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Uncommon Hereditary Coagulation Disorders

By

Joel L. Moake

, MD, Baylor College of Medicine

Last full review/revision Jan 2020| Content last modified Jan 2020
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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 and Treatment of Inherited Blood Coagulation Defects). The rare inherited coagulation disorders can involve factors II, V, VII, X, XI, and XIII. Of these, factor XI deficiency is the most common. (See also Overview of Coagulation Disorders.)

In patients with a deficiency of factor XI, there is no clear association between factor XI plasma levels and the severity of bleeding, suggesting that the molecular action of factor XI in normal hemostasis is not precisely understood.

In the other rare coagulation disorders (excluding hemophilia A and B), normal hemostasis usually requires a plasma level of the deficient factor in excess of about 20% of normal.

The drugs fitusiran and concizumab may be useful treatments for several of the rare congenital coagulation disorders, but clinical trials will be needed.

Table
icon

Screening Laboratory Test Results and Treatment of Inherited Blood Coagulation Defects

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

No treatment required

PTT long

PT normal

Factor XI

Autosomal recessive

Increased frequency in Ashkenazi Jews

Posttraumatic and perioperative bleeding

Diagnosis by specific factor assay

For treatment of bleeding: plasma-derived factor XI concentrate or fresh frozen plasma, plus inhibition of fibrinolysis by aminocaproic acid or tranexamic acid

Plasma factor XI half-life = 50 hours

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

For treatment of bleeding: factor replacement

Plasma factor VIII half-life = 8–12 hours

Plasma factor IX half-life = 18–34 hours

PTT normal

PT long

Factor VII

Autosomal recessive, rare

Diagnosed by specific factor assay

For treatment of bleeding: Recombinant activated factor VII or plasma-derived factor VII concentrate

Plasma factor VII half-life = 4–6 hours

PTT long

PT long

Factor X, V, or prothrombin

Autosomal recessive, rare

Mild to severe bleeding

Diagnosed by specific assays

For treatment of bleeding due to factor X or prothrombin deficiency:

  • Fresh frozen plasma

  • Prothrombin complex concentrate

  • Plasma-derived factor X concentrate

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

Plasma half-life of factor X = 40–60 hours

Plasma half-life of prothrombin = 3–4 days

Plasma half-life of factor V = 36 hours

In afibrinogenemia (fibrinogen < 10 mg/dL [< 0.1 g/L]), no clotting in PTT or PT because machine end point is not triggered

In hypofibrinogenemia (fibrinogen 70–100 mg/dL [0.7–1 g/L]), 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 of bleeding:

  • Cryoprecipitate (contains fibrinogen, as well as the VWF–factor VIII complex and factor XIII)

  • Fresh-frozen plasma

  • Plasma-derived fibrinogen concentrate

Plasma half-life of fibrinogen = 2–4 days

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

For treatment of bleeding:

  • Plasma-derived factor XIII concentrate

  • Recombinant factor XIII A chain

  • Cryoprecipitate (contains factor XIII)

  • Fresh frozen plasma

Plasma half-life of factor XIII = 9–12 days

PTT and PT normal

Clot lysis times in 5M urea or saline accelerated

Alpha 2-antiplasmin deficiency

Severe bleeding in homozygotes

Posttraumatic and perioperative bleeding in heterozygotes

Specific assay required for confirmation of diagnosis

For treatment of bleeding: Inhibition of excessive fibrinolysis using aminocaproic acid or tranexamic acid

* PT results are typically reported as INR.

PT = prothrombin time; PTT = partial thromboplastin time.

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 trauma or surgery in people who are homozygotes or compound heterozygotes for factor XI gene abnormalities. There is no precise relationship between plasma factor level and severity of bleeding.

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).

Drugs Mentioned In This Article

Drug Name Select Trade
AMICAR
CYKLOKAPRON
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