Aspirin-Induced Prolongation of the Ivy Bleeding Time—Its Diagnostic Usefulness

Ivy bleeding time values before and two hours after ingestion of 600 mg of aspirin (aspirin tolerance test) were studied in normal persons, in patients with a disorder of primary hemostasis and in patients with various coagulation factor deficiencies. Aspirin produced a significant prolongation of the bleeding time in patients with von Willebrand''s disease, uremia, and primary platelet disease, and in two patients with Factor XI deficiency. Dextropropoxyphene hydrochloride caused no prolongation of the bleeding time in normal persons.     

Porcine Model of Hemophilia A

Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8). Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.     

Hemostatic profile during late pregnancy and early postpartum period in mares

Hemostasis is a physiological process that prevents excessive blood loss and represents a protective mechanism at the time of delivery. Peripartum hemorrhage is a recurring hazardous condition to mare's health; therefore, we aimed to study mares' hemostatic profile to investigate whether physiological adjustments occur during late pregnancy and early postpartum. Fifteen pregnant mares have been monitored from the 34th week of pregnancy until the third week after foaling. Fifteen nonpregnant mares were used as control group. Jugular blood samples were analyzed for platelet count (Plt), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen (Fb). Platelet count showed significant changes at foaling (P < 0.05) and a negative correlation (r = −0.968; P = 0.032) with postpartum. Prothrombin time changed (P < 0.05) showing a significant correlation (r = 0.675; P = 0.016) with late pregnancy. Fibrinogen concentrations changed throughout the experimental period (P < 0.0001). The linear regression model revealed a positive correlation (r = 0.9210; P < 0.0001) between Fb and late pregnancy and a negative correlation (r = −0.9583; P = 0.042) between Fb and early postpartum. The shortening in PT recorded in the imminence of parturition along with the increase in Plt and Fb at foaling might reflect a physiological hypercoagulable state that constrains excessive bleeding, enhancing mares' odds of surviving. Our research improves the knowledge about blood coagulation in periparturient mares providing specific information on routine coagulation tests that may support in monitoring mare's hemostatic profile during late pregnancy and early postpartum.     

Rare acquired bleeding disorders

Accurate diagnosis of the cause of bleeding is a prerequisite for determination of the optimal therapeutic response. Clinicians are generally aware of the more prevalent hemorrhagic syndromes but some rare acquired conditions are also of importance. In many of these, inhibitors of coagulation factors or of platelet adhesion/aggregation cause bleeding. These inhibitors are generally, but not always, immunoglobulins. In this review, the less common inhibitors of coagulation and hemostasis, as well as some important but rare nutritional, iatrogenic and disease associated hemorrhagic disorders, are described.     

高剂量生长抑素、奥美拉唑联合止血芳酸治疗急性上消化道出血合并凝血功能障碍患者的临床效果

目的:探讨高剂量生长抑素、奥美拉唑联合止血芳酸治疗急性上消化道出血合并凝血功能障碍患者的临床效果及安全性。方法:选择我院2014年1月~2017年12月收治的92例急性上消化出血合并凝血功能障碍的患者,并按随机数表法将其分为对照组和研究组。对照组予以常规剂量生长抑素、奥美拉唑联合止血芳酸治疗,研究组予以高剂量生长抑素治疗,其余奥美拉唑及止血芳酸用法同对照组。治疗后,比较两组的临床疗效、止血情况、住院时间,治疗前后血常规指标、凝血功能的变化及并发症的发生情况。结果:治疗后,研究组总有效率明显高于对照组[91.30%vs.74.42%](P0.05),而平均止血时间、再止血率及住院时间均明显短于对照组(P0.05);两组白细胞计数(WBC)、部分活化凝血酶原时间(APTT)及凝血酶原时间(PT)均较治疗前明显下降,血红蛋白(Hb)、红细胞计数(RBC)、红细胞压积(Hct)及血小板计数(PLT)均较治疗前明显上升,且研究组以上指标变化较对照组更明显(P0.05)。两组并发症的发生率比较差异均无统计学意义(P0.05)。结论:高剂量生长抑素、奥美拉唑联合止血芳酸治疗急性上消化道出血合并凝血功能障碍的效果明显优于常规剂量生长抑素、奥美拉唑联合止血芳酸治疗,其能够更有效缩短止血时间,避免再出血,且未增加药物不良反应,安全性高。     

DIAGNOSIS OF HEMORRHAGIC DISEASES—Evaluation of Procedures—Part II Preoperative Tests

Routine preoperative tests such as the determination of bleeding time and coagulation time are unnecessary and are not recommended. Rulings which require routine preoperative tests result in the adoption of inferior and unreliable time-saving methods in the laboratory. If the clinical staff insists that laboratory procedures to predict hemorrhage be performed on every patient scheduled for operation, approved methods of performing the tests should be employed.Preoperative procedures should include a personal and a family history, a careful and complete physical examination and screening laboratory tests such as urinalysis, hematocrit, leukocyte count and smear examination, including estimation of the number of thrombocytes.Special hemorrhagic studies are indicated on selected patients. These selected patients include those who have a history of abnormal bleeding, those who consider themselves “easy bleeders” or who have apprehension concerning hemorrhage at the time of operation, and those who have physical signs of hemorrhage. Special hemorrhagic studies should also be performed on patients who have diseases that are known to be associated with vascular and coagulation abnormalities, infants who have not been subjected to tests of trauma and on patients from whom a reliable history cannot be obtained.Extra precaution should be taken if operation is to be performed in hospitals or clinics that do not have adequate blood banking facilities and if the operation to be performed is one in which difficulty in hemostasis is anticipated.The preoperative tests that are indicated on selected patients should include as a minimum: The thrombocyte count, determination of the bleeding time by the Ivy method, determination of the coagulation time by the multiple tube method and the observation of the clot. Where facilities are available, the hemorrhagic study should also include the plasma and serum prothrombin activity tests.     

Splenectomy Improves Hemostatic and Liver Functions in Hepatosplenic Schistosomiasis Mansoni

Background

Schistosomiasis mansoni is a chronic liver disease, in which some patients (5–10%) progress to the most severe form, hepatosplenic schistosomiasis. This form is associated with portal hypertension and splenomegaly, and often episodes of gastrointestinal bleeding, even with liver function preserved. Splenectomy is a validated procedure to reduce portal hypertension following digestive bleeding. Here, we evaluate beneficial effects of splenectomy on blood coagulation factors and liver function tests in hepatosplenic schistosomiasis mansoni compared to non-operated patients.

Methodology/Principal Findings

Forty-five patients who had undergone splenectomy surgery were assessed by laboratory analyses and ultrasound examination and compared to a non-operated group (n = 55). Blood samples were obtained for liver function tests, platelet count and prothrombin time. Coagulation factors (II, VII, VIII, IX and X), protein C and antithrombin IIa, plasminogen activator inhibitor-1 were measured by routine photometric, chromogenic or enzyme-linked immunosorbent assays, while hyperfibrinolysis was defined by plasminogen activator inhibitor-1 levels. Both groups had similar age, gender and pattern of periportal fibrosis. Splenectomized patients showed significant reductions in portal vein diameter, alkaline phosphatase and bilirubin levels compared to non-operated patients, while for coagulation factors there were significant improvement in prothrombin, partial thromboplastin times and higher levels of factor VII, VIII, IX, X, protein C and plasminogen activator inhibitor-1.

Conclusion/Significance

This study shows that the decrease of flow pressure in portal circulation after splenectomy restores the capacity of hepatocyte synthesis, especially on the factor VII and protein C levels, and these findings suggest that portal hypertension in patients with hepatosplenic schistosomiasis influences liver functioning and the blood coagulation status.     

Disturbances of coagulation and fibrinolysis in patients with acute leukemia]

In 30 patients with acute leukemia--18 with myeloblastic acute leukemia, 1 with promyelocytic acute leukemia, 4 with myelo-monocytic acute leukemia, 4 with chronic myelocytic leukemia exacerbation--coagulation and fibrinolysis tests were performed in different stage of the disease. Most of the disorders were noted in the III period of the disease (significant levels of the factors II, IX decrease, clot contractility weakness and platelets count decrease). I in patients with manifestation of haemorrhagic diathesis and in patients without them disturbances in examined tests were similar, but platelets count in patients with bleeding was always significantly reduced. The main reasons of the bleeding in acute leukemias are thrombocytopenia together with the in coagulation factors.     

Coagulation factor III (tissue factor) is required for vascularization in zebrafish embryos

Tissue factor (coagulation factor III) is a cell surface receptor for coagulation factor VII/VIIa; it was initially recognized as an initiator of the extrinsic coagulation pathway. Recently, the zebrafish tissue factor gene (TF) has been cloned. Paralogs encode coagulation factors IIIa and IIIb; both show remarkable sequence identity to the human and mouse coagulation factor III gene. It has been reported that TF could have additional properties that are essential for normal embryonic development, since knockout of the murine coagulation factor III gene resulted in 90% embryonic lethality. We examined the role of coagulation factor IIIb (f3b) during zebrafish embryonic development. Expression analysis revealed that endogenous f3b was chronologically expressed in the pectoral fins and in the vicinity of the pharynx. Knockout of f3b by injection of an f3b morpholino at the one-to-two cell stage caused distinctive morphological defects in embryos, including edema in the fourth brain ventricle at early embryonic stages and occasional bleeding at later stages. Furthermore, f3b morphants displayed abnormal vascular patterning. We conclude that f3b is required for brain vascular development and for development of part of the somatic vasculature during embryogenesis in the zebrafish.     

High-dose intravenous therapy with immune globulin before delivery for idiopathic thrombocytopenic purpura.

A 15-year-old girl with a 9-year history of idiopathic thrombocytopenic purpura resistant to high-dose steroid therapy and to splenectomy was admitted to hospital at 35 weeks'' gestation with a platelet count of 10 X 10(9)/L. The bleeding time was normal, and measures of platelet aggregation were nearly so. Treatment with high intravenous doses of polyvalent immune globulin led to a rise in the platelet count to more than 110 X 10(9)/L within 5 days. An elective cesarean section was performed through the lower uterine segment with good hemostasis. After delivery the platelet count fell to its former level, but no postpartum bleeding occurred. There was a brief episode of thrombocytopenia in the infant, with some petechiae but no other hemorrhagic manifestations. No untoward effects of the immune globulin infusion were observed in either mother or daughter.     

Dynamics of blood coagulation factor XIII in ulcerative colitis and preliminary study of the factor XIII concentrate

Blood coagulation studies were performed in twenty patients with ulcerative colitis (UC). At the active stage of UC, a marked increase in platelet count and fibrinogen concentration, and a marked decrease in Factor XIII activity level were observed. At the active stage of UC, four patients were treated with Factor XIII concentrate leading to reduction of pain, bleeding and endoscopic findings.     

Role of Platelets in Hemostasis and Thrombosis

Platelets interact with the coagulation factors in a complex way to arrest bleeding or generate thrombi. Recently, the platelet''s relationship to endothelial alteration and atheroma production has received renewed attention. At present, tests of platelet function better define “hypocoagulable” rather than “hypercoagulable” states.     

冻伤对大鼠血凝系统某些因素的影响

本研究观察了大鼠双后足局部冻伤后其血凝系统某些因素的改变。结果表明,冻伤后大鼠的出血时间及凝血时间明显缩短,血小板数增加,血小板聚集率增高,血浆血栓素Ａ２、纤维蛋白原及钙离子浓度均明显增加,且上述指标的改变与冻伤程度有密切关系,冻伤愈重,改变愈明显,恢复亦愈慢。结果提示,冻伤可使血凝系统发生改变,血液处于高凝状态,这对浆伤后发生的血液循环障碍最终导致冻伤组织坏死的病理过程起重要作用。     

Model of disseminated intravascular coagulation

Vascular-thrombocytic and plasma hemostasis was studied in dogs after blood loss (40--50 ml/kg weight) and subsequent hypervolemic (60--65 ml/kg weight) transfusion of homologous (from 3 donors) platelet and leukocyte rich in plasma. After a short phase of hypercoagulation all the tested dogs displayed hypocoagulation accompanied by a decrease in the count of platelets and a fall of their aggregation function, prolongation of bleeding time, diminution of capillary wall resistance, a decrease of plasma fibrinogen concentration and factor XIII activity, and by a rise of blood fibrinolytic activity. The data obtained show the development of the acute disseminated intravascular coagulation syndrome (DIC). DIC model is porposed on the basis of the results obtained.     

Anticoagulants and the propagation phase of thrombin generation

The view that clot time-based assays do not provide a sufficient assessment of an individual''s hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may provoke fewer bleeding episodes. More generally, the study shows that computational modeling of the response of core elements of the coagulation proteome to a physiologically relevant tissue factor stimulus may improve the monitoring of a broad range of anticoagulants.     

凝血因子Ⅶ及其重组表达新进展

凝血因子Ⅶ是一种维生素K依赖型的单链糖蛋白,在凝血过程中发挥着极其重要的作用,在临床上有广泛的应用,可用于伴有抑制物的血友病、先天性FⅦ缺乏症、血小板无力症及外科手术或严重外伤导致的创伤出血等止血用途.基因重组技术提供了能够大规模制备人凝血因子Ⅶ的有效途径,近年来已尝试并建立了多种人凝血因子Ⅶ的重组表达系统.对重组人凝...     

Hepatocerebral dysfunction

Routine preoperative tests such as the determination of bleeding time and coagulation time are unnecessary and are not recommended. Rulings which require routine preoperative tests result in the adoption of inferior and unreliable time-saving methods in the laboratory. If the clinical staff insists that laboratory procedures to predict hemorrhage be performed on every patient scheduled for operation, approved methods of performing the tests should be employed. Preoperative procedures should include a personal and a family history, a careful and complete physical examination and screening laboratory tests such as urinalysis, hematocrit, leukocyte count and smear examination, including estimation of the number of thrombocytes. Special hemorrhagic studies are indicated on selected patients. These selected patients include those who have a history of abnormal bleeding, those who consider themselves "easy bleeders" or who have apprehension concerning hemorrhage at the time of operation, and those who have physical signs of hemorrhage. Special hemorrhagic studies should also be performed on patients who have diseases that are known to be associated with vascular and coagulation abnormalities, infants who have not been subjected to tests of trauma and on patients from whom a reliable history cannot be obtained. Extra precaution should be taken if operation is to be performed in hospitals or clinics that do not have adequate blood banking facilities and if the operation to be performed is one in which difficulty in hemostasis is anticipated. THE PREOPERATIVE TESTS THAT ARE INDICATED ON SELECTED PATIENTS SHOULD INCLUDE AS A MINIMUM: The thrombocyte count, determination of the bleeding time by the Ivy method, determination of the coagulation time by the multiple tube method and the observation of the clot. Where facilities are available, the hemorrhagic study should also include the plasma and serum prothrombin activity tests.     

Autosomal recessive deficiencies of coagulation factors

Deficiencies of coagulation factors that cause a bleeding disorder, other than factor VIII and factor IX, are inherited as autosomal recessive traits and are generally rare, with prevalence in the general population varying between 1 in 500 000 and 1 in 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations where consanguineous marriages are frequent. As a consequence of the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for hemophilia A and B. This article reviews these disorders, in terms of clinical manifestations and characterization of the molecular defects. The general principles of management are also discussed.     

Silver-Russell syndrome: genetic basis and molecular genetic testing

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.     

Variability in response to cryoprecipitate treatment for hemostatic defects in uremia

Cryoprecipitate is frequently administered as treatment for hemostatic defects in patients with uremia. The only published data supporting this approach however, involves seven patients described by Janson and colleagues in whom bleeding times were shortened and bleeding complications reduced after cryoprecipitate infusion. We retrospectively reviewed our institution's experience with cryoprecipitate in this setting. Five patients had sufficiently complete data for evaluation of the efficacy of therapy with cryoprecipitate, including pretreatment bleeding time greater than 15 minutes, normal coagulation studies, and platelet count greater than 100,000/microliters. Two patients had normalization of their bleeding time and a favorable clinical outcome after cryoprecipitate infusion. Three patients failed to shorten their bleeding time after cryoprecipitate infusion or, in one case, multiple infusions. One of these latter patients had correction of his abnormal bleeding time after subsequent administration of deamino-8-D-arginine vasopressin (DDAVP). We conclude that the hemostatic response to cryoprecipitate therapy is variable, and that cryoprecipitate therapy does not achieve restoration of normal hemostasis in some patients with uremic bleeding.