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Flashcards in Thrombophilia Deck (14):
1

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

2

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

3

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

4

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)

5

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)

6

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

7

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

8

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

9

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

10

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

11

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

12

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)

13

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

14

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