F5: THROMBOTIC DISORDERS

• THROMBOSIS


  Refers to an increased tendency to develop thrombi or emboli.
• Thrombosis sometimes called as hypercoaguable state 

• Multifaceted disorder


  resulting from abnormalities in blood flow
• THROMBOPHILIA


  Abnormality of blood coagulation that increases the risk of thrombosis

  • Acute or chronic inflammation
  • Inappropriate or uncontrolled platelet activation
  • Uncontrolled triggering of the plasma coagulation system
  • Inadequate control of coagulation impaired fibrinolysis
• CLASSIFICATION OF THROMBOSIS

  1. VENOUS THROMBOSIS
  2. ARTERIAL THROMBOSIS
  3. GENETIC/CONGENITAL THROMBOSIS
• VENOUS THROMBOSIS

  1. Deep Vein Thrombosis
  2. Portal Vein thrombosis
  3. Renal Vein Thrombosis
  4. Jugular Vein Thrombosis
  5. Budd Chiari Syndrome
  6. Paget Schoetter disease
  7. Cerebral Venous Sinus Thrombosis
• Deep Vein Thrombosis


  • Formation of blood clot within a deep vein
  • Affects superficial leg veins from the iliac, popliteal and femoral veins of the upper legs and calves
  • Swelling, pain and redness in the affected area especially the entire legs
• Portal Vein thrombosis 


  Form of venous thrombosis affecting the hepatic portal vein which can lead to portal hypertension and reduction of supply to the liver
• Renal Vein Thrombosis


  Obstruction of the renal vein by a thrombus
• Jugular Vein Thrombosis 


  • May occur during infection, malignancy or infusion of intravenous drug
  • Systemic sepsis, pulmonary embolism, papilledema
• Budd Chiari Syndrome


  • This is the form of thrombosis that presents abdominal pain, hepatomegaly and ascites.
  • There is a blockage of the inferior vena cava by a thrombus
• Paget Schoetter disease 


  • Condition that usually occurs after exercise
  • There is an obstruction of the upper extremity vein by a thrombus
• Cerebral Venous Sinus Thrombosis


  • Rare from of thrombosis
  • Result from the blockage of the durnal venous sinuses by a thrombus
  • Same symptoms of stroke, headache, abnormal vision
• ARTERIAL THROMBOSIS

  It is the formation or accumulation of thrombi within an artery known as "atherosclerotic plaque” or "atherothrombosis"
• GENETIC/CONGENITAL THROMBOSIS


  Suspected when thrombotic events occur in young adults and their unusual sites (renal or axillary veins)
• INCREASED LEVELS OF NATURAL PROCOAGULANTS

  1. PROTHROMBIN 20210 MUTATION
  2. HYPERHOMOCYSTEINURIA
  3. FACTOR V LEIDEN MUTATION OR ACTIVATED PROTEIN C RESISTANCE
  4. ELEVATED LEVEL OF CLOTTING FACTORS
• PROTHROMBIN 20210 MUTATION


  • alteration of guanine to adenine at the base of the 20210 of the 3 untranslated region of prothrombin gene
  • Second most common inherited thombophilic tendency in patients with family history of DVT
  • Associated with higher levels of prothrombin averaging to 130
• HYPERHOMOCYSTEINURIA 


  Deficiency in 3 enzymes

  • Methionine synthase
  • Cystathionine B synthase
  • 5 10 methyl tetrahydrofolate reductase

  Plasma homocysteine levels are 10 fold in homozygous cystathionine ß synthase deficiency
• FACTOR V LEIDEN MUTATION OR ACTIVATED PROTEIN C RESISTANCE


  • top leading cause of blood clots among white population.
  • mutation happens in Factor V protein, which is known as the “Leiden protein”.
• Factor V Leiden homozygotes 


  posses only the Leiden protein and an 80 fold

  increased risk of clotting disorder compared to the general unaffected population
• Factor V Leiden heterozygotes 


  believed to produced about 50 of Leiden protein and have 5 7 fold increased risk of clotting disorder compared to the

  general population.
• OTHER FACTOR V MUTATION

  Factor V Cambridge mutation & Factor V Hongkong mutation
• ELEVATED LEVEL OF CLOTTING FACTORS

  • Factor VIII
  • Factor IX
  • Factor XI
  • Factor I
  • vwf
• DECREASED LEVELS OF NATURAL ANTICOAGULANTS

  1. ANTITHROMBIN DEFICIENCY
  2. PROTEIN C DEFICIENCY
  3. PROTEIN S DEFICIENCY
  4. HEPARIN COFACTOR II DEFICIENCY
  5. THROMBOMODULIN DEFICIENCY
• ANTITHROMBIN 


  serine protease inhibitor serpin that neutralizes thrombin, Factor IXa, Xa, XIa, XIIa

  • activity is enhanced by unfractionated heparin, LMW heparin, and systemic entasaccharide
  • First of the plasma coagulation control protein to be identified and first assayed in the laboratory
• ANTITHROMBIN: Acquired 


  • Liver disease
  • Nephrotic syndrome
  • Prolonged heparin therapy
  • Oral contraceptives
  • DIC (AT is rapidly consumed)
• ANTITHROMBIN-Congenital:

  • Defect in heparin binding sites causing severe clotting tendencies that usually presents in early stage of life.
  • Type I AT deficiency
  • Type II AT deficiency
• Type I AT deficiency


  genetic alteration usually leads to drastic decrease

  levels in AT
• Type II AT deficiency


  genetic alteration leads to abnormal function of the

  plasma protein.
• Type I Protein C deficiency


  low protein C levels and activity
• Type II Protein C deficiency


  low protein C activity due to genetic alteration of protein C

  sequence resulting to abnormal functioning
• Homozygous Protein C Deficiency 


  • Appears in newborn infants
  • Can cause Purpura fulminans in children
• Warfarin Induced Skin Necrosis 


  Caused by rapid drop in protein C and Factor VII resulting to temporary super clotting state in the extremities
• PROTEIN S DEFICIENCY


  Can also cause neonatal purpura fulminans which is clinically indistinguishable from Protein C deficiency
• Type I Protein S Deficiency


  there a proportional decrease in the level and activity of Protein S.
• Type II Protein S Deficiency 


  levels of the free and bound forms are normal, but there is an abnormal function due to genetic alteration in the gene sequence.
• Type III Protein S Deficiency 


  There is a normal level to total protein S but with clinically

  significant decrease in free protein S levels.
• HEPARIN COFACTOR II DEFICIENCY


  Deficiency leads to increased thombi formation due to low/deficient activity to inhibit thrombin
• Type I (Quantitative) 


  decreased in both levels and functional capacity
• Type II (Qualitative)


  decreased in functional capacity but with normal levels of heparin cofactor II