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TABLE 2

Common Testing Strategies for Bleeding Disorders

ConditionFrequencyInheritanceScreening TestsSn and Sp, %PPV and NPV,%Confirmatory Test
Factor abnormalities/deficiencies       
 VWD type 1 1/1000 AD PFA-100 Sn = 79–96a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2A Uncommon AD or AR PFA-100 Sn = 94–100a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2B Uncommon AD PFA-100 Sn = 93–96a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2M Uncommon AD or AR PFA-100 Sn = 94–97a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2N Uncommon AR, or compound heterozygote aPTT NA NA VWF-Factor VIII binding assay 
 VWD type 3 1/300 000–1 000 000 AR, or compound heterozygote PFA-100 Sn = 94–100a PPV = 93.3 VWAgb 
Ristocetin cofactor 
Sp = 88–96a NPV = 98.2 VWF multimer analysis 
Factor VIII activity 
 Factor II deficiency (prothrombin) 26 reported cases, estimated 1/1–2 million  aPTT, PT (may be normal) Sn = variable NA Factor II activity ± antigen levels 
 Factor V deficiency 1/1 million AR aPTT, PT Sn = variable NA Factor V activity 
 Combined Factor V/Factor VIII deficiency 1/1 million AR aPTT>PT Sn = variable NA Factor V and factor VIII activities 
 Factor VII deficiency 1/300 000–500 000 AR PT Sn = variable NA Factor VII activity 
 Factor VIII deficiency 1/5000 male births X-linked aPTT Sn = variable NA Factor VIII activity 
 Factor IX deficiency 1/20 000 male births X-linked aPTT Sn = variable NA Factor IX activity 
 Factor X deficiency 1/1 million AR aPTT, PT, RVV Sn = variable NA Factor X activity 
 Factor XI deficiency 1/100 000 AR aPTT Sn = variable NA Factor XI activity 
 Factor XIII deficiency 1/2–5 million AR Clot solubility Sn = variable NA Factor XIII activity 
Fibrinolytic defects       
 α-2 antiplasmin deficiency ∼40 reported cases AR Euglobin lysis test Sn = variable NA α-2 antiplasmin activity 
 PAI-1 deficiency Very rare AR  Sn = variable NA PAI -1 antigen and activity 
Defects of fibrinogen       
 Afibrinogenemia 1/500 000 AR PT, aPTT Sn = high NA Fibrinogen level 
 Hypofibrinogenemia Less than afibrinogenemia  PT, aPTT Sn = variable NA Thrombin time, fibrinogen activity 
 Dysfibrinogenemia 1/million  Thrombin time, fibrinogen level Sn = variable NA Thrombin time, fibrinogen antigen and activity level comparison, reptilase time 
Platelet disorders       
 ITP Age-related NA CBC Sn = high NA Antiplatelet Ab (rarely needed) 
 Glanzmann thrombasthenia Very rare AR PFA-100 Sn = 97–100 NA Platelet aggregation testing Flow cytometry 
 Bernard Soulier syndrome Rare AR PFA-100 Sn = 100 NA Platelet aggregation testing Flow cytometry 
 Platelet release/storage disorders Unknown, more common than other platelet function disorders variable PFA-100 Sn = 27–50 NA Platelet aggregation and secretion 
Electron microscopy 
Molecular and cytogenetic testing 
ConditionFrequencyInheritanceScreening TestsSn and Sp, %PPV and NPV,%Confirmatory Test
Factor abnormalities/deficiencies       
 VWD type 1 1/1000 AD PFA-100 Sn = 79–96a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2A Uncommon AD or AR PFA-100 Sn = 94–100a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2B Uncommon AD PFA-100 Sn = 93–96a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2M Uncommon AD or AR PFA-100 Sn = 94–97a PPV = 93.3 VWAgb 
VWF activity 
Sp = 88–96a NPV = 98.2 VW multimer analysis 
Factor VIII activity 
 VWD type 2N Uncommon AR, or compound heterozygote aPTT NA NA VWF-Factor VIII binding assay 
 VWD type 3 1/300 000–1 000 000 AR, or compound heterozygote PFA-100 Sn = 94–100a PPV = 93.3 VWAgb 
Ristocetin cofactor 
Sp = 88–96a NPV = 98.2 VWF multimer analysis 
Factor VIII activity 
 Factor II deficiency (prothrombin) 26 reported cases, estimated 1/1–2 million  aPTT, PT (may be normal) Sn = variable NA Factor II activity ± antigen levels 
 Factor V deficiency 1/1 million AR aPTT, PT Sn = variable NA Factor V activity 
 Combined Factor V/Factor VIII deficiency 1/1 million AR aPTT>PT Sn = variable NA Factor V and factor VIII activities 
 Factor VII deficiency 1/300 000–500 000 AR PT Sn = variable NA Factor VII activity 
 Factor VIII deficiency 1/5000 male births X-linked aPTT Sn = variable NA Factor VIII activity 
 Factor IX deficiency 1/20 000 male births X-linked aPTT Sn = variable NA Factor IX activity 
 Factor X deficiency 1/1 million AR aPTT, PT, RVV Sn = variable NA Factor X activity 
 Factor XI deficiency 1/100 000 AR aPTT Sn = variable NA Factor XI activity 
 Factor XIII deficiency 1/2–5 million AR Clot solubility Sn = variable NA Factor XIII activity 
Fibrinolytic defects       
 α-2 antiplasmin deficiency ∼40 reported cases AR Euglobin lysis test Sn = variable NA α-2 antiplasmin activity 
 PAI-1 deficiency Very rare AR  Sn = variable NA PAI -1 antigen and activity 
Defects of fibrinogen       
 Afibrinogenemia 1/500 000 AR PT, aPTT Sn = high NA Fibrinogen level 
 Hypofibrinogenemia Less than afibrinogenemia  PT, aPTT Sn = variable NA Thrombin time, fibrinogen activity 
 Dysfibrinogenemia 1/million  Thrombin time, fibrinogen level Sn = variable NA Thrombin time, fibrinogen antigen and activity level comparison, reptilase time 
Platelet disorders       
 ITP Age-related NA CBC Sn = high NA Antiplatelet Ab (rarely needed) 
 Glanzmann thrombasthenia Very rare AR PFA-100 Sn = 97–100 NA Platelet aggregation testing Flow cytometry 
 Bernard Soulier syndrome Rare AR PFA-100 Sn = 100 NA Platelet aggregation testing Flow cytometry 
 Platelet release/storage disorders Unknown, more common than other platelet function disorders variable PFA-100 Sn = 27–50 NA Platelet aggregation and secretion 
Electron microscopy 
Molecular and cytogenetic testing 

AD, autosomal dominant; AR, autosomal recessive; CBC, complete blood cell (count); NA, not available or not applicable; NPV, negative predictive value; PAI-1, plasminogen activator inhibitor-1; PPV, positive predictive value; RVV, Russell viper venom (test); Sn, sensitivity; Sp, specificity; VW, von Willebrand; VWAg, von Willebrand antigen; VWF, von Willebrand factor Ab, antibody.

a

Values derived from data before 2008 National Institutes of Health Consensus guidelines. Sn and Sp using current diagnostic cutoffs unknown but would be expected to have higher Sp with lower Sn.

b

May be reasonable to proceed directly to diagnostic testing depending on availability. See accompanying technical report for detailed discussion.24 

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