Development of antibodies to human thrombin and factor V in a pediatric patient exposed to topical bovine thrombin

Bovine topical thrombin is commonly used for local hemostasis in pediatric surgery. Acquired inhibitors to coagulation factors, particularly to factor V and bovine thrombin, have been infrequently reported in the pediatric population. We report a 3-year-old male who developed a coagulopathy and clinical bleeding after cardiothoracic surgery, during which bovine topical thrombin was used for local hemostasis. Laboratory tests revealed elevated prothrombin, partial thromboplastin, and thrombin times, and a low factor V activity level. He was found to have both human-thrombin and factor V inhibitors, among the first reported cases of these combined inhibitors secondary to bovine topical thrombin. He was treated with intravenous immunoglobulin and steroids with a rapid and durable response.     

Acquired coagulation factor inhibitors in children after topical bovine thrombin exposure

Acquired inhibitors of coagulation factors, particularly to factor V (FV) and thrombin, after topical bovine thrombin exposure may result in clinically important coagulopathies. While bovine thrombin is commonly used in pediatric patients for surgical hemostasis, the reported cases of acquired inhibitors in children are few. We report two cases of children who developed factor inhibitors after bovine thrombin exposure. One child developed a FV inhibitor at 3 months of age after exposure to bovine thrombin during cardiac surgery. The inhibitor resolved with intravenous immunoglobulin (IVIG) and steroids. The other child developed concomitant FV and bovine thrombin inhibitors after cardiac surgery at age 11 years. The presence of these inhibitors complicated post-operative anti-coagulation management, but the inhibitors were transient. In addition to these two cases, we identified all the pediatric patients with bovine thrombin-induced inhibitors who were reported in the world's literature, and reviewed their clinical characteristics. These cases underscore the fact that bovine thrombin can be antigenic in infants and children and can result in significant coagulopathies.     

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.     

Brain haemorrhage in five infants with coagulopathy

Most intracranial haemorrhages in infants after the neonatal period are secondary to non-accidental injury. Occasionally brain haemorrhages in non-mobile infants are due to an inherited coagulopathy. This may often be diagnosed with a coagulation screen on admission. Little is known about the neurological outcome of infants in the latter group. Five infants are described who presented with acute spontaneous brain haemorrhage secondary to an inherited coagulopathy (n = 3) and vitamin K deficiency in alpha(1) antitrypsin deficiency (n = 1) and Alagille's syndrome (n = 1). Despite the critical clinical presentation and the severe imaging findings, these five infants made a good neurological recovery. Infants presenting with spontaneous ICH due to a significant (inherited) coagulopathy are usually easy to differentiate from non-accidental shaking injury; their bleeding pattern within the brain seems different from non-accidental shaking injury and neurodevelopment outcome appears better.     

Brain haemorrhage in five infants with coagulopathy.

Most intracranial haemorrhages in infants after the neonatal period are secondary to non-accidental injury. Occasionally brain haemorrhages in non-mobile infants are due to an inherited coagulopathy. This may often be diagnosed with a coagulation screen on admission. Little is known about the neurological outcome of infants in the latter group. Five infants are described who presented with acute spontaneous brain haemorrhage secondary to an inherited coagulopathy (n = 3) and vitamin K deficiency in alpha(1) antitrypsin deficiency (n = 1) and Alagille's syndrome (n = 1). Despite the critical clinical presentation and the severe imaging findings, these five infants made a good neurological recovery. Infants presenting with spontaneous ICH due to a significant (inherited) coagulopathy are usually easy to differentiate from non-accidental shaking injury; their bleeding pattern within the brain seems different from non-accidental shaking injury and neurodevelopment outcome appears better.     

Clinical and laboratory features of 178 children with recurrent epistaxis

PURPOSE: To determine the clinical and laboratory features of 178 children referred for the evaluation of recurrent epistaxis to an outpatient hematology clinic in a university medical center. PATIENTS AND METHODS: Medical records of 3681 outpatient pediatric hematology referrals were retrospectively review, and 178 children with recurrent epistaxis from 1985 to 1999 were identified. Historic (other bleeding symptoms: gingival bleeding, easy bruising, menorrhagia, and gross blood in the urine or stool: duration and severity of the epistaxis episodes; and family history of bleeding) and laboratory (complete blood count and coagulation tests) data were analyzed. RESULTS: There were 103 boys and 75 girls with a median age of 84 months (range 15-219 months). Sixty-seven percent (n = 119) did not have a coagulopathy diagnosed and 33% (n = 59) did. The diagnoses included von Willebrand disease in 33, platelet aggregation disorders in 10, thrombocytopenia in seven, mild factor VIII deficiency in three, Bernard-Soulier syndrome in two, factor VII deficiency in one, factor IX deficiency in one, and factor XI deficiency in one, and coagulation inhibitor in one. Of the historic data, only a family history of bleeding was predictive of diagnosing a coagulopathy (P = 0.023). The duration and severity of the epistaxis and the presence of other bleeding symptoms had no predictive value. Children with a coagulopathy diagnosed had a longer median partial thromboplastin time (PTT) (33.1 vs. 30.5 seconds; P = 0.012). CONCLUSIONS: One-third of children presenting with recurrent epistaxis have a diagnosable coagulopathy. A positive family history and a prolonged PPT are useful predictive data.     

Hautblutungen bei Kindern

Bruises in children are commonly seen and mainly caused by minor injury. However, they might be the first sign of a coagulopathy. Therefore, it is necessary to distinguish between normal bruises and relevant bleeding symptoms. Apart from the clinical examination, a detailed, standardized history of both the child and its family is mandatory. If a bleeding disorder is suspected, extended coagulation tests are necessary, because conventional screening tests (activated partial thromboplastin time (aPTT) and Quick) cannot exclude common disorders like von Willebrand disease. In the following contribution, the necessary diagnostic procedures with an emphasis on relatively common disorders are described.     

Is the use of rFVIIa safe and effective in bleeding neonates? A retrospective series of 8 cases

BACKGROUND: Recombinant activated factor VII (rFVIIa), originally developed for the treatment of life-threatening bleeding in hemophilic patients with inhibitors to factors VIII or IX, has been increasingly used to control hemorrhage unresponsive to conventional treatment, in the absence of a defined coagulopathy or thrombocytopathy. To date, clinical experience of rFVIIa administration in neonates, especially preterms, is rather limited, because of the lack of controlled studies and based solely on some published case reports and 1 prospective pilot study. The objective of this study was to retrospectively evaluate the clinical outcome of newborns treated with recombinant activated factor VII for intractable bleeding or severe coagulation disturbances, resistant to conventional hemostatic therapy. METHODS: The medical records of 8 neonates treated with rFVIIa (100 micro g/kg) were retrospectively reviewed for the course of hemorrhage and the hemostatic interventions performed before and up to 24 hours after the administration rFVIIa. Coagulation parameters of 3 different time-points were assessed and compared: before administration of any blood product (time-point 1), before administration of the first dose of rFVIIa (time-point 2), and 4 hours after the administration of the last dose of rFVIIa (time-point 3). The safety and tolerability profile of rFVIIa in bleeding neonates was also evaluated. RESULTS: Six preterm and 2 term patients were included in the study. Seven patients presented with refractory bleeding and 1 was diagnosed with severe coagulopathy unresponsive to the conventional treatment. Prompt hemostasis was achieved in half of the patients with their coagulation profile being restored within 4 hours after the administration of the first dose of rFVIIa. Improvement in prothrombin time, activated partial thromboplastin time, and fibrinogen after rFVIIa administration was statistically significant, as compared with that observed after conventional treatment. No major safety issues were observed during the study. All 8 patients survived and had their hemorrhage or coagulopathy controlled within 4 hours after transfusion of the last dose of rFVIIa. CONCLUSIONS: In this study, the hemostatic agent rFVIIa was well-tolerated and behaved in a safe and efficacious manner in all infants treated for life-threatening bleeding and coagulation disorders. Future prospective controlled trials are needed to determine the efficacy, safety, tolerability, and possibly the optimal dose and timing of rFVIIa administration.     

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.     

Management of coagulation disorders in children

Children may be born with an inherited coagulation disorder or can develop an acquired coagulopathy as a consequence of another disease or disorder. The correct diagnosis in either case is essential to appropriate management, to reduce the morbidity and mortality associated with inaccurate diagnosis or the incorrect treatment. The treatment of these disorders is often very expensive and there may be risks to the child associated with the administration of products used to treat coagulation disorders; these must be minimized when possible. For these reasons, the child may require referral to a tertiary specialist centre for further investigations and management. In children presenting with bruising or more severe bleeding manifestations, it is not uncommon for the first presumed diagnosis to be non-accidental injury, and it is essential that a true coagulation defect is excluded in these children.     

Diagnosis of hemorrhagic diseases (author's transl)]

Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).     

Inhibitor to factor V after exposure to fibrin sealant during cardiac surgery in a two-year-old child

Muntean W, Zenz W, Finding K, Zobel G, Beitzke A. Inhibitor to factor V after exposure to fibrin sealant during cardiac surgery in a two-year-old child. Acta Prediatr 1994;83:84–7. Stockholm. ISSN 0803–5253
A two-year-old infant developed an inhibitor to factor V after cardiac surgery, with application of fibrin sealant containing bovine thrombin. Investigation of this inhibitor by means of inhibition experiments and immunoblot analysis revealed that the inhibitor reacted strongly with bovine, but only weakly with human factor V. Plasmapheresis proved effective in increasing factor V levels. This patient provides further evidence that exposure to topical thrombin preparations may lead to the development of inhibitors in the postoperative period that may cause bleeding complications.     

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     

REFRACTORY COAGULOPATHY IN AN INFANT WITH LOSS OF CLOTTING PROTEINS INTO ASCITIC FLUID

ABSTRACT. Report of a newborn with massive ascites who developed a severe coagulopathy due to multiple intrinsic and extrinsic clotting factor deficiencies. All deficient coagulation factors were present in measurable quantities in the infant's ascitic fluid. It is postulated that she sustained loss of coagulant proteins by transudation into her peritoneal cavity. A similarly acquired coagulopathy should be suspected in all patients with a known increase in extravascular fluid compartments.     

Disseminated intravascular clotting in kwashiorkor.

The role of disseminated intravascular clotting (DIC) in the pathogenesis of the bleeding diathesis kwashiorkor was investigated in 22 patients. According to the severity of the clinical and haematological findings, two grades of DIC were observed. A severe grade of DIC was shown in 6 cases (5 fatal) presenting with thrombocytopenia, hypofibinogenaemia, and multiple coagulation defects, and with abnormally prolonged partial thromboplastin,prothombin, and thrombin times]. A second goups of 16 patients (7 fatal) showed a less severe grade of DIC manifested by thrombocytopenia, low fibringoen level, and a clotting factor defect shown by rpolonged prothrombin and thrombin times.     

COAGULOPATHY IN NON-CIRRHOTIC PORTAL FIBROSIS

A 12-year-old girl suffering from non-cirrhotic portal fibrosis is presented. The clinical picture is characterized by splenomegaly without hematemesis and ascites. Portal hypertension was found without evidence of intra- or extra-hepatic obstruction. Liver function test results were mildly disturbed. Open liver biopsy revealed fairly well preserved structure of the liver except for increased fibrosis confined to the portal spaces but without characteristic cirrhotic changes. Coagulation studies revealed disturbance of various coagulation factors, the most important being thrombocytopenia, hypofibrinogenemia and low levels of factors 11, VII and X. It is suggested that the primary underlying cause fcr these findings is a chronic consumptive coagulopathy and not liver disease. Appreciation of the coagulopathy accompanying this syndrome may contribute to our understanding of the pathogenesis of this entity.     

Pathogenesis of intraventricular haemorrhage in newborn infants

The ventricular CSF of a group of preterm infants dying in the newborn period contained a large excess of protein which appeared to be a plasma filtrate. This excess was found whether or not an intraventricular haemorrhage (IVH) was also present. After consideration of the clinical features of the infants, their coagulation status, and the findings at necropsy, we suggest that increased cerebral venous and capillary pressure, usually caused by heart failure resulting from hypoxia and acidosis, was responsible both for the IVH, by rupturing the terminal veins, and for promoting the filtration of plasma proteins into the CSF. Abnormalities of haemostasis, though very common, did not seem to provide an adequate explanation for the initiation of intraventricular bleeding, though they may have exacerbated it.     

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.     

Recombinant factor VIIa improves coagulopathy caused by liver failure

OBJECTIVE: Coagulopathy is an important cause of morbidity and mortality in patients with liver failure. The benefit of traditional therapies to correct coagulation is often limited and short-lived. Our aim is to identify indications for rFVIIa use and the outcome of treatment in children with liver failure. METHODS: A retrospective review from July 2000 to December 2001 was performed to identify consecutive patients with acute or chronic liver failure who received rFVIIa. Prothrombin times (PT) before and after therapy were compared by paired t test. RESULTS: Fifteen patients were treated with rFVIIa for coagulopathy caused by liver failure. All were receiving fresh frozen plasma (mean infusion rate, 39.7 mL/kg/day) when rFVIIa therapy was started. The mean PT before rFVIIa was 32.0 +/- 7.0 seconds. One hour after infusion, the PT normalized to 13.7 +/- 2.4 seconds (P < 0.0001) and remained significantly reduced at 6 hours (19.8 +/- 5.3 seconds; P < 0.0001). A sustained improvement was maintained during the subsequent 3 days. Five of seven patients with bleeding complications improved clinically after rFVIIa treatment. Two of the bleeding patients also benefited from improved fluid balance as fresh frozen plasma support was reduced. No thrombotic events were attributed to rFVIIa therapy. CONCLUSIONS: In patients with liver failure, rFVIIa therapy quickly normalizes the PT and maintains improved hemostasis, even when coagulopathy has been refractory to fresh frozen plasma. Therapy subjectively reduces clinical bleeding and can improve fluid balance, without complications.     

Activation of the coagulation system occurs within rather than outside cutaneous haemangiomas

Haemangiomas are the commonest tumours of infancy. They can become even more serious if followed by consumption coagulopathy and even life-threatening in cases of Kasabach-Merritt syndrome, with thrombocytopenia and haemorrhage. Data exist concerning systemic coagulation abnormalities in children with haemangiomas but to our knowledge there are no data on local consumption coagulopathy in haemangioma per se . We examined blood coagulation and fibrinolysis parameters in blood withdrawn from haemangioma blood vessels and blood withdrawn from the systemic vein in 14 children with cutaneous haemangiomas (3M, 11F; age range 3 mo to 10 y). Compared with controls, significant decreases in fibrinogen levels, FVII activity, antithrombin and plasmin inhibitor levels and increases in international normalized ratio (INR) and D-dimer levels were observed in the blood samples withdrawn directly from haemangioma blood vessels. Fibrinogen and antithrombin levels in samples withdrawn from systemic veins were reduced in relation to control values whilst INR values increased, but within normal ranges. D-dimer levels were increased in peripheral blood. The fibrinogen level was significantly lower and the INR and D-dimer levels were significantly higher in blood samples from haemangiomas compared to systemic blood. Clinical signs of systemic disseminated intravascular coagulation were not observed.

Conclusions : Our results suggest a strong local activation and local consumption coagulopathy in haemangioma, along with less conspicuous but observable systemic changes in coagulation and fibrinolysis parameters, although without signs of consumptive coagulopathy. These systemic changes could be a reflection of intra-lesion coagulation activation although there is no evidence to suggest truly systemic disseminated intravascular coagulation.