Common Testing Strategies for Bleeding Disorders
| Condition . | Frequency . | Inheritance . | Screening Tests . | Sn 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 |
| Condition . | Frequency . | Inheritance . | Screening Tests . | Sn 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.
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.
May be reasonable to proceed directly to diagnostic testing depending on availability. See accompanying technical report for detailed discussion.24