The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes.

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.

Osteonecrosis of the Femoral Head in Patients with Hypercoagulability-From Pathophysiology to Therapeutic Implications.

Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients' quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance.

The impact of foetal restrictions on mode of delivery in women with inherited bleeding disorders.

OBJECTIVES: Management of pregnancy in women with congenital bleeding disorders (CBD) is challenging and requires understanding of risks conferred to both the mother and the foetus. Some elements of labour management are considered to increase the risk of neonatal bleeding and are not recommended for neonates at risk of a significant bleeding disorder. The impact of these restrictions on obstetric outcomes in women with CBD is unknown. METHODS: We retrospectively reviewed obstetric outcomes in a large cohort of women with CBD attending a specialised obstetric/haematology antenatal clinic over a 6-year period. RESULTS: Ninety-four pregnancies in 76 women with a wide variety of CBDs were assessed. Foetal precautions were recommended in the majority of cases (88%). Twenty (21.2%) were delivered by elective Caesarean section (CS), predominantly for obstetric indications. Of the 63 women who laboured with foetal precautions in place, 6 (10%) had a CS that was performed because of these precautions. There was no neonatal bleeding but primary postpartum haemorrhage (PPH) occurred in 12.2% of women. CONCLUSIONS: These data show that foetal precautions in labour recommended for women with CBDs will influence mode of delivery in approximately 10% of cases. This is important information for counselling these women about labour and delivery.

Bleeding related to disturbed fibrinolysis.

The components and reactions of the fibrinolysis system are well understood. The pathway has fewer reactants and interactions than coagulation, but the generation of a complete quantitative model is complicated by the need to work at the solid-liquid interface of fibrin. Diagnostic tools to detect disease states due to malfunctions in the fibrinolysis pathway are also not so well developed as is the case with coagulation. However, there are clearly a number of inherited or acquired pathologies where hyperfibrinolysis is a serious, potentially life-threatening problem and a number of antifibrinolytc drugs are available to treat hyperfibrinolysis. These topics will be covered in the following review.

Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders.

Platelets play a crucial role in haemostasis by preventing bleeding at the site of vascular injury. Several defects in platelet morphology and function have been identified and described over the years. Although a range of methodologies is available to assess platelet function, a significant proportion of subjects with bleeding symptoms and normal coagulation parameters still appear to have normal results on platelet function testing. This might suggest that the reason for bleeding is multifactorial and is due to a combination of several minor defects in platelet function and/or other parts of the haemostatic system or might indicate that the currently available platelet function tests do not provide optimal diagnostic power. This review will summarize the established platelet function tests used for diagnosing inherited platelet abnormalities in adults and children, and discuss the newly developed methodologies as well as unmet challenges and potential areas for further improvement in this field.

Rare bleeding disorders - bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency.

Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FVII, combined FV+FVIII, FX, FXI and FXIII. These disorders usually have a low prevalence in the general population and constitute approximately 3-5% of all coagulation disorders. However, in some countries they may have the same prevalence as haemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs is highly variable and can vary markedly from mild to severe, making both diagnosis and optimal treatment quite challenging. This review focuses on: (i) the efforts to establish a bleeding assessment tool adequate to RBDs, (ii) the optimal management of patients affected with FXI deficiency and (iii) the correlation between clinical severity and laboratory diagnosis when determining the minimum coagulant activity required to prevent bleeding in each RBD.

Present day management of inherited bleeding disorders in pregnancy.

INTRODUCTION: How specifically to prevent post-partum haemorrhage (PPH) remains a challenge in pregnant women with an inherited bleeding disorder. There exists a morbidity of 5-10% of patients as well as increased mortality. AREAS COVERED: This review will survey the literature based on Medline review and various society monographs. Numerous societies have developed guidelines in hopes of reducing the risk of PPH. The guidelines are congruent in stating that the von Willebrand factor (VWF) /Factor VIII (FVIII) level must be > 50% to both permit safely epidural analgesia but also to prevent PPH. However, specific guidance is lacking in terms of how high and long a level should be achieved. Recent studies report a high rate of PPH in these treated patients despite aiming for levels > 50-100% suggesting that a postpartum post-replacement VWF/FVIII level of 50-100% is inadequate and follow up dosing should maintain higher levels then typically achieved per 'guidelines'. Expert commentary: Future studies to reduce PPH in women in the third trimester with levels < 50% should incorporate concurrent post-partum antifibrinolytic agent therapy and/or double utertonics and/or aiming for a higher trough factor level closer to 200% than 100% and maintaining such a level for several days postpartum.

Inherited defects of platelet function.

Inherited platelet defects bleeding syndromes underlie of varying severity. The Bernard-Soulier syndrome and Glanzmann thrombasthenia are disorders of membrane glycoproteins. In the former, a deficiency of the GPIb-IX-V complex leads to defective platelet adhesion, while in thrombasthenia, platelet aggregation does not occur in the absence of the integrin alphaIIbbeta3. Defects of primary receptors for stimuli are increasingly being described, and include a defect of a newly cloned Gi-protein-linked, seven transmembrane domain, ADP receptor. These lead to agonist-specific deficiencies in the platelet function response, as do abnormalities in the many intracellular signaling pathways of platelets. Defects affecting secretion from dense bodies and alpha-granules, of ATP production and generation of procoagulant activity, are also encountered. Some disorders are exclusive to megakaryocytes and platelets, while in others, such as the Chediak-Higashi, Hermansky-Pudlak and Wiskott-Aldrich syndromes; the molecular lesion extends to other cell types. Disorders affecting platelet morphology, the so-called "giant platelet" syndromes should also be considered. In familial thrombocytopenias, platelets are produced in insufficient quantities to assure hemostasis. Platelet disorders are examples of rare diseases; nevertheless they have provided essential information in the elucidation of the molecular basis of platelet function.

The spectrum of inherited bleeding disorders in pediatrics.

Inherited bleeding disorders (IBDs) are caused by quantitative and qualitative alterations of either platelets or plasma proteins involved in coagulation and fibrinolysis. Hemophilias are the most frequent IBDs; however, accumulated data from various studies reported that von Willebrand disease (VWD) is the most common cause of IBD, with an increased incidence of platelet function defects, mostly due to the increased rate of consanguinity in some communities. VWD is an inherited disorder of homeostasis due to quantitative or qualitative defect of von Willebrand factor. Data on its epidemiology and impact in developing countries are limited. The objective of this study was to assess the local prevalence of some IBD and establish the clinical and historical variables that are predictive for those bleeding disorders in pediatrics. The study involved 43 children with various bleeding manifestations and 15 age- and sex-matched controls, recruited from the Pediatrics Hematology Clinic at the National Research Centre, Sausan Mubarek children's hospital in Cairo, Egypt and the King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Hematological profile included platelet counts and function, prothrombin time, partial thromboplastin time, factor VIII antigen and its activity, factor IX antigen and its activity, von Willebrand factor and its activity assayed with multimeric analysis. A total of 12 (27.9%) children had VWD, 11 (25.5%) had hemophilia A, three (7%) had hemophilia B, seven (16.3%) had platelet dysfunction and 10 (23.3%) had bleeding with undiagnosed cause. Two of the VWD cases had type I, three had type II, four had type III and one case appeared to have type IIM and another to have IIB VWD. Bruising and epistaxis were the main symptoms in all children with VWD The majority of platelet dysfunction disorders were diagnosed as Glanzmann's thrombasthenia. VWD and Glanzmann's thrombasthenia should be considered not uncommon causes of IBDs in children in Egypt and Kingdom of Saudi Arabia. Routine hematological screening should be mandatory in children with positive family history of bruising and bleeding as a predictor for IBD.

Hereditary thrombophilia in ethnic Omani patients.

Hereditary thrombophilias are a group of inherited conditions that predispose to thrombosis. Mutations like factor V Leiden, prothrombin gene variant 20210A, and hereditary hyperhomocysteinemia are associated with an increased risk for thromboembolism as compared to mutations in natural inhibitors of coagulation. There is also evidence that multiple defects co-exists in persons with a tendency for thrombosis. We studied prothrombotic determinants, namely protein C, protein S, and AT along with factor V Leiden (1691G-->A), prothrombin gene mutation (20210G-->A), CBS 844ins68 mutation, and MTHFR mutation (677C-->T) in consecutive ethnic Omani patients with first episode of a thrombophilic event, namely, deep vein thrombosis (DVT), and/or pulmonary embolism (PE) or thrombosis at an unusual site. Fasting plasma homocysteine was also analyzed. Factor V Leiden and the prothrombin gene mutation were not seen in any patient nor in any control subject studied. The thermolabile MTHFR mutation (677C-->T) was present in 14 patients (35.89%) whereas the CBS 844ins68 mutation was documented in 6 patients (15.38%); 3 patients were common in both groups. Six patients had low protein C (15.38%), two patients had low protein S (5.12%), but none had low AT levels. Interestingly, one patient had triple abnormality, namely, PC deficiency with both CBS 844ins68 mutation as well as the MTHFR mutation (677C-->T) whereas another two patients had the latter two mutations together. This data set, although small, reflects the importance of multiple screening strategies. The yield appears high, emphasizing the referral pattern to a tertiary health center. Of these patients, 43.58% had either or both the hyperhomocysteinemic mutations studied, whereas in 38.46% of these patients, no underlying cause for thrombophilia could be documented.