Coagulation Thrombotic Disorders

• Hemophilia A


  Most common inherited X-linked recessive severe hemophilia due to deficiency or absence of FVIII
• Hemophilia A


  • Severe - characterized by spontaneous bleeding, FVIII level less than 1 U/dl
  • Moderate - excessive bleeding due to minor trauma, FVIII level 1-5 U/dl
  • Mild - excessive bleeding after surgery/major trauma, FVIII level usually greater than 5 U/dl
• Laboratory diagnosis of Hemophilia A

  1. Increased APTT but corrects completely with mixing studies using pooled normal plasma

  2. Platelet count, PT, and TT show normal results

  3. FVIII is a labile factor, thus testing should be done promptly

  4. Neonates already show normal FVIII levels, thus decreased levels may already be considered as diagnostic

  5. Female carriers usually have greater than 50% activity of FVIII and show normal APTT without bleeding tendencies

  6. FVIII gene, Xq28, is considered to be a large one possessing 26 exons and numerous disease-causing mutations have been identified

  7. Antibodies to FVIII have been found in among one third of patients who receive FVIII replacement therapy
• Hemophilia B

  an x-linked recessive, genetic disease characterized by missing or deficient FIX, also known as Christmas disease
• Laboratory diagnosis of Hemophilia B

  1. Increased APTT but corrects completely with mixing studies using pooled normal plasma

  2. Platelet count, PT, and TT show normal results

  3. Essential to distinguish it from vitamin K deficiency, liver disease and coumadin ingestion

  4. FIX levels are normally low among neonates; thus, diagnosis may not be possible among newborns

  5. Factor IX Leiden - type of Hemophilia B characterized by spontaneous remission following puberty
• Factor XIII deficiency


  Autosomal recessive in nature but heterozygotes may show mild, delayed bleeding
• Factor XIII deficiency


  • Other symptoms include umbilical stump bleeding, frequent miscarriages, delayed wound healing and the formation of hypertrophic scars
  • Homozygous FXIII deficiency shows bleeding diathesis
  • Laboratory results show normal PT, APTT, and TT
  • Clot stability test or 5M Urea Solubility test are the traditional tests for detection of FXIII deficiency
• Fibrinogen abnormalities


  May be congenital or acquired, and may be quantitative (afibrinogenemia, hypofibrinogenemia) or qualitative (dysfibrinogenemia)
• Inherited afibrinogenemia or hypofibrinogenemia

  • The most common initial manifestation is umbilical cord hemorrhage; congenital afibrinogenemia is often associated with a prolonged PT and APTT accompanied by clinical bleeding disorder similar to moderate to severe Hemophilia A
• Dysfibrinogenemia


  • Depending upon the type of mutation, this qualitative fibrinogen abnormality may be asymptomatic (50-60%), show signs of bleeding (30-40%), or cause thrombosis (10-20%)
• Inherited isolated deficiency of Factors II, V, VII, X, or XI

  Autosomal recessive inheritance with milder bleeding tendencies compared to Hemophilia A or B
• Factor VII deficiency


  • Most common autosomal recessive deficiency characterized by increased PT result, but FVII levels is not usually associated with severity of bleeding
• Factor V deficiency


  • Characterized by prolonged PT and PTT but TT is normal
• Factor X deficiency


  • PT, APTT and DRVVT are prolonged but TT is normal; the acquired type of FX deficiency is seen in amyloidosis
• Factor XI deficiency


  • Found mainly among the Ashkenazi Jews (gene frequency may be as high as 5-10%), most cases are mild and this deficiency has been associated with the Noonan syndrome
• Familial Combined Factor Deficiencies (FCFD)

  • FCFD Type I - Deficiencies of Factors V and VIII, gene involved: LMAN1 (ERGIC-53)
  • FCFD Type II - Deficiencies of Factors VIII and IX, gene unknown
  • FCFD Type III - Deficiencies of Factors II, VII, IX, X, Protein C and S, gene: Vitamin K Carboxylase
  • FCFD Type IV - Deficiencies of Factors VII and VIII, gene unknown
  • FCFD Type V - Deficiencies of Factors VIII, IX, and XI, gene unknown
  • FCFD Type VI - Deficiencies of Factors IX and XI, gene unknown
• Acquired Factor Deficiencies


  • Liver disease - may lead to decreased synthesis of the different coagulation factors, characterized by prolonged PT, hypo- and dysfibrinogenemia reflecting pronged TT, and impaired clearance of the D-dimer
  • Vitamin K deficiency - leads to impaired production of the vitamin K dependent factors (II, VII, IX, X, Protein C, and Protein S); patients with protein C deficiency may have transient thrombotic states manifested by skin necrosis when treated with warfarin
  • Disseminated Intravascular Coagulation (DIC) - the formation of widespread microvascular thrombi stimulated when there is a circulating substance capable of behaving like tissue factor, the resulting consumption of coagulation factors in numerous small clots may lead to bleeding diathesis
• Common causes of DIC: overwhelming infections (usually Gram negative), obstetric complications (e.g., abruption, amniotic fluid emboli), mucin secreting adenocarcinoma, extensive trauma, prostatic surgery, Acute Myelogenous Leukemia type M3, and some venomous snake bites
• Transient thrombotic states

  Skin necrosis when treated with warfarin
• Hemorrhagic disease of the newborn

  Congenital form of Vitamin K deficiency that usually presents at around third day post-partum
• Vitamin K deficiency


  Can be seen among prolonged users of antibiotics that could destroy the gut flora
• Disseminated Intravascular Coagulation (DIC)


  Formation of widespread microvascular thrombi stimulated when there is a circulating substance capable of behaving like tissue factor. The resulting consumption of coagulation factors in numerous small clots may lead to bleeding diathesis.
• Common causes of DIC

  • Overwhelming infections (usually Gram negative)
  • Obstetric complications (e.g., abruption, amniotic fluid emboli)
  • Mucin secreting adenocarcinoma
  • Extensive trauma
  • Prostatic surgery
  • Acute Myelogenous Leukemia type M3
  • Some venomous snake bites
• Laboratory tests for DIC

  • Elevated D-dimer (most sensitive test)
  • Low platelet count
  • Low Fibrinogen (most specific test)
  • Prolonged PT and APTT
• ISTH Scoring System for DIC

  Scoring system developed by the International Society of Thrombosis and Hemostasis to diagnose DIC
• Parameters in ISTH DIC Scoring System

  • Platelet count
  • D-dimer or FDP
  • Prolongation of PT
  • Fibrinogen
• Probable DIC

  Total score of 5 or more
• Non-confirmatory DIC

  Total score less than 5, follow serially
• Differential diagnosis of thrombophilia based on type of thrombosis

  • Arterial thrombosis
  • Venous thrombosis
• Common causes of arterial thrombosis

  • Antiphospholipid syndrome (anticardiolipin antibody [ACA])
  • Prothrombin mutation (20210)
  • HIT syndrome
• Common causes of venous thrombosis

  • APCR
  • Prothrombin mutation (20210)
  • Antiphospholipid syndrome (ACA & lupus anticoagulant [LAC])
  • Protein C deficiency
  • Protein S deficiency
  • ATIII deficiency
• Uncommon causes of arterial thrombosis

  • Elevated PAI-1 activity
  • Hyperhomocysteinemia
  • TPA deficiency
• Uncommon causes of venous thrombosis

  • Hyperhomocysteinemia
  • Heparin cofactor II
  • FXII deficiency
• Other factors to consider for arterial thrombosis

  • Anomalous coronary arteries
  • Vasculitis
• Other factors to consider for venous thrombosis

  • Immobilization
  • Trauma
  • Pregnancy
• Activated Protein C (APC) Resistance (Factor V Leiden)


  APC normally inhibits coagulation by degrading FVa and FVIIIa. Factor V Leiden is due to a G to A point mutation at nucleotide 1691 in the factor V gene, leading to substitution of glutamine for arginine at position 506 (FV R506Q) in the factor V, an inherited autosomal dominant trait. Responsible for up to 50% of all cases of hereditary thrombophilia. Clinical findings include venous thromboembolism and recurrent miscarriages.
• Laboratory tests for APC Resistance

  Screening clot-based assay where 2 APTTs are performed (one with patient plasma only and the other with patient plasma with APC); the normal ratio of the APTT result with and without APC should be greater than 2. Neonates have transient Protein C resistance due to low endogenous protein C levels.
• Prothrombin Variant (Prothrombin G20210A mutation)


  Caused by a single nucleotide substitution of glutamine for arginine at position 20210 in the 3' untranslated region of the prothrombin gene that would result in elevated levels of prothrombin. Considered the most common cause of inherited thrombophilia (autosomal dominant trait) and mutation is present in 10% of those with the factor V Leiden mutation. Clinical findings include venous thromboembolism, miscarriage and some patients tend to be at higher risk for cerebral thrombosis.
• Laboratory diagnosis of Prothrombin Variant

  Elevated levels of prothrombin of up to more than 115%.
• Antithrombin (AT) deficiency

  AT inhibits factors II, IXa, Xa, XIa, and XIIa. When bound to heparin, the activity of AT is enhanced. AT deficiency is usually inherited as an autosomal dominant trait usually due to a mutation in the antithrombin gene, SERPINC1. AT deficiency can also be acquired such as in nephrotic syndrome, L-asparaginase therapy, estrogen therapy, pregnancy, acute thrombosis, DIC and in colitis. Clinical findings include venous thromboembolism with particular risk among pregnant individuals, some patients manifest heparin resistance.