Acute health events in adult patients with genetic disorders: The Marshfield Epidemiologic Study Area
Congenital Fibrinogen Disorders
Congenital fibrinogen disorders encompass a heterogeneous group of inherited conditions affecting either the quantity or quality of fibrinogen, a critical glycoprotein in the coagulation cascade. Quantitative anomalies, such as afibrinogenemia and hypofibrinogenemia, lead to markedly reduced levels of fibrinogen in circulation, while qualitative defects, including dysfibrinogenemia and hypodysfibrinogenemia, result in the production of dysfunctional molecules. These disorders pose clinical challenges, manifesting as bleeding complications, thrombotic events or, in some cases, remaining asymptomatic, and have significant implications for surgical and obstetric management. Advances in molecular genetics and functional assays have substantially improved diagnostic accuracy and allowed for better genotype–phenotype correlations, thereby enhancing the global understanding and management of these rare coagulopathies.
Research from Nature PortfolioRecent investigations have also focused on enhancing diagnostic methodologies and elucidating exceptional case studies that broaden our understanding of congenital fibrinogen disorders. Notably, the development and validation of innovative qualitative assays using clot waveform analysis have demonstrated superior sensitivity and specificity in differentiating between quantitative and functional fibrinogen abnormalities [3]. Additionally, case studies involving de novo mutations in the fibrinogen gamma gene have shed light on familial transmission and the challenges of managing affected individuals during pregnancy and childbirth, thereby underscoring the importance of tailored therapeutic strategies [4]. These contributions are instrumental in bridging laboratory findings with clinical practice.
Research from all publishersRecent studies continue to unravel the molecular underpinnings of congenital fibrinogen disorders. Comprehensive systematic reviews have collated data on genetic mutations, diagnostic criteria and clinical manifestations, highlighting the variability and complexity associated with these conditions [1]. In parallel, targeted investigations employing molecular modelling and sequencing have identified novel mutations that perturb fibrinogen assembly and secretion, offering insights into the mechanisms by which these alterations contribute to both bleeding and thrombotic phenotypes [2]. Furthermore, research integrating functional assays with laboratory coagulation parameters is refining the diagnostic landscape, providing clinicians with robust tools for early detection and personalised management.
Technical TermsAfibrinogenemia: A complete absence of fibrinogen in the circulation, typically resulting in severe bleeding manifestations.
Hypofibrinogenemia: A condition characterised by abnormally low levels of circulating fibrinogen.
Dysfibrinogenemia: A qualitative abnormality in fibrinogen where levels may be normal but the protein is functionally defective.
Clauss Assay: A laboratory test used to assess the functional activity of fibrinogen based on clot formation kinetics.
What Is Congenital Amegakaryocytic Thrombocytopenia (CAMT)?
CAMT is a serious and often life threatening genetic disorder. It leads to bleeding problems that are typically present from birth. A timely stem cell transplant is the only cure.
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare and serious inherited genetic disorder. It often leads to bleeding and low counts of many types of blood cells.
"Congenital" means a trait or condition is present when you're born.
Megakaryocytes are cells that help your body make platelets. The term "amegakaryocytic" in CAMT means you have few or no megakaryocytes.
Platelets, aka thrombocytes, are responsible for blood clotting. If your platelet count is low, it's called thrombocytopenia.
Let's examine what causes CAMT and what doctors can do about it.
CAMT occurs from a change (mutation) in your genes. Based on the gene responsible, doctors can split CAMT into two categories: CAMT-MPL and CAMT-THPO.
Your THPO gene is responsible for your liver's production of the hormone thrombopoietin, which tells your body to make megakaryocytes. These megakaryocytes, in turn, make platelets.
When your body makes thrombopoietin, this hormone connects to other cells with a specific receptor. Instructions for how to make this receptor are found in your MPL gene.
Mutations to either gene can lead to a lack of megakaryocytes. Both types of mutations can lead to CAMT with many of the same symptoms, but the timing and treatment options are different.
CAMT is an inherited genetic condition. This means it occurs from the combination of genes you get from your biological parents.
It's also an autosomal recessive disease. This means you need two copies of the mutation (one from each parent) that causes CAMT to have the condition.
If you have only one copy, you are a carrier of CAMT. You won't have the disease, but you can have children with CAMT if the other parent also has the mutation.
It's possible to be a carrier of CAMT and not know it. If you have relatives with CAMT, you might consider genetic counseling to learn whether you're a carrier.
Treatment for CAMT depends on whether you have CAMT-MPL or CAMT-THPO.
CAMT-MPL is more common. The main treatment is allogeneic hematopoietic stem cell transplant (HSCT). This type of stem cell can turn into any type of blood cell. It can come from donors who are genetically similar (but not identical twins).
HSCT can be a cure for CAMT. Doctors tend to consider it as early as possible, usually before age 3 years. Complications from HSCT can be fatal up to 20% of the time.
HSCT is not an effective treatment for CAMT-THPO. Instead, a doctor might prescribe medications, such as romiplostim and eltrombopag, to increase platelet counts.
Enzyme Replacement Therapy Curbs Bleeding Events In Congenital Blood Clotting Disorder
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Key takeaways:Among patients with congenital thrombotic thrombocytopenic purpura, prophylactic therapy with recombinant ADAMTS13 restored normal levels of the enzyme, according to results of a randomized phase 3 study.
The findings — published in The New England Journal of Medicine — revealed that no patient who received prophylaxis with recombinant ADAMTS13 experienced an acute thrombotic thrombocytopenic purpura (TTP) event during the study period, researchers reported. Meanwhile, markedly fewer treatment-related adverse events occurred among study participants who received recombinant ADAMTS13 compared with control patients who received standard therapy with plasma-derived products.
Data derived from Scully M, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314793."This trial showed that recombinant ADAMTS13 was an effective prophylactic therapeutic approach for patients with congenital TTP," Marie Scully, MD, of University College London Hospitals, and researchers wrote. "Recombinant ADAMTS13 treatment was associated with approximately normal maximum ADAMTS13 activity and low levels of disease related events and manifestations. No safety concerns were noted with recombinant ADAMTS13, and no neutralizing antibodies to ADAMTS13 were detected."
Background, methodsTTP is the result of a severe hereditary deficiency of the ADAMTS13 enzyme; the efficacy and safety of recombinant ADAMTS13 and standard therapy administered via routine prophylaxis or on-demand treatment among patients with TTP is unknown.
Researchers conducted an open-label study in 48 patients with TTP. They randomly assigned study participants in a 1:1 ratio to receive two 6-month cycles of prophylaxis plus either recombinant ADAMTS13 (40 IU/kg IV) or standard therapy, followed by an alternate treatment.
Afterward, all patients then received an additional 6 months of recombinant ADAMTS13.
Trial completion by at least 30 participants served as the trigger for an interim analysis. Acute TTP events served as the study's primary outcome, with manifestations of TTP, safety and pharmacokinetics also being assessed.
Patients who experienced an acute TTP event could receive on-demand treatment.
Of the 48 patients randomly assigned to a treatment group, 32 completed the trial.
Results, next stepsResearchers observed no acute TTP events during prophylaxis with recombinant ADAMTS13 but did note one patient experienced an acute TTP event during prophylaxis with standard therapy.
Thrombocytopenia appeared to be the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy).
Researchers also noted adverse events in 71% of patients with recombinant ADAMTS13 and in 84% of patients with standard therapy; 9% of patients with recombinant ADAMTS13 had adverse events considered to be related to the trial drug, compared with 48% of patients with standard therapy.
None of the patients receiving recombinant ADAMTS13 had a trial-drug interruption or discontinuation due to adverse events, whereas eight patients with standard therapy did.
Researchers noted a mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment of 101%, compared with 19% after standard therapy.
"Until recently, no medications were specifically approved for routine prophylaxis in patients with congenital TTP," researchers wrote. "Recombinant ADAMTS13 was approved by the Food and Drug Administration in November 2023 for prophylactic or on-demand ADAMTS13 replacement therapy in adults and children with congenital TTP.
"It is difficult to compare rates of TTP events reported here with those in previous observational studies, because the event criteria varied," they added. "In this trial, criteria were designed to be objective and laboratory-based but were probably conservative as compared with clinical practice and existing literature."
Sources/DisclosuresCollapse Disclosures: Takeda Development Center Americas and Baxalta Innovations funded the study. Scully reports grants from or consulting roles with Alexion Pharmaceuticals, Octapharma USA, Sanofi US Services and Takeda Oncology. Please see the study for all other researchers' relevant financial disclosures.Add topic to email alerts
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