Factor II Deficiency

In the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease. This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium. Thrombin is responsible for inducing platelet aggregation and activating several other mediators in the coagulation cascade. It converts fibrinogen to fibrin, which then polymerizes to form a clot around platelet aggregates. Thrombin also converts factor XIII to factor XIIIa, an enzyme that cross-links and stabilizes fibrin polymers.

The prothrombotic effects of thrombin are ultimately suppressed by the binding of thrombin to thrombomodulin on endothelial cell surfaces to form a complex that activates protein C. Protein C then degrades factors Va and VIIIa to inhibit the coagulation cascade. Thrombin also has cytokine and growth-factor functions, inducing mitosis and chemotaxis in cell lines, including smooth muscle, fibroblasts, endothelial cells, and mononuclear phagocytes. Decreased levels or a dysfunctional structure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. Thus, thrombin functions not only in the clotting cascade, but also as a cytokine and growth factor capable of inducing mitosis and chemotaxis in several different cell lines. Several specific missense mutations of the prothrombin gene have been documented. These single amino acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia. In fact, most hypoprothrombinemia-associated mutations are missense ones.

Acquired factor II deficiency has several possible etiologies. Because prothrombin is synthesized almost exclusively in the liver, severe liver disease can have a dramatic impact on prothrombin levels. Vitamin K deficiency can also result in decreased prothrombin levels. Vitamin K is produced in the gut by enteric flora, and levels can be affected by intestinal malabsorption, bile duct obstruction, or antibiotic administration. Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be seen in neonates. Finally, acquired factor II deficiency can sometimes be observed in patients with lupus anticoagulant. These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body. This condition, sometimes referred to as "lupus anticoagulant hypoprothrombinemia syndrome," is most often seen with systemic lupus erythematosus (SLE).

The lupus anticoagulant hypoprothrombinemia syndrome may also occur in individuals without SLE. Bleeding attibuted to acquired hypoprothrombinemia caused by antiphospholipid antibodies may follow acute adenovirus gastroenteritis and mycoplasma pneumonia. The lupus anticoagulant hypoprothrombinemia syndrome is associated with a high mortality.

History

Patients with a factor II deficiency may report a family history of bleeding disorders. They may also report a history of the following symptoms:

• Prolonged bleeding following circumcision
• Postpartum bleeding
• Easy bruising
• Umbilical cord stump bleeding at birth
• Intracranial bleeding
• Epistaxis
• Menorrhagia
• Prolonged postsurgical bleeding
• Melena
• Bleeding gums
• Soft-tissue hemorrhages

Laboratory Studies

Clotting factor assay results in patients with factor II deficiency are as follows:

• In hypoprothrombinemia, functional and antigenic levels of factor II are decreased
• In dysprothrombinemia, functional levels are decreased; antigenic levels are within reference ranges or are slightly decreased
• In isolated factor II deficiency, assays of other clotting factors should reveal normal levels
• In factor II deficiency due to liver disease, vitamin K deficiency, or vitamin K antagonist use, assays of other clotting factors reveal a decrease in the level of all vitamin K–dependent factors (ie, factor II, factor VII, factor IX, factor X, protein C)

Coagulation study results in patients with factor II deficiency are as follows:

• Prothrombin time (PT) is prolonged
• Activated partial thromboplastin time (aPTT) is prolonged
• Bleeding time is within reference ranges

Treatment

Treatment options include the following:

• Infusion of fresh frozen plasma (FFP) is usually sufficient to treat most cases of bleeding; a loading intravenous (IV) dose of 15-20 mL/kg is administered, followed by a maintenance dose of 3-6 mL/kg IV q12-24 h
• Plasma exchange transfusion may be used to increase factor II levels before surgery
• Prothrombin complex concentrates (PCCs) have also been used to increase factor II levels ^[45] ; PCCs contain factors II, VII, IX, and X, along with protein C; however, PCCs should be used judiciously because of the risk of thromboembolic complications
• Vitamin K administration may be useful in patients with acquired factor II deficiency

Source :

http://emedicine.medscape.com/article/209742-medication#2

http://emedicine.medscape.com/article/209742-overview#a5

Key Differences Between Hemophilia C and Hemophilia A and B

Table 1. Key Differences Between Hemophilia C and Hemophilia A and B
Key Characteristic	Difference Between Hemophilia C and Hemophilia A & B
Incidence	Hemophilia C is more common among persons of Ashkenazi (European) Jewish descent.1,2 Hemophilia A and B affect all racial and ethnic groups equally.
Bleeding tendency	The frequency of bleeding with hemophilia C is not determined by the patient’s factor level or severity of the deficiency. Hemophilia C affects men and women equally. In hemophilia C, unpredictable (or inconsistent) bleeding patterns can complicate management. Individuals with hemophilia C are not likely to bleed spontaneously (or without known injury); bleeding tends to occur after trauma or surgery. Unlike hemophilia A and B, hemophilia C is not commonly associated with bleeding into joints and muscles. Physical signs of the disorder (e.g., bruising) are rare.
Cause	Hemophilia C is primarily an inherited autosomal disorder Unlike hemophilia A and hemophilia B, it is not linked to the X chromosome and affects both genders equally
Treatment	Individuals with hemophilia C do not require treatment or prophylactic (preventive) therapy for daily activities. Replacement therapy is required for dental extractions and surgery Treatment options depend on the type of procedure. Individuals with hemophilia C may experience milder symptoms than those living with hemophilia A or B, but they still require effective treatment to achieve optimal outcomes after surgeries or injuries

Source :
http://www.ihtc.org/medical-professionals/blood-disorders/bleeding-disorders/hemophilia-c/

Hemophilia C

Hemophilia C

Definition

Hemophilia is a disease that causes the body lacks the protein needed for blood clotting process when there is bleeding. This protein is commonly called a clotting factor or coagulation factors.

While factor VIII and factor IX deficiencies are the best known and most common types of hemophilia, other clotting factor deficiencies also exist. Low levels of factor XI (FXI) cause hemophilia C

Even in severe deficiency of factor XI, the bleeding tendency is mild. Unlike the bleeding tendency in hemophilia Aor hemophilia B, which is clearly related to the factor level, the bleeding risk in hemophilia C is not always influenced by the severity of the deficiency, especially in individuals with partial deficiency. Indeed, some patients with severe deficiency do not have a bleeding tendency, whereas some patients with mild deficiency bleed excessively.

FXI plays an important role in tissue factor-dependent thrombin generation on the surface of activated platelets.¹ The formation of the initiating complex, TF-FVIIa-FXa, results in the generation of a small amount of thrombin. This is insufficient to produce a stable fibrin clot but stimulates a number of reactions in the amplification loop, including the activation of FXI. Subsequent formation of the tenase complex (FIXa-FVIIIa), followed by the prothrombinase complex (FXa-FVa), leads to a large burst of thrombin

This unpredictability, which is not fully understood, makes hemophilia C more difficult to manage than hemophilia A or B.

Severe deficiency is defined as factor XIc activity of 15-20 U/dL or lower. However, this is no longer suitable terminology since the bleeding disorder is not clinically severe, even at very low levels of factor XI. Spontaneous bleeding rarely occurs, but bleeding may occur after surgery, more commonly in those with the lowest levels. The levels in this range, less than about 15 U/dL, generally identify individuals who have 2 FXIgene mutations. Patients with partial deficiency, generally heterozygous with a single FXI gene mutation, have levels of about 20-60 U/dL (ie, the lower limit of the normal range). About 30-50% of individuals with partial deficiency may have excessive bleeding; however, identifying these persons in advance is difficult. Furthermore, normal infants without hemophilia C are likely to have low factor XIc levels until they are older than 6 months.

Bleeding Tendency

Unlike with hemophilia A and hemophilia B, the frequency of bleeding with hemophilia C is not determined by the patient’s factor level.¹An unpredictable (or inconsistent) bleeding pattern occurs in people with this disorder.^1-4 The inability to predict bleeding complicates treatment. Individuals with hemophilia C do not commonly bleed spontaneously; bleeding tends to occur after surgery or injury, especially to the mucocutaneous lining of the oral or nasal cavities and the urinary tract.

Procedures with an increased risk of bleeding include the following:

• dental extractions
• tonsillectomies
• surgery in the urinary and genital tracts
• nasal surgery
• Additional clotting factor disorders, especially von Willebrand disease, or a more subtle change in hemostatic balance
• Variant factor XI molecules (ie, those with a discrepancy between factor XI clotting activity compared with antigen): These variants are rare, and no correlation between mutation type and bleeding tendency has been identified.
• Increased fibrinolysis at certain surgical sites

Unlike individuals with hemophilia A and hemophilia B, patients with hemophilia C do not commonly experience joint bleeds. They may, however, experience the following: bruising, nosebleeds, or blood in the urine; and for women, menorrhagia and prolonged bleeding after childbirth.^1-4Injury may cause bleeding in muscles, joints and other areas.

Diagnosis of Hemophilia C

Obtaining a detailed personal and family bleeding history of a patient is very important in the diagnosis of hemophilia C. Although this condition is found in all racial and ethnic groups, it is helpful to establish the patient’s background, as this may give an indication of the likely disorder. Various screening coagulation tests are utilized to diagnose hemophilia C, the most common being the activated partial thromboplastin time (APTT) and a FXI activity assay

Treatment of Hemophilia C

Patients with severe hemophilia C do not require treatment or prophylactic (preventive) therapy for daily activities. However, replacement therapy is required for dental extractions and surgery, and treatment options depend on the type of procedure.

Fresh frozen plasma, since FXI is not concentrated in fresh frozen plasma, a large volume of this product may be required to raise the FXI activity to a hemostatic level

Patients with severe factor XI deficiency may develop an inhibitor, as seen in hemophilia A or B. The development of an inhibitorgenerally complicates treatment options. Approximately one-third of patients with severe (<1%) FXI deficiency who use plasma product replacement therapy may develop an inhibitor. There are a few case reports describing the successful use of recombinant FVIIa in these patients; however, recombinant FVIIa should be used with caution because thrombotic complications have been reported.

Antifibrinolytic agents such as epsilon aminocaproic acid (Amicar®) or tranexamic acid may be useful for treating mucocutaneous bleeding in individuals with hemophilia C.²Antifibrinolytic agents are generally not used concomitantly with FXI concentrate, because of an increased risk of thrombotic complications. They are also relatively contraindicated in treating bleeding from the urinary tract because of potential clot retention.¹ Desmopressin may be used in some cases to produce modest rises in FXI activity in partial deficiency,⁶but the evidence for efficacy is unconvincing.

Complications of Hemophilia C

The complications of hemophilia C are those primarily associated with the use of fresh frozen plasma. While today’s blood products are much safer than those of the past, transmission of hepatitis A, hepatitis C, and newly discovered blood-borne diseases remain a risk for people treated with plasma-derived products. Immunization against hepatitis A and B is recommended for all individuals with hemophilia. No vaccination currently exists for hepatitis C.

See Also

Hemophilia A 

Hemophilia B 

Hemophilia C 
Key Differences Between Hemophilia C and Hemophilia A and B  

Source :

http://emedicine.medscape.com/article/955690-overview

http://www.ihtc.org/medical-professionals/blood-disorders/bleeding-disorders/hemophilia-c/