Other inherited coagulation factor deficiencies
What every physician needs to know:
Inherited deficiencies of coagulation factors, other than hemophilia A and B and von Willebrand disease, are rare bleeding disorders transmitted in an autosomal recessive pattern. The majority of symptomatic patients are homozygous or compound heterozygous with higher prevalences in certain communities (i.e., factor Xl (FXl) deficiency in Ashkenazi Jews) or where consanguineous marriages are common.
The bleeding tendency in these deficiencies can be variable and is usually related to the extent of the deficiency. Some mutations can give rise to dysfunctional proteins (as for factors II, VII and X), whereas for factors V, XI and XIII true protein deficiencies can be found. Up-to-date registries of mutations can be obtained from the International Society of Thrombosis and Haemostasis, the Human Gene Mutation Database or the International Registry of Rare Bleeding Disorders (see references at the end of this chapter for web addresses).
Are you sure your patient has one of the other inherited coagulation factor deficiencies? What should you expect to find?
The most common symptoms in rare inherited factor deficiencies occur during or after surgical procedures (i.e., dental extractions, circumcision). In women, menorrhagia and postpartum hemorrhage are common. It is important to note that the relationship between baseline clotting factor levels and the clinical picture of hemorrhage is sometimes weak. However, some symptoms are more common in specific deficiencies:
Umbilical stump bleeding, hemarthroses, retroperitoneal and soft tissue bleeding, and intracranial hemorrhage tend to occur with higher frequency in patients with afibrinogenemia, or with factor (F) II, X or XIII deficiency.
Poor wound healing due to abnormal fibrin crosslinking and increased sensitivity to fibrinolysis is typical of FXIII deficiency.
Miscarriages have been reported in females with afibrinogenemia, as well as prothrombin and FXIII deficiency.
Individuals with combined deficiency of the vitamin K-dependent factors (II, VII, IX, X, proteins C and S), although rare, can present with umbilical stump bleeding and intracerebral hemorrhage.
Factor V deficiency can present with mild, moderate and severe bleeding. Patients with a factor level <1% usually develop symptoms within the first years of life. Hemarthroses may occur, but is usually traumatic in origin. Patients with FV levels above 20% are usually asymptomatic and, in many cases, not diagnosed until adulthood.
Clinical manifestations in patients with FVII deficiency vary from one patient to another with a poor correlation between baseline factor level and bleeding symptoms. In general, individuals with factor VII levels between 2-10% have mild bleeding symptoms (easy bruising and mucocutaneous bleeding, including menorrhagia). Postoperative bleeding is common, but not predictable. Those with FVII levels < 1% tend to have bleeding equivalent to that seen in hemophilia A and B, with hemarthroses, chronic arthropathy, retroperitoneal bleeding, and cerebral hemorrhage. There are occasional patients with factor VII levels < 1% whose bleeding manifestations can be mild or non-existent.
In Factor XI deficient individuals, bleeding is usually related to trauma or surgery. It is more likely to occur in homozygotes and compound heterozygotes within tissues rich in fibrinolytic activity – especially the oral/pharyngeal/nasal cavity and urinary tract. Heterozygous individuals tend to have milder bleeding. Postpartum hemorrhage can occur in up to one fourth of affected women. Inhibitors to FXI have been described in patients with severe factor XI deficiency who have received plasma replacement therapy.
The contact factors
Individuals with a deficiency of any of the contact factors (factor XII, high molecular weight kininogen, prekallikrein) do not have a bleeding tendency, even during major surgery or trauma, and do not require replacement therapy.
Dysfibrinogenemia can be associated with thrombosis in approximately 20% of cases.
Beware of other conditions that can mimic the other inherited coagulation factor deficiencies.
Acquired fibrinogen abnormalities must be excluded. Disseminated intravascular coagulation (DIC) can present with low levels of fibrinogen, but usually other coagulation factors and platelets are also decreased. In patients with liver disease, acquired hypofibrinogenemia can occur.
Prothrombin deficiency must be distinguished from other congenital coagulation deficiencies that prolong the prothrombin time (PT) and activated partial thromboplastin time (aPTT), such as fibrinogen, factor V, and factor X. Acquired prothrombin deficiency can be seen in patients with liver disease, vitamin K deficiency and with the administration of vitamin K antagonists. Low levels of prothrombin can also be seen in patients treated with antibiotics containing the N-methyl-thiotetrazole (NMTT) side chain (i.e., third generation cephalosporins) that inhibit the vitamin K-dependent gamma-carboxylation of glutamic acid residues required for production of normal prothrombin.
Acquired antibodies against prothrombin are rare but can be seen in patients with the lupus anticoagulant or antiphospholipid syndrome, producing an accelerated clearance of prothrombin in antibody-prothrombin complexes.
Congenital factor V deficiency can occur in combination with congenital factor VIII deficiency. This is type I familial combined factor deficiency (FCFD). Acquired factor V deficiency may be seen in patients with advanced liver disease or DIC.
FCFD type II – Combined factor deficiency of FVIII and FIX.
Vitamin K deficiency, warfarin use, and liver disease are the most common causes of acquired factor VII deficiency. It can also be seen in other rare familial combined factor deficiencies such as:
FCFD type III – combined deficiency of all the vitamin K-dependent factors [FII, FVII, FIX, FX, and proteins C and S];
FCFD type IV – combined deficiency of FVII with FVIII.
Isolated acquired factor X deficiency can sometimes be seen in patients with amyloidosis due to absorption of factor X onto amyloid fibrils. It has also been reported in association with infections, malignancies, and exposure to certain chemicals.
Congenital factor XI deficiency is also part of the familial combined factor deficiencies type V and type Vl:
type V – combined deficiencies of FVlll, FlX, and FXl;
type VI – combined deficiencies of FlX and FXI.
It can also be associated with other diseases, including the enigmatic Noonan syndrome, von Willebrand disease, and factor VIII deficiency.
Acquired antibodies against FXIII have been reported in individuals without a congenital deficiency. These antibodies have been described in patients taking isoniazid, penicillin, and phenytoin, but they may be idiopathic.
Which individuals are most at risk for developing other inherited coagulation factor deficiencies?
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Screening tests of coagulation – the PT (prothrombin time) and aPTT (activated partial thromboplastin time) – are usually sufficient to identify clinically significant inherited coagulation deficiencies. The aPTT is usually abnormal with factor deficiencies of <0.3 to 0.4 U/mL. Specific factor assays should be performed when there is strong suspicion of a deficiency.
An isolated prolongation of the PT is indicative of factor VII deficiency.
A prolonged aPTT with a normal PT suggests a deficiency of factor VIII, IX, XI or XII, or an inhibitor to one of these factors. The inhibitor can be either factor specific (i.e., antibody against FVIII) or factor non-specific, such as a lupus anticoagulant.
In cases where there is prolongation of both PT and aPTT, a single deficiency of fibrinogen, prothrombin, factor V, or factor X may be present, or an inhibitor to one of these factors, or a combined factor deficiency.
In asymptomatic individuals with a prolonged aPTT, defects of the contact phase should be ruled out by specific assays (Table I)
To differentiate between a factor deficiency and the presence of an inhibitor against one of the coagulation factors, a “mixing study” of the PT or aPTT combining the patient’s plasma with a similar volume of normal plasma is useful. If the mixture normalizes the prolonged PT or aPTT, a deficiency is likely. If the mixture remains prolonged, an inhibitor is probably present.
Screening tests (PT, aPTT) are usually normal in subjects with FXIII deficiency. The thrombin time (TT) occasionally may be prolonged. Solubility of the fibrin clot in 5 M urea or 1% monochloroacetic acid indicates that FXIII deficiency is likely.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of other inherited coagulation factor deficiencies?
If you decide the patient has one of the other inherited coagulation factor deficiencies, what therapies should you initiate immediately?
Replacement therapy in patients with rare congenital deficiencies consists mainly of the administration of plasma when concentrates are not available. Specific recommendations are based on the hemostatic level necessary for each factor and the plasma half-life, as described inTable I and Table II .
Either purified fibrinogen concentrate or cryoprecipitate is the treatment of choice as prophylaxis or for bleeding episodes in afibrinogenemia or hypofibrinogenemia. Prothrombin complex concentrates (PCCs) contain coagulation factors II, VII, IX, and X, and are an alternative to fresh-frozen plasma (FFP) for major bleeding or as prophylactic treatment before surgery. Although these concentrates are plasma derived, they are rarely associated with the transmission of pathogens; however, they have been associated with thromboembolic complications. Therefore, the minimal dose required for hemostasis should be used (see Table II.
No commercial factor V concentrate is available, and so fresh-frozen plasma is the treatment of choice.
For minor bleeding, an anti-fibrinolytic agent may be sufficient.
Recombinant FVIIa is now the treatment of choice for factor VII deficiency. Doses of 15–30 micrograms per kilogram of body weight are sufficient for hemostasis.
Patients with severe FXI deficiency usually require replacement therapy with plasma or FXI concentrates. These concentrates are available in Europe, but not in the United States; however, they can be associated with thrombosis and laboratory signs of DIC. Activated prothrombin complex and recombinant FVIIa have been used successfully in patients who develop inhibitors to FXI and require surgical procedures.
Therapy for the familial combined factor deficiencies consists of fresh-frozen plasma and factor VIII concentrates (type I, II, IV, and V). It may be difficult to raise factor V levels above 30% with plasma infusion without the risk of fluid overload. Therefore, plasma exchange is an option before major surgery.
Replacement therapy for FXIII deficiency can be done using fresh-frozen plasma, cryoprecipitate, or pasteurized plasma concentrates. Because only low levels of factor XIII activity (2–5%) are needed for hemostasis, and the half-life is long (10–14 days), prophylactic therapy is feasible. Prophylaxis with FXIII concentrate can be administered every 5–6 weeks. During pregnancy, plasma can be given every 14 days or FXIII concentrate every 21 days in an effort to prevent fetal loss.
More definitive therapies?
What other therapies are helpful for reducing complications?
For deficiencies that require fresh-frozen plasma as replacement therapy, loading doses of 15–20 ml/kg can be given, followed by 3–6 ml/kg body weight every 24 hours. In patients with prothrombin and factor X deficiency, PCCs can be infused at a dose of 20 to 30 U per kilogram of body weight every 24 hours.
Antifibrinolytic agents – aminocaproic acid or tranexamic acid – can be used alone in mild bleeding episodes or in combination with plasma for more severe hemorrhage.
What should you tell the patient and the family about prognosis?
Bleeding manifestations in these rare congenital deficiencies are more pronounced in homozygous individuals. Heterozygozity may be associated with bleeding during trauma or surgery.
When the diagnosis of a rare congenital deficiency is made in a family member, it is important to notify the patient and offer testing and genetic counselling to other family members.
What if scenarios.
Although these deficiencies are rare, hematologists will be consulted for abnormal coagulation tests. Any prolonged coagulation screening test should be investigated, including taking a detailed personal and family history.
The mode of inheritance of the rare congenital deficiencies is autosomal recessive.Table IIIdescribes the chromosomal location and incidence of these deficiencies.
Selected abnormalities of prothrombin, factor VII and factor X are listed inTable IV, Table V, Table VI, respectively. The clinical severity of bleeding depends on the particular defect. Homozygous and double heterozygous individuals represent the majority of the symptomatic cases.
What other clinical manifestations may help me to diagnose other inherited coagulation factor deficiencies?
What other additional laboratory studies may be ordered?
Definitive diagnosis of the rare congenital coagulation deficiencies requires specific assays to measure the functional activity of one or more coagulation factors. These assays are available in most coagulation laboratories.
Immunologic (antigenic) assays can be performed, usually in association with functional assays, in order to assess quantitative or qualitative abnormalities in clotting factor proteins.
A quantitative factor XIII assay should be done if the (screening) clot solubility test is abnormal. This test is not available in many hospital laboratories.
Sequencing of coagulation factor molecules or genomic analysis requires specialized techniques that are not routinely available in clinical laboratories.
What’s the evidence?
“International Society of Thrombosis and Haemostasis. Registries and Databases”. (A comprehensive database of coagulation and platelet proteins and genes with protein features, reference sequences, and locus specific mutation database links.)
“HGMD Professional. The Human Gene Mutation Database”. (The Human Gene Mutation Database includes a vast repertoire of mutations causing or associated with human inherited disease, in addition to disease-associated polymorphisms reported in the literature. This is an excellent source of information.)
“International Registry of Rare Bleeding Disorders. Rare Bleeding disorder database”. (Since 1996 this international network has investigated patients with rare bleeding disorders from multiple countries. There is a collection of considerable amount of clinical, laboratory and treatment data from approximately 400 patients.)
Bolton-Maggs, PHB, Perry, DJ, Chalmers, A, Parapia, LA. “The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organization”. . vol. 10. 2004. pp. 593-628. (General recommendations from UK experts for the treatment of rare inherited coagulation disorders.)
Acharya, SS, Coughlin, A, Dimichele, DM. “Rare bleeding disorder registry: deficiencies of factorsII, V, VII, X, XII, fibrinogen and dysfibrinogenemias”. . vol. 2. 2004. pp. 248-56. (Comprehensive North American registry on rare inherited bleeding disorders. Information about prevalence, clinical manifestations, treatment and prophylaxis strategies and related complications described in 294 individuals.)
Lechler, E. “Use of prothrombin complex concentrates for prophylaxis and treatment of bleeding episodes in patients with hereditary deficiency of prothrombin, factor VII, factor X, protein C, protein S, or protein Z”. . vol. 95. 1999. pp. S39-50. (General recommendations on the use of prothrombin complex concentrates for the management of patients with congenital deficiencies of rare coagulation disorders.)
Roberts, HR, Escobar, MA, Hoffman, R, Benz, EJ, Shattil, SJ. “Other clotting factor deficiencies”. Hematology: Basic Principles and Practice. vol. 2081. 2005. pp. 95(Concise review of the rare congenital coagulation deficiencies. Easy to read and illustrated with multiple tables.)
Asselta, R, Tenchini, ML, Duga, S. “Inherited defects of coagulation factor V: the hemorrhagic side”. . vol. 4. 2006. pp. 26-34. (Concise description on the structural, procoagulant and anticoagulant properties of the factor V gene. Bleeding disorders associated with this deficiency are also described.)
Giansily-Blaizot, M, Verdier, R, Biron-Adreani, C. “Analysis of biological phenotypes from 42 patients with inherited factor VII deficiency: can biological tests predict the bleeding risk?”. . vol. 89. 2004. pp. 704-9 . (This is a retrospective study of 42 patients with congenital FVII deficiency were FVII and FVIIa levels are used as possible predictors of bleeding phenotype.)
Asakai, R, Chung, DW, Davie, EW, Seligsohn, U. “Factor XI deficiency in Ashkenazi Jews in Israel”. . vol. 325. 1991. pp. 153-8. (This study describes 102 Ashkenazi Jew patients with FXI deficiency and their mutations, plasma levels and bleeding phenotype.)
Zhang, B, Ginsburg, D. “Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders”. . vol. 2. 2004. pp. 1564-1572. (This paper provides an overview of the current understanding of the molecular mechanisms underlying the combined deficiency of vitamin K depending clotting factors and the combined deficiency of factors V and VIII.)
Escobar, M.A, Roberts, H.R.. “Less Common Congenital Disorders of Hemostasis, in Consultative Hemostasis and Thrombosis, CS Kitchens,”. 2013. (This chapter provides and excellent overview of the multiple inherited coagulation deficiencies including disorders of fibrinogen, prothrombin, factorsV, VII, X, and XI. In addition the non-bleeding disorders associated with deficienciesofFXII, prekallikrein and high molecular weight kininogen. Also rare deficiencies of FXIII,alpha-2-plasmin inhibitor, alpha-1-antitrypsin Pittsburg and protein Z are described.)
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- Other inherited coagulation factor deficiencies
- What every physician needs to know:
- Are you sure your patient has one of the other inherited coagulation factor deficiencies? What should you expect to find?
- Beware of other conditions that can mimic the other inherited coagulation factor deficiencies.
- Which individuals are most at risk for developing other inherited coagulation factor deficiencies?
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of other inherited coagulation factor deficiencies?
- If you decide the patient has one of the other inherited coagulation factor deficiencies, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose other inherited coagulation factor deficiencies?
- What other additional laboratory studies may be ordered?
- What’s the evidence?