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Clinical significance of lupus anticoagulants in children

OBJECTIVES To determine the spectrum of associated clinical manifestations and time course of lupus anticoagulants (LA) in children. STUDY DESIGN Retrospective study of 95 consecutive children (46 boys and 47 girls), with a median age of 5.3 years (range, 1.7 to 17.1 years), diagnosed with presence of LA at a hemostasis referral center; 83 were followed up over a median of 2.9 years (range, 6 weeks to 21.6 years). RESULTS At diagnosis, 80 of 95 (84%) children were free of symptoms, and presence of LA was found incidentally. Nine children (10%) had bleeding symptoms, 5 (5%) had thrombotic events, and 1 had systemic lupus erythematosus. Among the patients with bleeding, 5 had transient severe hypoprothrombinemia after adenovirus infections, and 3 had thrombocytopenia. None of the children who were initially free of symptoms had bleeding, thrombotic complications, or autoimmune disease subsequently. At follow-up, 48 of 83 (58%) patients had normal activated partial thromboplastin time values after 1.9 years (5 weeks to 19.1 years). Thirty-two (38%) still had activated partial thromboplastin time elevations but did not fulfill all criteria for presence of LA after 3.2 years (7.4 months to 9.3 years). Three (4%) patients, who had presented with thrombosis, had persistent positive LA, anti-cardiolipin, and antinuclear antibodies after 1.4, 2.8, and 7.5 years, respectively. One of these had recurrent thrombosis. CONCLUSIONS In most children the presence of LA did not lead to clinical complications and was transient. Bleeding occurred with additional hypoprothrombinemia or thrombocytopenia. Thrombosis was rare and strongly associated with persistently positive LA.

Large Amounts of Vascular Endothelial Growth Factor at the Site of Hemostatic Plug Formation In Vivo

Vascular endothelial growth factor (VEGF) is important for the proliferation, differentiation, and survival of microvascular endothelial cells. It is a potent angiogenic factor and a specific endothelial cell mitogen that increases fenestration and extravasation of plasma macromolecules. Recently, large quantities of VEGF were detected in human megakaryocytes. Incubation of human platelets with thrombin in vitro resulted in the release of large amounts of VEGF. To investigate whether VEGF is released from platelets during coagulation activation in vivo, we measured in human subjects VEGF at the site of plug formation, ie, in blood emerging from a standardized injury made to determine bleeding time (shed blood). VEGF was also determined in the same volunteers after treatment with the specific thrombin inhibitor recombinant hirudin (r-hirudin). In a double-blind, randomized, crossover study, 17 healthy male volunteers (aged 20 to 35 years) were investigated. VEGF concentrations were measured in venous blood and in shed blood by the use of an immunoassay 10 minutes after intravenous administration of r-hirudin (0.35 mg/kg of body weight) or physiological saline. Prothrombin fragment f1.2 (f1.2) and beta-thromboglobulin (beta-TG) were determined as indicators of coagulation and platelet activation, respectively. Concentrations of VEGF, f1.2, and beta-TG in shed blood 4 minutes after injury were significantly higher than in venous blood (VEGF, 55.8+/-9.2 versus <20 pg/mL, P<0.001; f1.2, 71.3+/-10.4 versus 0.78+/-0.03 nmol/L, P<0. 001; beta-TG, 2290+/-170 versus 53.2+/-14.0 ng/mL, P<0.001). Administration of r-hirudin caused a >50% inhibition of the beta-TG and f1.2 levels in shed blood. In a similar manner, much lower amounts of VEGF were detectable at the site of plug formation after r-hirudin treatment (69.0+/-9.5 versus 37.8+/-2.6 pg/mL per minute; P=0.0015). Our data indicate that substantial quantities of VEGF are released from platelets during the interaction with the injured vessel wall in vivo. This finding may be relevant with respect to wound healing and tissue repair, tumor vascularization, or arterial thrombus formation.

Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study

Abstract A total of 168 patients with de novo AML were retreated with chemotherapy at relapse following first CR; 66 patients (39%) achieved a second complete remission (CR). The probability of achieving a second CR was highly dependent on the duration of the first remission. Patients who received no or conventional postremission chemotherapy after second CR had a median remission duration of 7.5 months, and the probability of remaining in remission at 3 years was 24%. Patients with a first CR of more than 12 months had a median second remission duration of 18 months. The probability of a second CCR was 35% at 3 years and 24% at 5 years, whereas none of the patients with a first CR of less than 12 months was in remission at 3 years. Only a poor correlation (p=0.31) was found when the durations of the first and second CR were compared in patients with a second relapse. Patients with long-lasting remissions and long-term survivors after second CR are characterized by a first CR duration of >12 months and favorable or normal cytogenetics. The type of salvage treatment seems to be less important for achievment of long-term remission, but it is probably important to administer consolidation chemotherapy after second CR. Other so-far ill-defined factors may be responsible for the supression of the leukemic clone in patients with long-lasting remissions following chemotherapy for relapse after second CR.

Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL)

SummaryOur purpose was to evaluate the ability of re-combinant human granulocyte colony-stimulating factor (r-metHuG-CSF) as an adjunct to induction chemo-therapy of acute lymphoblastic leukemia (ALL) to ameliorate chemotherapy-induced neutropenia and thus allow patients to receive full doses of chemotherapy on time. Sixteen consecutive patients with adult ALL (13 de novo, three relapsed) were treated with induction chemo-therapy according to the BMFT protocol and received in addition r-metHuG-CSF (200μg/m2/day). Patients who were treated with the same induction chemotherapy but without G-CSF between 1982 and 1990 served as controls. Fifteen of the 16 patients achieved complete hematological remission. One patient died because of fungal septicemia. Compared with historical controls, G-CSF-treated patients had a significantly faster neutrophil recovery in phase I, resulting in neutrophil counts > 1000/μl at day 17 vs day 26 (in median) in controls. In phase II, the onset of severe leukocytopenia (< 1500/μl) was significantly (p = 0.01) delayed and the degree of leukocytopenia less pronounced (mean nadir 3300/μl) in G-CSF-treated patients compared with controls (1880/μl). The number of days of febrile neutropenia was not different in phase I. In phase II it was lower in study patients (0 vs 1.1 days), but the difference did not reach statistical significance (p = 0.09). Full doses of chemo-therapy could be given on time to 11/13 (85%) G-CSF pa-tients but to only 7/30 (23%) controls. These data indicate that (a) G-CSF can be given along with chemotherapy in induction treatment of ALL without compromising efficacy; (b) the duration of neutropenia in phase I is markedly shortened and the degree of leukocytopenia in phase II ameliorated; (c) these beneficial effects allow patients to receive full doses of chemotherapy on time.

The risk of recurrent venous thromboembolism: The Austrian Study on Recurrent Venous Thromboembolism

ZusammenfassungDie venöse Thromboembolie (VTE) ist eine chronische Erkrankung. Nach Beendigung der oralen Antikoagulantientherapie erleidet ca. ein Drittel der Patienten ein neuerliches thromboembolisches Ereignis. 5% dieser Patienten sterben an der Pulmonalembolie. Die Austrian Study on Recurrent Venous Thromboembolism (AUREC) ist eine prospektive Kohortenstudie und hat zum Ziel, die Gesamtrezidivrate der VTE, den prädiktiven Wert von Laboruntersuchungen, die Bedeutung von angeborenen und erworbenen thrombotischen Risikofaktoren und den Einfluss einer länger dauernden bzw. modifizierten sekundären Thromboseprophylaxe auf das Rezidivrisiko von Hochrisikopatienten zu untersuchen. Bislang gelang es den AUREC Untersuchern Subgruppen von Patienten mit einem erhöhten Rezidivrisiko zu identifizieren. Patienten mit einer anamnestischen VTE, erhöhten Faktor VIII-, Faktor IX- und Faktor XI-Spiegeln, einer anamnestischen Pulmonalembolie oder einer oberflächlichen Venenthrombose nach VTE sowie Patienten mit Hyperhomocysteinämie. Patienten mit der Faktor V Leiden Mutation oder der G20210A Mutation im Prothrombingen haben kein erhöhtes Rezidivrisiko und benötigen daher keine länger dauernde Sekundärprophylaxe. Zur Zeit werden interventionelle Studien bei Patienten mit hohem Faktor VIII oder Hyperhomocysteinämie durchgeführt um zu untersuchen, ob eine länger dauernde Sekundärprophylaxe mit oralen Antikoagulantien oder die Verabreichung von Folsäure, Vitamin B6 und Vitamin B12 das Rezidivrisiko senken.AbstractVenous thromboembolism (VTE) is a chronic disease. After withdrawal of oral anticoagulation at least a third of patients will experience a subsequent episode of venous thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The Austrian Study on Recurrent Venous Thromboembolism (AUREC) is a prospective cohort study aiming to investigate the overall rate of recurrent VTE, the predictive value of laboratory assays, the importance of acquired or congenital risk factors for thrombosis and the impact of extended or modified secondary thromboprophylaxis on the risk of recurrence among high-risk patients. So far, the AUREC investigators have identified subgroups of patients with a particular high risk of recurrence: patients with a history of venous thrombosis, elevated levels of coagulation factors VIII, IX and XI, pulmonary embolism or superficial venous thrombosis and a history of venous thrombosis and hyperhomocysteinemia. Patients with a history of venous thrombosis and mutations in genes encoding for coagulation factors (factor V Leiden, factor II, G20210A) do not have an enhanced risk of recurrence and, thus, do not qualify for extended secondary thromboprophylaxis. At present, interventional trials are in progress in patients with high factor VIII or hyperhomocysteinemia in order to investigate if these patient groups might benefit from extended oral anticoagulation or vitamin supplementation, respectively.

Hemostatic and fibrinolytic parameters in patients with acute myeloid leukemia: Activation of blood coagulation, fibrinolysis and unspecific proteolysis

SummaryBlood coagulation, fibrinolytic and unspecific proteolytic parameters were investigated in 34 patients with acute myeloid leukemia. An increased activity of the coagulation system, documented by elevated thrombin-antithrombin III-complex (TAT) plasma levels, was found in 91% of the patients; 50% had increased elastase plasma levels. Hyperfibrinolysis, as shown by elevated fibrin split-product D-Dimer plasma levels, was detected in 91% of AML patients. Activation of these enzyme systems was not associated with relevant defects in blood coagulation or fibrinolysis in the majority of the patients investigated. In selected cases of promyelocytic M3 and monoblastic M5 leukemia, however, hypofibrinogenemia and α2-plasmininhibitor defiency was found, most likely due to depletion of these proteins in the course of disseminated intravascular coagulation and secondary hyperfibrinolysis. Significant correlations were calculated between TAT and fibrinogen (r = −0.57,P < 0.005), TAT and D-Dimer (r = 0.89,P < 0.0005), and D-Dimer and α2-plasmininhibitor (r = −0.77,P < 0.0005) levels. Indications of a pathogenetic importance of primary hyperfibrinolysis or unspecific proteolysis for hypofibrinogenemia and α2-PI deficiency were not found.

Cerebral sinus thrombosis in a patient with hereditary protein S deficiency : case report and review of the literature

SummaryHereditary protein S deficiency is an established risk factor for venous thrombosis. The common sites of thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history of deep leg vein thrombosis, who developed thrombosis of the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized tomography and carotid angiography. Lysis of the thrombus occurred during heparin treatment. The hereditary nature of protein S deficiency was documented by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases of cerebral vein thrombosis and a deficiency of either antithrombin III, protein C, or protein S were reviewed. Compared with patients without a deficiency state, the clinical features of cerebral vein thrombosis were similar except for an earlier onset and a positive medical history of venous thromboembolic events in a considerable number of patients.

Hepatic and splenic abscesses — a common complication of intensive chemotherapy of acute myeloid leukemia (AML)

SummaryIn order to determine the frequency of hepatosplenic abscesses in AML patients during chemotherapy and to evaluate the clinical and laboratory characteristics of this complication we performed a prospective study over a 28-month period. Fifty-five consecutive patients with de novo AML or relapse who received intensive chemotherapy underwent regular ultrasound examinations. In 16 patients (29.1%) hepatic and/or splenic abscesses were detected sonographically. Histopathological evidence for abscess formation was obtained in five of these 16 patients. In three patients granulation tissue and in one patient necrotizing granulomas were found. Causative micro-organisms were proven in only three patients:Candida hyphae were demonstrated in one patient, gram-positive cocci in another. Bacteria and fungi were seen in the tissue specimen of the third patient. Patients with hepatosplenic abscesses had significantly prolonged fever after neutrophil recovery but did not differ from patients without abscesses in any other laboratory or clinical features. Due to the absence of specific alerting clinical and laboratory signs and symptoms of hepatosplenic abscesses, routine ultrasound examination is required for detection of this complication. The presence of hepatic and/or splenic abscesses does not necessarily worsen the prognosis, but it may influence the decision on further chemotherapy and antimicrobial treatment.

Effects of Recombinant Hirudin (r-Hirudin, HBW 023) on Coagulation and Platelet Activation In Vivo Comparison With Unfractionated Heparin and a Low-Molecular-Weight Heparin Preparation (Fragmin)

In a double-blind, randomized, crossover study, we investigated in 15 healthy male volunteers the effects of recombinant (r-) hirudin (HBW 023, 0.35 mg/kg body wt SC), unfractionated heparin (UFH, HeparinNovo; 150 IU/kg body wt SC), and a low-molecular-weight heparin preparation (LMWH, Fragmin; 75 IU/kg body wt SC) on coagulation and platelet activation in vivo by measuring specific coagulation-activation peptides (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin-III complex [TAT], and beta-thromboglobulin [beta-TG]) in bleeding-time blood (activated state) and venous blood (basal state). In bleeding-time blood, r-hirudin and the heparin preparations significantly inhibited formation of both TAT and F1 + 2. However, the inhibitory effect of r-hirudin on F1 + 2 generation was short-lived and weaker compared with that of UFH and LMWH, and the TAT-to-F1 + 2 ratio was significantly lower after r-hirudin than after UFH or LMWH. Thus, in vivo, when the coagulation system is in an activated state, r-hirudin exerts its anticoagulant effects predominantly by inhibiting thrombin (factor IIa), whereas UFH and LMWH are directed against both factors Xa and IIa. A different mode of action for UFH and LMWH was not detectable. In venous blood, r-hirudin caused a moderate reduction in TAT formation and an increase (at 1 hour) rather than a decrease in F1 + 2 generation. Formation of TAT and F1 + 2 was suppressed at various time points following both UFH and LMWH. There was no difference in the TAT-to-F1 + 2 ratio after r-hirudin and heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

IIB von Willebrand's disease: pathogenetic and therapeutic studies.

Summary. Infusion of 1‐deamino‐(8‐D‐arginine)‐vasopressin (DDAVP) into patients with IIB von Willebrands disease (vWD) has been reported to induce thrombocytopenia. In some families with this disorder thrombocytopenia is present even in the resting state. We have investigated the basis of this chronic thrombocytopenia in one such patient by performing platelet recovery and survival studies. Increased platelet consumption was suggested by a decrease in platelet recovery (40.5%, normal 45%) and mean platelet survival (112 h, normal range 144–224 h). In addition, we have administered test infusions of DDAVP and observed the effect on bleeding time and platelet count. DDAVP caused a decrease in the median platelet count from 86 × 109/1 (range 30–221) to 60 × 109/1 (range 5‐144), the individual decline in the nine subjects ranging from 12% to 84% compared to the pretreatment values. Formation of platelet aggregates was observed in all patients following DDAVP. The bleeding time was prolonged before DDAVP in all patients and lengthened further in two after the infusion. However, partial correction of the bleeding time was seen in three and normalization in one patient following DDAVP infusion.