Hypercoagulable disorders (Thrombophilias)

Hypercoagulable disorders (Thrombophilias): Thrombophilias are disorders that show an increased tendency to form blood clots. They may be hereditary or acquired. Factor V Leiden deficiency and prothrombin 20210 gene mutation are the most common causes of hereditary thrombophilia. Acquired thrombophilia is seen in surgery, cancer, pregnancy or drugs like OC pills and following HRT.

Factor V Leiden mutation/thrombophilia: Factor V Leiden is the most common inherited form of thrombophilia. It is more prevalent in people with European ancestry. It is a hypercoagulable condition caused by a mutation in the F5 gene that codes for a procoagulant factor V. Factor V is normally inactivated by cleavage by activated protein C or APC. However, in people with factor V Leiden thrombophilia, coagulation factor V cannot be inactivated normally by APC. It presents with DVT, PE, miscarriages, preeclampsia, IUGR and abruptio placentae. Homozygous patients have increased risk for thrombosis compared to heterozygotes. It can be diagnosed by APC resistance assay (screening test) and confirmed by targeted mutation analysis of F5 gene for Leiden mutation. Heparin and warfarin are used as treatment in some cases. Treatment is titrated according to risk for thrombosis.

Protein C and protein S deficiency: 1) Protein C (PROC) deficiency is an AD disorder caused by mutations in the PROC gene. Protein C is a Vit K dependent naturally occurring anticoagulant that inactivates factors Va and VIIIa. PROC deficiency may be type I or II. Type I is caused by PROC gene mutations that result in reduced levels of protein C, while type II is caused by PROC gene mutations that result in the production of an altered protein C with reduced activity. Severity depends on the actual number of mutations. It manifests as hypercoagulability that is exacerbated by obesity, surgery, old age, pregnancy and inactivity; presenting with DVT, PE in young and old age group, warfarin-induced skin necrosis and purpura fulminans in neonates soon after birth. Purpura fulminans is a life threatening condition characterized by wides[pread clotting throughout small blood vessels all over the body, followed by bleeding. Skin necrosis and purple patches are also seen. Lab diagnosis is by assay to determine Protein C levels and activity and molecular genetic testing for PROC mutations. In clotting assays prolongation of the clotting time is proportional to the activity of Protein C.

Acquired PROC deficiency is relatively frequent and is seen in hepatic failure, vitamin K deficiency, DIC and warfarin/coumarin therapy. On the other hand, increased concentration of Protein C is seen in pregnancy, drugs like ovulation inhibitors or anabolics.

2) Protein S deficiency is an AD disease caused by mutations in the PROS1 gene. Acquired deficiency is seen in pregnancy, OCP use, SLE and renal diseases like nephrotic syndrome. Protein S (PROS) is a vit K dependent naturally occurring anticoagulant that acts in conjunction with Protein C, by acting as the binding protein for Protein C. Deficiency manifests as thrombotic tendency with DVT, PE, mesenteric and cerebral venous thrombosis, purpura fulminans in newborns and skin necrosis. Young adults with the disorder can also present with blood clotting. Diagnosis is by assays for PROS levels and molecular genetic testing for PROS1 mutations.

Antithrombin III deficiency: It is caused by inherited or acquired deficiency of antithrombin III or AT3. Hereditary antithrombin deficiency is an AD disorder, caused by mutations in the SERPINC1 gene that normally codes for AT3. The physiological role of AT3 is as an anticoagulant as it inhibits the action of thrombin as well as factors Xa and IXa. Acquired causes are drugs like L-asparaginase, liver failure, nephrotic syndrome, heparin , DIC, sepsis, cancers and trauma. It presents with increased thrombosis, even in young adults, pregnancy loss, DVT, PE, superficial thrombophlebitis, venous thrombosis, AMI and strokes. Heparin action is dependent on antithrombin III, patients with this disorder cannot be adequately anticoagulated with heparin or develop thrombosis while on heparin therapy. Diagnosis is by low levels on AT3 assays. To avoid false negative results, repeat assay should be done when the patient is not acutely ill or on heparin. Treatment is with AT 3 concentrate.

Antiphospholipid antibody syndrome/ lupus anticoagulant/ anticardiolipin antibodies: It is an autoimmune disorder caused by the development of antibodies to phospholipids or proteins like beta 2 glycoprotein 1 and prothrombin. There is higher risk in females and in individuals suffering from other autoimmune disorders like SLE. Symptoms can be triggered by smoking, prolonged bed rest, pregnancy and the postpartum period, birth control pills, hormone therapy, cancer and kidney disease. It presents with venous and arterial thrombosis, most commonly affecting the lower limbs, brain and lungs causing strokes, chorea, seizures, DVT, PE, central retinal artery occlusion; livedo reticularis, leg ulcers and gangrene, MR, thrombocytopenia, AIHA, symptoms resembling multiple sclerosis, dementia, recurrent abortions, IUGR, preeclampsia and vision changes. Diagnosis is by detection of anticardiolipin antibody immunoassay that detects antibodies to beta 2 glycoprotein 1 or antiphospholipid antibodies or assays for lupus anticoagulant antibodies. Interestingly, the APTT is prolonged in APS even though it is a hypercoagulable disorder. It occurs due to the presence of lupus anticoagulant that binds to phospholipids and increases APTT. Treatment is with aspirin, heparin and warfarin. Pregnant women with APS are treated with heparin and aspirin.

Prothrombin G20210A mutation: It is a hypercoagulability disorder caused by mutation in the F2 gene (that codes for factor II or prothrombin), resulting in an overactive F2 gene that produces excess prothrombin. Prothrombin thrombophilia is the second most common inherited form of thrombophilia after factor V Leiden thrombophilia. Homozygotes are at higher risk than heterozygotes. It is seen with a frequency of 1 in 50 people in the white population in the United States and Europe. It presents with DVT, PE, miscarriages, preeclampsia, abruptio placentae, IUGR etc. Molecular genetic or DNA testing by DNA sequencing is done for diagnosis. PCR can detect the G20210A single nucleotide polymorphism. Prothrombin levels will be elevated. Treatment is with heparin and warfarin.

Hyperhomocysteinemia: Homocysteine is derived from the metabolism of amino acid methionine. It is seen in mutations of enzyme methylene-tetrahydrofolate reductase or MTHFR, deficiency of cobalamin/Vit B12, folate or pyridoxine/Vit B6, end stage renal disease, hypothyroidism, estrogen deficiency, ALL, psoriasis, smoking, drugs like phenytoin, methotrexate and sulfasalazine. Hyperhomocysteinemia increases the risk for AMI, stroke, carotid artery stenosis, venous thrombosis, DVT, PE, peripheral vascular disease and dementia. Endothelial damage, increased atherosclerosis, upregulation of procoagulant factors XII and V and decreased nitric oxide mediate the vascular damage in hyperhomocysteinemia. Homocysteine levels will be elevated and molecular genetic testing shows MTHFR mutations. There is no consensus on treatment. Supplementation with Vit B12, B6 and folic acid may help lower homocysteine levels in some patients but may still not prevent cardiac events. Some studies show increased thrombotic events after triple supplementation.

Hypoplasminogenemia or congenital plasminogen deficiency: It is an AR disorder caused by mutations in PLG gene that codes for plasminogen. It results in low levels or reduced activity of plasminogen in blood. It is not associated, by itself, to increased thrombosis. It is characterized by mucosal growths in the conjunctiva and oral cavity. Ligneous conjunctivitis is seen, with buildup of fibrin and conjunctivitis that leads to thick, woody or ligneous yellow, white or red growths. Corneal scarring may occur. Mucosal growth can also develop in GIT and GUT leading to ulceration, dysphagia and airway obstruction. Rarely, hydrocephalus is seen. Testing for plasminogen and molecular genetic testing are used for diagnosis. Plasminogen concentrates are given as therapy.