Central nervous system bleeding in patients with rare bleeding disorders

Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia.

Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder.

High incidence of intracranial bleeding in factor V-deficient patients with homozygous F5 splicing mutations.

A retrospective study on clinical manifestations of neonates with FXIII-A deficiency

Intracranial haemorrhage (ICH) is the most dreadful complication, and the main cause of death among patients with rare bleeding disorders (RBD) and prenatal diagnosis (PND) is a preventative lifesaving program. A total of 39 PNDs were reported in the literature through a search on PubMed, EMBASE, SCOPUS and Web of Science databases, most often for congenital factor (F) XIII and FVII deficiencies and rarely in FX, FV deficiencies and afibrinogenemia. The main cause to request a PND is ICH and related morbidity and mortality. Different molecular methods including direct sequencing and linkage analysis as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for a specific mutation are the most common used methods for PND, while factor assay and combination of molecular and factor assay also were used. In this research, 7 severely affected foetuses were identified during PND including 3 foetuses with FXIII deficiency, 3 with FVII deficiency and 1 with FX deficiency. Out of these 7 cases, intrauterine ICH occurred in 1 case with FXIII deficiency, 1 was electively aborted and 1 case with severe FVII deficiency received intrauterine factor transfusion. Postdelivery ICH was reported for 1 patient with severe FVII deficiency within the first month of life. All other pregnancies were uneventful.

Factor VII (FVII) deficiency is a rare bleeding disorder that can present as either inherited or acquired. Inherited FVII deficiency arise from mutations in the F7 gene, resulting in a highly heterogeneous and wide range of phenotypic expressions from asymptomatic individuals to those experiencing severe and life-threatening hemorrhagic episodes. Notably, the severity of symptoms is typically not correlated with plasma FVII levels. Diagnosis generally involves a combination of coagulation assays, including prothrombin time (PT), assessment of FVII activity and antigenic levels, and a thorough consideration of the patient's clinical context. Management of FVII deficiency requires personalized treatment strategies. For inherited forms, on-demand replacement therapy is commonly employed, utilizing recombinant activated FVII, plasma-derived FVII, prothrombin complex concentrates, or fresh frozen plasma during bleeding episodes, as well as for prophylactic measures. Long-term prophylaxis is particularly critical for patients with severe deficiencies who have a history of central nervous system or gastrointestinal bleeding, especially those at an elevated risk of subsequent major or potentially life-threatening bleeding events. This review evaluates current therapeutic approaches, highlights emerging challenges in the management of FVII deficiency, and underscores the importance of tailored treatment strategies aimed at optimizing patient outcomes.

Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with a prevalence of 1 in 3 million in the general population. Compared to its global incidence, it has the greatest prevalence in Sistan and Baluchistan Province in the southeast of Iran. The high incidence of FXIIID in this region causes a high rate of morbidity and mortality among the affected individuals because of life-threatening episodes such as central nervous system (CNS) bleeding, umbilical cord bleeding, as well as miscarriage. CNS bleeding leads to a considerable number of neurological and behavioral complications. Therefore, we have designed an established prenatal diagnosis (PND) program to prevent the increasing incidence of life-threatening bleeding episodes and related complications among neonates with congenital FXIIID. This study was conducted from September 2013 to August 2014. A consent form was signed by the parents. Fetal sampling was done via abdominal chorionic villus sampling passage under local anesthesia and ultrasonic guidance within the first trimester of pregnancy. Fetal DNA was extracted, and PCR-restriction fragment length polymorphism was performed for the only reported mutation of FXIII (Trp187Arg) in the southeast of Iran. During the period of study, PND was performed on eight fetuses. Six fetuses were offspring of parental consanguineous marriages, and all of them had a positive family history of FXIIID. Seven out of the eight fetuses had a family member with CNS bleeding due to FXIIID. Four fetuses had a FXIIID-related death. One of the fetuses bore homozygous Trp187Arg mutation, whereas six were heterozygous, and one of the mothers gave birth to an unaffected fetus. To the best of our knowledge, PND is a possible solution to control high incidence of life-threatening episodes of FXIIID in southeast Iran.

With 473 patients, Iran has about one third of the world's patients with severe congenital factor XIII (FXIII) deficiency. A considerable number of patients with FXIII deficiency (FXIIID) are affected by life-threatening bleeding episodes, such as central nervous system (CNS) bleeding or recurrent miscarriage and umbilical cord bleeding (UCB), that cause a high rate of morbidity and mortality in Iranian patients with FXIIID. Among 317 Iranian patients with FXIIID, 145 cases experienced 166 CNS bleeds (CNSBs) that recurred in 21 cases. CNSB caused different types of neurological complications in 69 patients. A total of 62 miscarriages were observed in 24 women of childbearing age, and 21 deaths were observed due to umbilical cord bleeding or mucosal bleeding. In fact, 49 deaths (15.4 %) were observed in these patients, which highlight the importance of early diagnosis and intensive health care among patients with FXIIID.

Diagnosis and classification of factor XIII deficiencies

Successful Control of Central Nervous System Bleeding in Two Newborns With Severe Factor VII Deficiency Using rFVIIa Administered via Port-a-Cath

Factor XIII (FXIII) deficiency, a rare coagulation disorder resulting from F13A1 gene mutations, can lead to severe bleeding episodes, especially in infants. The authors' case study featuring a 16-year-old female with a history of this deficiency revealed intracranial hemorrhage necessitating immediate medical intervention. The text emphasizes the importance of understanding the epidemiology and genetics of FXIII deficiency, as well as the challenges in diagnosis and management. A 16-year-old female with FXIII deficiency presented to the Emergency Department (ER) after a fall, experiencing weakness on her right side, headache, seizures, and altered consciousness. Neurological examination showed weakness and increased tone on the right side of the body. Computed tomography (CT) scan revealed an intracranial subdural hemorrhage overlying the superior parietal lobe. Treatment included IV fluids, sodium valproate, antibiotics, fresh frozen plasma, and mannitol. Serial neurological assessments were normal, and the patient remained stable. MRI later confirmed hemorrhage. Upon discharge, she was prescribed medication and physiotherapy, leading to significant improvement at the 6-month follow-up. The prevalence of FXIII deficiency, a rare disorder, is higher in populations with consanguineous marriages, particularly in regions like Pakistan, India, Tunisia, Finland, and Iran due to specific genetic mutations. Diagnosis involves thorough evaluation and specific lab tests, with varied clinical symptoms including prolonged bleeding, especially in newborns. FXIII deficiency can also develop in association with conditions like hepatic failure and leukemia, complicating diagnosis. Treatment options include blood products and recombinant FXIII, with management of intracranial bleeding requiring a multidisciplinary approach. The case underscores the critical need for early identification and specialized care for individuals with FXIII deficiency to mitigate life-threatening complications like intracranial hemorrhage, promoting tailored treatment approaches and improved patient outcomes.

BACKGROUND: Congenital FXIII deficiency is a rare genetic bleeding disorder that is inherited in an autosomal recessive pattern with a frequency of 1/2 million individuals in the human population. Deficiency of FXIII is associated with significant bleeding disorders.AIMS: This study aimed to evaluate the demographic parameters, clinical presentations, and outcome of patients who were diagnosed with congenital factor XIII deficiency.SUBJECTS AND METHODS: A retrospective descriptive study of patients who were diagnosed with congenital FXIII deficiency over a period from August 2008 to August 2016 was conducted. The study included patients who were diagnosed by having bleeding tendency and normal standard coagulation tests (normal platelet count, normal prothrombin time; normal partial thromboplastin time, and normal bleeding time) and the diagnosis was confirmed by clot solubility test in 5M urea. The diagnosis was made in the Hemophilia Ward, Children Welfare Teaching Hospital, Medical City, Baghdad.RESULTS: There were 111 cases of other coagulation factors' deficiency (rare bleeding disorders) registered in the center, congenital FXIII deficiency represented 24 (22%) of them. Males represented 14 (58.3%) and females 10 (41.7%) of patients. Most of the patients (41.7%) had their symptoms during the 1st year of life. Positive consanguinity was found in 100% of patients and 14 (58.3%) patients had a family history of FXIII deficiency. Umbilical cord bleeding and gum bleeding were present in 37.5% and 20.8%, respectively, and they were the most common first presenting symptoms of FXIII-deficient patients, while muscle hematoma (28.5%) and joint bleeding (24.7%) were the most common presenting symptoms in follow-up visits. The majority of the patients (79.1%) did not develop complications, the complications were developed in 3 (12.4%) patients, which were intracranial bleeding in 2 (8.3%) patients and liver hematoma in 1 (4.1%) patient. One patient (4.1%) developed recurrent abortion and one patient (4.1%) developed hepatitis C. No death was reported during the study period.CONCLUSIONS: FXIII deficiency founded to be a more common rare bleeding disorder among Iraqi patients, with a high rate of consanguineous marriage. Umbilical cord bleeding and gum bleeding were the most common presenting symptoms for FXIII deficiency. There was a considerable delay in the diagnosis of FXIII deficiency in the majority of patients.

2073 Background: Bevacizumab is widely used and may cause life-threatening bleeding, usually at sites of disease involvement such as the CNS. We attempted to identify clinical characteristics associated with CNS hemorrhage in a broad population. Methods: We did a retrospective review of the FDA Medwatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Results: We searched the database for keywords bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke, and brain. 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1041 reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage was the most frequent event reported (n=39), followed by intracranial hemorrhage (n=20) and subarachnoid hemorrhage (n=18). Median age was 62 years; 54% of patients were female. Primary cancer was colorectal (42%), glioma (13%), and breast cancer (10%). Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. 54% of patients received myelosuppressive chemotherapy, and 30% had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. For 70 patients, information on CNS involvement was not reported. Death was reported as a complication of hemorrhage in 48% of patients. Nine patients with brain metastases died and CNS hemorrhage was the cause of death in seven. Six patients with glioma died, and CNS hemorrhage was the cause in three. One patient with brain metastases, and one patient with glioma also experienced a non-CNS bleed. Five patients in each group had received heparin, warfarin or NSAIDs. Low platelet counts were reported in 3 patients with CNS metastases and 2 patients with glioma. The most common factor associated with CNS hemorrhage was medication predisposing to bleeding, followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, was reported in 4 patients with brain metastases, and 2 patients with glioma. Conclusions: In this database, 154 of 1195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in more than half of the cases.

ABSTRACTObjectives: Congenital factor XIII (FXIII) deficiency is a rare severe bleeding disorder. Intracranial hemorrhage (ICH) is the leading cause of mortality and morbidity in FXIII deficiency. However, its pathogenesis is not well understood yet. In this study, we investigated the expression and CpG island methylation status of matrix metalloproteinase-2 (MMP-2) and MMP-9 in patients with FXIII deficiency and ICH.Methods: Forty patients with FXIII deficiency including twenty patients with ICH, and twenty without ICH were recruited as case and control groups, respectively. Methylation status was determined by bisulfite sequencing polymerase chain reaction (PCR), and gene expression was assessed by quantitative real-time PCR.Results and discussion: We found an unmethylated pattern for both MMP-2 and MMP-9 genes in the case group. Both genes were partially methylated in the control group, while the percentage of methylated CpGs was significantly higher in MMP-9 than MMP-2 (P = 0.001). Furthermore, higher expression of MMP-9 (in both the mRNA and protein levels) was found in the case than control group (P = 0.008 and P = 0.009, respectively). On the other hand, there was no significant difference in MMP-2 expression level (neither mRNA nor protein) between the two groups (P = 0.12 and P = 0.25, respectively).Conclusion: Our findings indicated that MMP-9 over-expression might be related to ICH in FXIII deficiency, and gene methylation effectively regulates its expression. Future researches will expand our understanding of the pathogenesis of ICH in congenital FXIII deficiency.

Intracranial hemorrhage (ICH) is a medical emergency. In congenital bleeding disorders, ICH is a devastating presentation accompanied with a high rate of morbidity and mortality. The prevalence of ICH is highly variable among congenital bleeding disorders, with the highest incidence observed in factor (F) XIII deficiency (FXIIID) (∼30%). This life-threatening presentation is less common in afibrinogenemia, FVIII, FIX, FVII, and FX deficiencies, and is rare in severe FV and FII deficiencies, type 3 von Willebrand disease and inherited platelet function disorders (IPFDs). In FXIIID, this diathesis most often occurs after trauma in children, whereas spontaneous ICH is more frequent in adults. About 15% of patients with FXIIID and ICH die; the bleeding causes 80% of deaths in this coagulopathy. Although in FXIIID, the bleed most commonly is intraparenchymal (> 90%), epidural, subdural, and subarachnoid hemorrhages also have been reported, albeit rarely. As this life-threatening bleeding causes neurological complications, early diagnosis can prevent further expansion of the hematoma and secondary damage. Neuroimaging plays a crucial role in the diagnosis of ICH, but signs and symptoms in patients with severe FXIIID should trigger replacement therapy even before establishment of the diagnosis. Although a high dose of FXIII concentrate can reduce the rate of morbidity and mortality of ICH in FXIIID, it may occasionally trigger inhibitor development, thus complicating ICH management and future prophylaxis. Nevertheless, replacement therapy is the mainstay of treatment for ICH in FXIIID. Neurosurgery is performed in patients with FXIIID and epidural hematoma and a hemorrhage diameter exceeding 2 cm or a volume of ICH is more than 30 cm3. Contact sports are not recommended in people with FXIIID as they can elicit ICH. However, a considerable number of safe sports and activities have been suggested to have more benefits than dangers for patients with congenital bleeding disorders, and are hence suitable for these patients.