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By virtue of a severely prolonged aPTT with a normal thromboplastin time (prothrombin time) and a normal thrombin time, severe FXII deficiency has been diagnosed in a woman without a bleeding diathesis or a history of thromboembolic complications. A deficiency of a factor of the contact activation system (FXII, prekallikrein, high molecular weight kininogen) is usually diagnosed during routine coagulation tests demonstrating a prolonged aPTT. The severe and partial deficiency of FXII, of prekallikrein or high molecular weight kininogen is not associated with a bleeding tendency. In contrast, severely factor XI deficient subjects may suffer from a mild hemorrhagic diathesis, whereas FVIII deficiency (hemophilia A, autoimmune "hemophilia", von Willebrand disease) and FIX deficiency (hemophilia B) are associated with a bleeding tendency of varying severity, depending on the clotting activity of FVIII or FIX, respectively. An isolated prolongation of the aPTT due to a lupus anticoagulant, however, is frequently associated with arterial and/or venous thrombosis. Therefore, in case of a prolongation of the aPTT, its cause has to be determined.

Seventy-five patients with chronic myeloproliferative disorders were studied to investigate platelet function by simultaneous measurement of platelet aggregation by the impedance method and ATP dense granule release using a whole blood platelet lumi-aggregometer, in an attempt to identify patients at risk for thrombosis and bleeding. Thirty-nine patients had at least one abnormal result indicating platelet hyperactivity (i.e. impedance or release with one agonist being above the reference range); 16 patients had platelet hypoactivity (i.e. at least one result was below the reference range), whilst 14 had co-existence of hyper- and hypoactivity. Six patients had normal results. 20/53 patients with platelet hyperactivity (alone or mixed) had a positive history of venous and/or arterial thrombosis; in comparison, only two of the other 22 patients had a positive history. During a median follow-up of 33 months, nine patients with and one patient without platelet hyperactivity respectively developed new thrombotic events before the addition of specific therapy. A total of 50 patients with and eight patients without platelet hyperactivity respectively received specific treatment including aspirin and/or cytotoxic therapy. All but one elderly patient with platelet hyperactivity have remained free of new thrombotic events on specific therapy. Two of the 17 patients with platelet hypoactivity had major clinical bleeding. These observations highlight the need to test platelets for hyper- as well as hypo-function and suggest a useful role for routine whole blood platelet aggregation studies to identify the patients at risk for thrombosis or bleeding.

We describe the peculiar and concomitant presence of a severe coagulation defect predisposing to bleeding and a mutation associated with inherited thrombophilia. A 6-year-old boy had a severe deficiency in factor V procoagulant activity and antigen and yet remained asymptomatic. This paradox might be explained by the hypothesis of the simultaneous presence of a thrombophilic disorder that might have restored hemostatic balance. The boy was a homozygous carrier of the Arg506Gln mutation of coagulation factor V, that renders this factor resistant to inactivation by its naturally occurring inhibitor, activated protein C. The family members, none of whom had bleeding or thrombotic symptoms, were heterozygotes for either the bleeding or the thrombophilic defect. Despite the severity of the bleeding defect, the absence of bleeding symptoms in the boy can be explained by the hypothesis that any residual amount of factor V present in his plasma is resistant to inactivation by activated protein C.

Background: In order to exclude hemorrhagic diathesis, e.g. before diagnostic measures carrying the risk of bleeding or in preoperative situations, a graded screening is advisable., Procedure: During the first stage, besides the anamnesis, clinical examination and classification of relevant concomitant diseases (e.g. liver cirrhosis or renal insufficiency), basic laboratory examinations such as prothrombin time, activated partial thromboplastin time (aPTT) and platelet count must be carried out. Should all these measures produce no noteworthy results, no further examinations are necessary. However, in the case of test results within normal limits accompanied by an unsatisfactory anamnesis and/or conspicuous clinical findings, the second stage should include examination of bleeding time according to Mielke to exclude a relevant platelet dysfunction. Should this be inconspicuous a third stage should follow in which successive implementation is made of fibrinogen according to Clauss, the Rumpel-Leede test (to exclude heightened capillary fragility), factor XIII and alpha 2-antiplasmin. The methodical snares of the parameters mentioned will be explained in full.

Hemorrhagic diathesis represents a high risk for oral surgery. In clinical practice various kinds of diathetic diseases are seen that are of plasmatic, vascular, thrombocytic and hypertensive origin. Usually these patients will be primarily referred to the hospital as high-risk cases. Therefore, a broad spectrum of diagnostic and therapeutic interdisciplinary methods are available, so that as a rule it is possible to obtain a clear picture of the severity of the bleeding tendency. We represent a case of a 58-year-old woman who had decayed teeth with chronic periodontal and periapical lesions, who could not be treated by oral surgery because of refractory idiopathic thrombocytopenic purpura (ITP) with 1000 platelets/microliters. The patient's history showed that various hematologic concepts had been tried, including splenectomy, but all had failed entirely. After therapy with steroids, immunosuppressive and cytostatic agents, and even after administering immunoglobulins and substitution with platelets, the count did not increase; thus, an absolute contraindication for all kinds of surgery was declared. This rare example indicates that unmanagable bleeding diseases still exist that should be known by dentists and oral surgeons to prevent making deleterious therapeutic decisions.

Protein Z is a vitamin-K-dependent plasma glycoprotein; its physiological function is not clear. Low protein Z levels were found in patients with otherwise unexplained bleeding disorders. It was therefore suggested that low protein Z levels might be associated with a bleeding diathesis. In the present study we measured protein Z levels in plasma samples of 48 patients with a suspected bleeding disorder and in plasma samples of 200 healthy adult individuals. We found protein Z to have a wide normal range in healthy men and women. Significantly lower protein Z levels were observed in women compared to men, whereas no correlation was found with age or other vitamin-K-dependent coagulation proteins. None of the 48 patients with a bleeding disorder had a protein Z level below the normal range. However, protein Z was significantly lower in the group of male patients with a bleeding history as compared to healthy men. In conclusion, our data indicate that low-normal protein Z levels are not associated with a bleeding tendency. However, it remains to be determined whether a low protein Z level is a weak cofactor associated with an increased bleeding tendency and whether decreased or absent protein Z (conditions not detected in our patients) might constitute a haemorrhagic diathesis.

We present the case of a 42-year-old woman with a recently acquired bleeding tendency. Coagulation studies and response to antifibrinolytic therapy suggested primary hyperfibrinogenolysis: markedly low levels of fibrinogen and alpha2-antiplasmin, normal levels of antithrombin III, protein C and protein S combined with an only borderline low number of platelets without evidence of microangiopathic haemolytic anaemia. A suspected causative adenocarcinoma of the lung was demonstrated. She was treated successfully with tranexamic acid and cryoprecipitate, until the tumor progressed and hyperfibrinogenolysis progressed to diffuse intravascular coagulation. Differential diagnosis of these coagulation disorders, with similar etiology, clinical and laboratory findings is reviewed. Therapeutic implications are discussed.

The May-Hegglin anomaly is an extremely rare, autosomal dominant inherited disorder characterized by alterations in white cells and in blood platelets. The granulocytes show basophilic inclusion bodies of no clinical importance. Usually moderate thrombocytopenia with variable platelet size, including giant platelets, is also found. Clinically a mild hemorrhagic diathesis may occur. We report on a so far asymptomatic patient from the second family described by Hegglin et al. in 1964 [1] who had to be treated for repeated life-threatening bleedings. A moderate prolongation of bleeding time was found, corresponding to the reduced platelet count; platelet aggregation induced by ADP, collagen, ristocetin or arachidonic acid was not impaired. Therefore, there is at present no evidence of a congenital platelet function defect in the May-Hegglin anomaly. The bleeding time improved temporarily in our patient on administration of DDAVP (Minirin); platelet substitution is indicated in special situations only.

Background: Skin and mucous membrane hemorrhages are distinctive manifestations of hereditary diseases of primary hemostasis and, among them, the different types of von Willebrand disease and of platelet function disorders are the most prevalent., Aim: To know the relative frequency of these disorders and to know the clinical features of patients with mucocutaneous hemorrhages., Patients and Methods: Five hundred eighty nine patients whose main symptom was the presence of mucocutaneous hemorrhages were studied. Bleeding time, platelet count, coagulant activity of factor VIII (FVIII:C), FvW: Ag and FvW: CoRis and ABO blood group were measured in all patients in a first stage. According to the results of these tests, further studies were decided., Results: In patients younger than 13 years old, male predominated and, in older patients, females consulted with higher frequency. There was a higher proportion of individuals with O blood type than in the normal population. Bleeding time was abnormal in 330 patients (56%). One hundred ten patients (19%) had won Willebrand disease and, among them, one third had a normal bleeding time. Isolated reduction of factor WII activity was found in 66 patients (11%, 51 males) and 32 of these had normal bleeding time. Eighty one patients (14%) were considered to have an hereditary platelet function defect. A precise diagnosis was not achieved in 332 patients (56%)., Conclusions: Among patients consulting for mucocutaneous hemorrhages, 19% had von Willebrand disease, 11 had an isolated reduction of factor VIII activity, 14% had platelet function defects and in 56%, a precise diagnosis was not reached.

We describe a patient with severe epistaxis, prolonged coagulation tests and decreased plasma factor V following exposure to bovine topical thrombin. Patient IgG, but not normal IgG, showed binding to immobilized thrombin (bovine > human) and fibrinogen, and to factor V by Western blotting; the binding to thrombin was inhibited by hirudin fragment 54-65. Electron microscopy of rotary shadowed preparations showed complexes with IgG molecules attached near the ends of trinodular fibrinogen molecules. Patient IgG inhibited procoagulant, anticoagulant and cell-stimulating functions of thrombin demonstrated by inhibition of fibrinogen clotting, protein C activation and platelet aggregation; thrombin hydrolysis of S-2238 was not inhibited. The results suggest that the antibody is targeted against anion-binding exosite and not catalytic site of thrombin. Antifibrinogen antibodies have not been reported in patients exposed to bovine thrombin. There is a pressing need to re-evaluate the role of bovine thrombin as a therapeutic agent.

Thrombosis and bleeding, reflecting the extreme ends of hemostasis, are common complications in patients with thrombocythemia in its primary form or in association with polycythemia vera. The pathogenesis of these thrombohemorrhagic predispositions is not clearly understood. In the present study we describe the paradoxical and sequential occurrence of thrombotic and bleeding complications in six patients with thrombocythemia. Strikingly, in all patients some abnormality of plasma von Willebrand factor was detected. The potential role of von Willebrand factor in the pathogenesis of these hemostatic complications is discussed.

The chronic myeloproliferative disorders (MPD), predominantly polycythemia vera and essential thrombocythemia, are characterized by a high incidence of thromboembolic and, to a lesser degree, hemorrhagic complications. The disease process in chronic MPD affects a pluripotent progenitor cell and results in trilineage hematopoietic proliferation. Clonal involvement of megakaryocytopoiesis is regarded as the main origin of thromboembolism in MPD and results in abnormal platelet production. These platelets show increased size heterogeneity and ultrastructural abnormalities, and their function in vitro is in many ways impaired with a high degree of individual variability. Elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface are common on chronic MPD, and may reflect an inappropriate state of platelet activation. Although a variety of platelet receptor deficiencies and some defects of intracellular signaling pathways have been identified, the different platelet defects in MPD could not be traced back to an underlying general pathogenetic mechanism. On progression of chronic MPD to more advanced stages of the disease, the number of platelet abnormalities tend to increase. Cytoreductive drugs may partly improve platelet dysfunction, and platelet inhibitory agents reduce symptoms of platelet activation. However, neither of these therapeutic principles is able to normalize platelet function in MPD. As an alternative to conventional treatment, specific suppression of clonal megakaryocyte growth and recovery of polyclonal hematopoiesis may be achieved by biologic agents such as interferon alpha. Such treatment strategies may prevent thromboembolic complications together with hematologic symptoms and progression of the disease and should be further evaluated in prospective studies.

Signal transduction on platelet activation involves phosphoinositide-specific phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositides and formation of inositol-1,4,5-triphosphate [I(1,4,5)P3], which mediates Ca2+ mobilization, and diacylglycerol (DG), which activates protein kinase C (PKC) to phosphorylate a 47-kD protein (Pleckstrin). We studied these events in two related patients previously reported (Blood 74:664, 1989) to have abnormal aggregation and 14C-serotonin secretion, and impaired intracellular Ca2+ mobilization in response to several agonists. Thrombin-induced I(1,4,5)P3 and phosphatidic acid formation were diminished. Pleckstrin phosphorylation was impaired on activation with thrombin, platelet-activating factor, and ionophore A23187, but was normal with PKC activator 1,2-dioctonyl-sn-glycerol (DiC8). Ca2+ mobilization induced by guanosine triphosphate (GTP) analog guanosine 5'-0-(3 thiotriphosphate) (GTP gamma S) was diminished. Pretreatment with either A23187 or DiC8 did not correct the impaired adenine diphosphate-induced secretion; however, upon stimulation with A23187 plus DiC8, pleckstrin phosphorylation and secretion were normal, indicating that both PKC activation and Ca2+ mobilization are essential for normal secretion. We conclude that these patients have a unique inherited platelet defect in formation of two key intracellular mediators [I(1,4,5)P3 and DG] and in the responses mediated by them due to a defect in postreceptor mechanisms of PLC activation.

Tumor necrosis factor and various haematological parameters were studied in 90 patients suffering from falciparum malaria. They were divided into three groups on the basis of haemoglobin level. The difference in haemoglobin level between group-1 (Hb < 7 gm/dl) and group-2 (Hb 7-10 gm/dl), as well as group-1 and group-3 was statistically significant. The geometric mean TNF alpha concentrations in group-1 (193.9 pg/ml) and group-2 (132.2 pg/ml) were higher as compared to group-3; however, the difference was statistically non-significant. The TNF concentration in group-2 correlated negatively with haemoglobin level (r = .43, p = .05). As a whole, 21% patients had leukocytosis, 3% leukopenia, 46% increased ESR and 26% elevated levels of fibrin degradation products. The platelet count was done only in 4 patients with bleeding problems. Twenty-five healthy subjects were included in the study as controls. The difference between TNF and haemoglobin level in group-1 and controls was statistically significant (p < .05, p < .001 each). The role of tumor necrosis factor in the production of these changes is discussed.

Platelets of anticoagulated whole blood forced at 40 mmHg through a fine filter are activated, aggregated and retained, so block the filter (platelet filter test, O'Brien JR, Salmon GP. Blood 1987; 1354-1361). Our clinical experiences with this simple and quick haemostasis test are summarized. Patients were investigated with different types of vWD (type-1 = 35, type-2A = 7, type-2B = 7, type-3 = 1), Glanzmann's thrombasthenia, congenital deficiency of cyclo-oxygenase, acquired Bernard-Soulier syndrome, FXII-, FXIII-deficiency and a control group. The cumulative drop count and the platelet retention were carefully measured during two phases of the filter test. Platelet count, bleeding time, vWF:Ag and vWF:Rcof activity were measured along with the platelet filter test. The filter was not blocked and the platelet retention was abnormally low in all patients with thrombasthenia, type-2a, type-2B, type-3 vWD. Treatment with 1-desamino-8-D-arginine-vasopressin (DDAVP) caused enhanced platelet retention in 16 patients with type-1 vWD. The test is simple, quick and cheap, has good reproducibility, and may be useful in clinical haemostasis laboratories for examination of high shear induced platelet functions.

Naturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational gamma-carboxy-glutamic acid (Gla) and beta-hydroxy aspartic acid (beta-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel beta-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

Protein Z is a vitamin K-dependent plasma protein synthesized by the liver. Protein Z promotes the association of thrombin with phospholipid surfaces. So far, nothing is known about the clinical relevance of protein Z except alterations measured in patients under oral anticoagulant treatment. We propose that in protein Z deficiency a bleeding tendency might result because of the interaction of protein Z with thrombin on phospholipid endothelial surfaces. Therefore, we examined 36 patients with bleeding tendency of unknown origin, who were not under oral anticoagulant treatment and had normal liver synthesis function. Mean protein Z value of the patients with bleeding tendency was significantly diminished in comparison to the healthy control group. Twenty-one of the bleeding patients had lower protein Z levels than the lowest protein Z level of the control group. In conclusion, protein Z deficiency is described as a new type of bleeding tendency.

We report on a 73 years old female patient receiving a recurrent epistaxis due to a severe plasmatic malcoagulation. In spite of since twenty years remaining diarrhoea coeliac disease has been diagnosed but now causative of the malcoagulation. On the occasion of this report clinical, current pathogenetical, immunological and pathohistological aspects of coeliac disease have been described. At last we agree to the differential diagnosis of anaemia in coeliac disease and in this connection to the metabolism of vitamin K too.

Tonsillectomies are the most frequently performed ENT surgical procedures and are potentially beset with a number of possible complications. Post-operative secondary hemorrhage still remains the most frequent complication despite improvements in surgical techniques and preoperative diagnostic evaluations. Besides unsuitable operative techniques, disturbances of circulation and wound infections, disturbances of hemostasis may play an important part. The objective of this paper was to examine the relative frequency of platelet functional disorders as a possible cause for secondary hemorrhage after tonsillectomies. In the past, most of these have been related to medication use. Eighty-nine patients were studied and historically showed no predisposition increased hemorrhage per se or in their families or gave reasons for other factors favoring secondary hemorrhage. The diminution or lack of collagen or ADP-induced agglutination served as an indication for a platelet functional disorder. Ten percent of the 89 patients experienced secondary hemorrhage, with platelet functional disorders proved in 40% of these patients. Because of these results a correlation was attempted between secondary hemorrhage and abnormal deficits of collagen and ADP-induced agglutinations in platelet functional tests, but this was not found. Necessary preoperative studies was attempted screening for hemostasis as well as medico-legal aspects connected with the prescription of medicines inhibiting platelet agglutination, especially use of acetylsalicylic acid before tonsillectomies, are discussed.

The mechanisms of haemostatic failure were studied in 87 patients bitten by the Papuan taipan (Oxyuranus scutellatus canni). Eighty (92%) had evidence of a coagulopathy on laboratory testing; 36 (41.4%) developed spontaneous systemic bleeding, although this was rarely of clinical significance. Coagulation assays in 48 completely defibrinated patients showed marked reductions in factors V and VIII and reductions in factors II, IX, XI, XII and XIIIA. There was a reduction in plasminogen and alpha 2-antiplasmin levels and both total and cross-linked fibrin(ogen) degradation products (FDP) levels were elevated. The mean platelet count was initially decreased and fell further during admission. Similar but less severe changes were seen in patients who were mildly defibrinated. Following treatment with antivenom, fibrinogen levels rose rapidly and coagulability was restored within 6-12 h in 93% of patients. These abnormalities may be primarily attributable to the prothrombin activator present in taipan venom, but it is likely that other uncharacterized venom components contributed.

Platelet glycoprotein VI (GPVI), a 62kD membrane protein, has been identified as one of the platelet receptors for collagen, since GPVI-deficient platelets exhibit abnormal responses to collagen and an abnormal bleeding tendency. We report a female patient with a mild bleeding history whose platelets expressed 10% GPVI of normal platelets. Shape change, aggregation and ATP release of the patient's platelets were completely absent in response to 1-5 micrograms/ml collagen but present normally in response to ADP and Ca2+ ionophore A23187. Adhesion of the patient's platelets to coated collagen was mildly affected (40-60% of normal platelets) in spite of only 10% expression of GPVI. Flow cytometrical studies revealed that the patient's platelets expressed normal amounts of the GPIa/IIa complex. These results suggest that platelet GPVI is less involved in adhesion to collagen than shape change and aggregation induced by collagen.

Dysplastic scoliosis often occurs with parallel hemostasis disorders and is fraught with the risk of intra- or postoperative risk of hemorrhagic complications. For early correction of hemostasis and adequate management of the patients, hemostasis parameters should be found out. Administration of indirect-action anticoagulants is risky. The use of heparin or fraxiparin is more valid. The latter of them maintains the threat of postoperative hemorrhage onset in the least degree.

A severe hereditary hemorrhagic diathesis in Simmental cattle has been identified in North America. Platelet numbers and coagulation profiles of affected cattle are normal. We have further characterized the severe dysfunction of platelet aggregation. All agonists tested elicited normal shape change. Aggregations in response to ADP, A23187, and collagen were absent. Aggregations were decreased or required more time for completion in response to PAF and thrombin. No ultrastructural abnormalities were observed in transmission electron micrographs. Dense granule release of ATP in response to PAF was normal. Thrombin-induced aggregation was dependent upon external calcium concentration in normal but not affected animals. Clot retraction in the blood from affected animals was abnormal. The data implicate a defect of Ca++ mobilization or utilization.

Several publications during the past 10-15 years report on the identification of acarboxyprothrombin (PIVKA II) in a varying proportion of examined newborn and babies (1.9 to 81.5%). These findings prove that the relevant infants were suffering from vitamin K deficiency. Hence, the researchers recommend to continue the prophylactic administration of Vitamin K to newborn. Another argument in favour of vitamin K prophylaxis is supplied by the results of epidemiological studies on the frequency of haemorrhages in newborn and babies caused by vitamin K deficiency. In respect of avoidance of haemorrhages, a single intramuscular injection of vitamin K appears to be the safest mode of application, but repeated peroral administration seems to be practically equally effective. The very frequently performed intramuscular injection of vitamin K is criticised not only because of possible local complications but also because of the greatly enhanced vitamin K concentrations in the blood after the injection. This enhanced concentration is accused of being responsible for the increased risk of malignant tumour growth in those babies who received vitamin K via the i.m. route, compared with the children who had not been given any injection or to whom vitamin K had been administered orally. For this reason vitamin K prophylaxis should be effected in newborn via the oral route (repeated administration), whereas the i.m. route should be an exception. Recommendations to this effect are already on record.

We have identified a new type of A alpha Gly-17 to Val substitution in a congenital dysfibrinogen, fibrinogen Bremen, derived from a 15-year-old boy having manifested easy bruising and delayed wound healing. The functional abnormality was characterized by altered fibrin monomer polymerization, which became evident by increasing the salt concentration and pH. A synthetic tetrapeptide with a sequence of the amino-terminal segment of normal fibrin alpha-chain, Gly-Pro-Arg-Val, substantially inhibited polymerization of both normal and the patient-derived fibrin monomers. A synthetic tetrapeptide with the Bremen type sequence of Val-Pro-Arg-Val inhibited polymerization of the patient's fibrin monomers partially at a peptide: fibrin monomer molar ratio of 4,000:1, and that of normal one at a much higher ratio of 10,000:1. Likewise, a synthetic peptide Ala-Pro-Arg-Val with a replacement of the Gly residue by another aliphatic amino acid Ala inhibited similarly the patient's fibrin monomer polymerization. Thus, the hypothetical two-pronged socket-like structure consisting of the alpha-amino group of the amino-terminal Gly and the guanidino group of an Arg at position 3 of the normal fibrin alpha-chain seems to be restored considerably in the mutant fibrin alpha-chain at low ionic strengths and pH's, despite the replacement of the amino-terminal Gly by another aliphatic amino acid Val.

Hereditary types of thrombocytopenia are often clinically misdiagnosed as chronic autoimmune thrombocytopenia. The Bernard-Soulier syndrome is a recessively inherited thrombocytopenia and -pathy associated with giant platelets. Bleeding time is usually prolonged, hemorrhage can be severe. In a Turkish thrombocytopenic boy autoimmune thrombocytopenia was diagnosed at the age of 11 months because the platelet count raised from 40.000/microliter to 100.000/microliters under treatment with steroids. The correct diagnosis of Bernard-Souiler syndrome was made at the age of 2 1/2 years. His also affected 13 year old sister had been treated for chronic autoimmune thrombocytopenia for years and suffered from severe hypermenorrhoea. Family history revealed consanguinity of the parents. Diagnosis of Bernard-Soulier syndrome was made by crossimmunoelectrophoresis and immunofluorescence showing absence of the glycoprotein complex Ib/IX.

In this study Protein C (PC) and antithrombin III (AT III) levels in childhood acute leukemia were investigated. The mean PC activity levels in 19 newly diagnosed cases of acute leukemia were significantly lower as compared with the normal controls (p < 0.05). A significant increase was found (p < 0.01) in the patients in remission. Prior to treatment 78.8 percent of patients had decreased PC activity levels, but all patients had normal PC activity during remission. Decreased PC activity levels were found to be independent of the leukocyte count and liver function. No statistically significant difference was found in the AT III antigen levels between the untreated patients, the patients in remission and the control group. Our results indicate that apart from thrombocytopenia, low PC activity levels and alterations in fibrinolysis and coagulation may be responsible for the hemorrhagic manifestations observed in cases of acute leukemia.

Two cases of postpartum inhibitors to F VIII are described. One patient had a severe bleeding tendency (iliopsoas bleeding, forearm bleeding). The maximum inhibitor titer was 800 BU/ml in case 1 and 120 BU/ml in case 2. Bleeding was controlled by treatment with human and porcine factor VIII concentrate and with activated prothrombin complex concentrate (FEIBA, Immuno AG, Vienna, Austria) in case 1, while no replacement therapy was given in case 2. Prednisone (given in both cases) and high-dose immunoglobulin (given in case 2) was without effect. Cyclophosphamide (100 mg per day), combined with small doses of prednisone led to complete disappearance of the inhibitor and normalization of factor VIII in case 1. In the other patient who refused treatment with cyclophosphamide the inhibitor titer remained high over a period of 13 months.

Presurgical coagulation diagnosis should--apart from coagulation monitoring in the laboratory based on a stepwise diagnosis for detection of coagulations disorders, starting with global tests (NT/APTT) followed by appropriate specific investigation in case of pathological findings--consist of an adequate hemostaseological anamnesis and physical checkup of the patient. This would allow detection of important signs of hemostaseological impairment during the pre-analytical phase already and permit subsequent initiation of more specific coagulation tests. The casuistics of a patient with factor XI-deficiency ("Minor Form"), a condition which is extremely infrequent in our country, demonstrates the coagulation diagnostic procedure which led to detection of his inherited factor XI-deficiency. In addition the pre-, peri- and postsurgical therapeutical management of this particular patient using an antifibrinolytic drug (tranexamic acid) is presented.

In this study, we examined the platelet von Willebrand factor (vWF)-binding domain in patients with liver cirrhosis. Direct binding studies were performed with the monoclonal antibody (mab) AN51 with specificity for the glycoprotein (GP) lb alpha. Specific binding of AN51 to intact washed platelets was monitored by an enzyme-linked immunoassay (ELISA). Half-maximum binding to intact washed platelets occurred at concentrations as low as 94 +/- 24 ng/ml; N = 12). Binding saturation analysis of with AN51 revealed a more than fifty percent reduction of AN51-binding sites (p < 0.001) in cirrhosis (N = 13) as compared to sex- and age-matched healthy controls (N = 12). These data demonstrate an impairment of the platelet surface vWF-binding domain in patients with liver cirrhosis. The resulting defect in primary haemostasis, i.e. the vWF-mediated attachment of platelets to the exposed subendothelium, is expected to contribute to the increased risk of haemorrhagic complications in these patients.

Hereditary Factor VII deficiency is one of the rare congenital coagulopathies. Prolonged prothrombin time (PT) with normal partial prothrombin time (PTT) may be an indicator for Factor VII deficiency. A family with hereditary heterozygous Factor VII deficiency is presented in whom no symptoms of a bleeding disorder were clinically detectable. A discussion of the therapeutic options follows.

The study of three adults with severe bleeding due to the presence of acquired anticoagulants that inhibit procoagulant action of Factor VIII and to a lesser degree of factors IX and XI, is described. In one case, this phenomenon occurred during the course of a rheumatoid arthritis, in one case coincided with a megaloblastic anemia (pernicious anemia) and the last case did not have any coexisting disease. Corticosteroids were useless, intravenous cyclophosphamide improved one patient and given orally failed in other patient. The circulating inhibitor disappeared in the patient successfully treated with cyclophosphamide and persisted and was the cause of death in the other two patients. In one patient, column fractioning demonstrated that the anticoagulant was an G immunoglobulin, with higher activity at pH 6.5.

Nafamostat mesilate (NM), an ultrashort-acting multi-enzymatic inhibitor, is a useful anti-coagulant in high bleeding risk patients needing hemodialysis. We applied NM as a membrane plasmapheresis (MP) anti-coagulant in patients with high bleeding risk. Eleven patients, the majority with hepatic failure and active hemorrhagic foci or severe bleeding diathesis, could be treated with MP 22 times under anti-coagulation by 20-40 mg/h/NM by continuous infusion without any trouble. Celite-activated coagulation time (CCT) at the plasma separator inlet and outlet was adequately prolonged during MP, but CCT in systemic blood showed no prolongation throughout the procedure, because NM was rapidly inactivated. There was no observable blood coagulation in the extracorporeal circuit including the plasma separator. No adverse reaction or exacerbation of hemorrhage was noted throughout the MP. NM thus appears to be a useful and safe anti-coagulant not only for hemodialysis but also for MP in high bleeding risk patients.

Twelve neonates with sacrococcygeal teratoma (SCT) have been treated at British Columbia Children's Hospital over the past 5 years. Clinically significant coagulopathy developed in four of these neonates and two died, one before surgical intervention could be undertaken. Disseminated intravascular coagulation (DIC) was found in one patient and thrombocytopenia in another on preoperative laboratory studies. Etiology of the coagulopathy is unclear, but appears to be multifactorial. Although several clinical reviews have noted mortalities due to exsanguinating hemorrhage, no study has focused solely on this issue. The diagnosis of SCT in the neonate at high risk for development of coagulopathy is usually made prenatally. Premature labor is often precipitated by associated polyhydramnios and large tumor size. Fetal distress, prematurity, and low birth weight are common. Presence of placentamegaly, hydrops fetalis, and congestive heart failure are ominous prognostic signs. Early identification of patients at increased risk for development of hemorrhagic complications may allow optimization of their management. Cesarean section should minimize trauma to the SCT during delivery. Expeditious resection of the lesion may improve survival.