THROMBOTIC DISORDERS

• Thrombosis

  Inappropriate formation of a platelet or fibrin clot that obstructs a blood vessel
• Thrombosis


  • Results from circulatory stasis and abnormalities in the coagulation system, coagulation control mechanisms, platelet function, the blood vessel wall, or leukocyte activation molecules
  • Causes ischemia (loss of blood supply) and necrosis (tissue death)
• Thrombophilia

  Predisposition to thrombosis secondary to a congenital or acquired condition
• Known causes of thrombophilia


  • Physical, chemical, or biological events such as chronic or acute inflammation that release prothrombotic mediators from damaged blood vessels or suppress blood vessel production of normal antithrombotic substances
  • Uncontrolled platelet activation
  • Uncontrolled blood coagulation system activation
  • Blood coagulation control protein deficiencies
  • Uncontrolled suppression of fibrinolysis
• From 2000 to 2010 the US death rate attributable to venous and arterial thrombotic disease declined 31% and the number of thrombosis-related deaths declined by 17% per year
• In 2010 thrombosis accounted for one of every three deaths in the United States
• 25% of initial thrombotic events were fatal, and many fatal thromboses went undiagnosed before autopsy
• Venous thromboembolism (VTE)

  Annual incidence of 1 in 1000 in the unselected US population, more prevalent in African Americans and in women of childbearing age
• Deep vein thrombosis (DVT)


  Most prevalent VTE, caused by clots that form in the iliac, popliteal, and femoral veins of the calves and upper legs
• Pulmonary embolism (PE)

  Caused by fragments of thrombi (emboli) that separate from the proximal end of a venous thrombus, move through the right chambers of the heart, and lodge in the arterial pulmonary vasculature, causing ischemia and necrosis of lung tissue<|>Nearly 95% of PEs arise from thrombi in the deep leg and calf veins<|>10% to 15% of the 250,000 US residents per year who suffer PE die within 3 months
• VTE risk factors

  • Advancing age
  • Obesity
  • Recent surgery or trauma
  • Immobilization and hospitalization
  • Hypertension
  • Hypercholesterolemia
  • Smoking
  • Diabetes mellitus
  • Metabolic syndrome
• Arterial thrombosis

  Approximately 80% of acute myocardial infarctions (AMIs) and 85% of strokes are caused by thrombi that block coronary arteries or carotid end arteries of the vertebrobasilar system
• Arterial thrombosis mechanism

  Vessel wall unstable atherosclerotic plaque, with activated platelets, monocytes, and macrophages embedding fatty plaque within the endothelial lining, suppressing the normal release of antithrombotic molecules and exposing prothrombotic substances
• Acquired thrombosis risk factors

  • Age
  • Immobilization
  • Diet
  • Lipid metabolism imbalance
  • Oral contraceptive use
  • Pregnancy
  • Hormone replacement therapy
  • Femoral or tibial fracture
  • Hip, knee, gynecologic, prostate surgery
  • Smoking
  • Inflammation
  • Chronic
  • Central venous catheter
• Diseases with thrombotic risk components


  • Antiphospholipid syndrome
  • Myeloproliferative neoplasms
  • Hepatic disease
  • Cancer: adenocarcinoma
  • Leukemia
  • Paroxysmal nocturnal hemoglobinuria
  • Chronic inflammation
  • Diabetes, cancer, infection, autoimmune disorder, obesity, smoking
• Congenital thrombosis risk factors

  • Antithrombin deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Activated protein C resistance
  • Factor V Leiden mutation
  • Prothrombin G20210A mutation
  • Hyperhomocysteinemia
• Homocysteinemia is associated with inadequate dietary folate, vitamin B6, or vitamin B12 levels and with polymorphisms in genes involved in homocysteine metabolism
• Thrombosis


  • Often associated with a combination of genetic defect, disease, and lifestyle influences
  • Just because someone possesses AT, PC, or PS deficiency does not mean that thrombosis is inevitable
  • Many heterozygotes experience no thrombotic event during their lifetimes, whereas others experience clotting only when two or more risk factors converge
• A woman who is heterozygous for the FVL mutation has a thirty-five-fold increase in thrombosis risk when using oral contraceptives
• In the Physicians' Health Study, homocysteinemia tripled the risk of idiopathic venous thrombosis, and the FVL mutation doubled it
• Those with multiple congenital thrombotic risk factors coupled with homocysteinemia experience increased thrombosis risk
• Predisposing congenital factors and thrombosis risk

  • AT deficiency
  • PC deficiency
  • Free PS deficiency
  • APC resistance
  • Prothrombin G20210A
  • Homocysteinemia
  • Hyperfibrinogenemia
• AT

  Inhibits serine proteases lla, IXa, Xa, and Xla, enhanced by heparin
• Activated PC


  Serine protease that hydrolyzes factors Va and Villa, requires protein S as a stabilizing cofactor
• PS

  Stabilizing cofactor for activated protein C, 40% free, 60% circulates bound to C4bBP
• Factor V Leiden (R506Q) mutation


  Gain of function renders factor V resistant to APC
• Prothrombin G20210A mutation

  Mutation in prothrombin gene untranslated 3' promoter region, moderate prothrombin activity elevation
• Homocysteinemia


  Associated with inadequate dietary folate, vitamin B6, or vitamin B12 levels and with polymorphisms affected the function of methylene tetrahydrofolate reductase (MTHFR) in the methionine metabolic pathway
• Folate supplementation in industrialized countries has reduced the incidence of homocysteinemia
• MTHFR polymorphisms are associated with homocysteinemia, but they do not correlate with incidence of arterial thrombosis
• Efforts to reduce plasma homocysteine concentration do not reduce the risk of arterial thrombosis
• APC resistance

  Found in 3% to 8% of Caucasians worldwide, extends to Arab and Hispanic populations, but nearly absent from African and East Asian populations
• APC resistance may exist in the absence of the FVL mutation and is occasionally acquired in pregnancy or in association with oral contraceptive therapy
• The FVL gene mutation is the most common inherited thrombosis risk factor, and the prothrombin G20210A gene mutation is the second most common inherited thrombophilia in patients with a personal and family history of deep vein thrombosis
• Altogether, PC, PS, and AT deficiencies are found in only 0.2% to 1.0% of the world population
• Thrombophilia laboratory test profile

  • LAC profile
  • ACL antibody
  • Anti-B2-GPI antibody
  • AT activity
  • PC activity
  • PS activity
  • Fibrinogen
  • Homocysteine
• LAC profile

  Minimum of two clot-based assays, primary assays based on DRVVT and PTT, secondary assays based on dilute PT, all include phospholipid neutralization follow-up test
• ACL antibody

  Immunoassay for immunoglobulins of APL family, depends on B2-GPI in reaction mix
• Anti-B2-GPI antibody

  Immunoassay for an immunoglobulin of APL family, B2-GPI is key phospholipid-binding protein in family
• AT activity

  Serine protease inhibitor suppresses lla (thrombin), IXa, Xa, Xla