AbstractGastrointestinal bleeding (GIB) is serious, intractable, and potentially life-threatening condition. There is considerable heterogeneity in GIB phenotypes among congenital bleeding disorders (CBDs), making GIB difficult to manage. Although GIB is rarely encountered in CBDs, its severity in some patients makes the need for a comprehensive and precise assessment of underlying factors and management approaches imperative. Initial evaluation of GIB begins with assessment of hematological status; GIB should be ruled out in patients with chronic anemia, and in presentations that include hematemesis, hematochezia, or melena. High-risk patients with recurrent GIB require urgent interventions such as replacement therapy for treatment of coagulation factor deficiency (CFD). However, the best management strategy for CFD-related bleeding remains controversial. While several investigations have identified CBDs as potential risk factors for GIB, research has focused on assessing the risks for individual factor deficiencies and other CBDs. This review highlights recent findings on the prevalence, management strategies, and alternative therapies of GIB related to CFDs, and platelet disorders.
AbstractIntracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.
Platelet a-granules regulate hemostasis and myriad other physiological processes but their biogenesis is unclear. Mutations in only three proteins are known to cause a-granule defects and bleeding disorders in humans. Two such proteins, VPS16B and VPS33B, form a complex mediating transport of newly synthesized a-granule proteins through megakaryocyte endosomal compartments. It is unclear how the VPS16B/VPS33B complex accomplishes this function. Here we report VPS16B/VPS33B associates physically with Stx12, a SNARE protein that mediates vesicle fusion at endosomes. Importantly, Stx12 deficient megakaryocytes display reduced a-granule numbers and overall levels of a-granule proteins, thus revealing Stx12 as new component of the a-granule biogenesis machinery. VPS16B/VPS33B also binds CCDC22, a component of the CCC complex working at endosome exit sites. CCDC22 competes with Stx12 for binding to VPS16B/VPS33B suggesting a possible hand-off mechanism. Moreover, the major CCC form expressed in megakaryocytes contains COMMD3, one of ten COMMD proteins. Deficiency of COMMD3/CCDC22 causes reduced a-granule numbers and overall levels of a-granule proteins, establishing the COMMD3/CCC complex as a new factor in a-granule biogenesis. Furthermore, P-Selectin traffics through the cell surface in a COMMD3-dependent manner and depletion of COMMD3 results in lysosomal degradation of P-Selectin and PF4. Stx12 and COMMD3/CCC deficiency cause less severe phenotypes than VPS16B/VPS33B deficiency, suggesting Stx12 and COMMD3/CCC assist but are less important than VPS16B/VPS33B in a-granule biogenesis. Mechanistically, our results suggest VPS16B/VPS33B coordinates the endosomal entry and exit of a-granule proteins by linking the fusogenic machinery with a ubiquitous endosomal retrieval complex that is repurposed in megakaryocytes to make a-granules.
The science of life which explains the knowledge of various guidelines to be followed to make a healthy living is called Ayurveda. With the expansion of facilities of travel and occupation, man has to undertake extensive journeys, through diverse modes such as rail, road, water, etc. Most of these situations cited have been principally implicated in the vaigunya (state of altered functioning) of Apanavayu. The manifestation of Apana vayu vaigunya varies from mild cases of constipation to severe cases of mental disturbances. One of the prominent factors highlighted as a cause of Apana vaigunya is Atiyana (excessive travel by any modality).
Symptoms of Apana Vayu vaigunya told in major classical books of Ayurveda were gathered to deduce a comprehensive understanding of the context. Apanavata is invariably associated with the component of pathogenesis in 45 diseases starting from Vatavyadi, Arsas(piles), Asmari, Prameha, Sosha, Jwara, Rakthapitta(Bleeding disorders), Vatarakta, Gulma(phatom tumour), Udara, Mutrakrcha(difficulty in urination), etc. Later the symptoms possibly associated with the vitiation of Apanavata present in diseases were listed and 332 symptoms were found to be associated with Apana kopa (vitiation of apana). These symptoms were further tabulated according to the order of frequency of occurrence as most repeatedly occurring symptoms, moderately repeated symptoms and least repeated symptoms. Thus out of 332 symptoms, 28 symptoms which can possibly occur due to atiyana were selected. In the modern era, due to irregular and bad habits of ahara, vihara along with the suppression of natural urges, the percentage of Apanavaigunyajanya vyadhis are increasing, which affects physical as well as psychological factors also. Work related travel is also now increasing, so it is the right time to concentrate this issue from the concepts of Ayurveda, Apana vayu vaigunya and athiyana. Based on these observations, aim of the present study is to explore the hidden concept of Apana vaigunya mentioned in Ayurvedic literature in relation with atiyana.
With improvements in medical care, the life expectancy of patients with bleeding disorders is approaching that of the general population. A growing population of older adult patients with bleeding disorders is at risk of age-related comorbidities and in need of various elective and emergent age-related procedures. The increased risk of thrombosis and volume overload in older adults complicates perioperative hemostatic management. Furthermore, antithrombotic treatment such as antiplatelet or anticoagulant therapy, which is frequently required for various cardiovascular interventions, requires a meticulous individualized approach. Evidence-based guidelines for the management of aging patients with bleeding disorders are lacking, largely due to the underrepresentation of older adult patients in clinical trials as well as the rarity of many such bleeding disorders. We discuss the current guidelines and recommendations in the perioperative hemostatic management of older adult patients with hemophilia and von Willebrand disease as well as other rare bleeding disorders. The optimal management of these patients is often complex and requires a thorough multidisciplinary and individualized approach involving hematologists, surgeons, anesthesiologists, and the specialists treating the underlying disorder.
Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.