nephrotic syndrome, during pregnancy, and in patients on oral contraceptives. Heparin and direct thrombin inhibitors may interfere in some functional assays, resulting in falsely elevated values.
Prevalence is estimated to about 0.2% to 0.5% of the general population. 3 times higher among Japanese compared to Caucasians.
Protein S Deficiency or Dysfunction
Protein S is a vitamin-K dependent anticoagulant that acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of Factor Va and Factor VIIIa. Decreased levels or impaired function of Protein S leads to decreased degradation of Factors Va & VIIIa and an increased propensity to VTEs.
Decreased levels of Protein S are found in acute thrombotic states, nephrotic syndrome, inflammatory syndromes (due to increased C4b-binding protein), DIC, liver disease, malnutrition (vitamin K deficiency), pregnancy, estrogen therapy, and with warfarin therapy.
Incidence - VTE develops in 60-80% of patients who are heterozygous for Protein S deficiency.
The deficiency is also associated with fetal loss in women, in the absence of VTE.
Hyperhomocysteinemia
High Homocysteine levels are generally due to Methylenetetrahydrofolate Reductase (MTHFR) mutation or vitamins B6, B12 or folic acid deficiencies. MTHFR Mutation is linked to an increased incidence of VTE and Cardiovascular Disease, which occurs more often in people with Above Minimal levels of homocysteine, about 6 μmol/L. Common levels in Western populations are 10 to 12.
Women have 10-15% less homocysteine during their reproductive decades than men, which may help explain the fact they suffer MI’s on average 10 - 15 years later than men.
Prevalence - MTHFR mutation is quite common about 10% of the world population.
Treatment - These individuals require adequate dietary Riboflavin in order for Homocysteine levels to remain normal (14).
Anti-thrombin III Deficiency or Dysfunction
Antithrombin III Deficiency or Dysfunction decreases the activity of the clotting process by inhibiting factors Xa, IXa, XIa, and thrombin. Inherited deficiency or acquired dysfunction of antithrombin can lead to a clot formation.
Prevalence: Among pts. with 1st Thrombotic Event, 0.5-1% have Antithrombin III deficiency.
Plasminogen Deficiency
This is a rare deficiency. Normally, Activated Plasminogen -> plasmin.
Plasmin helps breaks clot's cross linked fibrin. Therefore, a deficiency would yield an increased propensity to clot.
Most of these patients present with eye problems from fibrin deposits.
Higher prevalence in females 2:1.
Fibrinolysis Disorder or Dysfibrinogenemia
This disorder is very rare and yields fibrin that does not break down normally. The inherited form is associated with increased risk of bleeding, thrombosis, or both in the same patient or family.
Most patients with abnormal Fibrin have laboratory results WNL. Abnormal tests of fibrin clot formation, the thrombin time and reptilase time are the screening tests, and the fibrinogen clotting activity-antigen ratio is the confirmatory test.
A small number have been reported to have thrombotic complications.
What Tests to Order?
CBC & Coag Panel
Factor V Leiden level, Activated Protein C resistance
Lupus anticoagulant
Anti-cardiolipin Antibody
Protein C level and activated Protein C
Protein S level and activated Protein S
Thrombin and Reptilase Time
Prothrombin mutation
Anti-β2 glycoprotein 1 Antibody
Homocysteine level
Bleed Time
