Coagulation Physiology
Hereditary Coagulation Deficiencies

Acquired Coagulation Deficiencies
Hypercoagulable States


Clotting factors:

I Fibrinogen   VIII Platelet Cofactor I
II Prothrombin   IX Christmas Factor
III Tissue Thromboplastin   X Stuart Factor
IV Calcium ion   XI Thromoplastin antecedent ("Labile Factor")
V Prothrombin Acccelerator   XII Hageman Factor
VI Accelerin   XIII Fibrin Stabilizing Factor
VII Autoprothrombin I      



First steps:

  1. Factor XII activated by contact with an irregular surface ("contact thromboplastin"), e.g. mural placque, prosthetic heart valve, nonhematologic tissue (extrinsic pathway?)
  2. Factor VII actifacted by "Tissue factor" (intrinsic pathway?)

(PT measures intrinsic pathway (nl control +/- 2sec); PTT measures extrinsic (nl control +/- 8sec))

XII ==> XIIa                      
  XI ==> XIa + Ca + VIIa <== VII        
      [-- - --- - ---]            
        IX ==> IXa              
          X ==> Xa + Ca + Va    
              [--- ---- --- - --]    
                II ==> IIa (Thrombin)      
                  V ========> Va    
                    VIII ==> VIIIa  
                      Fibrinogen ==> Fibrin


I. Hemophilias

  1. "Hemophilia A"
    1. A deficiency in factor VIII
      1. Degree of deficiency is variable from individual to individual and determines severity of disease
    2. X-linked recessive, so more common in males; female carriers may have mild disease
    3. More common, and usually more severe, then hemophilia B
  2. "Hemophilia B", aka "Christmas disease"
    1. A deficiency in factor IX
      1. Degree of deficiency is variable from individual to individual and determines severity of disease
    2. X-linked recessive, so more common in males; female carriers may have mild disease
  3. Diagnosis-Direct measurement of levels of factors VIII and IX (note that factor VIII levels can be low in some cases of von Willebrand disease; see below)
  4. Clinical Features of hemophilias
    1. Presentation may be in infancy, or later if disease is less mild
    2. Initial bleeding in children is generally musculskeletal (muscle and/or hemarthrosis) and less commonly, CNS, GI, or GU
    3. Typical lab findings
      1. Prolonged PTT
      2. Normal PT
      3. Normal platelet count
  5. Treatment
    1. Recombinant clotting factor concentrates appropriate to type
    2. Desmopressin (DDAVP)-Increases release of factor VIII from endothelium into circulation; can be used to treat mild hemophilia A
    3. Antifibrinolytic therapy e.g. tranexamic acid (Cyklokapron) and epsilon aminocaproic acid (EACA, Amicar) can be used to enhance clot stability

II. von Willebrand disease

  1. A group of inherited disorders
  2. Generally autosomal dominant inheritance
  3. Associated with a deficiency in factor VII and impaired platelet aggregation
  4. Initial bleeding is usually mucocutaneous e.g. epistaxis, ecchymoses

III. Considerations re: general care for children with hereditary coagulation deficiencies

  1. Try to vaccinate with smallest possible gauge needle
  2. Vaccination for hep A and hep B are very important because of the likelihood these patients will receive transfusions
  3. Counsel parents/caregivers re: appropriate exercise (avoid high risk of trauma)
  4. Avoid aspirin and NSAIDs if possible


  1. Vit K deficiency / Warfarin toxicity (consider Celiac Disease as a cause for the former)
  2. Liver disease
  3. Massive bleeding (tx with FFP)
  4. Disseminated intravascular coagulation (give FFP or cryoprecipitate)-Massive intravascular thrombin deposition results in lots of activation of factors V and VIII (see "Coagulation Physiology"). Va and VIIIa are removed from circ. by liver, so get V and VIII deficiency

You can distinguish above by "5 & 10" test where you measure quantity of factors V and X:

  1. If both are low, it's prob. liver dis.
  2. If only X is low, prob. vit. K deficiency
  3. If only V is low, prob. DIC

Hereditary telangiectasia (Osler-Weber-Rendu Sd.)

  1. Delicate vessel walls, much bleeding
  2. Get a Fe-deficiency anemia


I. Acquired risk factors for hypercoagulability

  1. Stasis of flow (immobility, CHF, extrinsic vessel compression)
  2. Endothelial injury, e.g. from prior DVT
  3. Recent surgery (reflecting A, B, & poss. also release of tissue thromboplastin)
  4. Estrogens (old OCPs > new OCPs > HRT), inc. pregnancy
  5. Cancer (unclear if an independent risk factor for venous thrombosis; strongest association is with adenocarcinomas & GI primaries)
  6. Antiphospholipid antibodies: Lupus anticoagulant and Anticardiolipin Ab
  1. Autoantibodies that bind to phospholipids
  2. May have false-positives, so if elevated consider confirmation after 6wks
  3. Different but associated; both can give false-positive RPR
  4. Associated with autoimmune diseases particularly Systemic Lupus Erythematosus
  5. Evidence supports association between APlAb'ss & the following in SLE, but not in non-SLE pts; there's no evidence that the Ab's themselves are causative:
  1. Thrombosis, venous & arterial
  2. Thrombocytopenia
  3. Neurologic disease
  4. Livedo reticularis
  1. May be associated with OB complications particularly recurrent miscarriage, also IUGR, preterm delivery, preeclampsia, and abruptio placentae
  1. Some suggest screening for APlAb and LA after 3 miscarriages, but unclear predictive value
  2. Also consider early ultrasound for correct dates and serial ultrasound for early dx of IUGR; also 3rd trimester fetal surveillance with NST's, etc.
  3. 202 pts w/ 2 or more fetal losses and lupus anticoagulant, anticardiolipin Ab, antinuclear Ab, anti-DNA Ab, or antilymphocyte Ab randomized to prednisone 0.5-0.8mg/kg/d + ASA 100mg/d vs. placebo; rates of live birth 65% in tx group vs. 56% w/placebo (non-sig) but there were significant increases in the active-treatment group in incidence of preterm labor, PROM, and preterm delivery w/tx group (NEJM 337:148, 1997-JWWH)
  4. ASA 75mg QD alone c/w ASA 75mg QD + heparin 5kU SQ QD was associated with no sig. diff. in live-birth rates  in a randomized trial of 98 women with h/o 3 or more consecutive pregnancy losses and positive lupus antigoagulant or anticardiolipin Ab (Obs. Gyn. 100:408, 2002-JW)
  5. One 2005 Cochrane meta-analysis suggested a 54% reduction in incidence of early pregnancy loss with treatment with unfractionated heparin and aspirin
  1. Treatment
    1.  In a retrospective study of 147 pts with APlAb and prior h/o thrombosis looking at thrombosis risk; 50% w/SLE, warfarin tx to target INR > 3 ass'd with lowest risk of thombosis; warfarin to target INR < 3 or ASA alone were equal; ASA + warfarin to target INR > 3 no better than warfarin to target INR > 3 alone (NEJM 332:993, 1995)
    2. 114 pts with antiphospholipid antibodies and prior arterial or venous thrombosis randomized to moderate- or high-intensity warfarin (target INR 2.0-3.0 and 3.1-4.0, respectively).  Over mean 2.7y f/u, no sig. diff. in incidence of recurrent thrombosis or major bleeding events (NEJM 349:1133, 2003--JW)
  1. Nephrotic syndrome
  1. Typically renal v. thrombosis
  2. May be secondary to acquired deficiency of AT3 or protein S
  3. Prophylactic anticoagulation should be considered if other risk factors for DVT are present
  1. Antineoplastic agents
  1. Bleomycin--can get pulm. vv. thromboses
  2. Cyclophosphamide--hepatic v. thrombosis
  3. MTX--Budd-Chiari
  4. Breast Ca chemotherapy--DVT
  1. Myeloproliferative Syndromes, e.g. polycythemia vera or essential thrombocythemia
  1. Us. hepatic v., hepatic portal v., or mesenteric v.
  2. Can have nl. CBC!
  1. Acquired deficiency of AT3 or Protein C or S (see below under inherited causes)
  1. DIC, liver dis., l-asparaginase, chemoRx, & nephrotic Sd can cause all
  2. OCP use can also cause AT3 def.
  3. ARDS, pregnancy, and post-op state can cause Prot. C/S def.

II. Inherited risk factors for hypercoagulability (For all these, anticoagulant Rx may distort lab tests, so if poss. wait to test until off anticoagulants; x2-3mos for coumadin)

  1. AT3 deficiency
  1. AT3 is a vit-K-dependent glycoprotein which
  2. Inactivates various coag. factors, inc. thrombin
  3. Has various genetic forms; prevalence 1:2000-5000
  1. Protein C deficiency
  1. Prot. C is a vit-K dependent protein, activated by thrombin to a protease that inactivates Va & VIIIa
  2. Unclear to what extent deficiency predisposes to DVT
  3. Prevalence 0.1-0.5%; not all are symptomatic
  1. Protein S deficiency
  1. Prot. S is a vit-K dependent protein; a cofactor for activated Prot. C
  2. Unclear clinical significance
  1. Clinical manifestations of A, B, and C:
  1. Us. get first thromboembolus in mid-teens to early 20's
  2. Us. DVT, PE, or superficial thrombophlebitis
  3. Highly variable clinical presentations for all 3
  4. ?????Because there is no convincing evidence of the need for long-term anticoagulation of [AT3, PC, PS] deficient patients after the first venous thromboembolus (VTE), we recommend testing only those patients who have hx?s of juvenile or recurrent VTE, or fmhx?s of thrombosis,? or thrombus in a weird place, e.g. mesenteric or cerebral v., or ?life-threatening? VTE x 1.
  1. Heparin cofactor II deficiency
  1. Is an antithrombotic glycoprotein, mostly inhibits thrombin
  2. Unclear physiologic significance; case reports only
  1. Dysfibrinogenemias
  1. Associated both with bleeding and thrombosis; mostly the latter
  2. PT/PTT us. nl; need more sensitive tests, e.g. TT
  3. Abnormally high levels of fibrinogen may be ass?d with incr. risk of thrombosis, esp. coronary thrombosis
  1. Impaired fibrinolysis--unclear sig., under investigation
  2. TF pathway inhibitor deficiency--inhibits conversion IX & X to IXa & Xa; unclear sig.
  3. Activated protein C resistance
  1. Frequently (but not always) caused by a mutation ("Leiden Mutation") in the gene coding for factor V, rendering it resistant to degradation by APC
    1. Population studies have shown prevalence of about 5% for heterozygosity for factor V Leiden mutation
    2. In a prospective cohort study of 470 asymptomatic carriers of the factor V Leiden mutation, over avg. 3.3y f/u, incidence of clinically recognized venous thromboembolism was seen in 9 pts (annual incidence 0.58%) which is higher than incidences reported in the general population (Ann. Int. Med. 135:322, 2001--JW)
    3. In a prospective study of 9,253 persons followed for 23y, heterozygotes for the factor V Leiden mutation, and homozygotes for same, had HR of 2.7 and 18.0 for venous thromboembolism compared with non-carriers of the gene (Ann. Int. Med. 140:330, 2004--abst)
    4. Other known mutations: "Cambridge," "Hong Kong"
    5. APC resistance is ass'd with increased risk for venous thromboembolism even in individuals who don't have the any of the known mutations including Leiden (Ann. Int. Med. 130:643, 1999--JW)
  1. Epidemiology
    1. 12% prevalence of heterozygosity for the Leiden mutation in women who had DVT or PE over an 8y f/u period
    2. 3-7% prevalence in healthy controls in US an Europe
    3. Most common in Caucasian population
  1. Pathophysiology
    1. Associated with venous but not arterial thromboembolism (e.g. MI, CVA)
    2. Homozygotes present at younger age than heterozygotes
    3. 25% of men > 60yo with DVT had it in one case series (NEJM 332:912, 1995)
    4. Ass'd with increased risk for recurrent miscarriage in a case-control study (Ann. Int. Med. 128:1000, 1998--JW)
    5. Penetrance appears to be low: In a study of 467 1st-degree relatives of 118 pts with venous thromboembolism & the factor V Leiden mutation, those w/the mutation had sig. higher but still low annual incidence of VTE than those w/o the mutation (0.45% vs. 0.10%)--authors conclude that it's not nec. to test relatives of even homozygotes for the Leiden mutation (Ann. Int. Med. 128:15, 1998--JW)
  1. Diagnosis: 2 options
    1. PCR assay for the Factor V Leiden mutation
    2. Functional assay where exogenous APC is added to plasma to see if PTT increases as it should (less reliable if pt is on anticoagulants or has lupus anticoagulant; not affected significantly by protein S deficiency)
  1. Abnormal Prothrombin (Factor II)
  1. Heterozygotes for the 20210A allele in the prothrombin gene are more likely to have venous thrombosis in a Dutch study (Blood 88:3698, 1996-UW Lab Medicine Newsletter, Fall 1997)
  1. Elevated factor VIII Levels--Associated with increased risk for recurrence of venous thrombosis in several prospective studies (e.g. NEJM 343:457, 2000--JW)

(Sources: Lancet 344:1739, 1994; Heme-Onc Clin. N. A. 7:1121, 1193; Ann. Int. Med 119:819, 1993; Core Content Review of Family Medicine, 2012; others as cited)