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

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.

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

To describe differences in characteristics among neonates treated with extracorporeal life support (ECLS) in the first week of life for respiratory failure compared with later in the neonatal period and to assess risk factors for central nervous system (CNS) hemorrhage and mortality among the two groups. Review of the Extracorporeal Life Support Organization registry from 2001 to 2010 of neonates ⩽30 days comparing two age groups: those ⩽7 days (Group 1) to those >7 days (Group 2) at ECLS initiation. Among 4888 neonates, Group 1 (n=4453) had significantly lower mortality (17 vs 39%, P<0.001) but greater CNS hemorrhage (11 vs 7%, P=0.02) than Group 2 (n=453). Mortality and CNS hemorrhage improved significantly with increasing gestational age only for Group 1 patients. CNS hemorrhage occurred more frequently in Group 1 patients receiving venoarterial (VA) than with venovenous ECLS (15 vs 7%, P<0.001). In Group 1, lower birth weight and pre-ECLS pH and VA mode were independently associated with mortality. In Group 2, higher mean airway pressure was independently associated with mortality. Complications of ECLS therapy, including CNS hemorrhage and renal replacement therapy were independently associated with mortality for both groups. Neonates cannulated for ECLS after the first week of life had greater mortality despite lower CNS hemorrhage than neonates receiving ECLS earlier. Premature infants cannulated after 1 week had fewer CNS hemorrhages than premature infants treated with extracorporeal membrane oxygenation starting within the first week of life.

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.

Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2 years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation.

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.

The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia–ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia–ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia–ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.

Bevacizumab is widely used and may cause life-threatening bleeding. We attempted to identify clinical characteristics associated with central nervous system (CNS) hemorrhage in a broad population. We performed a retrospective review of the FDA MedWatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Our search used keywords: bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke and brain. A total of 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1,041 reports described non-CNS bleeds. Median age was 62 years, and the primary cancers were consistent with indications for bevacizumab. Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. Thirty percent had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. Death was reported as a complication of hemorrhage in 48 %. The most common predisposing factor for CNS bleeds was use of medications associated with bleeding, followed by thrombocytopenia. In this database, 154 of 1,195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in two-thirds of cases.

Intracranial Hemorrhage

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.

The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring. The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring.

Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated. Over a 6-year period (2012-2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes. Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke. In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

Background: Factor XIII Deficiency (FXIIID) is an inherited rare bleeding disorder with some life threatening clinical manifestation including Intracranial Haemorrhage (ICH). Among all polymorphisms found in FXIIID, Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Thr325Ile gene polymorphism increases probability ofICHabout 20 fold in patients with FXIII .So, in this study we aimed to evaluate TAFI Thr 325 Ile polymorphism in Chorionic villus samples (CVS) of fetuses with positive family history of FXIIID andICH. Materials and Methods: This study was performed on chorionic villus of pregnant mothers ´ with positive history of FXIIID accompanied with ICH in first-degree relatives of their fetus. All parents of the fetuses were completed consent form for doing Prenatal diagnosis (PND). Chorionic villus DNA was extracted from each sample using the DNA extraction kit and PCR-RFLP was performed for TAFI Thr 325Ile polymorphism in Exon 4 of FXIII A gene. Results: All of 8 fetuses had positive family history of FXIIID. Seven out of eight fetuses (87.5%) had a family member with CNS bleeding due to FXIIID. Four fetuses had history of death due to FXIIID. There were 5 case (62.5%) that were homozygote for TAFI Thr 325 Ile, one (12.5%) was heterozygote and two (25%) were non mutant. Conclusion: Detection of TAFI Thr 325 Ile polymorphism by PND program in fetuses with positive family history of ICH is seems necessary and it will help to fill many gaps in preventing life threatening features of FXIIID in newborn at the time of delivery by prophilaxy receiving and precautionary measures. K e y w o r ds: Factor XIII deficiency, intracranial hemorrhage, TAFI Thr 325Ile

Congenital factor XIII (FXIII) deficiency is a rare coagulopathy with the highest incidence in Iran. Iranian patients with FXIII deficiency (FXIIID) presented high rate of bleeding episodes, some of them are major cause of disability and mortality among these patients. Hemarthrosis and intracranial hemorrhage (ICH) can affect activity and social productivity of patients. ICH, recurrent miscarriage and umbilical cord bleeding are the major cause of mortality. Hematoma, and prolonged menstrual bleeding as well as post-surgical bleeding are other significant bleeding in Iranian patients with FXIIID. Present of severe life threatening bleeding episodes and other notable bleedings, can significantly reduce working activities and social productivities of patients. Although Iranian patients with FXIIID, experienced significant diseases related complications, early diagnosis accompany by appropriate therapeutic regimes can prevent most of these problems.

Cranial Ultrasonography