Coagulation Factor Deficiencies Research Articles

Monitoring prothrombin activation in plasma through loss of Förster resonance energy transfer

BackgroundCurrent assays that monitor thrombin generation in plasma rely on fluorogenic substrates to follow the kinetics of zymogen activation, which may be complicated by substrate cleavage from other proteases. In addition, these assays depend on activation following cleavage at the prothrombin R320 site and fail to report the cleavage at the alternative R271 site, leading to the shedding of the auxiliary Gla and kringle domains of prothrombin. ObjectivesTo develop a plasma assay that directly monitors prothrombin activation independent of fluorogenic substrate hydrolysis. MethodsCleavage at the R271 site of prothrombin is monitored through loss of Förster resonance energy transfer in plasma coagulated along the extrinsic or intrinsic pathway. ResultsThe availability of factor (F)V in plasma strongly influences the rate of prothrombin activation. The rate of thrombin formation is equally perturbed in FV or prothrombin-depleted plasma, implicating that the thrombin-catalyzed feedback reactions that amplify the coagulation response play an important role in generating sufficient amounts of FVa required for the assembly of prothrombinase. Congenital deficiencies in FVIII and FIX significantly slow down cleavage at R271 in plasma coagulated along the extrinsic and intrinsic pathways. Prothrombin activation in FXI-deficient plasma is only perturbed when coagulation is triggered along the intrinsic pathway. ConclusionThe Förster resonance energy transfer assay enables direct monitoring of prothrombin activation through cleavage at R271 without the need for fluorogenic substrates. The assay is sensitive enough to assess how deficiencies in coagulation factors affect thrombin formation.

Assessing the value of bypassing agent therapy used prophylactic versus on-demand, during immune tolerance induction for treatment of inhibitors: a retrospective chart review

BackgroundHaemophilia A is a bleeding disorder caused by deficiency of coagulation factor VIII (FVIII) which leads to severe and repeated bleedings. There is a need to understand the optimal treatment pathway for FVIII inhibitors with the use of immune tolerance induction (ITI) and the role of haemostatic ‘bypassing’ agents (BPA) on-demand (OD) or prophylactically (Px). The aim of this study was to gain a better understanding of the real-world use of BPA therapy administered prophylactically or on-demand concomitant with ITI, for the treatment of an inhibitor to FVIII replacement therapy in patients with severe haemophilia A.MethodsRetrospective observational data were used to capture disease management information for patients who were aged 16 or under and had received ITI and BPA treatment for their most recent inhibitor from Jan-2015 to Jan-2019, for 47 patients in the UK and Germany. Descriptive comparisons of the clinical effectiveness and resource utilisation of Px and OD BPA therapy during ITI were conducted.ResultsDuring ITI and BPA treatment, for an inhibitor, bleeding events averaged 1.5 and 1.2 for Px and OD treatment respectively. Compared to only BPA therapy we see 3.4 and 1.4 bleeding events for Px and OD respectively during an inhibitor.ConclusionBaseline disease characteristics differed between BPA therapy cohorts and this resulted in higher clinical effectiveness of ITI treatment alongside BPA Px than BPA OD during an inhibitor.

An investigation to find the correlation between lupus anticoagulant and coagulation abnormalities in COVID-19 patients; a narrative review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) which is associated with nonspecific respiratory syndromes, varying from mild symptoms of upper airway to required mechanical ventilation hypoxemia. A unique feature of this disease is COVID-19-associated coagulopathy (CAC) that linked with disease severity and hospital mortality. These patients have a profound hypercoagulable state and in patients with severe type arterial and venous thrombotic events are frequent. Abnormal coagulation parameters such as activated partial thromboplastin time (aPTT) were observed in patients with COVID-19. Regarding the above finding it could be considered as a reason to avoid anticoagulation at the both doses of therapeutic and prophylactic. A prolonged aPTT may indicate a coagulation factor deficiency or inhibitor of coagulation, which can be specific (antibody to factor VIII) or nonspecific (lupus anticoagulant, LA). LA can affect laboratory tests of blood coagulation, but is not usually associated with bleeding; however, it can be associated with thrombotic risk as a part of the antiphospholipid syndrome. In a phospholipid concentration-dependent manner LA recognizes a type of antiphospholipid antibodies (aPLs) that prolong clotting tests. In patients with antiphospholipid syndrome (APS) LA is considered as one of the laboratory criteria representing a significant risk factor of both thrombosis and pregnancy morbidity. Similarities between some of the pathophysiological features of COVID-19 and APS has been focused in several reports particularly in the most severe form, catastrophic APS. This study aimed to evaluate the effect of LA on the incidence of thrombophilia in patients with COVID-19, as well as its impact on the inflammation and finally the mortality final rate.

Evaluation of Response to High-Dose Intravenous Vitamin K Administration.

Essential to the coagulation pathway, vitamin K (phytonadione) is used to correct clotting factor deficiencies and for reversal of warfarin-induced bleeding. In practice, high-dose intravenous (IV) vitamin K is often used, despite limited evidence supporting repeated dosing. This study sought to characterize differences in responders and nonresponders to high-dose vitamin K to guide dosing strategies. This was a case-control study of hospitalized adults who received vitamin K 10 mg IV daily for 3 days. Cases were represented by patients who responded to the first dose of IV vitamin K and controls were nonresponders. The primary outcome was change in international normalized ratio (INR) over time with subsequent vitamin K doses. Secondary outcomes included factors associated with response to vitamin K and incidence of safety events. The Cleveland Clinic Institutional Review Board approved this study. There were 497 patients included, and 182 were responders. Most patients had underlying cirrhosis (91.5%). In responders, the INR decreased from 1.89 at baseline (95% CI = [1.74-2.04]) to 1.40 on day 3 (95% CI = [1.30-1.50]). In nonresponders, the INR decreased from 1.97 (95% CI = [1.83-2.13]) to 1.85 ([1.72-1.99]). Factors associated with response included lower body weight, absence of cirrhosis, and lower bilirubin. There was a low incidence of safety events observed. In this study of mainly patients with cirrhosis, the overall adjusted decrease in INR over 3 days was 0.3, which may have minimal clinical impact. Additional studies are needed to identify populations who may benefit from repeated daily doses of high-dose IV vitamin K.

Mild and Moderate Hemophilia A: Neglected Conditions, Still with Unmet Needs

Hemophilia A (HA) is an inherited X-linked bleeding disorder, caused by the deficiency of coagulation factor VIII (FVIII), with variable clinical phenotypes [...].

Fatal acquired coagulation factor V deficiency after hepatectomy for advanced hepatocellular carcinoma as a possible immune checkpoint inhibitor-related adverse event: a case report

BackgroundAtezolizumab plus bevacizumab therapy was recently introduced as the first line for unresectable advanced hepatocellular carcinoma (HCC), but immune-related adverse events (IrAEs) due to atezolizumab are a great concern. Here, we report the case of a patient who developed fatal acquired coagulation factor deficiency after hepatectomy for HCC, treated with atezolizumab and bevacizumab before surgery.Case presentationA 70-year-old man received right trisegmentectomy of the liver with hepaticojejunostomy for advanced HCC with bile duct invasion, after atezolizumab and bevacizumab therapy. The patient suffered the sudden onset of severe multiple coagulation factor deficiency (II, V, VII, VIII, IX, X, XI and XII) immediately following reoperation for anastomotic leakage of hepaticojejunostomy, 7 days after hepatectomy. The coagulation factor deficiency did not reverse even with intensive treatment, and the patient died of uncontrollable bleeding 32 days after hepatectomy. An IrAE due to atezolizumab was suspected because the patient had developed the possible IrAE of enthesitis of the right gastrocnemius muscle before surgery, and specific inhibitors against factor V and anti-factor V autoantibodies were detected, leading to an ultimate diagnosis of autoimmune FV/5 deficiency (AiF5D).ConclusionSevere acquired coagulopathy should be recognized as a possible life-threatening IrAE when using atezolizumab and bevacizumab for HCC.

Von Willebrand Disease, Hemophilia, and Other Inherited Bleeding Disorders in Pregnancy.

Inherited bleeding disorders, which comprise von Willebrand disease (VWD), hemophilia, other congenital clotting factor deficiencies, inherited platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Although mild platelet defects may actually be more prevalent, the most common diagnosed bleeding disorder among women is VWD. Other bleeding disorders, including hemophilia carriership, are much less common, but hemophilia carriers are unique in that they are at risk of giving birth to a severely affected male neonate. General guidance for maternal management of inherited bleeding disorders includes obtaining clotting factor levels in the third trimester, planning for delivery at a center with hemostasis expertise if factor levels do not meet the minimum threshold (eg, less than 0.50 international units/1 mL [50%] for von Willebrand factor, factor VIII, or factor IX), and using hemostatic agents such as factor concentrates, desmopressin, or tranexamic acid. General guidance for fetal management includes prepregnancy counseling, the option of preimplantation genetic testing for hemophilia, and consideration of delivery of potentially affected male neonates with hemophilia by cesarean delivery to reduce the risk of neonatal intracranial hemorrhage. In addition, delivery of possibly affected neonates should occur in a facility where there is newborn intensive care and pediatric hemostasis expertise. For patients with other inherited bleeding disorders, unless a severely affected neonate is anticipated, mode of delivery should be dictated by obstetric indications. Nonetheless, invasive procedures such as fetal scalp clip or operative vaginal delivery should be avoided, if possible, in any fetus potentially affected with a bleeding disorder.

Performance characteristics of 5 numerical indexes in mixing test interpretation under coexistence of lupus anticoagulant and coagulation factor deficiency

BackgroundThe mixing test is useful to investigate the cause of unexpectedly prolonged activated partial thromboplastin time (APTT). Several indexes are available for distinguishing correction from non-correction (ie, factor deficiency from inhibitors), but their performance characteristics may differ because of their different formulas. Furthermore, it is unclear how each index performs under the coexistence of factor deficiency and inhibitors. ObjectivesThe objective of this study was to examine the differences in indexes, depending on factor VIII activity (FVIII:C) levels and lupus anticoagulant (LA) titers in test samples. MethodsAPTT was measured in spiked samples with various FVIII:C levels and LA titers, normal pooled plasma (NPP), and their 4:1, 1:1, and 1:4 mixtures. The following 5 indexes were calculated: index of circulating anticoagulant, mixing test normalized ratio, 4:1 and 1:1 percent corrections, and an APTT difference between the 1:1 mixture and NPP. The samples with LA, showing correction, were measured for FVIII:C in a one-stage assay to check parallelism. ResultsAll indexes showed correction under FVIII deficiency and non-correction under higher LA titers. However, under lower LA titers, some indexes showed non-correction but others showed correction because of dilution effects and variations in formulas and/or sample mix ratios. The differences among the indexes were more pronounced under coexistent FVIII deficiency and LA, even though LA titers were equal in the tested samples; samples with lower FVIII:C showed correction, whereas those with normal FVIII:C showed non-correction. The samples tested for FVIII:C showed non-parallelism. ConclusionEach index had different performance characteristics to LA samples, which were pronounced under low FVIII:C levels in test samples.

Impact of Emicizumab on Hemophilia Management

Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII(FVIII) that occurs in approximately 1 in 5,000 male births. Patients with plasma factor activity levels < 1% areclassified as having severe hemophilia. To prevent recurrent joint bleeding, which leads to QOL loss due to severearthropathy, patients need to receive regular intravenous infusions (prophylaxis) of FVIII products. However,there are many concerns regarding 1) the requirement of 2–3 times/week venipuncture for intravenous infusion, 2)frequent visits to the hospital (2–3 times/week in childhood), and 3) one-third of patients with severe hemophiliaA developing anti-FVIII neutralizing alloantibodies (inhibitors) toward the infused factor. Given this, patients andtheir caregivers encounter not only physical stress but also mental and social stress. To resolve these problems,prophylaxis with subcutaneous long-acting nonfactor products that improve in vivo thrombin generation is nowsuccessfully employed in hemophilia patients. These nonfactor products caused a paradigm shift in the treatmentand management of hemophilia. The novel agent emicizumab (Hemlibra®) is a recombinant humanized, bispecificmonoclonal antibody that simultaneously binds to activated factor IX and factor X, thereby mimicking the cofactor function of activated FVIII. Emicizumab has been shown to be safe and effective for the prevention of bleedsin patients with severe hemophilia A, both with and without inhibitors, but it has no indication in hemophilia B.One time/2 or 4 weeks administration was required for maintenance therapy. These benefits contributed by thelong half-life and subcutaneous administration make emicizumab an attractive therapeutic option for prophylaxisin infants with severe hemophilia; however, clinical data to inform treatment decisions in infants are almost absent. As the QOL of hemophilia patients and their caregivers is improved by emicizumab administration, emicizumab might be changed as a mainstream treatment for severe hemophilia in all patients, including infants.

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The History of Factor XIII Deficiency.

Despite the early discovery of factor XIII (FXIII) in 1944, the diagnosis of FXIII deficiency was not made until 1960, after all the other coagulation factor deficiencies, most likely due to the normality of routine coagulation testing in FXIII deficiency. Although the first case was detected by the clot solubility test and this test has long since been used to detect FXIII deficiency, the test is no longer recommended by experts. Over the past 60 years, knowledge about FXIII deficiency has expanded considerably, between 1992, when the first variant was identified, and 2022, 197 mutations have been reported. Almost all missense mutations have a similar effect on FXIII, leading to instability and faster degradation of mutant FXIII protein. Therapeutic options have evolved from historical fresh frozen plasma (FFP), old plasma, whole blood, and cryoprecipitate, to plasma-derived and recombinant FXIII concentrates, respectively available since 1993 and 2012. These concentrate products were respectively approved by the Food and Drug Administration in 2011 and 2013. This historical review covers various aspects of FXIII related disorders, including the discovery of the FXIII, associated disorders, molecular basis, diagnosis, and treatment of FXIII deficiency.

Diagnosis and treatment of autoimmune acquired coagulation factor deficiency

Autoimmune coagulation factor deficiency (AiCFD) is an acquired bleeding disorder caused by immunoglobulins (autoantibodies) that target a single coagulation factor. Most of these autoantibodies are polyclones and primarily neutralizing antibodies (inhibitors) that inhibit the function of coagulation factors; however, non-neutralizing autoantibodies that enhance clearance are also present. AiCFD has been reported in nearly all coagulation factors and von Willebrand factor, and its representative disease is acquired hemophilia A, which is caused by autoantibodies against coagulation factor VIII. The treatment for AiCFD consists of hemostatic therapy according to the bleeding symptoms and immunosuppressive therapy to eradicate autoantibodies. Hemostatic treatment varies depending on the deficient coagulation factor, and coagulation factor replacement therapy, platelet or fresh frozen plasma transfusions, and bypassing agents are provided. Although AiCFD is a rare disease, raising awareness of this disease is necessary because general physicians may also encounter it.

Performance and Interpretation of Clot Waveform Analysis.

The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are two basic tests for routine purposes, which are widely used in the clinical screening of coagulopathies. PT and aPTT are useful tests for detecting both symptomatic (hemorrhagic) and asymptomatic defects, but they are unsuitable for studying hypercoagulable states. However, these tests are available for studying the dynamic process of clot formation by means of the detection of the clot waveform analysis (CWA), which has been introduced several years ago. CWA can provide useful information on both hypocoagulable and hypercoagulable states. Nowadays it is possible to detect the whole clot formation both in the PT and aPTT tubes starting from the initial step of fibrin polymerization by means of specific and dedicated algorithm implemented in a coagulometer. In particular, CWA provides information on the velocity (first derivative), acceleration (second derivative), and density (delta) of clot formation. CWA has been applied to several pathologic conditions such as coagulation factor deficiency (including congenital hemophilia from factor VIII, IX, or XI deficiency), acquired hemophilia, disseminated intravascular coagulation (DIC), sepsis, replacement therapy management, chronic spontaneous urticarial, and liver cirrhosis, in patients with high venous thromboembolic risk before LMWH prophylaxis, and in patients with different hemorrhagic patterns along with an electron microscopy evaluation of the clot density. We report here materials and methods used for detecting the additional clotting parameters available in both PT and aPTT.

"Familial Multiple Coagulation Factor Deficiencies of FXI and FXII in an Asymptomatic Saudi Woman".

Factor XI deficiency (FXI) is the third most common coagulation factor deficiency after hemophilia A and B, ie, in the hierarchy after factors VIII and IX, taking into account von Willebrand's factor deficiency, as bleeding disorders are higher than in hemophilia C. Factor XII deficiency (FXII) is a congenital condition, inherited in the vast majority of cases in an autosomal recessive manner, more often associated with thromboembolic complications. A combination of both factor deficiencies has been found very rarely, and it can be familial multiple coagulation factor deficiency (FMCFD). This study reports the case of a 39-year-old woman from Saudi Arabia who had the combination of FXI and FXII deficiencies, known to be on treatment for hypothyroidism and was referred to a hematology clinic with an incidental finding of prolonged activated partial thromboplastin time (aPTT). Although there was no history of bleeding tendency, her siblings had a family history of an unknown type of bleeding disorder. On physical examination, the patient did not show any bruising, petechiae, or ecchymosis. The aPTT was 69 seconds (27-38) with normal use of other hemostatic agents and was corrected after a 50:50 mixing study. Intrinsic coagulation factors were evaluated, and they revealed severe FXI and moderate FXII deficiencies. Due to a strong family history, the patient was diagnosed with FMCFD. In conclusion, familial combined multiple clotting factor deficiency (FCMFD) is a rare condition that requires attention and reporting. The management strategy in such cases has not been well studied, especially in the long-term symptomatic patient with severe but asymptomatic combined FXI and FXII deficiencies, which is an area for review and further study.

Применение временной баллонной окклюзии внутренних подвздошных артерий при родоразрешении беременных с плацентарной адгезивно-инвазивной патологией

Study Objective: to evaluate the effects of temporary bilateral balloon occlusion of the internal iliac arteries on the volume of blood loss during operative delivery of pregnant women with placental adhesive-invasive pathology to internal cervical os and complete placenta previa. Study Design: randomized study. Materials and Methods. We analyzed 37 histories of patients with placental adhesive-invasive pathology to internal cervical os and complete placenta previa, who had operative delivery during 2018–2019. All examined women were divided into two clinical groups. The fact of using X-ray endovascular methods during delivery by caesarean section was the main principle of dividing the study participants. Group I is represented by women (n = 18) who underwent temporary balloon occlusion of the internal iliac arteries, group II (n = 19) is represented by women who delivered without X-ray endovascular methods. Study Results. Among the risk factors for placental adhesive-invasive pathology, the following can be distinguished: in the main group, 7 women (38.9%) had miscarriage in early pregnancy, 3 women (16.7%) had genital tract infection, 2 patients (11.1%) had endometriosis, myomectomy — in 1 case (5.5%), intrauterine interventions in 5 cases (27.8%), in the comparison group: 8 (42.1%), 5 (26.3%), 3 (15.8%), 1 (5.3%),2 (10.5%) respectively. In the main group, 7 patients (38.9%) had one operative delivery in history, 5 pregnant women (27.7%) had two cesarean sections, 3 women (16, 7%) had a scar on the uterus after 3 cesarean sections, and 3 women (16,7%) had a scar on the uterus after 4 caesarean sections, in the comparison group — 4 (21.05%), 8 (42.1%), 3 (15.8%), 4 (21.05%) respectively. In both groups, in 100% of cases, the operations were organ-preserving. In the main group, the volume of intraoperative blood loss, taking into account the volume of blood collected by the CellSaver device and by the gravimetric method, was 650.0 [500.0; 800.0] ml versus 866.0 [750.0; 1400.0] ml in the comparison group and was significantly lower (p &lt; 0.05). 7 (36.8%) patients from the comparison group required transfusion of fresh frozen blood plasma to replace the deficiency of coagulation factors. Assessment of newborns on the Apgar scale at 1/5 minutes did not show significant differences in the study groups. Conclusion. Endovascular temporary bilateral balloon occlusion of the internal iliac arteries is becoming an extremely necessary procedure to ensure the elimination of blood flow in the system of internal iliac arteries, reduce the collateral blood supply to the uterus and reduce intraoperative blood loss. This technique can reduce the amount of intraoperative blood loss by 33–43% in case of patients having placental adhesive-invasive pathology to internal cervical os and placenta previa. Keywords: placenta previa, pregnancy, placental adhesive-invasive pathology, temporary balloon occlusion of the internal iliac arteries.

Lupus Anticoagulant Testing: Dilute Prothrombin Time (dPT).

Lupus anticoagulants (LA) rarely affect routine prothrombin time assays because the high phospholipid (PL) content in thromboplastin reagents tends to overwhelm the antibodies. Dilution of thromboplastin to create a dilute prothrombin time (dPT) screening test renders the assay sensitive to the presence of LA. Technical and diagnostic performances are enhanced if recombinant thromboplastins are employed in place of tissue-derived reagents. Presence of an LA cannot be deduced from an elevated screening test alone since other coagulation disturbances can prolong clotting times. Confirmatory testing with less dilute or undiluted thromboplastin reveals the PL-dependent nature of LA by reducing the clotting time relative to that of the screening test. Where appropriate, such as a known or suspected coagulation factor deficiency, mixing tests are valuable in correcting factor deficiencies and evidencing inhibitory properties of LA, to increase diagnostic specificity. Although LA testing is commonly restricted to dilute Russell's viper venom time and activated partial thromboplastin time, dPT is sensitive to LA unreactive in those assays, and inclusion in routine testing increases detection rates of clinically significant antibodies.

Therapeutic options for hemarthrosis in severe hemophilic patients

the coagulation factors VIII (FVIII) or IX (FIX), respectively. The primary therapeutic approach is to replace the deficient coagulation factor, which can be achieved with factors derived from human plasma or recombinants. However, despite having a therapeutic approach, most severe cases are symptomatic and may have complications, mainly in the muscles and joints. One example of such disorder is hemarthrosis. This manifestation tends to affect mainly the knee, ankle, or elbow joints in about 80% of cases. Objective: to describe the primary forms of treatment for joint bleeding in patients with severe hemophilia. Methods: This is a qualitative research of the integrative review type meant to identify productions on topics associated with hemarthrosis and severe hemophilia. The articles were searched through the databases PubMed, Scientific Electronic Library Online (Scielo) and Virtual Health Library (BVS) with the following search descriptors: “hemarthrosis andhemophilia”; “joint diseases and Hemophilia” and corresponding terms in Portuguese. The inclusion criteria were as follows:a) scientific articles b) available in full-text c) studies available in Portuguese, English, or Spanish d) randomized clinical trials e) articles published between 2016 and 2021 f) articles containing hemarthrosis caused by severe hemophilia. As exclusion criteria, texts that had no relation to the theme, did not answer the guiding question, other types of articles that did not include randomized clinical trials and/or presented duplicates were discarded. Results: In total, 42 articles were found in the selected databases; eight were duplicated, and 25 were excluded for not being randomized clinical trials or because they did not contemplate the theme. After careful reading, nine articles that met the inclusion and exclusion criteria were identified. Of the eligible studies, one reported factor replacement, and eight reported physiotherapeutic treatment. Conclusion: Factor replacement for hemophilic patients is essential and, based on the information obtained, early replacement is beneficial for the patient to avoid joint complications. Prophylaxis is indicated in severe hemophilia and its main objective is to prevent recurrent hemarthrosis, which can cause permanent functional deformities. Some physiotherapeutic interventions are indicated to prevent joint damage in severe hemophilic patients. The findings show diversity in the physical therapy modalities employed. The complete prevention of joint damage is still a challenge. A combination of treatments and a multidisciplinary team follow-up is necessary to ensure health and quality of life of patients.

Hematologist Bracha Ramot (1927-2006): Between the bedside and the bench.

The Hebrew University of Jerusalem opened the first medical school in Israel in May 1949. One of the select 45 students of its first class was Bracha (Chweidan) Ramot. After completing her medical studies with distinction, she went on to specialize in internal medicine and hematology and soon became a central figure in the development of hematology in Israel. In 1958, Ramot established the Hematological Institute at Tel-Hashomer hospital and served as its director until 1991. She devoted much of her time and effort to researching environmental and genetic factors that influence hematological conditions: deficiencies in coagulation factors, glucose metabolism disorders, and especially leukemias and lymphomas, including the type known as Hodgkin's disease. In 2001, Ramot, "The Doyenne of Israeli Hematology" as she was called in publications of the Albert Einstein Institute, was awarded the Israel Prize in Medical Sciences, the country's most prestigious prize. Her biography personifies the ability to overcome obstacles and challenges in one's personal life while concurrently becoming an exceedingly successful physician and researcher of extraordinary achievement.

High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study

BackgroundWomen with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, may have a higher risk of postpartum hemorrhage (PPH). Information on this patient category is lacking in the existing PPH guidelines because data on PPH in patients with RBDs are scarce. ObjectiveTo describe the prevalence of PPH in women with an RBD and evaluate the use of peripartum hemostatic prophylaxis. MethodsIn the Rare Bleeding Disorders in the Netherlands (RBiN) study, patients with RBDs (n = 263) were included from all 6 Dutch hemophilia treatment centers. Patient–reported information on delivery, peripartum hemostatic prophylaxis, and occurrence of PPH was collected retrospectively. If available, information about the precise volume of postpartum blood loss was extracted from electronic patient files. PPH was defined as blood loss ≥500 mL (World Health Organization guideline). ResultsA total of 244 pregnancies, including 193 livebirths, were reported by 85 women. A considerable proportion of these women experienced PPH, ranging from 30% in factor V deficiency to 100% in hyperfibrinolysis. Overall, PPH was reported in 44% of deliveries performed with and 53% of deliveries performed without administration of peripartum hemostatic prophylaxis. Blood loss was significantly higher in deliveries without administration of hemostatic prophylaxis (median 1000 mL) compared to deliveries with administration of prophylaxis (median 400 mL) (p = 0.011). Patients with relatively mild deficiencies also frequently experienced PPH when peripartum hemostatic prophylaxis was omitted. ConclusionPPH is common in rare coagulation factor deficiencies, both severe and mild, and fibrinolytic disorders, especially when peripartum prophylactic hemostatic treatment was not administered. The use of prophylactic hemostatic treatment was associated with less postpartum blood loss.

Thromboembolic Disease in Haemophilic Patients Undergoing Major Orthopaedic Surgery: Is Thromboprophylaxis Mandatory?

Haemophilia is a rare genetic disorder, that results from various degrees of deficiency of coagulation factor VIII (haemophilia A), or factor IX (haemophilia B), with an X-linked transmission. The patients affected are in the majority of cases males (who inherit the affected X-chromosome from the maternal side), with rare cases of females with haemophilia (FVIII or FIX &lt; 40 IU/dL), situations in which both X-chromosomes are affected, or one is affected, and the other one is inactive (known as carrier). The hypocoagulable state due to the deficiency of clotting factors, manifests as an excessive, recurrent tendency to bleeding, which positively correlates with plasmatic levels. Severe haemophilia results in hemarthrosis, although recent data have shown that moderate or even mild disease can lead to joint bleeding. Recurrent episodes of haemorrhages, usually affecting large joints such as knees, elbows, or ankles, lead to joint remodelling and subsequent haemophilic arthropathy, which may require arthroplasty as a last therapeutic option. Orthopaedic patients have the highest risk among all for deep vein thrombosis (DVT) and venous thromboembolism (VTE) with morbid and potentially fatal consequences. While for the rest of the population thromboprophylaxis in orthopaedic surgery is efficient, relatively safe, and widely used, for patients with haemophilia who are considered to have a low thromboembolic risk, there is great controversy. The great heterogeneity of this particular population, and the lack of clinical trials, with only case reports or observational studies, makes thromboprophylaxis in major orthopaedic surgery a tool to be used by every clinician based on experience and case particularities. This review aims to briefly summarise the latest clinical data and to offer an insight into the current recommendations that readers would find useful in daily practice.