Week of 21–27 September 2026¶
How do patients with dysfibrinogenemia present?¶
Answer: Congenital fibrinogen disorders are rare inherited quantitative (afibrinogenemia, hypofibrinogenemia) or qualitative (dysfibrinogenemia, hypodysfibrinogenemia) abnormalities of fibrinogen. They typically present with bleeding complications; however, equally important is the risk of thrombotic disease (both arterial and venous).
Proposed mechanisms include impaired thrombin clearance due to a lack of fibrin formation and structurally abnormal fibrin clots that promote thrombin release into the circulation or hinder fibrinolysis. In afibrinogenemia, the absence of fibrinogen leads to increased circulating free thrombin, while in dysfibrinogenemia, structurally abnormal fibrinogen enhances thrombotic risk.
— The thrombotic paradox in congenital fibrinogen deficiencies: from pathophysiology to practice (RPTH 2025)
Registry data — Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database (Blood Adv 2024), 123 patients:
| Subtype | Any bleeding | Thrombosis |
|---|---|---|
| Afibrinogenemia (n = 30) | 100% | 11% |
| Hypofibrinogenemia (n = 33) | 66% | 10% |
| Dysfibrinogenemia (n = 55) | 58% | 6% |
| Hypodysfibrinogenemia (n = 5) | 40% | 0% |
| All (n = 123) | 70% | 8% |
- Gynecologic and obstetric complications — Gynecologic and obstetric complications in women with congenital fibrinogen disorders: insights from the Prospective Rare Bleeding Disorders Database (RPTH 2025):
In qualitative CFDs, live birth, PPH, and miscarriage rates were 64%, 23%, and 36%.
- Distinct from fibrinogen amyloidosis: the genetic abnormalities in fibrinogen disorders (typically the thrombin binding site) are distinct from those that cause hereditary fibrinogen Aα-chain amyloidosis (C-terminal region of the fibrinogen Aα chain, most commonly E526V).
Related: 0032 — Dysfibrinogenemia presentation in women covers the gynecologic and obstetric picture from the same registry in detail.
Source: The thrombotic paradox in congenital fibrinogen deficiencies: from pathophysiology to practice
What treatment options are available to manage heavy menstrual bleeding in women receiving full anticoagulation?¶
Answer: Evidence to guide management is very sparse, and treatment options are limited but can be effective. The principle of therapy is to avoid anticoagulant dose reduction, skipped doses, or premature discontinuation, particularly in the acute phase of treatment (first 3–6 months).
Options:
- Hormonal therapy to control heavy menstrual bleeding, including abnormal uterine bleeding (AUB) and dysfunctional uterine bleeding (DUB), is safe while the patient is on full-dose anticoagulation.
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The MEDEA randomized trial looked at three strategies in women on factor Xa inhibitors:
- switching to dabigatran;
- continuing the factor Xa inhibitor with the addition of tranexamic acid (TXA);
- continuing without any intervention.
The trial was stopped prematurely due to poor recruitment, with only 16 randomized. The main outcome was reduction in pictorial blood loss assessment chart (PBAC) score. No conclusions could be drawn; however, adding TXA seemed promising compared with the other options. 3. The T-REX HMB RCT will start recruiting patients, randomized to TXA vs no TXA. 4. Screen for and treat iron deficiency.
Source: Management of heavy menstrual bleeding on anticoagulation
What is the role of genetic testing in the diagnosis of bleeding disorder of unknown cause (BDUC)?¶
Answer: Genetic testing complements the diagnosis but is unlikely to influence or change management for the majority of patients. The most important aspect of diagnosing a patient with a bleeding disorder is the clinical phenotype, period.
In true BDUC — where first-line hemostatic testing is normal — the diagnostic yield of genetic testing is very low: 3.2% in the largest panel study (below).
Genetic testing could be helpful in the following circumstances:
- Refining the classification and resolving overlapping phenotypes, such as type 2N von Willebrand disease or mild hemophilia — although these disorders will generally have abnormal first-line testing.
- Inherited platelet function disorders: this group of disorders is the most diagnostically challenging to confirm, given the heterogeneity in the available tests and the limited specificity of platelet function testing.
- Syndromes associated with other disorders that require specific monitoring, such as MYH9-related disorders or RUNX1 variants.
- A family history.
The evidence:
- Yield depends on phenotype. In 2396 index patients sequenced on a targeted panel, a molecular diagnosis was made in 49.2% across thrombotic, coagulation, platelet count, and platelet function disorders, but in only 3.2% of patients with unexplained bleeding and normal hemostasis tests (Downes et al., Blood 2019).
- In defined factor deficiencies the yield is high. A 22-gene panel in 515 patients with inherited coagulation factor deficiencies found a disease-causing variant in 69% of those with complete phenotypic data (Borràs et al., Haemophilia 2025).
- The GT4BD RCT will answer the question of when to introduce whole genome sequencing in the diagnostic pathway: newly referred patients with a suspected inherited bleeding disorder are randomized to early genome sequencing vs the standard pathway, with diagnostic yield as the primary outcome.
Related: 0021 — Diagnosing BDUC gives the ISTH minimum laboratory work-up that must be normal before the BDUC label applies.