Rare Coagulopathies: Hereditary Blood Coagulation Factor II, VII, X Deficiency: Clinical Guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

APCC – anti-inhibitor coagulant complex

BT – bleeding time

GI – gastrointestinal tract

PCC – prothrombin complex concentrates – individual drugs from the B02BD group according to the ATC classification: #blood coagulation factors II, VII, IX, and X in combination [prothrombin complex]** and #blood coagulation factors II, IX, and X in combination** (off-label for children – efficacy and safety have not been sufficiently studied)

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

PT – prothrombin time

RBD – rare bleeding disorders

FFP – fresh frozen plasma

TF – tissue factor

TT – thrombin time

CNS – central nervous system

FII – blood coagulation factor II

FVII – blood coagulation factor VII

FVIII – blood coagulation factor VIII

FIX – coagulation factor IX

FX – blood coagulation factor X

ISTH – International Society on Thrombosis and Haemostasis

rFVIIa – eptacog alfa (activated)** (blood coagulation factor VIIa)

Terms and Definitions

Stuart-Prower disease is factor X deficiency.

Hemarthrosis is bleeding into the joint cavity.

Hematoma is a localized accumulation of blood in closed or open injuries of organs and tissues accompanied by vascular rupture, resulting in the formation of a cavity containing liquid or clotted blood.

Hematuria is the presence of red blood cells in the urine above physiological norms.

Hemostatic therapy is therapy aimed at stopping bleeding.

Hypoproconvertinemia is coagulation factor VII deficiency.

Hypoprothrombinemia is coagulation factor II deficiency.

Dysprothrombinemia is functional deficiency of coagulation factor II.

Coagulopathy is a disorder of the blood coagulation system.

Coagulation factor is a protein found in blood plasma and platelets that participates in blood coagulation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hereditary coagulation factor II deficiency (hypoprothrombinemia) is a hemorrhagic disorder characterized by decreased plasma prothrombin activity resulting from genetic defects that cause quantitative (hypoprothrombinemia) or qualitative (dysprothrombinemia) abnormalities of coagulation factor II (FII).

Hereditary coagulation factor VII deficiency (hypoproconvertinemia) is a hemorrhagic disorder resulting from a genetically determined decrease in plasma coagulation factor VII (FVII) activity.

Hereditary coagulation factor X deficiency is a hemorrhagic disorder resulting from a genetically determined quantitative or qualitative defect in FX, leading to a decrease in plasma FX activity [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Rare bleeding disorders (RBDs) refer to monogenic coagulopathies caused by a deficiency of plasma proteins involved in hemostasis, excluding von Willebrand disease and hemophilia A or B. RBDs include hereditary deficiencies or abnormalities of fibrinogen, prothrombin (factor II), and coagulation factors V, VII, X, XI, XII, and XIII. In the vast majority of cases, all these disorders lead to impaired fibrin formation [2].

The causes of RBDs are typically the recessive inheritance of a unique disorder or rare nucleotide variations in genes encoding coagulation factors or in proteins required for post-translational modifications of these factors. RBDs are most prevalent in ethnic groups with high rates of consanguineous marriage due to a higher probability of homozygous carrier state for the gene defect.

Until recently, published reports of RBDs historically consisted of case-control studies or small cohort studies. However, over the past 10 years, several specific registries [2–7] have emerged, improving the understanding of RBDs. The establishment of the international RBD database contributed to the definition of clear laboratory criteria for the severity of most RBDs, which were developed under the auspices of the International Society on Thrombosis and Haemostasis (ISTH) in 2012.

Hereditary coagulation factor II (prothrombin) deficiency is an autosomal recessive disorder. Characteristics: FII is a glycoprotein produced in the liver in the presence of vitamin K. Under the influence of activated coagulation factor X (FXa) in the initiation phase of the coagulation cascade and the prothrombinase complex (amplification phase), it is converted into thrombin. Thrombin, in turn, activates other plasma coagulation proteins and platelets with the ultimate formation of a fibrin clot. In addition, thrombin participates in the activation of coagulation inhibitors and the regulation of fibrinolysis.

FII deficiency is caused by variations in the F2 gene encoding prothrombin. There is no direct correlation between the F2 genotype and the disease phenotype. The hemostatically sufficient level of FII is about 40%. The half-life of FII is approximately 60 hours.

Hereditary coagulation factor VII deficiency is an autosomal recessive disorder. The physiological role of FVII is to initiate blood coagulation at the site of vascular wall injury. In a complex with tissue factor (TF), FVIIa activates FX and FIX, which are involved in thrombin generation.

The half-life of FVII is 4–6 hours. A sufficient hemostatic level is at least 10%. In severe trauma, clinically significant bleeding may develop even when FVII activity exceeds 20%.

Hereditary coagulation factor X deficiency is an autosomal recessive disorder. FX activation occurs in the initiation phase of blood coagulation with the participation of the TF-FVIIa complex and in the amplification phase with the tenase complex. Activated FX (FXa) and its cofactor, coagulation factor V (FV), form part of the prothrombinase complex, which activates prothrombin.

The half-life of FX is 30–50 hours. Sufficient hemostatic level: bleeding is not observed in individuals with FX activity >40% [8].

1.3 Epidemiology of the Disease or Condition

The prevalence of hereditary coagulation factor II (prothrombin) deficiency in most countries is 1:2,000,000 of the population.

The prevalence of hypoproconvertinemia is 1:300,000–500,000 of the population.

The average prevalence of sporadic forms of hereditary coagulation factor X deficiency is 1:1,000,000 of the population [1].

1.4 Features of Coding the Disease or Condition

D68.2 – Hereditary deficiency of other clotting factors

1.5 Classification of the disease or condition

There are 3 severity grades of RBDs depending on the laboratory-determined activity of FII, FVII, and FX (Table 1) [9].

Table 1. RBD severity grades

Severe factor deficiency is generally associated with severe spontaneous bleeding/hemorrhages.

Moderate factor deficiency manifests as mild to moderate spontaneous and post-traumatic bleeding episodes.

Mild forms of factor deficiency are asymptomatic in most cases.

1.6 Clinical presentation of the disease or condition

Bleeding/hemorrhages occurring spontaneously or as a result of trauma are typical for RBDs. The hemorrhagic syndrome manifests as mucosal bleeding (epistaxis, gingival bleeding, tooth socket bleeding), ecchymoses, soft tissue hematomas of various locations, bleeding during and after surgical interventions, menorrhagia, hematuria, and less commonly joint hemorrhages (hemarthrosis). In addition, patients with significant factor deficiencies experience life-threatening bleeding, which includes [8,10,11]:

• CNS bleeding/hemorrhages;

• gastrointestinal bleeding/hemorrhages;

• neck/throat bleeding/hemorrhages;

• retroperitoneal hematoma.

In hypoprothrombinemia with FII activity < 10%, more severe bleeding is typically observed compared to bleeding occurring at FII activity ≥ 10%. In the latter case, mild and moderate mucosal bleeding is most typical. Patients with FII activity less than 4% have not been described.

Dysprothrombinemia is characterized by a weak correlation between the clinical and laboratory phenotypes of the disease. Heterozygous carriers of FII deficiency generally have FII activity in the range of 40–75% with an asymptomatic course of the disease.

In hypoproconvertinemia, approximately 60% of cases are asymptomatic, and the reason for diagnosis is the incidental finding of a prolonged PT. CNS hemorrhages are reported in 3–10% of patients with FVII deficiency.

Severe bleeding is most characteristic when FVII activity is ≤ 1%. Patients with FVII activity > 1% generally experience moderate to mild mucosal bleeding or an asymptomatic disease course. However, in some cases, severe manifestations of hemorrhagic syndrome are reported in individuals with FVII activity > 20%, indicating a lack of direct correlation between the clinical and laboratory phenotype of the disease.

Heterozygous carriers of FVII deficiency generally have FVII activity in the range of 40–60% with an asymptomatic course of the disease.

In FX deficiency, severe bleeding is most typical for patients with FX activity ≤ 10%. Patients with FX activity > 10% generally experience moderate to mild mucosal bleeding, post-surgical bleeding, or an asymptomatic disease course. CNS hemorrhages, gastrointestinal mucosal bleeding, and hemarthroses are observed in patients with FX activity ≤ 2%. Nevertheless, in some cases, severe manifestations of hemorrhagic syndrome are reported in individuals with FX activity of 0.1–39%, thus indicating a lack of direct correlation between the clinical and laboratory phenotype of the disease.

In heterozygous carriers of FX deficiency, FX activity is typically around 50%, and the disease has an asymptomatic course [8].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: the following criteria must be used to diagnose inherited factor II, VII, and X deficiencies, regardless of the presence of hemorrhagic syndrome in the personal or family history [8,9,12–16]:

1. absence of data indicating acquired coagulation factor deficiency;

2. decrease in FII/FVII/FX activity below reference values;

3. presence of FII, FVII, or FX gene mutations.

A diagnosis of inherited factor II, VII, and X deficiency is established if at least two of the three aforementioned criteria are met.

2.1 Complaints and Anamnesis

Diagnosis of inherited factor II, VII, and X deficiency begins with the identification of clinical symptoms of a hemorrhagic condition or (in the absence of signs of excessive bleeding) by eliciting a family history of blood coagulation disorders.

Comments: approximately 2/3 of patients have no history of hemorrhagic manifestations in close relatives. Data from the personal history may contain information about hemorrhagic manifestations in the patient. When taking the disease history, attention should be paid to the presence of hemorrhagic manifestations in the neonatal period in the form of cephalhematomas, intracranial hemorrhages, bleeding and prolonged healing of the umbilical stump; in infants – ecchymoses unrelated to significant trauma, soft tissue hematomas after minor bruises, or spontaneous hematomas. It is important to pay attention to the discrepancy between the severity of hemorrhagic manifestations and the severity of preceding trauma, relapses of bleeding after primary cessation not associated with re-trauma, massive and/or multiple hematomas, and the systemic nature of hemorrhagic manifestations (manifestations of various localizations). In individuals with minor coagulation factor deficiencies, bleeding may be absent until the first trauma or surgical intervention. Collecting complaints and history will help determine the scope of the patient's examination.

2.2 Physical Examination

Comments: detection of signs of joint involvement is unlikely.

2.3 Laboratory Diagnostics

To diagnose inherited factor II, VII, and X deficiency, phased laboratory studies are performed – coagulological screening, factor activity determination, and molecular genetic diagnostics [10,13,14,17,18]. Obtaining the maximum amount of data helps to verify the diagnosis and exclude acquired deficiencies of coagulation factors II, VII, and X, as well as exclude deficiencies of other coagulation factors.

Comments: The screening test parameters for FII, FVII, and FX deficiency are presented in Table 2.

Table 2. Screening coagulological tests for the diagnosis of inherited factor II, VII, and X deficiency

With any prolongation of PT, all types of acquired prothrombin complex factor deficiencies must be excluded, primarily those caused by severe liver pathology, obstructive jaundice, the toxic effect of indirect anticoagulants, and endogenous vitamin K hypovitaminosis.

It should be borne in mind that acquired FII deficiency may occur in antiphospholipid syndrome with the production of antibodies to prothrombin and other blood proteins, which differs from inherited FII deficiency in its clinical course and the presence of antiphospholipid antibodies, as well as in liver and biliary tract diseases, vitamin K deficiency, and the use of vitamin K antagonists. Isolated acquired FVII deficiency is typically due to immune disorders and may be observed in systemic amyloidosis and nephrotic syndrome. Acquired FX deficiency can occur in 9 - 14% of cases in systemic amyloidosis, after severe infections, and in cancer patients.

Comments: The diagnosis of inherited factor II, VII, and X deficiency is considered established when an isolated decrease in the activity of the respective factors — FII, FVII, or FX — is detected.

Comments: to exclude acquired FII, FVII, and FX deficiencies.

2.4 Instrumental Diagnostics

• esophagogastroduodenoscopy,

• joint ultrasound,

• abdominal ultrasound,

• urinary tract ultrasound,

• pelvic ultrasound,

• retroperitoneal ultrasound,

• magnetic resonance imaging of the joint, soft tissues,

• brain magnetic resonance imaging,

• joint X-ray,

• chest computed tomography,

• brain computed tomography,

• endoscopic rhinoscopy,

• sigmoidoscopy,

• colposcopy,

• hysteroscopy,

• colonoscopy.

Level of Recommendations C Level of Evidence 3

Comments: studies allow visualization of bleeding/hemorrhages of various localizations, as well as the identification of complications developed as a result of hemorrhagic manifestations.

2.5 Other Procedures

• traumatologist-orthopedist,

• surgeon,

• urologist,

• neurologist,

• otorhinolaryngologist,

• dentist,

• obstetrician-gynecologist

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: allow the identification of disorders in various organs and systems resulting from current or previous bleeding/hemorrhage.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Comments: #PCCs are administered intravenously. Bolus infusion is used at the rate recommended by the manufacturer. The potency of PCCs is usually indicated according to the activity of the coagulation factor IX (FIX) contained within them. Therefore, it is necessary to separately verify the FII content, which is stated in the instructions. As a rule, PCCs contain approximately equal amounts of FIX, and when calculating the dose and replacement therapy regimen, it must be taken into account that the administration of 1 IU of FII per 1 kg of the patient's body weight increases FII activity by an average of 1.5–1.9% (FII activity recovery – recovery test = 2). The half-life of FII is approximately 60 hours. Thus, the standard therapeutic dose of PCCs of 20–30 IU/kg of the patient's body weight (hereinafter calculated based on FIX) increases plasma FII activity to 40–60%. In patients with active bleeding, this value may be lower [8,13,20,28].

In case of severe bleeding or major surgical interventions in patients with FII deficiency, PCC is prescribed at an initial loading dose of 20–50 IU/kg of the patient's body weight, followed by repeated infusions of the product at a dose of 10–30 IU/kg of the patient's body weight at intervals of 24–48 hours to achieve and maintain FII activity > 20% [29,30].

Comments: there are no reports of the possible development of alloantibodies to FII.

If PCC is unavailable, quarantined fresh frozen plasma (FFP) can be used at a dose of 15–25 ml/kg of the patient's body weight, which increases plasma FII activity to 30–40%. The use of FFP is possible in exceptional cases and should not be standard practice.

Comments: Hemostatic therapy with coagulation factor FVII** (#FVII** off-label in children under 6 years of age) is carried out upon the development of bleeding/hemorrhage at a dose of 20–30 IU/kg of the patient's body weight every 4–6 hours until the hemorrhagic syndrome is stopped. To prevent the occurrence of bleeding, replacement therapy with coagulation factor VII** can be performed at a dose of 10–30 IU/kg of the patient's body weight 3 times a week [36–38].

An alternative to coagulation factor VII** for the treatment of patients with hypoproconvertinemia is #eptacog alfa (activated)** [8,35,36]. To stop mild bleeding, the drug is administered as a single dose of 30–50 mcg/kg of the patient's body weight (off-label dosage) [36]. In the event of moderate or severe bleeding, as well as in cases of a high risk of hemorrhagic complications during and after surgical interventions, repeated administrations of eptacog alfa (activated)** at a dose of 15–30 mcg/kg of the patient's body weight at intervals of 4–6 hours are recommended (usually at least 3 infusions) [8,39].

When performing minor surgical interventions or invasive procedures, the minimum dose of eptacog alfa (activated)** should be 15 mcg/kg of the patient's body weight prior to the procedure and administered at least twice after the procedure with an interval of 4–6 hours [5,35,36].

During surgical treatment, the frequency of drug administration is determined by the scope of the surgical intervention. It is recommended to monitor the prothrombin time (PT) at least once every 12 hours and perform replacement therapy if the INR drops below 1.3.

Comments: The frequency of drug administration is selected individually, taking into account the clinical presentation of the disease. Prophylactic administration of drugs can be either short-term (e.g., in uterine bleeding: #eptacog alfa (activated)** at a dose of 20–40 mcg/kg of the patient's body weight, 3–4 infusions with an interval of 12–24 hours until a clinical response is achieved (off-label dosage) [31], or long-term (e.g., in recurrent hemarthrosis – administration of #coagulation factor VII** at a dose of 20–30 IU/kg of the patient's body weight 3 times a week) [31].

Comments: The efficacy of therapy with coagulation factor VII** and #eptacog alfa (activated)** is identical. There are reports of the potential appearance of alloantibodies to FVII during replacement therapy. Provided equal efficacy and satisfactory individual tolerability, the choice of medicinal product for replacement therapy depends on the availability of an uninterrupted supply of this product to the patient.

Comments: Due to the increased risk of thrombosis when using these products, a repeat injection is possible no earlier than 24 hours after the previous administration.

Comments: The use of FFP is possible in exceptional cases and should not be standard practice.

Comments: Currently, 2 PCC products containing FX are registered in the Russian Federation: PCC – coagulation factors II, VII, IX, and X combination [prothrombin complex]** and coagulation factors II, IX, and X combination**

Comments: PCCs are administered intravenously. A bolus infusion is used at the rate recommended by the manufacturer. PCC potency is usually expressed in terms of the FIX activity it contains. Therefore, it is necessary to separately check the FX content specified in the instructions. PCCs contain FIX and FX in approximately equivalent potency. When PCC is administered at a dose of 1 IU/kg of the patient's body weight, FX activity increases on average by 2% (FX recovery activity – recovery test = 2). Thus, the standard therapeutic dose of #PCC of 30 (FIX) IU/kg of the patient's body weight (20–30 (FIX) IU/kg of body weight in children) raises plasma FX activity to 40–60% [8,13,31,43,45].

In case of severe bleeding or major surgical procedures in patients with FX deficiency, #PCC is prescribed at an initial loading dose of 20–30 (FIX) IU/kg of the patient's body weight, followed by repeated infusions of the drug at a dose of 10–20 (FIX) IU/kg of the patient's body weight at intervals of 24–48 hours to achieve and maintain FX activity > 20% [8,13,43].

• In FX deficiency, it is recommended to administer long-term prophylactic treatment to patients to prevent the development of hemorrhagic syndrome if there is a personal or family history of a severe clinical phenotype of previous bleeding or if FX activity is < 2% [8,13,24,31,40,43,45,46].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: #PCC is prescribed at a dose of 20–30 (FIX) IU/kg of the patient's body weight 2–3 times a week to maintain FX activity > 1% in adults and > 2% in children [13,31,43,45]. There are no data on the potential development of isoantibodies to FX.

Comments: The use of FFP is possible in exceptional cases and should not be standard practice.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation has not been developed for patients with rare coagulopathies. Rehabilitation measures are indicated for patients after central nervous system hemorrhages and with musculoskeletal system disorders . The development of rehabilitation measures should be carried out jointly by rehabilitation specialists, balneologists, and hematologists with experience in treating patients with blood coagulation disorders. Treatment can be carried out in general sanatorium-resort facilities within the patient's climate zone of residence, as well as at balneological resorts.

It is advisable to conduct psychological adaptation schools for patients with RIBD.

5. Prevention and Dispensary Observation

Comments: The main principle of preventing hemorrhagic episodes is the timely administration of replacement therapy with deficient factor concentrates.

Prophylactic therapy may be initiated after informed consent is signed by the patient or their legal representatives. Prophylactic treatment may be carried out at home by the patient or their relatives.

Comments: it is advisable to conduct an annual medical check-up (dispensary observation) of patients in a specialized hemostasis disorders center, provided the center has adequate clinical and laboratory facilities. Dispensary observation of patients with RIBD should include:

1. mandatory dynamic monitoring of the patient's condition with assessment of adverse events during replacement therapy: development of an inhibitor to blood coagulation factors, individual drug intolerance, viral contamination, changes in the psychological or social status of the patient, and assessment of the condition of the peripheral venous system.

2. treatment of RIBD complications: correction of iron deficiency, inhibitors.

3. detection and treatment of comorbid conditions, especially dental, oral, gastrointestinal, ENT diseases, cardiovascular pathology, etc.

6. Organization of Medical Care

Indications for elective hospitalization:

1) elective surgical treatment.

Indications for emergency hospitalization:

1) life-threatening bleeding;

2) emergency surgical intervention.

Indications for discharging the patient from the hospital:

1) complete cessation of bleeding

7. Additional Information

Use of non-specific hemostatic agents.

In addition to specific hemostatic and replacement therapy, a hematologist may use additional medications in the treatment of patients with RIBD, for example, hormone therapy in women with recurrent severe uterine bleeding.

Tranexamic acid** and other antifibrinolytic agents can be used to treat menorrhagia and mild mucosal bleeding, with the exception of renal bleeding. Antifibrinolytic agents can be used as monotherapy or in addition to blood coagulation factor concentrates. In case of a high risk of thrombotic complications, the use of antifibrinolytic agents is unacceptable. To prevent surgical or obstetric bleeding, tranexamic acid** should be administered orally or intravenously no later than 2 hours before surgery or childbirth to achieve peak plasma levels during the procedure. Tranexamic acid** should be used with caution concomitantly with PCC due to the high risk of thrombotic complications.

Features of FII deficiency in children.

Manifestations of FII deficiency in children may include umbilical bleeding or central nervous system hemorrhages. It is important to remember that in infants during the first 6 months of life, normal FII activity is 26–70%. FII activity reaches adult values by 6 months of age. Repeated follow-up examinations of the patient are required after reaching 6 months of age. Therefore, a definitive diagnosis of FII deficiency can be established in children older than 1 year. In any case, when diagnosing prothrombin time prolongation in children at this age, the administration of vitamin K1 preparations is indicated [1,20,41,48].

Management of women with FII deficiency during pregnancy and childbirth.

During a normal pregnancy, FII activity does not change significantly and usually remains insufficient for uncomplicated delivery in women with severe prothrombin deficiency. When FII activity is < 20%, to prevent hemorrhagic complications during delivery, a single administration of PCC* at a dose of 20–40 IU/kg of the patient's body weight is necessary at the onset of labor or before cesarean section to achieve an FII activity of 20–40%. Repeated infusions of the drug are performed at 48-hour intervals at a dose of 10–20 IU/kg of the patient's body weight to maintain FII activity > 20% for at least 3–5 days after vaginal delivery or 5–7 days after cesarean section [8]. If there are no clinical manifestations of the disease during pregnancy, replacement therapy with PCC is not performed; in the event of bleeding, therapy is conducted according to general principles [49].

Features of the course of hypoproconvertinemia in children.

In newborns with FVII deficiency, there is a risk of spontaneous CNS hemorrhages or umbilical bleeding. Other manifestations of hemorrhagic syndrome are uncommon. The physiological activity of FVII at birth ranges from 28% to 104% and reaches normal values by 6 months of age. Therefore, the final diagnosis is established after 6–12 months of age [41,42].

Management of women with hypoproconvertinemia during pregnancy and childbirth.

During a normal pregnancy, FVII activity physiologically increases. Women with mild FVII deficiency may achieve the necessary hemostatic level of FVII activity by the time of delivery without specific replacement therapy.

Pregnant women with severe FVII deficiency are at risk of hemorrhagic complications during labor. Women with FVII activity ≤ 20% prior to Cesarean section or with the onset of labor require replacement therapy with eptacog alfa (activated)** at a dose of 15–30 mcg/kg of the patient's body weight every 4–6 hours for at least 3 days. For all other women with FVII deficiency, eptacog alfa (activated)** is prescribed only in the event of bleeding according to general FVII therapy principles [50,51].

Clinical features of FX deficiency in children.

In newborns with FX deficiency, CNS hemorrhages or umbilical bleeding are possible. The physiological activity of FX at birth ranges from 12% to 68% and increases by 6 months of age. Therefore, the definitive diagnosis of FX deficiency in newborns requires mandatory comparison of the obtained laboratory test results with reference intervals of values acceptable in the neonatal period and re-examination of the patient after reaching 6 months of age. If decreased FX activity is detected in infants during the first six months of life, administration of vitamin K1 preparations (group B02BA according to the ATC classification) is indicated [4,19,41–43].

Management of women with FX deficiency during pregnancy and childbirth.

Women with FX activity of less than 30% may experience conception difficulties. Pregnancy is complicated by early miscarriages in the first trimester and hemorrhagic manifestations (most commonly hemorrhagic cystitis) in the second and third trimesters. The required FX level before and during pregnancy should be at least 30%.

Despite the physiological increase in FX activity during a normal pregnancy, in women with severe FX deficiency its level by delivery usually remains insufficient to ensure normal hemostasis. Women with FX activity ≤ 30% in the third trimester of pregnancy with a history of bleeding prior to pregnancy, as well as prior to Cesarean section with the onset of labor, require replacement therapy with PCC: #coagulation factors II, VII, IX and X in combination [prothrombin complex]** or coagulation factors II, IX and X in combination** (off-label for children – efficacy and safety have not been sufficiently studied) at a dose of 20–40 (FIX) IU/kg of the patient's body weight to achieve FX activity > 40%. Subsequent #PCC infusions are administered at 24-hour intervals at a dose of 10–20 (FIX) IU/kg of the patient's body weight for at least 3 days in order to maintain FX activity at no less than 30% [8,46,47,52].

Laboratory testing.

Laboratory tests are fundamental to the diagnosis and monitoring of patients with rare inherited coagulation disorders (RICD). Requirements for the conditions and technique of sample collection and testing do not differ from standard ones. An important aspect of laboratory testing is participation in a quality control system. In the diagnosis of RICD, it is optimal to participate in both national and international laboratory quality control systems covering the main coagulological parameters [10,14,17,18].

Vaccination.

Patients with RICD can be vaccinated. Vaccination against hepatitis B is particularly important. When vaccinating, oral or subcutaneous administration of the preparation is preferred over intramuscular or intradermal routes. If only the intramuscular route is available for a given vaccine, replacement therapy is necessary to prevent hematoma formation. In this case, replacement therapy is administered on the eve of vaccination. Administration of the preparation on the day of vaccination is not recommended. Vaccination must not be performed during bleeding [8].

Patient and family education.

Education of patients and their family members is a prerequisite for ensuring adequate care for patients with RICD. Education begins immediately after diagnosis establishment and is conducted on an ongoing basis by the physicians and nurses of the center where the patient is followed. Education is provided individually during center visits and within the framework of the RICD patient school.

Main areas of education for the patient and family members: what RICD is, specific features of the disease in childhood, skills in assessing the child's condition, skills in assessing symptoms, nature and severity of bleeding, storage and use of coagulation factor concentrates, indications and doses of replacement therapy, home infusion skills, vein care, use of other hemostatic agents, physical activity, psychological and social adaptation, vocational guidance, legal aspects.

In addition to physicians and nurses, psychologists, legal experts, and representatives of patient advocacy organizations for bleeding disorders should be involved in educating patients and their families.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Zozulya Nadezhda Ivanovna, MD, National Research Center for Hematology of the Russian Ministry of Health, Moscow, National Hematology Society

Svirin Pavel Vyacheslavovich, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, Moscow, National Society of Pediatric Hematologists and Oncologists

Zharkov Pavel Alexandrovich, MD, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Moscow, National Society of Pediatric Hematologists and Oncologists

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists

2. Pediatricians

3. Internists

4. Surgeons

5. Dentists

6. Otolaryngologists

7. Trauma and orthopedic surgeons

8. Obstetricians-gynecologists

Methods used for evidence collection/selection:

• Search for publications in specialized peer-reviewed periodicals with an impact factor > 0.3.

• Search in electronic databases.

Databases used for evidence collection/selection:

The evidence base for the recommendations consists of publications included in the PUBMED, MEDLINE, and Cochrane Library databases. The search covered a depth of more than 20 years.

Methods used for evidence analysis:

• Reviews of meta-analyses, randomized prospective controlled crossover clinical trials.

• Reviews of published case-control or cohort studies.

• Systematic reviews with evidence tables.

• Methods used for assessing the quality and strength of evidence:

• Expert consensus;

• Evaluation of the significance of evidence in accordance with the evidence-grading rating system.

Methodology for developing recommendations:

Description of the methodology for evidence analysis and recommendation development

When selecting publications as potential sources of evidence, the methodology used in each study must be examined to ensure its compliance with the principles of evidence-based medicine. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Methodological review focuses on the features of the study design that had a significant impact on the quality of results and conclusions.

To eliminate the influence of subjective factors, each study is evaluated by at least two independent members of the authoring team. Discrepancies in evaluation are discussed at meetings of the working group of the authoring team for these recommendations.

Based on the analysis of evidence, sections of clinical recommendations were developed with an assessment of strength in accordance with the grading system of recommendation evidence (Appendix 2).

Methods used to formulate the recommendations:

• Expert consensus.

• Evaluation of the significance of recommendations in accordance with the recommendation grading rating system.

Methodology for validation of recommendations:

Methods of recommendation validation:

• External expert review.

• Internal expert review.

Description of the methodology for validating recommendations:

Draft recommendations are peer-reviewed by independent experts who are asked to comment on the quality of evidence interpretation and guideline development. An expert assessment of the presentation style and readability of the recommendations is also conducted.

Draft recommendations are submitted for discussion at scientific hematology conferences of the National Hematology Society, meetings of the Profile Commission for Hematology, the Working Group for the Development of Clinical Guidelines of the Hematological Research Center, as well as by leading specialists of relevant Federal Centers of the Russian Federation and practicing physicians.

Comments from outpatient and inpatient hematologists regarding the clarity and importance of the recommendations as a tool for daily practice are reviewed.

Remarks and comments received from experts are carefully systematized and discussed by the authoring group. If necessary, changes and additions are made to the text of the recommendations.

Final Version:

For the final version and quality control, the recommendations are re-analyzed by members of the authoring group to confirm that all significant remarks and comments from experts have been taken into account, and the risk of bias during development has been minimized.

The final version of the clinical guidelines is reviewed and approved at a meeting of the Profile Commission for Hematology, the Working Group for the Development of Clinical Guidelines of the Hematological Research Center, and ultimately at the congress (conference, plenum) of the National Hematology Society.

Table 1. Scale for assessing levels of reliable evidence (LRE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

No.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Patient guide for RICD

1. The treatment of patients with RICD is based on specific replacement therapy with preparations containing the deficient (reduced or absent) coagulation factor. Providing these preparations and training patients and their family members in their use are fundamentally important tasks in organizing care for patients with RICD.

2. Replacement therapy with coagulation factor concentrates should be used to stop bleeding. When performing specific replacement therapy, preference should be given to recombinant or highly purified virus-inactivated plasma-derived coagulation factor concentrates over fresh frozen plasma (FFP).

3. For patients with rare inherited coagulation disorders (RICD), a home treatment strategy should be implemented whenever possible. The core elements of this strategy are: the patient having hemostatic drugs on hand (stored where the patient is located), the decision to administer the hemostatic drug being made by the patient or their relatives in accordance with the hematologist's recommendations, and the patient and/or their relatives being trained.

4. Effective doses of coagulation factor concentrates must be administered immediately. Inadequate dosing will fail to stop bleeding, lead to wasted time, progression of hemorrhagic syndrome, and unjustified consumption of expensive medication.

5. Hemostatic therapy should be initiated as early as possible (ideally within the first 2 hours after injury, onset of bleeding, or appearance of the first subjective signs of hemorrhage); therefore, the basis for starting therapy can be the patient's subjective sensations or the fact of injury. It is desirable to stop bleeding or hemorrhage before significant clinical manifestations develop.

6. Treatment of mild and moderate bleeding should be carried out at home by the patient or their relatives in accordance with the hematologist's recommendations. If life-threatening bleeding develops, therapy must be initiated as early as possible (at home) and continued under the supervision of a hematologist in an inpatient or outpatient setting.

7. A key aspect of improving health status and quality of life in the management of RICD is the prevention of bleeding: hemarthrosis, life-threatening bleeding, and hemorrhages (into the central nervous system (CNS), gastrointestinal tract (GIT), etc.).

8. All patients with RICD must be registered and monitored at a specialized center. The patient or the physicians they consult must have round-the-clock access to contact a hematologist experienced in treating patients with blood coagulation disorders.

9. Monitoring and treatment of patients with RICD should be carried out by a multidisciplinary team of specialists including a hematologist, pediatrician, orthopedist, dentist, physical therapist, exercise therapy physician, and psychologist experienced in working with patients with blood coagulation disorders.

10. Examinations by a hematologist and dentist should be conducted at least once a year; evaluations by other specialists as needed. Routine dental examinations and teeth cleaning can be performed without factor replacement therapy.

11. For patients with RICD, maintaining oral hygiene is important as it helps prevent periodontal disease and caries. A soft toothbrush must be used for teeth cleaning.

12. During dental procedures, local anesthesia in patients with severe and moderate forms of FII, FVII, and FX deficiencies should be performed only after the administration of a specific coagulation factor concentrate.

13. When providing dental care, close cooperation between the oral and maxillofacial surgeon and the hematologist is essential. Tooth extraction or surgical procedures must be performed under strict hemostasis control and following a hematologist's consultation.

14. During dental procedures, tranexamic acid** or other antifibrinolytic agents may be used to reduce the need for factor concentrate replacement therapy. Local hemostatic agents may be used after tooth extractions.

15. For extensive dental procedures (suturing, multiple tooth extractions), hospitalization of the patient may be required.

16. For patients with musculoskeletal system impairments: long-term treatment of joint and muscle injuries and functional rehabilitation are required.

17. Identification and treatment of comorbid conditions are mandatory, especially diseases of the teeth, oral cavity, gastrointestinal tract, ENT organs, etc.

18. Prior to any invasive procedures, administration of a coagulation factor concentrate or non-specific agents (fibrinolysis inhibitors) is necessary, depending on the severity of the coagulation factor deficiency.

19. Intramuscular injections and arterial punctures should be avoided.

20. Regular exercise that promotes muscle development, joint protection, and physical fitness should be encouraged (e.g., therapeutic gymnastics, swimming, terrain cures).

21. Patients must avoid situations associated with a high risk of injury, including contact sports, heavy ball games, exercising on sports apparatus, etc. When deciding on the feasibility of participating in a particular physical activity, the severity of the disease must be considered.

22. Patients should refrain from using NSAIDs, particularly acetylsalicylic acid. Paracetamol may be used for pain relief.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

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