Hypoprothrombinemia

Prothrombin (factor II of the coagulation cascade) is a critical protein in hemostasis. Decreased levels of prothrombin can lead to a bleeding diathesis. The most common manifestations of hypoprothrombinemia are associated with mucocutaneous bleeding. However, hemorrhage involving deep structures can be observed with severe prothrombin deficiency.

Hypoprothrombinemia may be acquired or inherited. Acquired forms may be secondary to decreased production or increased consumption. Acquired isolated hypoprothrombinemia is usually autoimmune and associated with the lupus anticoagulant. A relatively common form of acquired hypoprothrombinemia is vitamin K deficiency. Levels of other vitamin K–dependent procoagulant factors (factors VII, IX, and X) and anticoagulant factors (protein C and protein S) are also decreased in vitamin K deficiency.

Inherited prothrombin deficiency is rare.[1] Two phenotypes are described: hypoprothrombinemia (type I deficiency) and dysprothrombinemia (type II deficiency). In type I deficiency, prothrombin levels and prothrombin activity are reduced. In type II deficiency, prothrombin activity is reduced, but prothrombin levels are borderline or in the reference range. Both disorders are autosomal recessive. The prothrombin gene is found on chromosome 11.

Heterozygotes for prothrombin deficiency have factor II levels of 30-60% of the reference range. Heterozygotes are usually asymptomatic, although a study by Girolami et al found that mean prothrombin activity was lower in patients who were heterozygous for prothrombin deficiencies than in controls (0.49 IU/dL vs 0.91 IU/dL, respectively), with bleeding manifestations found in 31.8% of the heterozygous individuals, compared with 6.8% of controls.[2]

Compound heterozygotes who have type I and type II mutations are occasionally reported.

The treatment of hypoprothrombinemia depends on the underlying etiology. Plasma-derived products that contain factor II are available. Vitamin K-1 (phytonadione) is used to treat vitamin K deficiency as well as warfarin overdose. In autoimmune disease, treatment is not entirely straightforward, and immunosuppressive therapy is used in severe cases.

Thrombin is paramount to proper hemostasis. This powerful protease is at the core of the coagulation cascade. It not only plays a critical role in clot formation but also activates the protein C anticoagulant system by binding to thrombomodulin on the endothelial surface, indirectly controlling its own production.

Activated factor Xa converts prothrombin to thrombin on phospholipid surfaces in a calcium-dependent proteolytic reaction, which results in the cleavage of prothrombin at 2 sites. Activated factor Va is an enzymatic cofactor that increases the prothrombinase activity of factor Xa by more than 10,000-fold. Thrombin is a potent protease. Its most important function is the cleavage of fibrinogen to create insoluble fibrin. Cross-linking fibrin monomers stabilize the fibrin clot. Factor XIIIa, activated by thrombin, carries out this function.

Thrombin also stimulates platelet activation and converts factors V and VIII into activated cofactors for factors Xa and IXa respectively. In addition to its procoagulant properties, thrombin assists in controlling its own production by activating protein C when it is bound to thrombomodulin. Activated protein C inactivates factors Va and VIIIa by means of proteolytic cleavage. Protein S is a cofactor for activated protein C. Antithrombin can inactivate thrombin; heparin facilitates this process.

Prothrombin is a vitamin K–dependent protein. It contains 10 gamma-carboxylated glutamic acid residues. These residues are important for the calcium-dependent interactions with phospholipid surfaces. Vitamin K is necessary for the posttranslational gamma-carboxylation of glutamic acid residues in the amino terminus of vitamin K–dependent coagulation factors. Therefore, in the absence of vitamin K or in the presence of vitamin K antagonists (eg, warfarin), dysfunctional vitamin K–dependent clotting factors are produced and a bleeding diathesis ensues.

Lupus anticoagulants are a heterogeneous group of antibodies directed against phospholipids and phospholipid-binding proteins. Lupus anticoagulants prolong the clotting time in phospholipid-dependent tests. Lupus anticoagulants are associated with thrombotic symptoms in most patients; however, when prothrombin is their antigenic target, the patient can develop severe hypoprothrombinemia and hemorrhagic symptoms. This condition is known as lupus anticoagulant-hypoprothrombinemia syndrome (LAHS).

Type I prothrombin deficiency (hypoprothrombinemia) is the result of decreased prothrombin production. Factor levels of 4-10% have been reported. Levels of factor II activity are also low. Type II prothrombin deficiency (dysprothrombinemia) is due to poor function of the prothrombin protein. Prothrombin antigen levels may be normal or low-normal, but activity is depressed.

Frequency

United States

Both acquired and inherited hypoprothrombinemia are exceedingly rare in the United States. Hypoprothrombinemia due to vitamin K deficiency is rarely seen because vitamin K injections are routinely given in the neonatal period.

International

The estimated prevalence of inherited prothrombin deficiency worldwide is 1 per 2,000,000 population. The prevalence is higher where consanguinity is common. In parts of the world where vitamin K is not routinely administered in the neonatal period, hypoprothrombinemia secondary to vitamin K deficiency is relatively common. The incidence of hemorrhagic disease of the newborn in the absence of active prophylaxis is about 1 in 500 newborns.

Mortality/Morbidity

In both acquired and inherited hypoprothrombinemia, the morbidity and mortality risks are related to the circulating level of factor II. The risks are less than 2% with severe deficiency, 2-10% with moderate deficiency, and 10-40% for mild deficiency.

In a prothrombin knockout-mouse model, complete prothrombin deficiency led to a 50% mortality rate on embryonic day 10.5.[3] Some embryos survive to birth but die from hemorrhaging on the first day. In humans, severe life-threatening hemorrhage, including intracranial hemorrhage, is described in neonates with severe prothrombin deficiency. Severe prothrombin deficiency is likely to lead to spontaneous abortion and fetal demise in some cases. Complete prothrombin deficiency in humans has not been reported; this omission suggests that this condition is incompatible with life.

Race

No race predilection for hypoprothrombinemia is apparent. However, in 2003, the North American Registry for Rare Bleeding Disorders reported that 62% of patients with prothrombin deficiency in the United States and Canada were Hispanic.[4]

Sex

Acquired hypoprothrombinemia associated with the lupus anticoagulant is slightly more common in women than in men. Severe inherited prothrombin deficiency typically has an autosomal recessive inheritance pattern. Therefore, unlike classic hemophilia, severe inherited prothrombin deficiency occurs with equal frequency in male and female individuals.

Age

Patients with inherited severe hypoprothrombinemia present early in life, whereas patients with mild forms present at various ages.[5] Vitamin K deficiency is most common in young infants. Patients with autoimmune hypoprothrombinemia can present at any age.

The most common initial presentations of hypoprothrombinemia include mucosal bleeding, soft tissue bleeding, and hemarthrosis. Severe prothrombin deficiency can result in deep hemorrhages[6] , including muscle hematomas, intracranial bleeding, pulmonary hemorrhage, umbilical bleeding, postoperative bleeding, and menorrhagia. Severe bleeding can result in anemia with associated symptoms.

Patients with lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) may have other symptoms of autoimmune disease. As an alternative, they may have a history of a preceding viral infection, usually an upper respiratory infection or gastroenteritis.[7]

Symptoms associated with hypoprothrombinemia include the following:

• Easy bruising

• Epistaxis

• Prolonged bleeding with injury, tooth extraction, or surgery

• Oral mucosal bleeding

• Melena

• Hematochezia

• Hematuria

• Intracranial hemorrhage

• Hemarthroses

• Menorrhagia

The most common physical findings are ecchymoses, bleeding from mucosal surfaces, and pallor secondary to blood loss. Petechiae are uncommon because platelet numbers and function are not affected. Other physical findings are specifically related to the hemorrhage site.

Hypoprothrombinemia may be inherited or acquired. Acquired hypoprothrombinemia may be an isolated factor deficiency or a condition associated with several factor deficiencies.

Acquired causes that are usually associated with isolated factor II deficiency include autoantibodies to prothrombin associated with the lupus anticoagulant or spontaneous formation of an inhibitor to prothrombin (autoantibody not associated with lupus anticoagulant). Lupus anticoagulant–hypoprothrombinemia syndrome may be the initial manifestation of systemic lupus erythematosus or may be postviral. Adenovirus is the viral pathogen most commonly involved, and it is associated with 50% of postviral cases.

Inherited prothrombin deficiency is autosomal recessive. Type I prothrombin deficiency is usually the result of a missense or nonsense mutation that decreases the production of prothrombin. Type II prothrombin deficiency is the result of a missense mutation in the cleavage sites for factor Xa and the serine protease region of prothrombin, which creates a protein with reduced activity.

Prothrombin deficiency can also be seen as part of a rare inherited deficiency of the vitamin K–dependent clotting factors. The disorder is the result of dysfunction in the vitamin K–dependent enzyme pathway that is common to factors II, VI, IX, and X. Inheritance is autosomal recessive, and fewer than 20 cases have been reported worldwide. Presentation and severity of bleeding symptoms widely vary. Some patients have responded to treatment with vitamin K.

Causes usually associated with multiple-factor deficiencies include vitamin K deficiency, severe liver disease, disseminated intravascular coagulation (DIC), and warfarin overdose.

Reports describe antibiotic-induced hypoprothrombinemia, which is usually due to beta-lactam antibiotics. Antibiotic-induced hypoprothrombinemia is thought to be related to decreased availability of vitamin K (due to loss of gut flora) or is caused by direct interference with the vitamin K cycle in the liver by thiol group–containing antibiotics. For example, in a study of hypoprothrombinemia secondary to hypovitaminosis K, Angles et al looked at the role of high-dose cefazolin treatment for methicillin-susceptible Staphylococcus aureus endocarditis. The authors suggested that cefazolin, by inhibiting vitamin K epoxide reductase and/or gamma-glutamyl carboxylase, thereby impacting the synthesis of vitamin K–dependent coagulation factors, can cause severe hemorrhagic complications in association with cardiac surgery.[8]

Hypoprothrombinemia is determined by performing a specific assay for factor II activity.

The prothrombin time (PT), usually indicated as an international normalized ratio (INR), and the activated partial thromboplastin time (aPTT) are elevated in hypoprothrombinemia. However, both the PT and the aPTT can be elevated in numerous single-factor and multiple-factor deficiencies; therefore, their elevation is not specific for hypoprothrombinemia.

First, determine if the prothrombin deficiency is isolated or associated with other factor deficiencies. Determine this status by performing assays for factors VII, IX, and X, which are the other vitamin K–dependent procoagulants.

Performing assays for factor V and VIII activity may also be helpful. Factor V activity is decreased in liver disease and DIC. Factor VIII activity is decreased in disseminated intravascular coagulation (DIC) but not often in liver disease.

If other vitamin K–dependent factors are decreased, rule out vitamin K deficiency, liver disease, or both. Vitamin K and vitamin K epoxide levels can be determined by select clinical laboratories. Warfarin levels can also be directly measured by some commercial clinical laboratories.

If multiple-factor deficiencies include factors other than vitamin K–dependent factors, evaluate the patient for DIC, liver disease, or both.

If isolated factor II deficiency is present, test for an inhibitor by performing a mixing study. In the presence of an inhibitor, the PT is not corrected when the patient's plasma is mixed 1:1 with normal pooled plasma. If an inhibitor is detected, suspect a lupus anticoagulant, which can be detected by using the dilute Russell viper venom test (DRVVT) or the tissue thromboplastin inhibition test. Anticardiolipin antibodies are found in about 60-70% of patients with a lupus anticoagulant. The presence of these antibodies helps to confirm the diagnosis of an antiphospholipid antibody syndrome as well.

In cases of suspected inherited prothrombin deficiency, assessment of factor II activity in family members may be helpful. Numerous research laboratories across the United States can perform tests for factor II antigen levels and screen for mutations in the prothrombin gene.

A study by Kocheril et al looked at five children with SLE and lupus anticoagulant-hypoprothrombinemia syndrome (LAHS). PT and aPTT were prolonged, with all patients in the study having low prothrombin levels and positive lupus anticoagulant. The investigators also found that most of the patients had low C3 and C4 levels, as well as positivity for antinuclear antibodies (ANA) and anti–double-stranded DNA (anti-dsDNA). Anticardiolipin positivity was found in three children, and one patient presented not only with LAHS but also with lupus nephritis. The investigators advised that a high index of suspicion is necessary when bleeding manifestations occur in children with lupus.[9]

Neonates found to have a severe inherited bleeding diathesis should undergo head CT scanning to evaluate for intracranial hemorrhage, regardless of their symptoms or signs.

Head ultrasonography may be used but is not as sensitive as CT scanning.

The bleeding time is not a useful test for evaluating hypoprothrombinemia. The bleeding time may or may not be elevated. Although it is certainly elevated in severe platelet function disorders, the degree of elevation is not predictive of bleeding risk, and its sensitivity for milder forms of platelet dysfunction is poor.

Other means of testing platelet function, such as platelet function assay (PFA) or platelet aggregation testing, are also not helpful in evaluating hypoprothrombinemia. Their use in screening for platelet function disorders has not been fully defined.

Thromboelastography and thrombin generation testing is abnormal in hypoprothrombinemia.

Initial treatment of hypoprothrombinemia is aimed at controlling hemorrhage. Numerous products that provide prothrombin are available. Frozen plasma contains about 1 U/mL of prothrombin. It is readily available and contains other factors that may be useful if the hypoprothrombinemia is associated with multiple factor deficiencies. Concentrates of prothrombin complex (eg, Proplex T, Konyne 80, Bebulin VH, Kcentra, Beriplex P/N, ThromboPlex, Prothrombinex-HT) are concentrated sources of prothrombin. However, these products also contain other vitamin K–dependent factors in high concentration, and use of these products at high doses has been associated with thromboembolic complications. Prothrombin-complex concentrates may contain activated clotting factors, and their use has been associated with thromboembolic complications. No pure concentrate of prothrombin factor is available.

When lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) is associated with systemic lupus erythematosus, treatment with steroids, intravenous immunoglobulin, fresh-frozen plasma, or azathioprine has been successful in reducing lupus anticoagulant levels, in increasing prothrombin levels, and in controlling bleeding. However, prothrombin levels have decreased in some patients when the drugs were tapered.

In vitamin K deficiency and warfarin overdose, vitamin K is the treatment of choice unless clinically significant bleeding is present and quick correction of the coagulopathy is desired. In these cases, use either frozen plasma or a prothrombin-complex concentrate.

The question of prophylactic treatment in patients with hypoprothrombinemia is controversial. No replacement protocols are standard. Prophylaxis has been reserved for patients who have had severe, recurrent episodes of bleeding. Case reports of patients with severe hypoprothrombinemia who were treated weekly with prothrombin-complex concentrates described a reduction in hemorrhagic episodes and improved quality of life.

Surgery could result in clinically significant bleeding in patients with hypoprothrombinemia. Avoid surgery whenever possible. Use concentrates of prothrombin complex in patients with factor II deficiency who require surgery. If an inhibitor is present, attempt to decrease the inhibitor titer before the surgical procedure, if possible.

Patients with hypoprothrombinemia must avoid activities and situations that could result in clinically significant trauma, especially head trauma.

Several variables determine a child's risk of bleeding. Among them are the nature and severity of the trauma, the severity of the bleeding disorder, and the speed at which treatment can be administered.

Risk of bleeding during athletic activity increases as the level of competition increases and as the likelihood of collision at top running speed increases.

The National Hemophilia Foundation has published guidelines regarding athletic activity in people with bleeding disorders.

The treatment of hypoprothrombinemia depends on the underlying etiology. Numerous products that provide prothrombin are available.

Class Summary

Vitamin K can be administered intravenously or orally. Slowly administer intravenous infusions over 10-20 minutes. In addition, premedicating the patient with diphenhydramine (Benadryl) may be helpful. The only current oral formulation of vitamin K available in the United States is in tablet form; however, a liquid formulation has been developed and is currently being used in Europe and Japan.

Acquired hypoprothrombinemia due to vitamin K deficiency is treated with vitamin K1 (phytonadione). In the presence of severe or life-threatening bleeding, frozen plasma or prothrombin-complex concentrates are administered to immediately increase the levels of vitamin K–dependent coagulation factors. Other clotting factors (eg, concentrate of clotting factors II, VII, IX, and X [Proplex T]) may also be required. Solvent-detergent–treated frozen plasma is now available.

Epsilon aminocaproic acid (Amicar) can be used to minimize the severity of mucosal bleeding and enhances hemostasis when fibrinolysis contributes to bleeding. Amicar is especially useful in acquired hypoprothrombinemia secondary to anti–factor II circulating antibodies because of the immediate neutralization of prothrombin upon infusing plasma or prothrombin-complex concentrates.

For inherited hypoprothrombinemia, concentrates of prothrombin complex (eg, Autoplex T) are used. No recombinant factor II product is available.

Aminocaproic acid (Amicar)

A 6-aminohexanoic acid that inhibits fibrinolysis by inhibiting plasminogen activator substances and, to some degree, antiplasmin activity.

Anti-inhibitor coagulant complex (Feiba VH Immuno)

Prothrombin-complex concentrates contain vitamin K–dependent clotting factors. Prepared from pooled normal human plasma. Some products contain more activated factors than others. Presence of activated factors increases risk of thromboembolic complications.

Phytonadione (AquaMEPHYTON, Mephyton)

Promotes liver synthesis of clotting factors. Aqueous colloidal solution of vitamin K1 for parenteral injection. This form has same activity as naturally occurring vitamin K. Vitamin K is essential cofactor for microsomal enzyme that catalyzes posttranslational carboxylation of several specific peptide-bound glutamic acid residues in inactive hepatic precursors of vitamin K–dependent factors. Results in gamma-carboxyglutamic acid residues necessary for calcium-dependent phospholipid membrane binding.

Fresh frozen plasma

Plasma is fluid compartment of blood that contains soluble clotting factors. For use in patients with deficiencies of blood products. Indications include bleeding in patients with congenital coagulation defects and deficiencies of multiple coagulation factors (severe liver disease).

Patients with inherited prothrombin deficiency should receive follow up with a hematologist at a comprehensive center that cares for patients with bleeding disorders. Follow-up should occur on a yearly basis as a minimum.

A hematologist should initially evaluate patients with acquired hypoprothrombinemia. Follow-up care depends on the underlying cause.

Patients with lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) after a viral infection can be expected to spontaneously recover. For example, in a study of children with LAHS, involving two cases studies and a literature review, Sarker et al reported that children with LAHS associated with autoimmune conditions had a prolonged disease course and required an extended period of immunosuppressive treatment. In contrast, children with LAHS related to viral infections either experienced spontaneous disease resolution or required only a short course of immunomodulating therapy.[10]

Few patients with systemic lupus erythematosus–associated LAHS (most cases) have spontaneously recovered. Immunosuppressive therapy successfully controls bleeding and increases prothrombin levels in most patients, though some have had a recurrence of symptoms when drug therapy was tapered.

The prognosis for patients with inherited prothrombin deficiency varies. The degree of deficiency does not always predict the clinical course, as patients with severe deficiency with only mild bleeding tendencies have been reported. Impairment of the procoagulant and anticoagulant activities of prothrombin are speculated to result in a delicate coagulation balance in patients who have mild or no symptoms.