Thrombophilia

Question 1

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

Answer 1

• 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

Question 2

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

Answer 2

• 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

Question 3

What are the major contributors to hemostatic balance?

Answer 3

• 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

Question 4

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

Answer 4

• 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)

Question 5

What is venous thrombosis?

Answer 5

• 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)

Question 6

List the major causes of venous thrombosis.

Answer 6

• 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

Question 7

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

Answer 7

• 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

Question 8

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

Answer 8

• 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

Question 9

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

Answer 9

• 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

Question 10

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

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

• 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)

Question 13

What is the algorithm for laboratory testing for thrombophilia?

Answer 13

• 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

Question 14

What are some downsides for testing for coagulation abnormalities?

Answer 14

• 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