Rare Bleeding Disorders

Factor XI Deficiency (Hemophilia C)

• Factor XI is the inactive precursor to a serine protease important for clot propagation via generating additional thrombin, and it also reduces fibrinolysis. Absent or reduced FXIa results in an inadequate thrombin burst and susceptibility of clots to fibrinolysis.
• Genetics: may be autosomal dominant or autosomal recessive.
• Pearl: common in Jewish populations (1 in 11 are heterozygotes; 1 in 450 are homozygous or compound heterozygotes).
• Sx: highly variable clinical phenotype; weak correlation between FXI:C and bleeding (a level of 20% or 10% does not predict bleeding phenotype).
• Bleeding after surgery or trauma is the most common manifestation, especially where fibrinolysis plays an important role (GI tract and oral mucosa). Spontaneous bleeding is rare.
• Diagnosis: prolonged PTT; FXI:C level. (Confirm by measuring factor XI activity.)
• Treatment: antifibrinolytics are the mainstay. Factor XI concentrates are not available in the U.S. rFVIIa can also be used in patients with severe bleeding.
• Factor XI replacement with FFP perioperatively:
  • Patients with a personal history of bleeding with surgery or trauma.
  • Patients with FXI levels <10% (although correlation of levels and bleeding is poor).
  • Use in conjunction with antifibrinolytics.

Factor VII Deficiency

• Genetics: autosomal recessive mutations in F7 (prevalence about 1 in 500,000).
• Sx: bleeding, mucocutaneous or resulting from trauma/surgery.
• Pearl: patients may develop thrombosis (VTE in 4%).
• Relatively poor correlation of FVII:C; most severe bleeding occurs if <10%.
• Diagnosis: prolonged PT/INR, normal aPTT, normal thrombin time and reptilase time. Confirm with factor VII activity.
• Treatment: rFVIIa, antifibrinolytics.

Factor X Deficiency

• Sx: bleeding may be mucocutaneous, soft tissue, GI tract, or visceral (but with a higher rate of intracranial bleed, ICH).
• Genetics: autosomal recessive (prevalence about 1 in 500,000).
• FX levels correlate well with bleeding symptoms.
• Pearl: can be seen in plasma cell dyscrasias (MM/MGUS/SMM and amyloidosis).
• Diagnosis: prolonged PT/INR and prolonged aPTT, normal thrombin time and reptilase time. Confirm with factor X activity. Deficiency of FV and prothrombin will also cause an increase in both PT and PTT.
• Treatment: FX concentrate, PCCs, FFP, and treatment of a plasma cell dyscrasia if present.

Factor V Deficiency

• Sx: bleeding may be mucocutaneous or resulting from trauma/surgery. Relatively poor correlation of FV:C with bleeding, but most severe bleeding occurs if <10%.
• Genetics: autosomal recessive mutations (prevalence about 1 in a million).
  • Can also coincide with FVIII deficiency (combined FV and FVIII deficiency, due to LMAN1 or MCFD2 mutations).
• Pearl: acquired FV deficiency:
  • Topical bovine thrombin used to treat topical bleeding, generating antibodies against bovine thrombin and/or factor V, which in some cases cross-react with human factor V.
  • Autoantibodies to FV: rheumatologic disorders, autoimmune disorders, malignancies, antibiotic use, and use of topical bovine thrombin.
  • Reported in patients with MPNs, who can have hemorrhage secondary to acquired platelet dysfunction and/or acquired von Willebrand syndrome. It is postulated that adsorption of plasma factor V by the large megakaryocytic-myeloid mass in MPN (similar to acquired factor X deficiency in amyloidosis) can lead to factor V deficiency. Liver dysfunction from extramedullary hematopoiesis and factor V inhibitors are also felt to be mechanisms.
  • Not acquired FV deficiency: Quebec platelet disorder (inherited, autosomal dominant PLAU duplication; excess platelet urokinase degrades platelet α-granule FV, plasma FV normal).
• Dx: prolonged PT/INR, prolonged aPTT, normal thrombin time and reptilase time. Confirm with factor V activity.
• Tx: FFP; platelet transfusions (platelets carry FV in alpha granules). The half-life of factor V is 16 to 36 hours, so patients may require daily infusions. Goal is to keep the factor V level >20% of normal. PCC will not work. There is no recombinant or plasma-derived factor V concentrate available.

Factor XIII Deficiency

• FXIII normally crosslinks fibrin gamma chains to protect the clot from fibrinolysis.
• Autosomal recessive (1 in 2 million). Mutations in the gene coding for the catalytic A subunit account for >95% (on chromosome 6p; the more important catalytic subunit); the carrier B subunit <5%. Heterozygotes can have bleeding symptoms.
• Acquired factor XIII inhibitors can be due to autoimmune conditions (SLE), plasma cell dyscrasias (MGUS/MM), and/or certain medications (e.g. ciprofloxacin, penicillin, phenytoin).
• Pearl: bleeding symptoms correlate with FXIII levels. Normal PT and PTT. Bleeding after surgery/trauma, from the umbilical stump, soft tissue, and ICH. Poor wound healing and pregnancy loss.
• Diagnosis:
  • Clot solubility test (only abnormal with severe deficiency, FXIII activity <1 to 5%): evaluates clot stability in 5M urea. Calcium is added to the patient's plasma to clot it, then incubated for 30 minutes at 37 °C; the clot is then placed in 5M urea for 24 hours at room temperature. Normal clots are stable, whereas clots in factor XIII deficiency (usually defined as <2%) readily dissolve. Only marginally useful because it is positive only with virtually undetectable levels.
  • FXIII activity; genetic testing (to determine if the A or B subunit is affected).
• Treatment:
  • A subunit deficiency: treated with recombinant FXIII A subunit (Tretten; NovoThirteen).
  • B subunit deficiency: treated with human plasma-derived (pd) FXIII (Corifact or Fibrogammin); if unavailable, give FFP or cryoprecipitate.
  • Prophylaxis in all patients with FXIII level <10% due to ICH risk. FXIII half-life is 17 days, so prophylaxis infusions can be given monthly.

Prothrombin (Factor II) Deficiency

• Sx: bleeding may be mucocutaneous, intramuscular, or resulting from trauma/surgery.
• Genetics: autosomal recessive (prevalence about 1 in 2 million). Heterozygotes (prothrombin level >30%) are minimally symptomatic.
• Poor correlation with level and bleeding, but severe manifestations are unlikely unless the prothrombin level is <10%.
• Dx: prolonged PT/INR, prolonged aPTT, normal thrombin time and reptilase time.
  • Confirm with a functional factor II activity assay (FII:C); prothrombin antigen distinguishes quantitative deficiency from dysprothrombinemia; genetic testing confirms the molecular defect.
  • Rule out acquired FII deficiency due to antiprothrombin antibodies (APAs) in a patient with antiphospholipid syndrome (APLS); these antibodies bind prothrombin and increase its clearance. Suspect it in an APLS patient who presents with an elevated PT and bleeding.
• Tx:
  • Nonactivated three-factor or four-factor PCC (e.g. Kcentra) for factor II replacement; FFP is an alternative. Activated PCC (FEIBA) is a bypassing agent for hemophilia with inhibitors and is not standard replacement for isolated factor II deficiency.
  • Prothrombin half-life is 60 hours, so PCCs can be given q2 to 3 days.
  • Prophylaxis only for patients with a history of severe bleeding and prothrombin levels <10%, using once-weekly PCC.

Fibrinogen Disorders

• Quantitative: afibrinogenemia (autosomal recessive, biallelic variants); hypofibrinogenemia (usually autosomal dominant, heterozygous, though recessive forms occur).
• Qualitative (dysfibrinogenemias): autosomal dominant.
• Bleeding is most severe in afibrinogenemia and with fibrinogen <100 mg/dL (mucocutaneous, surgery, ICH, soft tissue, umbilical stump).
• Dysfibrinogenemia carries a thrombotic risk of 20 to 30%.
• Diagnosis: TT and reptilase time (RT) are the sensitive screens (markedly prolonged in afibrinogenemia); PT and aPTT may be normal in dysfibrinogenemia or mild hypofibrinogenemia. Classify with fibrinogen activity and antigen.
  • Reptilase time (RT) is ordered to evaluate the cause of a prolonged TT. Heparin prolongs TT but not RT; RT is prolonged with decreased or abnormal fibrinogen.
  • Fibrinogen level.
• Treatment: fibrinogen concentrate, cryoprecipitate, FFP. Consider prophylaxis only in the most severe cases.

Vitamin K-Dependent Coagulation Factor Deficiency (VKDCFD)

• Mutation in gamma-glutamyl carboxylase or vitamin K epoxide reductase (a very rare cause of combined deficiency of the vitamin K-dependent factors).
• <30 families worldwide.
• Diagnose by showing combined deficiency of factors II, VII, IX and X (plus proteins C/S), excluding warfarin, dietary deficiency and liver disease, with normal plasma vitamin K (phylloquinone) and GGCX or VKORC1 mutation on genetic testing.
• Treat with vitamin K.

Per-factor review table