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Uncommon Hereditary Coagulation Disorders

By Joel L. Moake, MD, Rice University;Baylor College of Medicine

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Most hereditary coagulation disorders other than hemophilia are rare autosomal recessive conditions that cause excessive bleeding only in homozygous people (see Table: Screening Laboratory Test Results in Inherited Defects in Blood Coagulation). The rare inherited coagulation disorders can involve factors II, V, VII, X, XI, and XIII. Of these, factor XI deficiency is the most common.

Screening Laboratory Test Results in Inherited Defects in Blood Coagulation

Screening Test Results*

Defect

Comments

PTT long

PT normal

Factor XII, high molecular weight kininogen, or prekallikrein

Laboratory test abnormality without clinical bleeding

Specific assays required to distinguish from factor XI deficiency, in which posttraumatic and perioperative bleeding may occur

PTT long

PT normal

Factor XI

Autosomal recessive

Increased frequency in Ashkenazi Jews

Posttraumatic and perioperative bleeding

Diagnosis by specific assay

For bleeding: Fresh frozen plasma 5–20 mL/kg/day to keep factor XI level > 30% of normal

PTT long

PT normal

Factor VIII or IX

Factor VIII deficiency ( hemophilia A)

Factor IX deficiency ( hemophilia B)

X-linked transmission

Mild or severe bleeding in males, depending on factor VIII or IX level

PTT normal

PT long

Factor VII

Autosomal recessive

Rare

If deficiency is severe (< 2% of normal values), serious bleeding

If levels are > 5%, mild or no bleeding

Therapy of choice: Recombinant activated factor VII

PTT long

PT long

Factor X, V, or prothrombin

Autosomal recessive

Rare

Mild to severe bleeding

Diagnosed by specific assays

For bleeding episodes due to factor X or prothrombin deficiency: Fresh frozen plasma or prothrombin complex concentrate

For treatment of factor V deficiency: Fresh frozen plasma with or without platelet concentrates (to supply platelet factor V)

In afibrinogenemia (fibrinogen < 10 mg/dL), no clotting in PTT or PT because machine end point is not triggered

In hypofibrinogenemia (fibrinogen 70–100 mg/dL), PTT and PT often prolonged by several seconds and thrombin time long

Fibrinogen

Severe bleeding in afibrinogenemia (homozygous state)

Posttraumatic and perioperative bleeding in hypofibrinogenemia (heterozygous state)

For treatment: Cryoprecipitate (5–10 bags, with each containing about 250 mg fibrinogen)

PTT and PT long

Thrombin time long

Dysfibrinogenemia

Various manifestations (no, or only mild, posttraumatic and perioperative bleeding, tendency for thrombosis, wound dehiscence)

Fibrinogen low in clotting assay but normal in immunologic assay

PTT normal

PT normal

Thrombin time normal

Clot lysis in 5M urea

Factor XIII

Autosomal recessive

Rare

Poor wound healing

Severe bleeding when levels are < 1% of normal

For treatment: Fresh frozen plasma (1–2 units q 4–6 wk is effective because half-life of factor XIII is about 10 days)

PTT and PT normal

Clot lysis times in 5M urea or saline accelerated

Alpha2-antiplasmin deficiency

Severe bleeding in homozygotes

Posttraumatic and perioperative bleeding in heterozygotes

Specific assay required for confirmation of diagnosis

*PT results are typically reported as INR.

Factor XI deficiency

Factor XI deficiency is uncommon in the general population but common among descendants of European Jews (gene frequency about 5 to 9%). Bleeding typically occurs after significant injuries, including trauma or surgery, in people who are homozygotes or compound heterozygotes.

Deficiency of alpha 2-antiplasmin

Severe deficiency of alpha 2-antiplasmin (levels 1 to 3% of normal), the major physiologic inhibitor of plasmin, can also cause bleeding as a result of poor control of plasmin-mediated proteolysis of fibrin polymers. Diagnosis is based on a specific alpha 2-antiplasmin assay. Aminocaproic acid or tranexamic acid is used to control or prevent acute bleeding by blocking plasminogen binding to fibrin polymers. Heterozygous people with alpha 2-antiplasmin levels of 40 to 60% of normal can occasionally experience excessive surgical bleeding if secondary fibrinolysis is extensive (eg, in patients who have released excessive amounts of urokinase-type plasminogen activator during open prostatectomy).

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