Hypercoagulable disorders (thrombophilias): Thrombophilias are disorders associated with an increased tendency to form blood clots. They may be hereditary or acquired. Factor V Leiden mutation and the prothrombin G20210A gene mutation are the most common causes of hereditary thrombophilia. Acquired thrombophilia is seen with surgery, cancer, pregnancy, and drugs such as oral contraceptive (OC) pills and hormone replacement therapy (HRT).
Factor V Leiden mutation/thrombophilia: Factor V Leiden is the most common inherited form of thrombophilia and is more prevalent in people with European ancestry. It is a hypercoagulable condition caused by a mutation in the F5 gene, which codes for the procoagulant factor V.
Factor V is normally inactivated when activated protein C (APC) cleaves it. In factor V Leiden thrombophilia, factor V cannot be inactivated normally by APC, so clotting activity persists.
It can present with DVT, PE, miscarriages, preeclampsia, IUGR, and abruptio placentae. Homozygous patients have a higher risk of thrombosis than heterozygotes.
Diagnosis is made with an APC resistance assay (screening test) and confirmed by targeted mutation analysis of the F5 gene for the Leiden mutation. Heparin and warfarin are used as treatment in some cases, and treatment is titrated according to the patient’s thrombosis risk.
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 vitamin K-dependent, naturally occurring anticoagulant that inactivates factors Va and VIIIa.
PROC deficiency may be type I or type II:
Severity depends on the number of mutations present.
It manifests as hypercoagulability that is exacerbated by obesity, surgery, old age, pregnancy, and inactivity. It may present with DVT and PE in young and older age groups, warfarin-induced skin necrosis, and purpura fulminans in neonates soon after birth.
Purpura fulminans is a life-threatening condition characterized by widespread clotting throughout small blood vessels all over the body, followed by bleeding. Skin necrosis and purple patches are also seen.
Lab diagnosis is by assays to determine protein C levels and activity, along with 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. Increased protein C concentration is seen in pregnancy and with drugs such as 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 such as nephrotic syndrome.
Protein S (PROS) is a vitamin K-dependent, naturally occurring anticoagulant that works with protein C by acting as a binding protein for protein C.
Deficiency manifests as a thrombotic tendency, including 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: Antithrombin III (AT3) deficiency may be inherited or acquired.
Hereditary antithrombin deficiency is an AD disorder caused by mutations in the SERPINC1 gene, which normally codes for AT3. AT3 is a physiologic anticoagulant that inhibits thrombin as well as factors Xa and IXa.
Acquired causes include drugs such as 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’s anticoagulant action depends on AT3. Patients with this disorder may not be adequately anticoagulated with heparin or may develop thrombosis while on heparin therapy.
Diagnosis is by low levels on AT3 assays. To avoid false-negative results, the assay should be repeated when the patient is not acutely ill and not on heparin. Treatment is with AT3 concentrate.
Antiphospholipid antibody syndrome/ lupus anticoagulant/ anticardiolipin antibodies: This is an autoimmune disorder caused by development of antibodies to phospholipids or to phospholipid-binding proteins such as beta 2 glycoprotein 1 and prothrombin. Risk is higher in females and in individuals with other autoimmune disorders such as 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. Manifestations include 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 antibodies (immunoassay detecting antibodies to beta 2 glycoprotein 1), antiphospholipid antibodies, or assays for lupus anticoagulant antibodies.
A key point is that APTT is prolonged in APS even though APS is a hypercoagulable disorder. This occurs because lupus anticoagulant 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: This is a hypercoagulability disorder caused by a mutation in the F2 gene (which codes for factor II, or prothrombin). The mutation results 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 occurs with a frequency of about 1 in 50 people in the white population in the United States and Europe.
It presents with DVT, PE, miscarriages, preeclampsia, abruptio placentae, and IUGR.
Diagnosis is by molecular genetic (DNA) testing, including DNA sequencing. PCR can detect the G20210A single nucleotide polymorphism. Prothrombin levels will be elevated. Treatment is with heparin and warfarin.
Hyperhomocysteinemia: Homocysteine is derived from metabolism of the amino acid methionine. Hyperhomocysteinemia is seen with mutations in methylene-tetrahydrofolate reductase (MTHFR), deficiency of cobalamin (vitamin B12), folate, or pyridoxine (vitamin B6), end-stage renal disease, hypothyroidism, estrogen deficiency, ALL, psoriasis, smoking, and drugs such as phenytoin, methotrexate, and sulfasalazine.
Hyperhomocysteinemia increases the risk of AMI, stroke, carotid artery stenosis, venous thrombosis, DVT, PE, peripheral vascular disease, and dementia.
Vascular damage is mediated by endothelial damage, increased atherosclerosis, upregulation of procoagulant factors XII and V, and decreased nitric oxide.
Homocysteine levels will be elevated, and molecular genetic testing may show MTHFR mutations. There is no consensus on treatment. Supplementation with vitamins 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: This is an AR disorder caused by mutations in the PLG gene, which codes for plasminogen. It results in low levels or reduced activity of plasminogen in the blood.
By itself, it is not associated with increased thrombosis. It is characterized by mucosal growths in the conjunctiva and oral cavity.
Ligneous conjunctivitis can occur, with buildup of fibrin and conjunctivitis leading to thick, woody (ligneous) yellow, white, or red growths. Corneal scarring may occur.
Mucosal growths can also develop in the GIT and GUT, leading to ulceration, dysphagia, and airway obstruction. Rarely, hydrocephalus is seen.
Diagnosis uses plasminogen testing and molecular genetic testing. Plasminogen concentrates are given as therapy.
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