Rare Inherited Coagulation Disorders Other than Hemophilia

Pier Mannuccio Mannucci

Flora Peyvandi

Massimo Franchini

The rare inherited coagulation disorders (RICDs), usually transmitted in an autosomal recessive fashion, represent 3% to 5% of all the inherited deficiencies of coagulation factors and include fibrinogen, factor (F)II, FV, FV+FVIII, FVII, FX, FXI, FXIII, and the multiple deficiency of vitamin K-dependent factors.¹^,² Their distribution is variable in the world, with a prevalence in the general population of the presumably homozygous forms ranging from approximately 1 in 2 million for prothrombin (FII) to 1 in 500,000 for FVII deficiency (the most common) (Table 53.1).³ In countries with large Jewish communities, FXI deficiency is more prevalent. In Middle Eastern countries and Southern India, where consanguineous marriages are customary, autosomal recessive traits occur more frequently in the homozygous state.⁴

Data on the distribution of patients affected by RICDs are limited. Given their rarity, few centers have the possibility to follow and manage a consistent number of patients, so that scientific reports are usually limited to small numbers. Two recent large registries help to derive the worldwide distribution of RICDs: one by the World Federation of Haemophilia (WFH, www.wfh. org) and the other by the International Rare Bleeding Disorders Database (RBDD, www.rbdd.org).⁵ The WFH database, which started in 1998 but collected information since 2004, includes information from 108 countries (2008 update), while the RBDD, developed in 2004, reports data from 68 countries. According to these registries, FXI and FVII deficiencies are the most prevalent RICD worldwide, with frequencies of 29% and 33% of the total RICDs, followed by FX (9%), fibrinogen (8%), FV (8%), FXIII (6%), and combined FV+FVIII (5%) and FII deficiencies (2%) (FIGURE 53.1).⁶ These results were also confirmed by smaller national registries, such as those of Central and South America, Egypt, France, India, Iran, and the United Kingdom.

There are considerable variations in bleeding patterns among patients with RICDs, but on the whole, bleeding manifestations affecting critical organs such as the central nervous and musculoskeletal systems appear to be less frequent than in hemophilia A and B.⁷ The laboratory diagnosis of RICDs is carried out by means of screening tests such as the activated partial thromboplastin time (APTT), the prothrombin time (PT), and the thrombin time (TT) in subjects reporting a clinical and family history of bleeding (Table 53.1).⁴ Abnormal results of screening tests should be followed by coagulation factor assays, in order to specify the diagnosis. Molecular diagnosis is based on the search of mutations in the genes encoding the corresponding coagulation factors. Exceptions are the combined deficiency of FV and FVIII, caused by mutations in genes encoding proteins involved in the intracellular transport of FV and FVIII (multiple coagulation factor deficiency 2 [MCFD2] and lectin mannose binding protein 1 [LMAN1]), and the combined deficiency of vitamin K-dependent proteins (FII, FVII, FIX, and FX), caused by mutations in genes that encode enzymes involved in posttranslational modifications and in vitamin K metabolism (γ-glutamyl carboxylase [GGCX] and vitamin K epoxide reductase [VKOR]). Genetic analysis is important mainly for prenatal and preimplantation genetic diagnosis, especially in countries with a high rate of RICDs and consanguinity.⁸ Because it is not always clear whether or not the identified mutation is the cause of the deficiency of a clotting factor, family history associated with allele frequency in the general population is important to rule out that the identified mutations are common polymorphisms.⁷

Treatment of RICDs is a difficult task, because information on the clinical management of RICDs is often scarce and replacement therapy of coagulation factors may require unlicensed products that are not readily available.⁹^,¹⁰ The patients’ personal and family history of bleeding are important guides for management.⁹ Dosages and frequency of replacement therapy with products containing the deficient factor depend on the minimal hemostatic level of the factor, its plasma half-life, and the type of bleeding episode. Unfortunately, information on the safety and efficacy of the few available products is scarce and experiences from their use are significantly more limited than those available for congenital hemophilia. Other treatments in RICDs are nontransfusional adjuvant drugs (i.e., antifibrinolytic amino acids, estrogen-progestogen).¹⁰

After these general statements on RICD, the next section will deal specifically with each factor deficiency.

FIBRINOGEN DEFICIENCY

Fibrinogen is a 340 kDa protein synthesized in the liver, with a plasma concentration of approximately 1.5 to 3.5 g/L and a half-life of approximately 4 days (Table 53.1). The fibrinogen molecule is a homodimer, each half consisting of the three nonidentical polypeptide chains Aα, Bβ, and γ. The genes encoding fibrinogen Bβ (FGB), Aα (FGA), and γ (FGG), ordered from centromere to telomere, are clustered on chromosome 4 in a region of approximately 50 kb (Table 53.1). Fibrin is produced by proteolytic cleavage of fibrinogen by thrombin, with the release of fibrinopeptides A and B and generation of insoluble fibrin monomer followed by polymerization. Fibrinogen is also important in primary hemostasis through its ability to support normal platelet aggregation.⁹

Fibrinogen deficiency is heterogeneous and two main phenotypes can be distinguished. In some cases, plasma and platelet levels of the protein are not measurable or very low, leading to afibrinogenemia and hypofibrinogenemia. In other cases,
low clottable fibrinogen contrasts with normal or moderately reduced fibrinogen antigen, causing dysfibrinogenemia and hypodysfibrinogenemia.³

Table 53.1 Epidemiologic, molecular, and laboratory characteristics of rare inherited bleeding disorders

					Coagulation Assays
Deficiency	Estimated Prevalence	Gene on Chromosome	Minimum Hemostatic Levels	Plasma Half-life	PT	PTT	TT
Fibrinogen	1:1,000,000	4	50 mg/dL	2-4 d	↑	↑	↑
Prothrombin	1:2,000,000	11	20%-30%	3-4 d	↑	↑	N
Factor V	1:1,000,000	1	15%-20%	36 h	↑	↑	N
Combined factor V+VIII	1:1,000,000	18 (LMAN1) 2 (MCFD2)	15%-20%	FV 36 h FVIII 12-14 h	↑	↑	N
Factor VII	1:500,000	13	15%-20%	4-6 h	↑	N	N
Factor X	1:1,000,000	13	15%-20%	40-60 h	↑	↑	N
Factor XI	1:1,000,000	4	15%-20%	40-70 h	N	↑	N
Factor XIII	1:2,000,000	6 (FXIII-A) 1 (FXIII-B)	2%-5%	11-14 d	N	N	N
Vitamin K-dependent coagulation factors	Reported in about 30 families	2 (GGCX) 16 (VKORC1)	15%-20%	See corresponding factors	↑	↑	N
PT, prothrombin time; APTT, activated partial thromboplastin time; TT, thrombin time.

Mutation Analysis

A homozygous deletion of approximately 11 kb of the FGA as a cause of inherited afibrinogenemia was for the first time identified by Neerman-Arbez et al.¹¹ in four members of a Swiss family. Since then many other mutations have been identified in afibrinogenemia (in homozygosity or in compound heterozygosity) or hypofibrinogenemia.⁸ While the majority of mutations are in the FGA gene, missense mutations leading to complete fibrinogen deficiency appear to be clustered in the highly conserved C-terminal globular domains of the Bβ and γ chains. Recent functional studies of these mutations in transfected cells have demonstrated either impaired assembly or secretion of the fibrinogen hexamer. To date, only two missense mutations located at the start of the coiled coil in FGA (Cys64Phe and Met70Arg) were found in fibrinogen deficiency.¹²^,¹³

FIGURE 53.1 Prevalence of RICDs derived from RBDD (green-filled bars) and WFH (yellow-filled bars) registries.

Besides the large number of rare, individual mutations identified in congenital afibrinogenemia, two common mutations were found in individuals of European origin, both in FGA: the Asp153SerfsX4 mutation and the FGA 11-kb deletion, both on multiple haplotypes. Two further residues of interest in screening for dysfibrinogenemia are residue Arg16 in exon 2 on FGA, which is part of the thrombin cleavage site in the fibrinogen Aα chain, and residue Arg275 in exon 8 on FGG, which is important for fibrin polymerization.¹⁴

Clinical Phenotype and Treatment

Whereas the majority of patients with dysfibrinogenemia do not bleed at all, afibrinogenemic patients have a bleeding tendency that may manifest in the neonatal period, with 85% of cases presenting with umbilical cord bleeding.¹⁵ Bleeding may also occur in the skin, gastrointestinal tract, or central nervous system, while recurrent joint and muscle bleeding leading to persistent damage to the musculoskeletal system is less frequent. Clinically milder symptoms such as epistaxis and menorrhagia are also frequent. First trimester abortion is common in afibrinogenemic women, less common in dysfibrinogenemia, and not reported so far in hypofibrinogenemia.¹⁶^,¹⁷ Postpartum bleeding is relatively frequent when no prophylactic replacement therapy is given. On the whole, bleeding problems are often not dramatic in patients with afibrinogenemia, despite the fact that screening coagulation tests (PT, APTT) usually result in no clot formation and that the skin bleeding time is prolonged.²

Both arterial and venous thromboembolic complications have been reported in afibrinogenemic patients, in spite of the fact that in the majority of patients no traditional thrombotic risk factors were present. One possible but as yet unproven explanation for this predisposition is that even in the absence of fibrinogen platelet aggregation does occur due to the action of von Willebrand factor. Moreover, in contrast to hemophiliacs, afibrinogenemic patients are able to generate thrombin, both in the initial phase of limited production and in the secondary burst of greater thrombin generation.²

Pertaining to replacement therapy, four products are available: fresh-frozen plasma (FFP), cryoprecipitate, virus-inactivated FFP, and fibrinogen concentrate. Safety commands avoidance of the first two if possible, because they are not virus inactivated. The latter is the treatment of choice, because it is virally inactivated and thus safer than cryoprecipitate or FFP and does not cause volume overload.¹⁸^,¹⁹ The conventional mode of treatment delivery is episodic and on demand, with fibrinogen administered as soon as possible after onset of bleeding. Long-term secondary prophylaxis (made possible thanks to the relatively long half-life of fibrinogen) with administration of fibrinogen every 7 to 14 days (particularly after central nervous system hemorrhages) has been proposed (Table 53.2). Prophylactic therapy also appears to be necessary for successful completion of pregnancy: fibrinogen replacement must begin at least at 5 weeks gestation to prevent abortion and to maintain fibrinogen
levels at >1.0 g/L throughout pregnancy (a level of >1.5 g/L is recommended for delivery).¹⁷

Table 53.2 Treatment of inherited coagulation disorders

Deficient Factor

On Demand

Surgery

Long-term Prophylaxis

Fibrinogen

SD-treated plasma (15-20 mL/kg)

Fibrinogen concentrate (50-100 mg/kg)

Target level: 50-100 mg/dL

Fibrinogen concentrate (50-100 mg/kg)

Minimum level: 100 mg/dL

Fibrinogen concentrate (30-100 mg/kg every week)

Target level: 50-100 mg/dL

Prothrombin

SD-treated plasma (15-20 mL/kg)

PCC (20-30 U/kg)

Target level: 20%-30%

SD-treated plasma (15-20 mL/kg)

PCC (20-30 U/kg)

Minimum level: 20%-40%

PCC (25-40 U/kg every week)

Target level: 20%-30%

Factor V

Factor V+VIII

SD-treated plasma (15-20 mL/kg)

Target level: 10%-20%

SD-treated plasma (15-20 mL/kg)

Minimum level: 25%

No data available

Factor VII

FVII concentrate (30-40 mL/kg)

PCC (20-30 U/kg)

rFVIIa (15-30 µg/kg every 4-6 h)

Target level: 10%-15%

FVII concentrate (30-40 mL/kg)

PCC (20-30 U/kg)

rFVIIa (15-30 µg/kg every 4-6 h)

Minimum level: 10%-15%

FVII concentrate (30-40 mL/kg, three times per week)

rFVIIa (10-20 µg/kg, two to three times per week)

Target level: 10%-15%

Factor X

SD-treated plasma (10-20 mL/kg)

PCC (20-30 U/kg)

FX/FIX concentrate (10-20 U/kg)

Target level: 10%-20%

SD-treated plasma (10-20 mL/kg)

PCC (20-30 U/kg)

FX/FIX concentrate (10-20 U/kg)

Minimum level: 10%-20%

PCC (30-40 U/kg, two to three times per week)

FX/FIX concentrate (20-40 U/kg, one to two times per week)

Target level: 10%-20%

Factor XI

SD-treated plasma (15-20 mL/kg a.d.)

FXI concentrate (15-20 U/kg a.d.)

Target level: 15%-20%

Antifibrinolytic agents (250 mg/d)

SD-treated plasma (15-20 mL/kg a.d.)

FXI concentrate (15-20 U/kg a.d.)

Minimum level: 15%-20%

No data available

Factor XIII

SD-treated plasma (3 mL/kg)

FXIII concentrate (10-20 U/kg)

Target level: 2%-5%

SD-treated plasma (3 mL/kg)

FXIII concentrate (10-20 U/kg)

Minimum level: 5%-10%

SD-treated plasma (15-20 mL/kg every 4-6 wk)

FXIII concentrate (10 U/kg every 4-6 wk)

Target level: 2%-5%

VKCFD

Vitamin K (10 mg i.v. or s.c.)

SD-treated plasma (15-20 mL/kg)

Target level: 20%-30%

Vitamin K (10 mg i.v. or s.c.)

SD-treated plasma (15-20 mL/kg)

Minimum level: 20%-30%

Vitamin K (10 mg orally every week)

SD, solvent/detergent; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated factor VII; VKCFD, vitamin K-dependent coagulation factors deficiency; i.v., intravenously; s.c., subcutaneously; a.d., alternate days..

PROTHROMBIN DEFICIENCY

Prothrombin (FII) is a 72 kDa single-chain glycoprotein synthesized by the liver. It is one of the vitamin K-dependent coagulation factors and requires posttranslational carboxylation to become functionally active. Prothrombin consists of four domains—the Gla domain, kringle 1 and kringle 2 domains, and a serine protease domain—and is encoded by a gene of approximately 21 kb located on chromosome 11. FXa activates prothrombin on the surface of platelets in the presence of FV and calcium. During prothrombin cleavage, the activation peptide fragment 1 + 2 is released.²⁰

Prothrombin deficiency is probably the rarest inherited bleeding disorder, with an estimated prevalence of 1:2,000,000 in the general population.⁴ Based on the measurement of prothrombin (FII) activity and antigen level in plasma, two main phenotypes are distinguished: hypoprothrombinemia (both levels are concomitantly low) and dysprothrombinemia (normal or near normal synthesis of a dysfunctional protein).²⁰ No living patient with undetectable plasma prothrombin has been reported so far, consistent with the demonstration that in mice complete prothrombin deficiency by gene knockout is incompatible with life, resulting in embryonic or neonatal lethality.²¹

Mutation Analysis

Genetic variants were identified all along the prothrombin gene, although frequently they involve the catalytic site, consistent with the fact that they affect the enzymatic activity of the protein.²² Mutations in different exons may cause similar phenotypic expression of prothrombin. Most of the mutant prothrombins derive from missense mutations (80%), although insertion/deletions (10%), nonsense (6%), and splice-site (4%) mutations have also been described. The abnormalities may be classified according to the site of the defects: (a) in the activation mechanism or (b) in the protease activity of thrombin. The latter can in turn be subdivided into two subtypes: one in which there is defective amidolytic activity and another in which there is a defective interaction of thrombin with substrates because of mutations in the molecular recognition domains.²³ Other mutations indirectly affect the catalytic activity of thrombin, by perturbating of the Na⁺ binding site of the enzyme. However, while in vitro Na⁺ binding seems to play a major role in thrombin activity, the natural mutant prothrombins with altered Na⁺ binding described so far (Arg517Gln and Lys556Thr, in exon 13 and 14, respectively) had only a mild hemorrhagic phenotype.²⁴ Recent biochemical characterization of the mutants Des-Lys9/10 and Phe299(7)Val revealed an important role of the A-chain for a correct function of the catalytic B-chain of thrombin. Perhaps these natural mutations affect the interaction of divalent metals with thrombin, recently localized at the interface between the A- and B-chain that seem to stabilize the active conformation of thrombin.²⁵^,²⁶

Clinical Phenotype and Treatment

Clinically, heterozygotes with prothrombin deficiency are usually asymptomatic, while homozygotes with activity levels <10% of normal experience severe bleeding manifestations, such as spontaneous hematomas and hemarthroses, intracerebral bleeding, and gastrointestinal hemorrhages. In homozygous women, menorrhagia is frequent.²⁴^,²⁷

Patients with a prothrombin coagulant activity above 20% usually do not require replacement therapy, but antifibrinolytic agents may be considered.²⁸ Replacement therapy is needed only in homozygous patients, in case of bleeding or to ensure adequate prophylaxis of bleeding before surgical procedures. Since no prothrombin concentrate exists, prothrombin complex concentrates (PCCs) are used to treat patients (Table 53.2),²⁰ because in several clinical settings, higher levels of prothrombin may be achieved with PCCs without the harm of potential volume overload induced by FFP. However, all PCCs contain other vitamin K-dependent coagulation factors, which increase unnecessarily in plasma of patients with normal levels and could potentially cause thrombotic complications.

FACTOR V DEFICIENCY

FV is a large glycoprotein of 249 kDa, encoded by a gene on chromosome 1, synthesized by hepatocytes and megakaryocytes (Table 53.1). FV and FVIII have approximately 40% amino acid homology in their respective A and C domains and their overall protein domain structures are identical.²⁹ Platelets contain approximately 20% of total circulating FV.³⁰ FV is activated by thrombin and the resulting heterodimer FVa acts as a cofactor for FXa in the conversion of prothrombin to thrombin.²⁹ FV also contributes to the anticoagulant pathway by downregulating FVIII activity, so that FV deficiency also may rarely result in a thrombotic tendency.³¹^,³² The majority of FV deficient cases are characterized by the concomitant deficiency of FV activity and antigen levels (type I deficiency), but approximately 25% of them have normal antigen levels, indicating the presence of a dysfunctional protein (type II deficiency).

Mutation Analysis

Studies of the molecular basis of severe FV deficiency started in 1998 with the identification of the first causative mutation.³³^,³⁴ So far, a total of 56 genetic defects have been identified.²⁹ Of them, 48 seem to be responsible for the type I deficiency, only one being recurrent (Tyr1702Cys, repeatedly found in Italians), confirming the remarkable allelic heterogeneity of the disease. A mild type I deficiency has also been associated with two FV variants: the functional Met2120Thr polymorphism, which causes about 25% reduction in FV levels, and the HR2 haplotype defined by a group of more than 10 polymorphisms. Among them, the dominant contribution of the Asp2194Gly variant was demonstrated by expression experiments in eukaryotic cells.³⁵ Only one genetic defect associated with type II deficiency Ala221Val has been reported so far.²⁹

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