Factor X Deficiency 

Updated: Jul 31, 2019
Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD 

Overview

Practice Essentials

Clotting factor X, or Stuart-Prower factor, is a vitamin K–dependent serine protease that serves as the first enzyme in the common pathway of thrombus formation. Factor X deficiency is a bleeding disorder that can be inherited or acquired. This disorder is one of the world's most rare factor deficiencies.

Inherited factor X deficiency is autosomal recessive, with heterozygotes most often remaining asymptomatic or having only a mild bleeding tendency.[1] Homozygous individuals may experience hemorrhagic symptoms, including easy bruising, hematuria, soft-tissue hemorrhages, hemarthroses, recurrent epistaxis, and menorrhagia.[2] Pedigree analysis of patients with congenital factor X deficiency often reveals consanguinity.

Acquired factor X deficiency can be caused by severe liver disease, vitamin K deficiency, or anticoagulant drugs such as warfarin. Factor X deficiency has also been reported in association with a variety of medical conditions, such systemic light-chain amyloidosis[3] —particularly in advanced cases[4] —and atypical chronic lymphoid leukemia.[5]

Treatment of factor X deficiency is individualized, but restoring circulating factor X levels to 10-40% of normal is usually adequate. Additionally, in patients with acquired factor X deficiency, treatment of the underlying cause may resolve the disorder.  Treatment options include factor X concentrate, fresh frozen plasma, and prothrombin complex concentrates (PCCs). Vitamin K is ineffective in hereditary factor X deficiency but may be useful in certain acquired cases. (See Treatment and Medication.)

For patient education information, see Bruises and Blood Spots Under the Skin and Blood in the Urine.

Background

In the 1950s, two independent groups first identified factor X deficiency. Telfer and colleagues reported a bleeding tendency in a 22-year-old woman named Prower in 1956[6] ; Hougie and colleagues described abnormal coagulation profiles in a 36-year-old man named Stuart in 1957.[7] Experiments demonstrated that mixing plasma or serum from Stuart and Prower did not mutually correct the abnormality, thus showing that the two lacked an identical factor. Based on these common clotting test results, the factor was designated Stuart-Prower factor. This factor became known as factor X.

The human gene encoding factor X is primarily expressed in the liver and is located on the long arm of chromosome 13, just downstream from the gene for factor VII.[8, 9] It is composed of 8 exons and contains 22 kilobases of DNA.[10] The gene encodes the following[11] :

  • A signal region
  • A propeptide region
  • A glutamic acid domain
  • An "aromatic stack" region
  • Two regions homologous to epidermal growth factor
  • A catalytic domain

The enzyme gamma-glutamyl carboxylase, in the presence of vitamin K, converts the glutamic acid residues to gamma-carboxyglutamic acid residues. These gamma-carboxyglutamic acid residues are necessary for the binding of prothrombin to phospholipids on platelet membranes.

Pathophysiology

In the blood coagulation cascade, factor X is cleaved to form factor Xa, an active serine protease. As the first step in the common pathway to thrombus formation, factor X can be activated by products of both the intrinsic and extrinsic clotting cascades. Activation by the extrinsic pathway occurs via the complex of tissue factor and factor VIIa. Activation by the intrinsic pathway occurs via the interaction of factor IXa and factor VIIIa. Both pathways of activation require the presence of calcium ions and a phospholipid surface.

Once formed, factor Xa is then responsible for the conversion of prothrombin to its active form, thrombin, which is responsible for activating fibrinogen and allowing clot formation. It also functions in a positive feedback loop by activating factor V, factor VII, and factor VIII. Factor Xa can suppress the coagulation cascade by inactivating both factor VIII and tissue factor. Factor Xa is ultimately inactivated by forming a complex with antithrombin, which then undergoes hepatic clearance.

Factor X deficiency may arise because of reduced synthesis of the protein, which is known as type I deficiency state, or because of production of a dysfunctional molecule, which is known as type II deficiency state. Authorities believe that a complete absence of factor X is incompatible with life. Studies of knockout mice have revealed a lethal phenotype, with death occurring in utero or within a few days of birth.[12] Most often, missense mutations are the cause of congenital factor X deficiency.[13, 14]

Congenital factor X deficiency

Several specific mutations have been reported.[13] Relatively recently identified mutations include Gly366Ser, Arg347His, Phe31Ser, Gly133Arg, Val196Met, Gly204Arg, Glu51Lys, and Cys364Arg.[15, 16, 17, 18, 19, 20, 21] Mutations in the Gla-domain of factor X, a 39 residue peptide that is part of its light chain, have been documented in at least 15 cases of factor X deficiency.[22]

In a Japanese patient with factor X deficiency, molecular analysis revealed a homozygous glutamine-to-glycine mutation at residue 32, which normally undergoes gamma-carboxylation within the gamma-carboxyglutamic acid–rich domain.[23] A factor X–deficient woman from France was identified as homozygous for a mutation in exon VIII, resulting in the substitution of serine 334 by proline.[24] This mutation is probably responsible for altering the orientation of the cleavage site of factor X, preventing activation of the molecule. Other reported consequences of this mutation include interference with protein folding, disruption of disulfide bonds, and inhibition of factor binding sites.

Factor X has a natural variant carrying the Asp-185 deletion. Paradoxically, this variant may be associated with only mild bleeding despite a severe factor X deficiency.[25]

Acquired factor X deficiency

Acquired factor X deficiency has a variety of possible etiologies. Because factor X is synthesized in the liver, severe hepatic disease can have a dramatic impact on protein levels. Vitamin K deficiency can also result in decreased factor X levels. In general, liver disease and insufficient vitamin K levels produce deficiencies of several clotting factors, not just factor X.

Vitamin K is produced by enteric flora, and vitamin K levels can be reduced by intestinal malabsorption, bile duct obstruction, or antibiotic administration. Vitamin K deficiency can also be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be observed in neonates.

Acquired factor X deficiency has been reported in association with a number of other medical conditions. Factor X deficiency occurs in an estimated 8% of patients with amyloidosis, including immunoglobulin light chain (AL) amyloidosis.[11, 26, 27, 28] Factor X binds to deposited amyloid fibrils and has a shortened half-life in the plasma.[29, 30]

Factor X deficiency has also been reported in association with myeloma, presumably because of binding of the protein to circulating light chains.[31] Acquired factor X deficiency has also been reported in association with leukemia and other neoplastic processes.[32, 33]

Decreases in factor X levels have also been noted in association with the following:

  • Mycoplasma pneumoniae infection [34]
  • Lupus anticoagulant [35]
  • Sodium valproate administration [36]
  • Upper respiratory tract infection [37]
  • Leprosy [38]
  • Severe burns in a child [39]
  • Topical thrombin administration [40]

Epidemiology

Frequency

Congenital factor X deficiency is among the most rare factor disorders, affecting an estimated one individual per 500,000-1,000,000 population worldwide.[41]   The prevalence of factor X deficiency in the United States presumably mirrors international rates.

Mortality/Morbidity

Congenital factor X deficiency is a lifelong bleeding disorder. Death can occur owing to massive hemorrhage resulting from trauma. Hemorrhage can also occur as a result of surgery if proper precautions are not taken. Cases of both fatal and nonfatal perinatal and infant intracranial hemorrhages have been reported.[42, 43, 44] Disabling hemarthroses can also occur.

Race-, Sex-, and Age-related Demographics

Factor X deficiency has no known racial or ethnic predilection. Males and females are equally affected.

Patients with congenital factor X deficiency can present at any age. Generally, patients with more severe cases present during infancy. Acquired forms may affect persons of any age group.

 

Presentation

History

Patients with factor X deficiency may report a family history of a bleeding disorder. Possible symptoms include the following:

  • Severe umbilical cord stump bleeding
  • Prolonged bleeding following circumcision
  • Recurring nose bleeds
  • Easy bruising
  • Hematuria
  • Menorrhagia at menarche (single case report) [45]
  • Spontaneous abortion in the first trimester
  • Excessive bleeding during or following surgery or trauma
  • Pseudotumors
  • Intracranial bleeding
  • Hemarthroses (in severe deficiency)
  • Bleeding in soft tissues, muscles, and gut

Physical

The physical examination of a patient with factor X deficiency may reveal petechiae, ecchymoses, or both, which commonly develop in areas of minor trauma. Ambulatory patients may have petechiae or ecchymoses in the ankle area, whereas bedridden patients may have them on the back. Petechiae may develop following blood pressure measurements in the area beneath the cuff. Additionally, patients may ooze from venipuncture sites. Patients with active hemorrhage may also be seen in emergency departments.

Central nervous system hematomas may occur in infants and children, including bilateral chronic subdural hematoma.[46]

In cases of acquired factor X deficiency, the physical examination may reveal signs of underlying disease, such as the following:

  • Liver disease
  • Intestinal malabsorption
  • Upper respiratory tract infection
  • Amyloidosis
  • Leprosy

Causes

Factor X deficiency may be hereditary or acquired. Congenital factor X deficiency is an autosomal recessive disorder.

The most common causes of acquired factor X deficiency include the following:

  • Liver disease
  • Vitamin K deficiency
  • Vitamin K antagonist use
  • Amyloidosis
  • Neoplasm

Complications

Women with congenital factor X deficiency are at increased risk of the following[47] :

  • Heavy menstrual bleeding
  • Recurrent ovulation bleeding with hemoperitoneum
  • Bleeding complications in pregnancy (eg, retroplacental hematoma, postpartum hemorrhage)
 

DDx

 

Workup

Laboratory Studies

Coagulation study findings in patients with factor X deficiency include the following:

  • The prothrombin time (PT) is prolonged
  • The activated partial thromboplastin time (aPTT) is prolonged
  • The Russell viper venom time (RVVT) is prolonged; Russell viper venom cleaves factor X to produce active factor Xa
  • Bleeding time is within the reference range

Results of factor X assays may vary, depending on whether the deficiency is type I (reduced synthesis of factor X) or type 2 (production of dysfunctional factor X). In patients with a type I deficiency, both functional and antigenic factor X levels are decreased. In patients with a type II X deficiency, the functional level is decreased and the antigenic level varies from within the reference range to a decreased level (production of dysfunctional factor X)

In isolated factor X deficiency, assays of other clotting factors should reveal levels within their respective reference ranges. In factor X deficiency due to vitamin K deficiency or vitamin K antagonist use, assays of other clotting factors reveal decreases in all vitamin K–dependent factors (ie, factor II, factor VII, factor IX, factor X, protein C). Liver disease causes a decrease in the levels of many clotting factors.

 

Treatment

Medical Care

Treatment of factor X deficiency is individualized for each patient. However, restoring circulating factor X levels to 10-40% of normal is usually adequate. Additionally, in patients with acquired factor X deficiency, treatment of the underlying cause may resolve the disorder.

Therapeutic measures may include the following:

  • Factor X, human (Coagadex) can be initiated with 25 IU/kg IV for on-demand treatment at the first sign of a bleeding episode. Calculation of desired in vivo peak increase in factor X is required for precise dose. It may also be used for mild hereditary factor X deficiency to decrease bleeding risk during and after surgical procedures.[48]

  • A high-purity, plasma-derived factor X concentrate has been recommended for patients with hereditary factor X deficiency. [49]  It is well tolerated and effective in women and girls as well as in men and boys, with similar pharmacokinetics. [5]
  • Infusion of fresh frozen plasma (Octaplas) is usually sufficient to treat most hemorrhagic episodes. A loading dose of 15-20 mL/kg intravenously is administered. Because of the relatively long half-life of factor X, the loading dose can be followed by maintenance doses of 3-6 mL/kg intravenously every 12-24 hours.

  • Prothrombin complex concentrates (PCCs) have also been used to increase factor X levels. PCCs contain factors II, VII, IX, and X and protein C. PCCs should be used cautiously to avoid factor X levels of more than 50% of normal, which can result in thromboembolic episodes. Perioperative prothrombin complex concentrate has also been employed to treat acquired factor X deficiency associated with systemic light-chain amyloidosis.[50]

  • Vitamin K administration may be useful in certain patients with acquired factor X deficiency; however, it has been amply demonstrated that patients with inherited factor X deficiency do not respond to vitamin K.

Cryoprecipitate does not contain factor X and is, therefore, ineffective in factor X deficiency.

Surgical Care

For patients with acquired factor X deficiency due to amyloidosis, splenectomy has proved beneficial in restoring circulating factor X levels.[51, 52] This presumably occurs via the debulking of splenic amyloid.

Consultations

Consultation in patients with factor X deficiency include hematologists and, in cases of congenital factor X deficiency, genetic counselors.

Diet and Activity

No dietary restrictions are necessary in individuals with factor X deficiency. Patients are advised to limit alcohol consumption to reduce the risk of liver disease.

Activity must be regulated based on the severity of the factor X deficiency and the presence or absence of symptoms. Because of the risk of hemorrhage following trauma, activities with high levels of physical contact are not recommended.

 

Medication

Medication Summary

The goals of pharmacotherapy in those with factor X deficiency are to reduce morbidity and to prevent complications. The following agents are used:

  • Fresh frozen plasma and prothrombin complex concentrates may be used to increase factor X levels
  • Supplemental vitamin K may be effective in acquired factor X deficiency related to vitamin K deficiency
  • Factor X, human (Coagadex) has been approved in the United States for hereditary factor X deficiency

Blood-Product Derivatives

Class Summary

Blood-product derivatives are indicated for the correction of abnormal hemostatic parameters.

Fresh frozen plasma (FFP, Octaplas)

Clotting factor X is contained in plasma, the fluid component of blood. Indications include bleeding in patients with congenital coagulation defects and multiple coagulation factor deficiencies (severe liver disease). Octaplas is a solvent detergent treated, pooled FFP.

Vitamins, Fat-Soluble

Class Summary

Vitamin K is key cofactor in activating clotting factors in the coagulation cascade.

Phytonadione (AquaMEPHYTON)

Absorbed by the gut and stored in the liver. Necessary for the function of clotting factors in the coagulation cascade. Used to replace essential vitamins that are not obtained in sufficient quantities in the diet or to further supplement levels.

Coagulation Factors

Class Summary

Provides replacement for temporary correction of various coagulation factor deficiencies.

Factor X, human (Coagadex)

Factor X replacement that increases plasma levels of factor X and can temporarily correct the coagulation defect in these patients, as reflected by decrease in the aPTT and PT. Indicated for hereditary factor X deficiency for on-demand treatment and control of bleeding episodes. It is also indicated for perioperative management of bleeding in patients with mild hereditary factor X deficiency.

Factor IX complex (Bebulin, Bebulin VH, Profilnine SD)

Product made from pooled human plasma. Contains factors II, VII, IX, and X; protein C; and trace amounts of heparin to guard against thrombosis. The dose can be calculated depending on the concentration of protein C in a preparation. Preparations may vary.

 

Follow-up

Prognosis

The prognosis for patients with factor X deficiency depends on the etiology and severity of the disease. Although acquired factor X deficiency may be eliminated by treating the underlying cause, the congenital form of the disease is lifelong and is among the most severe clotting factor disorders. In general, patients with very low levels of functional factor X have a greater tendency to hemorrhage and face a greater risk of life-threatening complications.[53]

Complications

Factor X deficiency can have noteworthy effects on pregnancy. In one survey, intrauterine growth restriction was noted in four women.[54]

 

Questions & Answers

Overview

What is factor X deficiency?

When was factor X deficiency first recognized?

What are the genetics of factor X deficiency?

What is the pathophysiology of factor X deficiency?

What is the pathophysiology of congenital factor X deficiency?

What is the pathophysiology of acquired factor X deficiency?

What other conditions are associated with factor X deficiency?

What is the prevalence of factor X deficiency?

What is the mortality and morbidity associated with factor X deficiency?

Which patient groups have the highest prevalence of factor X deficiency?

Presentation

What are the signs and symptoms of factor X deficiency?

Which physical findings are characteristic of factor X deficiency?

Which physical findings are characteristic of acquired factor X deficiency?

What causes factor X deficiency?

What are most common causes of acquired factor X deficiency?

DDX

Which conditions are included in the differential diagnoses of factor X deficiency?

What are the differential diagnoses for Factor X Deficiency?

Workup

Which coagulation study findings suggest factor X deficiency?

What are results on factor X assay suggest factor X deficiency?

Treatment

How is factor X deficiency treated?

What is the role of splenectomy in the treatment of factor X deficiency?

Which specialist consultations are beneficial to patients with factor X deficiency?

Which dietary modifications are used in the treatment of factor X deficiency?

Which activity modifications are used in the treatment of factor X deficiency?

Medications

What is the role of medications in the treatment of factor X deficiency?

Which medications in the drug class Coagulation Factors are used in the treatment of Factor X Deficiency?

Which medications in the drug class Vitamins, Fat-Soluble are used in the treatment of Factor X Deficiency?

Which medications in the drug class Blood-Product Derivatives are used in the treatment of Factor X Deficiency?

Follow-up

What is the prognosis of factor X deficiency?

What are the possible complications of factor X deficiency?