AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Congenital dysfibrinogenemia is a term used to describe a relatively rare condition wherein an inherited abnormality in the fibrin molecule results in defective fibrin clot formation. The complications associated with abnormal clot formation range from asymptomatic to life threatening. Fortunately, 40% of patients with congenital dysfibrinogenemia are asymptomatic; however, 50% of patients have a bleeding disorder and the remaining 10% have a thrombotic disorder or combined thrombotic and bleeding tendencies. Acquired dysfibrinogenemias, often called dysfibrinogenemia of liver disease, are the most common causes. Up to 50% of patients with severe liver disease secondary to cirrhosis, hepatoma, or hepatitis exhibit bleeding complications.

Pathophysiology

In the clotting cascade, the various blood coagulation factors function in concert to produce a balance between fibrin clot formation and its subsequent degradation. When any factor in the cascade is absent, decreased, or abnormal, the delicate balance is disrupted, possibly leading to bleeding or thrombotic disorders. The clinical manifestations range from no symptoms to life-threatening events depending on which coagulation factor is affected and the degree to which it is affected. In normal fibrin clot formation, a fibrin monomer forms after thrombin cleaves fibrinopeptide A and B from the alpha and beta chains of the fibrinogen molecule. Factor XIIIa then catalyzes the cross-linkage between different fibrin chains, forming a stabilized fibrin polymer or clot. Eventually, plasmin lyses the fibrin clot.

Acquired dysfibrinogenemia occurs most often in patients with severe liver disease. The impairment of the fibrinogen, which is manufactured in the liver, is due to a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule. Rarely, dysfibrinogenemia may also be associated with malignancies, most commonly primary or secondary liver tumors, but acquired dysfibrinogenemia has also been reported in patients with renal cell carcinoma.

One of the rarer disorders of coagulation is congenital dysfibrinogenemia, a qualitative abnormality of the fibrin molecule. Multiple variations of these dysfibrinogenemias are elucidated. Each is named for the city where it was first discovered. With only rare exceptions, the congenital dysfibrinogenemias are inherited in an autosomal dominant or codominant fashion. Depending on the fibrinogen abnormality, defects may occur in one or more of the steps in fibrin clot formation, although the most common defect involves polymerization of the fibrin monomer.

Bleeding may ensue when a fibrin clot forms that cannot be effectively stabilized. Bleeding in patients with congenital dysfibrinogenemia tends to be relatively mild or even absent; it is only a laboratory curiosity and is not life threatening. In contrast to the bleeding experienced by approximately half of the patients with congenital dysfibrinogenemia, one subset of patients (diagnosed with fibrinogen Oslo I) has an abnormal fibrinogen that is associated with thromboembolic complications that are often relatively mild. The abnormal fibrinogen in these patients forms a fibrin clot that is resistant to fibrinolysis by plasmin.

Frequency

International

Only 200-300 families are reported to have congenital dysfibrinogenemia. Hereditary transmission is autosomal dominant or codominant except in a few cases that appear to be transmitted recessively. Approximately 50% of patients with severe liver disease exhibit bleeding secondary to abnormal fibrinogen molecules.

Mortality/Morbidity

While many patients with congenital dysfibrinogenemias are asymptomatic, those who experience symptoms commonly have only mild bleeding or thrombotic events, although these are extremely rare. Severe hemorrhagic episodes may characterize a few abnormal fibrinogen variants (eg, Imperate, Dettori, Detroit).

Patients with dysfibrinogenemia of liver disease often have a more severe bleeding disorder than patients with an inherited disorder. The condition tends to worsen as the liver disease worsens.

Race

Prevalence is not increased in any race.

Sex

Prevalence is not increased in either sex.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Bleeding occurs in approximately 50% of patients with an inherited disorder. Usually the bleeding is mild and may not manifest until after a surgical procedure. Patients with severe liver disease may experience extreme bleeding. Bleeding may occur due to the following:
• • Menorrhagia
  • Postoperative bleeding
  • Epistaxis
  • Postoperative wound dehiscence
  • Defective wound healing
  • Bruising
  • Severe hemorrhage (rare)
  • Mild soft tissue hemorrhage
• Intraoperative bleeding
• Thrombotic events attributable to dysfibrinogenemia occur in less than 10% of patients with hereditary dysfibrinogenemias. Thrombotic events that may occur include the following:
• • Venous thrombosis (usually mild)
  • Arterial thrombosis (rare)
  • Thromboembolic event
  • Spontaneous miscarriage
• Combined bleeding and thrombotic tendencies are extremely rare and associated only with congenital dysfibrinogenemias.

Physical

Although many patients with inherited dysfibrinogenemia remain asymptomatic, signs that arise tend to be associated with poor wound healing, surgical wound dehiscence, and postsurgical bleeding out of proportion to that expected.

Causes

• Congenital dysfibrinogenemias are most often inherited in an autosomal dominant or codominant fashion. Several variants are inherited autosomal recessively.
• Acquired dysfibrinogenemias occur in severe liver disease. The fibrinogen molecule produced by the impaired liver is not functional or able to form a stable fibrin clot.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Afibrinogenemia
Hypodysfibrinogenemia
Hypofibrinogenemia
Plasminogen deficiency
Factor V Leiden deficiency
Hyperhomocystinemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Expect prothrombin time (PT) to be prolonged.
• Expect activated partial thromboplastin time (aPTT) to be prolonged.
• Thrombin time (TT) is the most sensitive screening test for dysfibrinogenemias. Expect TT to be prolonged in patients with bleeding tendencies. Shortened TT may occur in patients prone to thrombosis (fibrinogen Oslo I).
• Expect reptilase time to be prolonged.
• The fibrinogen level may be low, within the reference range, or high. However, a level within the reference range or a high level does not imply that the fibrinogen molecule functions appropriately. For this reason, assess both the clottable (functional) fibrinogen, which should be decreased, and the antigenic fibrinogen (detected only by immunoassay), which should be within the reference range. Definitive characterization of the abnormal fibrinogen can be performed in a research laboratory.
• Euglobulin clot lysis time may aid in the diagnosis. It is a crude measure of fibrinolytic potential. Elevate this value when the abnormal fibrinogen is more sensitive to lysis than usual.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Medical treatment is not indicated in the majority of patients.
• Fresh frozen plasma (FFP) or cryoprecipitate may be transfused depending on the severity of the bleeding.
• Patients with recurrent thrombotic events may require long-term anticoagulation with Coumadin or subcutaneous heparin.
• Administration of prophylactic cryoprecipitate may prevent recurrent miscarriages.

Consultations

Hematologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

When patients experience bleeding, FFP or cryoprecipitate may be transfused, depending on the severity of the bleeding. Patients with recurrent thrombotic events may require long-term anticoagulation with Coumadin or subcutaneous heparin.

Drug Category: Clotting factor replacement therapies

These are used to replace the clotting factors needed when moderate-to-severe bleeding occurs. This most often occurs in acquired dysfibrinogenemias caused by a severely damaged liver that is unable to make clotting factors.

Drug Name	Fresh frozen plasma
Description	Plasma is the fluid compartment of blood containing the soluble clotting factors. Indications for using FFP include bleeding in patients with congenital coagulation defects and multiple coagulation factor deficiencies (severe liver disease).
Adult Dose	8-10 mL/kg IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	A - Safe in pregnancy
Precautions	Viral contamination and infection are possible but unlikely because of prescreening

Drug Category: Anticoagulants

Prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.

Drug Name	Warfarin (Coumadin)
Description	Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to maintain an INR in the range of 2-3.
Adult Dose	5 mg PO qd initially; increase to desired INR
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hemorrhagic tendencies; recent surgery of CNS or eye; traumatic surgery resulting in large open surfaces; overt bleeding of the GI tract, CNS, or aorta; threatened abortion; eclampsia or preeclampsia; unsupervised patients with senility, alcoholism, or psychosis
Interactions	Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen and sulindac
Pregnancy	X - Contraindicated in pregnancy
Precautions	Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; periodic determination of INR is essential

Drug Name	Enoxaparin (Lovenox)
Description	Chronic subcutaneous therapy may be required in patients with recurrent thrombotic episodes. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	1 mg/kg q12h SC injection (LMW heparin) enoxaparin
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate reverses the effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Prognosis is good for patients with congenital dysfibrinogenemias. Events of bleeding or thrombosis are usually relatively mild.
• Acquired dysfibrinogenemia carries a worse prognosis because it is due to a severely damaged liver.

Patient Education

• Educate patients with congenital dysfibrinogenemias that it is an inherited condition and other family members may also be affected.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose and treat bleeding or thrombosis
• Failure to counsel patients that other family members may be affected

Special Concerns

• Women who experience multiple miscarriages may benefit from prophylactic administration of cryoprecipitate.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bazzan M, Tamponi G, Vaccarino A, et al. Natural and acquired inhibitors of hemostasis in selected symptomatic outpatients with venous thromboembolic disease. Haematologica. Jul-Aug 1997;82(4):420-2. [Medline].
• Galanakis DK. Inherited dysfibrinogenemia: emerging abnormal structure associations with pathologic and nonpathologic dysfunctions. Semin Thromb Hemost. 1993;19(4):386-95. [Medline].
• Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost. Jan 1995;73(1):151-61. [Medline].
• Martinez J. Quantitative and qualitative disorders of fibrinogen. In: Hoffman, et al, eds. Hematology: Basic Principles and Procedures. 2nd ed. Philadelphia, Pa: Churchill Livingstone;1995:1703-13, 2011-13.
• Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol. Sep 1997;4(5):357-65. [Medline].
• Mori T, Ikeda Y. [Acquired dysfibrinogenemia]. Ryoikibetsu Shokogun Shirizu. 1998;(21 Pt 2):529-31. [Medline].
• Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost. 1999;25(3):311-9. [Medline].
• Rodgers GM, Greenberg CS. Inherited coagulation disorders. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins;1999:1702-3.
• Schorer AE, Singh J, Basara ML. Dysfibrinogenemia: a case with thrombosis (fibrinogen Richfield) and an overview of the clinical and laboratory spectrum. Am J Hematol. Nov 1995;50(3):200-8. [Medline].

Article Last Updated: Apr 13, 2006