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Flashcards in Thrombophilia Deck (14):

What is the definition of the following: Hemostasis,Thrombosis, Coagulation, Hemophilia, Thrombophilia?

  • Hemostasis: the way blood vessels, blood components, and procoagulants stop bleeding
  • Thrombosis: pathological occlusion of vessels
  • Coagulation (or clotting): physiologic control of bleeding by clot formation
  • Hemophilia: a bleeding tendency
  • Thrombophilia: a tendency to form thrombi: more logical than the term hypercoagulability


What are the three major categories of factors that promote thrombosis?

  • The factors promoting thrombosis were grouped into 3 major categories by Virchow some 150 years ago, and were vessel wall injury, stasis, and thrombophilia
  • Injury to the endothelium induces:
    • platelet adherence and activation
    • followed by binding of clotting factors
    • generation of thrombin
    • formation of fibrin
    • altered blood flow
    • trapping of red cells and white cells


What are the major contributors to hemostatic balance?

  • The coagulation system is engineered to maintain blood fluidity and prevent intravascular thrombosis
    • This is accomplished by the non-wettable endothelial surface and the rapid, pulsatile blood flow
    • In addition, endothelium provides:
      • nitric oxide and prostacyclin (vasodilators that also inhibit platelet aggregation)
      • ecto-ADPase (inhibits platelet aggregation)
      • tissue factor pathway inhibitor
      • thrombomodulin (activates protein C bound to the endothelial cell protein C receptor)
      • proteoglycans (inhibit thrombin)
  • Other physiologic antithrombotic proteins are:
    • protein S
    • protein Z
    • Z-protease inhibitor
    • antithrombin
    • heparin cofactor-2
  • In addition, annexin V and ß2-glycoprotein-1 bind to membrane phospholipids, preventing attachment of procoagulants
  • Thrombus formation is also limited by the fibrinolytic system, which speeds thrombus dissolution
    • However, excess inhibitors of fibrinolysis, such as plasminogen activator inhibitor-1 (PAI-1), retard thrombus resolution
  • Thrombosis occurs when the hemostatic balance is shifted in favor of thrombotic factors


What are the major features of arterial thrombosis? What are the major vessels affected? What are some causes of injury?

  • A platelet-driven process initiated by von Willebrand factor binding platelet aggregates to the injured (often atherosclerotic) artery wall
    • Arteries usually affected are:
      • coronaries - myocardial infarction
      • cerebral - stroke
      • peripheral large vessels - limb gangrene
  • Causes of injury to arteries are:
    • hypertension
    • hypercholesterolemia
    • diabetes
    • hyper-homocysteinemia
    • immune-complexes
  • Obesity is associated with release of inflammatory cytokines
    • Adipose tissue exposes procoagulant tissue factor, releases PAI-1, and has decreased production of adiponectin
  • Arterial thrombosis may also be due to:
    • excessive numbers of platelets (thrombocythemia, a myeloproliferative disease)
    • abnormally rigid erythrocytes (sickle cell disease)
    • autoantibodies to ADAMTS13
      • resulting in circulating high molecular weight VWF complexes (thrombotic thrombocytopenic purpura)


What is venous thrombosis?

  • Low flow/venous stasis:
    • prolonged immobilization
    • varicose veins
    • vein compression syndromes
  • Thrombi develop in valve sinuses
  • Mutations in coagulation proteins are often associated with venous thrombosis, and are classified according to whether they are gain of function (affecting procoagulants) or loss of function (affecting anticoagulants)


List the major causes of venous thrombosis.

  • Major causes:
    • Gain of function
    • Factor V Leiden
    • Prothrombin G20210A
    • Elevated procoagulants (Factors VIII, IX, XI)
  • Loss of function:
    • Proteins C, S, and Z
    • Antithrombin
  • Hyperhomocysteinemia


What is Factor V Leiden? What is the prevalence and risk factors?

  • A mutation in base 1691 codes for a glutamic acid at position 506 (normally an arginine), rendering activated factor V (Va) relatively resistant to cleavage by activated protein C (aPC)
    • Also, the mutated factor V is unable to serve as a cofactor for the aPC-mediated cleavage of factor VIIIa
    • Persistence of Va & VIIIa increases thrombosis risk
  • The prevalence of FVLeiden in persons with European ancestry is 3%-9%, but <1% in Asians and Africans
  • The use of oral contraceptives or hormone replacement therapy by persons with FVLeiden increases risk of thrombosis by 30%
    • Since the baseline incidence of thrombosis with these agents is very low (about 1/10,000), the absolute number of women experiencing thrombosis is still low (3/1000)
  • Risk for venous thrombosis in adults, and arterial thrombosis in special populations-children, women who smoke
    • Increased rate of miscarriage due to placental infarcts


What is Prothrombin G20120A? What is the prevalence and risk factors?

  • A mutation in the promotor region of the gene codes for an increase in prothrombin synthesis (levels about 130%-150%)
    • Thrombosis risk correlates with prothrombin concentration
  • Prothrombin protects factor Xa from antithrombin, and the increase in prothrombin results in more thrombin and higher levels of thrombin-activatable fibrinolysis inhibitor (TAFI)
  • Same populations affected as for FVLeiden, but more common in Hispanics
  • Same risks for venous thrombosis, arterial thrombosis, miscarriage, and thrombosis recurrence as for FVLeiden. Risks enhanced by use of O.C.
    • Also, risk for cerebral venous thrombosis


How does elevated levels of procoagulants affect the risk for venous thrombosis?

  • Factor VIII, IX, and XI are the affected factors.
  • Might be on a genetic basis
  • However, in the case of FVIII, could be secondary to:
    • increased VWF (released by activated endothelium)
    • decreased clearance mechanisms (lipoprotein-related protein [LRP] is hepatic receptor for FVIII)
    • decreased clearance (and higher plasma levels) with blood groups A & B
  • Couls also be due to IL-6 & other cytokines that stimulate synthesis/release


How does the loss of function of proteins C, S, and Z affect the risk for venous thrombosis?

  • Inherited disorders are due to mutations in the respective genes giving rise to molecules with impaired function
  • Homozygosity for most mutations is lethal in utero or results in purupara fulminans in the neonate (widespread thrombosis in skin and muscle) - fatal unless the defective protein is replaced
  • Heterozygosity associated with venous thrombosis occurring after puberty if other risk factors are present (surgery, trauma, use of estrogens, etc.)
    • Some heterozygotes never experience a thrombosis
    • Only levels of free protein S <10% associated with thrombosis, and protein Z defects associated with thrombosis only if combined with FVLeiden or other major thrombotic risk
  • Acquired deficiencies occur in:
    • liver disease
    • vitamin K deficiency
    • nephrotic syndrome (lost in urine)
    • inflammatory bowel disease (protein-losing enteropathy)
  • Proteins C & S consumed during clot formation and return to normal weeks after thrombotic episode
  • C4BP increases with infection, making less free protein S available and raising risk of thrombosis


How does a loss of function in antithrombin lead to an increased risk of venous thrombosis?

  • A member of the SERPIN (serine protease inhibitor) family, inactivates thrombin
    • Binds reversibly to a specific pentasaccharide sequence on heparin and proteoglycans, forming a tri-molecular (antithrombin, thrombin, heparin) complex that irreversibly inactivates thrombin
    • Heparin increases activity 1000-fold
  • Inherited defects due to mutations in regions that inactivate thrombin or bind heparin
    • Acquired deficiencies due to:
      • liver disease
      • prematurity (immature liver)
      • l-asparaginase therapy (used to treat leukemia)
      • nephrotic syndrome
      • inflammatory bowel disease (lost in urine or stool)
      • malnutrition
    • Homozygosity is lethal
  • Cilincal findings:
    • neonatal thrombosis
    • venous thrombosis in young adults
    • thrombosis during pregnancy
    • increased fetal loss
    • relative heparin resistance
    • recurrent thrombotic episodes
  • Lifelong anticoagulation required


How does homocystinemia affect the risk of venous thrombosis. What is the clinical presentation, presentation, and management?

  • Homocysteine is a byproduct of methionine metabolism
    • Normally found in plasma in concentrations of less than 10 nmol
    • When increased:
      • injures endothelium → decreasing nitric oxide formation → down-regulating thrombomodulin → inhibiting prostacyclin synthesis
      • also, enhances oxidation of LDL and increases the affinity of Lp(a) for fibrin, inhibiting fibrinolysis
  • Genetic hyperhomocysteinemia due to mutations in cystathione synthase, methylene tetrahydrofolate reductase
    • Increases with folate, B6 or B12 deficiencies
  • Other causes of increased levels are:
    • aging
    • renal disease
    • hypothyroidism
    • psoriasis
    • certain drugs
  • Associated with:
    • venous or arterial disease
    • fetal loss
    • recurrent episodes of thrombosis
  • Treatment:
    • give folate, B6, or B12, to lower homocysteine, but minimal effect on thrombosis, suggesting that increased homocysteine may simply be a marker for another thrombogenic factor (high levels of FVIII often present)


What is the algorithm for laboratory testing for thrombophilia?

  • Suspect thrombophilia if there is no obvious inciting cause for thrombosis, such as trauma or surgery
  • The following algorithm is helpful in deciding on further evaluation of the patient with thrombosis:
    • Family history of thrombosis
    • Unusual sites of thrombosis, such as venous dural sinuses, axillary, or mesenteric veins
    • Recurrent episodes of thrombosis
    • Young (under 40) age at time of initial thrombotic event


What are some downsides for testing for coagulation abnormalities?

  • Although testing for coagulation abnormalities may indicate potential risk factors for thrombosis, actual risk is unknown because of system complexity
    • For example, a person with a low protein C may have high levels of antithrombin and low levels of FVIII, and therefore be at much less risk than another individual with the same level of protein C but low levels of antithrombin and high FVIII
    • Furthermore, there may be factors that are currently not assessed, such as endothelial protein C receptor, which may modify thrombosis risk
    • In addition, at present there is no way to correct gene mutations, such as factor V Leiden
  • For persons with such mutations, one can only recommend measures to reduce thrombotic risk, such as:
    • exercise during long airplane flights
    • early mobilization after surgery
    • weight reduction
    • many of these are applicable to the population at large
  • In advising patients about thrombophilia testing, one should note the limitations described above, and have a management plan in place should test results be abnormal