In the 1800’s, the German physician Rudolph Virchow identified a triad of risk factors for thrombosis; endothelial injury, stasis, and hypercoagulability.
The last category, hypercoagulability or thrombophilia, occurs when the normal physiological balance between clot formation and clot lysis is tipped towards clot formation.
Before going into the individual thrombophilia disorders, let’s go through the normal coagulation system. The coagulation pathway is divided into an extrinsic and intrinsic pathways, which join into a common pathway that ultimately forms a clot made of strong fibrin mesh.
Let's start with the extrinsic pathway. It starts when trauma damages a blood vessel, and exposes the cells under the endothelial layer, which have tissue factor in their membrane.
Activated factor VII binds to tissue factor, forming a complex that then binds to and activates factor X.
The intrinsic pathway starts when a circulating factor XII, activates factor XI, which then activates factor IX.
Finally, factor IX forms a complex with factor VIII, and this complex binds to and activates factor X.
In the common pathway, activated factor X activates factor V, which converts prothrombin to thrombin, or factor II.
Thrombin then converts fibrinogen into fibrin, which cross-links to form a fibrin clot.
In order to regulate coagulation, the liver makes protein S, which activates protein C.
Protein C inactivates factors V and VIII.
Finally, a protein called antithrombin III inhibits factor X and factor II.
The prothrombin time, or PT assesses the extrinsic and common coagulation pathways, while the partial thromboplastin time, or PTT assess the intrinsic and common coagulation pathways.
Alright, so you can imagine that increasing or decreasing certain factors in the coagulation pathway can lead to thrombophilia.
Disorders that cause thrombophilia can be genetically inherited, like factor V Leiden, prothrombin gene mutation, and protein C and S deficiency, or acquired like antiphospholipid syndrome - which is an autoimmune condition.
The most common presentation of thrombophilia is in the form of a venous thromboembolism, which includes deep vein thrombosis of the upper and lower limbs, as well as pulmonary embolism.
And the key is knowing when to screen for these rare thrombophilias in a person with venous thromboembolism.
Risk factors include having it before 40 years of age, having more than one, or having a venous thromboembolism at an odd location, like in the mesenteric, cerebral, or portal veins.
Another situation when screening for causes of thrombophilia is indicated is in a woman with recurrent miscarriages.
Finally, the risk of having a venous thromboembolism in some of the thrombophilias can be quite low, but that risk can increase when there’s an additional risk factor, like surgery, pregnancy, prolonged immobility, or oral contraceptive use.
Alright, let’s start with the inherited thrombophilias - the most common one being factor V Leiden.
It results from an autosomal dominant point mutation in the gene encoding for factor V, causing it to become resistant to inactivation by protein C.
The best initial screening test is a clotting assay, in which the patient’s plasma is extracted, and activated protein C is added, but it fails to inactivate factor V.
If this test is positive, factor V Leiden is confirmed by looking for the mutation in the factor V gene using PCR.
Factor V Leiden is an inherited condition that only mildly increases the risk of recurrent venous thromboembolism.
So venous thromboembolism prophylaxis with anticoagulants is not recommended in asymptomatic patients, unless the patient is in a high-risk situation, like surgery or pregnancy.
If, on the other hand, a patient with Factor V Leiden has already had a venous thromboembolism, then the management includes anticoagulation with unfractionated or low-molecular weight heparin, followed by warfarin for 3 to 6 months.
Next up, is the second most common inherited thrombophilia, the autosomal dominant prothrombin G20210A mutation.
This mutation involves the substitution of adenine for guanine at position 20210 in the noncoding region of the prothrombin gene, causing an increase in the circulating levels of prothrombin.
The diagnosis is straightforward, using PCR to detect the mutation.
And again, the management of venous thromboembolism is prophylaxis only in high-risk settings, and treatment only for individuals who actually have a venous thromboembolism.
Alright, now onto protein C and S deficiency. Proteins C and S are vitamin K-dependent anticoagulant proteins that are made in the liver.
In the presence of protein S as a cofactor, protein C acts by enzymatically inactivating factors V and VIII.
