eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Dysfibrinogenemia

Wendy Brick, MD, Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Russell Burgess, MD, Department of Internal Medicine, Division of Hematology/Oncology, East Carolina Internal Medicine; Guy B Faguet, MD, Former Professor, Department of Medicine, Section of Hematology and Oncology, Medical College of Georgia

Updated: Nov 17, 2009

Introduction

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.¹

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.²

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.³

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

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.

Differential Diagnoses

Other Problems to Be Considered

Afibrinogenemia
Hypodysfibrinogenemia
Hypofibrinogenemia
Plasminogen deficiency
Factor V Leiden deficiency
Hyperhomocystinemia

Workup

Laboratory 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

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.
• Miesbach et al described the use of fibrinogen concentrates to avoid pregnancy loss in women with dysfibrinogenemia.⁴ (The obstetric complications of dysfibrinogenemia include first-trimester pregnancy loss, along with hemorrhage, placental abruption, and thrombosis.) The investigators performed a retrospective study of 4 women from the same family, each of whom had dysfibrinogenemia and a history of recurrent pregnancy loss. The patients received fibrinogen concentrates from the start of pregnancy until delivery, with 3 of the 4 women achieving delivery.

Consultations

Hematologist

Medication

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.

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.

Cryoprecipitate

Precipitate formed when FFP is thawed. Contains factor VIII, fibrinogen, vWF, and fibronectin. Primarily used to treat bleeding in patients with fibrinogen deficiencies or abnormalities.

Dosing

Adult

1-4 U/10 kg IV (goal is measured fibrinogen >100 mg/dL)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Viral contamination and infection are remotely possible but unlikely because of prescreening

Fresh frozen plasma

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).

Dosing

Adult

8-10 mL/kg IV

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Viral contamination and infection are possible but unlikely because of prescreening

Anticoagulants

Prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.

Heparin

Used in patients with thrombotic tendencies who develop deep venous thrombosis, arterial thrombosis, or pulmonary embolism.

Dosing

Adult

80 U/kg IV infusion initially, followed by 18 U/kg/h continuous infusion

Pediatric

Not established

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, ASA, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity

Contraindications

Documented hypersensitivity; severe thrombocytopenia with uncontrollable active bleeding; subacute bacterial endocarditis; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) from benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when administering IM injections

Warfarin (Coumadin)

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.

Dosing

Adult

5 mg PO qd initially; increase to desired INR

Pediatric

Not established

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

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

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

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

Enoxaparin (Lovenox)

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.

Dosing

Adult

1 mg/kg q12h SC injection (LMW heparin) enoxaparin

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

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

Medicolegal 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

1. Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia. Nov 2008;14(6):1151-8. [Medline].

2. Kotlin R, Reicheltova Z, Maly M, et al. Two cases of congenital dysfibrinogenemia associated with thrombosis - Fibrinogen Praha III and Fibrinogen Plzen. Thromb Haemost. Sep 2009;102(3):479-86. [Medline].

3. Morris TA, Marsh JJ, Chiles PG, et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood. Aug 27 2009;114(9):1929-36. [Medline].

4. Miesbach W, Galanakis D, Scharrer I. Treatment of patients with dysfibrinogenemia and a history of abortions during pregnancy. Blood Coagul Fibrinolysis. Jul 2009;20(5):366-70. [Medline].

5. 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].

6. Galanakis DK. Inherited dysfibrinogenemia: emerging abnormal structure associations with pathologic and nonpathologic dysfunctions. Semin Thromb Hemost. 1993;19(4):386-95. [Medline].

7. 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].

8. Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol. Sep 1997;4(5):357-65. [Medline].

9. 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.

10. Mori T, Ikeda Y. [Acquired dysfibrinogenemia]. Ryoikibetsu Shokogun Shirizu. 1998;(21 Pt 2):529-31. [Medline].

11. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost. 1999;25(3):311-9. [Medline].

12. 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.

13. 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].

Keywords

congenital dysfibrinogenemia, fibrinogen, fibrin, fibrinolysis, clotting cascade, coagulation factor, coagulation factors, clotting factor, clotting factors, coagulation disorders, coagulation disorder, abnormal clot formation, fibrinopeptide, thrombotic events

Contributor Information and Disclosures

Author

Wendy Brick, MD, Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Wendy Brick, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Russell Burgess, MD, Department of Internal Medicine, Division of Hematology/Oncology, East Carolina Internal Medicine
Russell Burgess, MD is a member of the following medical societies: American College of Physicians and American Medical Association
Disclosure: Nothing to disclose.

Guy B Faguet, MD, Former Professor, Department of Medicine, Section of Hematology and Oncology, Medical College of Georgia
Guy B Faguet, MD is a member of the following medical societies: American Association of Immunologists, American Society of Hematology, International Society of Hematology, New York Academy of Sciences, Southern Medical Association, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Clinical guidelines:
Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. British Committee for Standards in Haematology - Professional Association. 2004 Jul. 18 pages. NGC:006191

Clinical trials:
Fibrinogen Concentrate (Human) − Efficacy and Safety Study

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)