Chronic consumption coagulopathy due to an occult splenic haemangioma: Kasabach-Merritt syndrome

We report an 11-year-old girl with a 2-year histor of bruising associated with thrombocytopenia and dysfibrinogenaemia. On admission she presented with a large subcutaneous haematoma and splenomegaly and was severely anaemic. Laboratory investigations revealed signs of consumption coagulopathy. Radiological examination showed splenic, retroperitoneal and intra-ossal haemangiomas. After splenectomy, platelet count and coagulation parameters returned to normal.Conclusion Contrary to widely held views, occult visceral haemangioma can lead to Kasabach-Merritt syndrome beyond infancy and is not necessarily associated with visible cutaneous haemangioma. It should be included in the differential diagnosis of chronic thrombocytopenia at any age. Early determination of fibrinogen degradation product levels is advised in order to detect an underlying chronic consumption coagulopathy prompted by an extensive search for multifocal liaemangioma.     

Distinction between fibrinogen and fibrin degradation products produced during disseminated intravascular coagulation in childhood

Fibrin-fibrinogen degradation products in serum from five children with disseminated intravascular coagulation (DIC) were characterized using a method of immunoabsorption followed by SDS-polyacrylamide gel electrophoresis. All of the samples contained not only fragment D-dimer which was produced on plasmin lysis of cross-linked fibrin, but also fibrinogen degradation products (fragments X, Y and D). These results suggest that both fibrinogenolysis and fibrinolysis take place simultaneously in DIC.     

Hemostatic system in early respiratory distress syndrome: reduced fibrinolytic state?

Previous studies suggest that there is a systemic activation of clotting and fibrinolysis in preterm infants with advanced respiratory distress syndrome (RDS). However, there are no data on the hemostatic status in the early stages of the disease; therefore, we studied some of the hemostatic parameters in these patients and made several studies at different times in preterm infants who did or did not develop RDS, using similar protocols. We found normal plasma fibrinogen, protein C, protein S, C4b-binding protein, thrombomodulin, antithrombin III, thrombin-antithrombin III complex, prothrombin fragment 1.2, plasminogen, tissue plasminogen activator, alpha-1 antitrypsin, alpha-2-macroglobulin and protein Z. However, lower D-dimer and higher plasminogen activator inhibitor and von Willebrand factor antigen levels were found within six hours of life in infants who later developed RDS compared to the control group. These findings suggest that disseminated intravascular coagulation is not prominent in the early stages of RDS. Moreover, reduced D-dimer and increased plasminogen activator inhibitor and von Willebrand factor antigen levels are probably related to the abnormalities in the fibrinolytic mechanism due to lung damage in RDS, but further studies are needed to show their pathogenic significance in RDS.     

GIANT HAEMANGIOMA WITH A DISORDER OF COAGULATION

The mechanism of the coagulation disorder in an infant with a large haemangioma of the right arm has been studied. The disorder was characterised by thrombocytopenia, prolonged bleeding time and the occurrence of fibrinolytic split products in the blood. The levels of various coagulation factors were normal. The mechanism of the disorder was further investigated by injection of ⁵¹Cr labelled platelets, which disappeared very rapidly from the circulation owing to the uptake by the haemangioma. Injection of ¹²⁵I labelled fibrinogen revealed a considerable increase in disappearance rate, which, however, was not as high as for ⁵¹Cr labelled platelets. Treatment with heparin in this case appeared inadvisable because the thrombocytopenia was found to be due mainly to mechanical destruction in the haemangioma while intravascular coagulation played only a subordinate role. On the other hand, the fibrinolytic activity in the tumour vessels was found to be high, which together with the occurrence of fibrinolytic split products in the blood was considered to indicate treatment with inhibitors of fibrinolysis (EACA). During this treatment the angioma decreased in size. It would therefore appear advisable to investigate the mechanisms of the coagulation disorders in these patients before deciding upon treatment.     

Post-trauma coagulation and fibrinolysis in children suffering from severe cerebro-cranial trauma

The present study was designed to evaluate the post-trauma haemostatic changes in 27 children with severe cranio-cerebral trauma defined by a modified Glasgow Coma Score (GCS) <10. Blood samples for coagulation studies (fibrinogen, von Willebrand factor (vWf), factor VIII:C, antithrombin, protein C, plasminogen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI), D-dimer) were obtained within two hours of admission, 24 h later, and on days 3-5, 7-9, 21 and 35. Data of this study indicate that alterations of coagulation in paediatric patients are similar to those in adults: On hospitalisation, activated haemostasis was found with decreased fibrinogen, antithrombin and protein C along with enhanced t-PA and PAI. Twenty-four hours later, hypercoagulability with significantly increased vWF and fibrinogen started, with a peak level within the second week. Within 24 h of admission, 17 children developed disseminated intravascular coagulation (DIC) with a clear-cut decrease of antithrombin and fibrinogen together with platelet consumption and enhanced D-dimer. The outcome of children with DIC was significantly poorer than in those without DIC. Complete recovery was seen in five patients; sequelae no handicap and moderate disability were each found in six patients. Severe disability was diagnosed in two children, and fulminant DIC with lethal outcome occurred in eight patients. The GCS (P < 0.01) and the occurrence of DIC (P < 0.005) showed the strongest association with the patients' clinical outcome. Conclusion Our data underline the significance of post-trauma disturbances of the haemostatic system for the clinical course and outcome in children with severe cranio-cerebral injuries.     

Kasabach-Merritt综合征研究进展

Kasabach-Merritt综合征是以巨大血管肿瘤伴发血小板减少和全身出血倾向为特征的一种综合征,其病理生理基础是血小板减少和弥漫性血管内凝血(DIC),与巨大血管肿瘤密切相关.治疗方案主要包括纠正DIC和血小板减少,根据具体情况选择外科治疗(手术切除、栓塞等)或内科药物治疗(糖皮质激素、α-干扰素、免疫抑制剂等)去除血管肿瘤.     

Anaemia, thrombocytopenia and coagulopathy due to occult diffuse infantile haemangiomatosis of spleen and pancreas

Diffuse infantile haemangiomatosis of the spleen is a very rare lesion. Large haemangiomas may cause trapping of platelets and coagulation disorders known as Kasabach-Merrit syndrome. We here report the case of an infant with splenic and pancreatic haemangiomatosis presenting with life-threatening thrombocytopenia, anaemia and intravascular coagulation. Diagnosis was hampered by reactive erythroblastosis and non-conclusive radiological findings. While treatment with corticosteroids was ineffective, administration of antithrombin III improved coagulation parameters. After splenectomy the child recovered promptly and has remained free of disease for 3 years to date. Conclusion Occult visceral haemangiomatosis without visible cutaneous haemangiomas should be included in the differential diagnosis of thrombocytopenia, anaemia and consumption coagulopathy. Antithrombin III treatment may be considered to overcome bleeding problems in patients with Kasabach-Merrit syndrome. Received: 8 July 1998 / Accepted in revised form: 21 September 1998     

Soluble fibrinogen—fibrin complexes in intrauterine growth retardation

Soluble fibrinogen—fibrin complex levels were found to be significantly higher in plasma samples from pregnant women with babies suffering from intrauterine growth retardation, when compared with levels found in normal pregnancy. As soluble fibrinogen—fibrin complexes, are formed following activation of the coagulation pathway in vitro and in vivo these findings may reflect the increased local intravascular coagulation within the placenta demonstrated histologically in pregnancies complicated by growth retardation. The use of more sensitive methods for detecting alterations in coagulation, fibrinolysis and platelet function may prove useful in the diagnosis of intrauterine growth retardation antenatally.     

Dysfunctional antithrombin III in sick premature infants

Antithrombin III, a major inhibitor of activated coagulation factors has low immunologic levels in the human infant. The objective of this study was to determine if the antithrombin III molecule is fully functional in sick premature infants. The populations studied included: adult controls (n = 20), full term healthy infants (n = 18), sick premature infants on day 1 (n = 16) and at greater than 7 days of age (n = 10), and infants with disseminated intravascular coagulation (n = 11). This was diagnosed in the presence of prolonged screening tests, decreased levels of fibrinogen, and platelets along with elevated fibrin degradation products. Plasma antithrombin III levels were measured biologically (chromogenic substrate S2238) and immunologically (radialimmunodiffusion), and expressed as a percent of adult pooled plasma. Crossed immunoelectrophoresis were performed in the presence and absence of heparin. The antithrombin III biologic/immunologic ratios for adults, healthy full term infants, and sick premature infants on day 1 of life were all near unity. In contrast sick premature infants beyond the 1st wk of life and infants with disseminated intravascular coagulation had lower biologic activity compared to immunologic (B/I = 0.77 +/- 0.28, 0.78 +/- 0.17, p less than 0.01), respectively. In all groups, the antithrombin III molecule was normal on crossed immunoelectrophoresis except for one infant with disseminated intravascular coagulation. Sick premature infants may acquire a dysfunctional antithrombin III molecule in the postnatal period.     

THE PROGRESSIVE ANTITHROMBIN ACTIVITY AND ITS RELATIONS TO OTHER FACTORS OF THE COAGULATION SYSTEM IN NEWBORNS

ABSTRACT. Weissbach, G., Domula, M., Lenk, H. and Schneider, P. (Paediatric Clinic of the Medical Department, Karl-Marx-University, Leipzig, DDR). The progressive anti-thrombin activity and its relations to other factors of the coagulation system in newborns. Acta Paediatr Scand, 63: 555, 1974.—The progressive antithrombin and its relations to other factors of the coagulation system have been studied in chronically asphyxiated newborns. The progressive antithrombin activity was determined in 44 healthy and in 40 chronically asphyxiated newborns according to the method described by Gerendas & Monkhouse. The activity was clearly depressed in the asphyxiated group as compared with healthy full-term newborns. Only within the group of asphyxiated newborns did the statistical analysis reveal close correlations between progressive antithrombin and the factors fibrinogen, plasminogen, thromboplastin time value, factor II, and thrombocytes. Furthermore, most of these were also closely correlated among themselves. The partly very close relations can be explained only by a simultaneous consumption of these constituents by disseminated intravascular coagulation processes and secondary hyper-fibrinolysis. The decrease in progressive antithrombin is due to an irreversible binding of the antithrombin III to thrombin, liberated within the vessels.     

全身炎症反应综合征患儿凝血功能改变及其临床意义的探讨

目的 研究全身炎症反应综合征(SIRS)患儿出凝血系统的功能改变和临床意义及其对预后的影响.方法 采用前瞻性病例对照设计,按照小儿/新生儿SIRS新定义将收住ICU的患儿分为SIRS组(24例)、非SIRS组(21例),另设正常对照组(28例).SIRS组按预后再分为死亡组(10例)和生存组(14例),监测血小板计数(PLT)、凝血酶原时间(PT)、部分凝血酶原时间(APTT)、纤维蛋白原(FBG)、凝血酶-抗凝血酶复合物(TAT)、抗凝血酶Ⅲ(AT-Ⅲ)、蛋白C(PC)、血栓调节蛋白(TM)、D-二聚体(DD)、组织型纤溶酶原激活物(TPA)共10项反映凝血系统功能的指标.结果 (1)SIRS组中PT、APTT、TAT、TM、DD、TPA水平均较非SIRS组及对照组升高(P<0.05);AT-Ⅲ、PC水平均较非SIRS组及对照组降低(P<0.05),非SIRS组PC水平较对照组降低(P<0.05);PLT、FBG水平在SIRS组、非SIRS组及对照组之间比较差异无显著性(P>0.05);(2)SIRS患儿中,死亡组与生存组各出凝血指标间比较差异无显著性(P>0.05).结论 (1)SIRS患儿存在凝血功能异常,主要表现为凝血活化、抗凝活性的降低和纤溶系统的活化;(2)出凝血分子标志物是疾病早期针对性反映患儿凝血系统所处状态的良好指标;(3)分子标志物对预后的意义尚需大样本进行评估.     

Blue rubber-bled naevus syndrome: Report of a case with consumption coagulopathy complicated by manifest thrombosis

Blue rubber-bleb naevus (BRBN) syndrome is a rare disorder characterized by subcutaneous and gastrointestinal haemangiomas. The latter may lead to bleeding complications. A case is reported in which a process of chronic intravascular coagulation resulted in serious thrombotic complications. In the presence of a chronic consumption coagulopathy, it remains uncertain whether antiplatelet drugs are of prophylactic antithrombotic value.     

Bleeding complications in acute myeloblastic leukemia (author's transl)]

Bleeding is common in acute myeloblastic leukemia (AML). At the time of diagnosis, the danger of bleeding cannot be predicted by laboratory means. However, the following factors represent increased risks: Promyeloblastic leukemia, high blast count, low fibrinogen, low plasminogen. From coagulation studies performed at the time of bleeding complications, the pathomechanism leading to bleeding complications usually cannot be detected. The question whether impairment of production, consumption coagulopathy, or primary fibrinolysis causes the bleeding complications can only be answered by controlling frequently clinical and hemostatic criteria, which include the thrombocytic stystem as well as plasmatic coagulation and fibrinolysis. At the present time, the therapy of bleeding complications in AML is symptomatic. It consists of transfusion with thrombocytes or fresh whole blood, respectively. Coagulation factor concentrates should only be given in combination with Heparin to prevent the deterioration of consumption coagulopathy.     

Correction of hemostatic imbalances induced by L-asparaginase therapy in children with acute lymphoblastic leukemia

Thirteen children with ALL and L-asp-induced alterations of the coagulation system were treated with fresh-frozen plasma and antithrombin III (AT III) concentrate. Fresh-frozen plasma was given three times daily to maintain fibrinogen levels greater than 100 mg/dl. AT III concentrate was administered in a continuous infusion over 24 h as long as replacement with fresh-frozen plasma was given. When fibrinogen was greater than 100 mg/dl and AT III less than 80% of normal, only AT III concentrate was administered in a continuous infusion. In all patients treated with the replacement regimen described, fibrinogen levels were maintained greater than 100 mg/dl and AT III levels greater than 80%. No bleeding or thrombosis and no signs of disseminated intravascular coagulation were observed. Our study shows that correction of the alterations of the coagulation system induced by asparaginase can be achieved with a replacement regimen substituting both procoagulant material and the most important inhibitor of the coagulation system.     

Treatment of disseminated intravascular coagulation with antithrombin III concentrate in children with verified infection]

Consumption coagulopathy in childhood is still a serious problem. Besides treatment of the underlying diseases therapy of consumption coagulopathy was performed with heparin and nowadays with substitution of coagulation factors, especially antithrombin III concentrate, alone or in combination with heparin. We performed administration of AT III concentrates only, without additional heparin treatment in children with proven septicaemia (preterm infants n = 21, children beyond the newborn period n = 18). Antithrombin III, platelet count, fibrinogen, PT, aPTT and TT were assayed. These coagulation parameters turned to be normal 48 hours after normalisation of the antithrombin III plasma level-AT III increased to normal values within 24 hours after the initial substitution in all children. Lethal outcome was not observed after sole administration of AT III as well as no other side effects have been seen. In summary, these data indicate that consumption coagulopathy in childhood can be managed successfully with early substitution of AT III concentrate.     

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目的研究婴幼儿肺炎并发不同程度心力衰竭时内皮素(ET)、D-二聚体(D-dimer)、纤维蛋白原(FBG)等变化及其内在联系,探讨该阶段血管内皮功能、凝血、纤溶功能的变化。方法选择2005-12—2006-8于邯郸市中心医院儿科就诊的肺炎及肺炎并发不同程度心力衰竭患儿80例作为观察组,健康婴幼儿20例作为对照组,均抽血检测ET、D-dimer、FBG、活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)值。结果各组间ET、D-dimer、FBG、APTT存在统计学差异,心衰程度越重,ET、D-dimer、FBG越高,APTT越低,其中以肺炎并发重度心衰组明显,ET与D-dimer间呈正相关(r=0.42,P<0.01);D-dimer与FBG间也呈正相关(r=0.30,P<0.01)。结论婴幼儿肺炎并发心力衰竭时存在内皮细胞功能紊乱和凝血、纤溶系统的激活。     

Haemangioma with coagulopathy: sustained response to prednisone.

Two cases of giant haemangioma with thrombocytopenia are described. A satisfactory and sustained response to prednisone was achieved in respect of both coagulation abnormalities and tumour size. It is proposed that prednisone is effective by enhancement of thrombosis and reduction of fibrinolysis within the tumour, thus promoting a natural form of resolution. It is suggested that prednisone therapy should be first-choice treatment of complicated haemangiomas.     

The coagulation system in septic newborns

Coagulation factors were examined in 48 newborns with spesis caused mainly by Klebsiella enterobacteriaceae and E. coli. The first examination revealed increased mean values of fibrinogen, antiplasmin, trypsin inhibitory capacity, factors II and X. Thrombocytes, plasminogen, antithrombin III, alpha 2-macroglobulin and factor V were reduced on average. Serial examinations brought to light turbulent dynamics of the parameters. In most cases the fibrinogen level increased first together with factors II, V and X, and with antiplasmin, and followed by antithrombin III and alpha 2-macroglobulin after several days. Trypsin inhibitory capacity decreases progressively, starting from extremely high levels or after an initial rapid increase. Thrombocytopenia is the last to correct. Close correlations between the fibrinogen level and factors II and X in the initial values, as well as in the course of the disease, point to the dynamics of these components being similar. These findings are reason to believe the pathogenetic importance of the disseminated intravascular coagulation in many cases. Rapid overproduction of components takes place after disseminated intravascular coagulation in sepsis; overproduction has its limits in production capacity and thrombocytopoiesis is the weakest link in newborns.Certain parameters are of low diagnostic significance. Sepsis in newborns is well characterized by the discrepancy between thrombocytopenia and high fibrinogen levels, and thus by the difference between fibrinogen level and thrombocyte count. The value of this criterion in separating healthy newborns and those with respiratory distress syndrome from newborns with sepsis has been proved.The study forms part of the medical research programme Perinatology of the Ministry of Public Health of the GDR     

Localised intravascular coagulation complicating venous malformations in children: Associations and therapeutic options

Venous malformations are slow‐flow congenital vascular malformations that enlarge as the child ages and may be associated with localised intravascular coagulation, a consumptive coagulopathy characterised by elevated D‐dimer and decreased fibrinogen levels. The authors review the known correlations between localised intravascular coagulation and venous malformation number, size and planes involved, and call attention to the concept of the progression of localised intravascular coagulopathy as the child ages and their venous malformations enlarge. The authors also discuss the identified therapeutic options for its investigation, management and treatment, including compression garments, anti‐coagulation therapy, sclerotherapy, endovascular laser, surgical excision and sirolimus (rapamycin). Evidence for protocol improvements that may be instigated for the optimal physical and medical therapy of venous malformations complicated by localised intravascular coagulopathy is reviewed.     

Low antithrombin III in neonatal shock: DIC or non-specific protein depletion?

Low antithrombin III (AT III) levels in shock are usually ascribed to disseminated intravascular coagulation (DIC). However, decreased activities of clotting factors and their inhibitors could reflect a generalised fall in plasma proteins rather than DIC. AT III and albumin were compared in 48 asphyxiated and non-asphyxiated newborn rabbits (pH 6.70-7.30). Both AT III and albumin were markedly decreased in the sickest animals and there was a direct linear relationship between the two proteins (P less than 0.001). Similar results were obtained in ten newborn infants suffering from shock and haemorrhagic diathesis. In all cases AT III and albumin were decreased below the normal range and significantly correlated (P less than 0.01). Our findings suggest that AT III is not a useful diagnostic marker of DIC. Further, a similar fall of clottable and non-clottable proteins in shock questions the general assumption that the ensuing coagulopathy is due to intravascular coagulation.