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Two patients with severe bleeding complications under oral anticoagulant treatment are presented, in one case caused by pharmacokinetic drug interference (phenylbutazone), in the other by genetic predisposition to bleeding induced by coumarin anticoagulants. Another patient with decreasing INR due to drug interference (rifampicin) is presented as well. The possibility of drug interferences with coumarin anticoagulants has to be anticipated, whenever the medication of an orally anticoagulated patient is changed. A founder mutation of the factor IX propeptide constitutes a genetic predisposition to bleeding in patients put on coumarins. Its presence should be excluded in any patient suffering from hemorrhagic complications after starting anticoagulation when INR values are in the target range.

We investigated the feasibility, quality and safety of patient self-control of oral anticoagulation. The patients were selected by their physicians on the basis of criteria such as compliance, skills and motivation. After theoretical and practical training they self-monitored and self-adjusted their anticoagulant dosage for 6 months by weekly self-measurement of their INR values using a capillary whole blood prothrombin time monitor (CoaguChek). Venous INR measurements once a month served as quality control. There were 51 study participants, who performed a median 5 INR measurements per month. 75.8% of all registered INR values were within the recommended individual INR target ranges. The coefficient of correlation between capillary (y) and venous (x) INR values was r = 0.87 (regression analysis y = 1.0 x -0.2). The concordance of capillary and venous INR values was 80% with respect to the individual INR target ranges. There were 5 minor bleeding episodes and no overt thromboembolic recurrences during the study period. In conclusion, the study demonstrated that patient self-control of oral anticoagulation is feasible and achieves a high percentage of INR values within the recommended target ranges. Therefore, self-control of oral anticoagulation can be offered to skilled and motivated patients as an alternative to physician-guided antiocogulation. However, specific training of these selected patients is necessary.

Two sisters having suffered from deep vein thrombosis while taking oral contraceptives are presented. Investigation for thrombophilia in 1993 was unrevealing. After the discovery of activated protein C (APC) resistance caused by the factor V R506Q (FV Leiden) mutation in 1993/1994, reinvestigation showed homozygous FV Leiden mutation in both sisters. APC resistance is the most frequent hereditary thrombophilia known so far. Diagnosis, prevalence and clinical significance of this thrombophilic defect are shortly discussed.

Congenital afibrinogenemia is a rare autosomal recessive hemostatic disorder leading to unclottable global coagulation tests. Furthermore, it is associated with abnormal platelet aggregation and with severe bleeding episodes if untreated. Surprisingly, thrombotic complications may be observed quite frequently in afibrinogenemic patients following replacement of fibrinogen. A case of congenital afibrinogenemia is described in a patient who suffered from severe bleeding episodes in the absence of replacement therapy but developed a deep vein thrombosis with multiple pulmonary emboli after fibrinogen replacement and surgical treatment of a hip fracture, despite conventional heparin prophylaxis.

We describe a 56-year-old patient with multiple myeloma and very high paraprotein concentration (IgG kappa). Coagulation studies showed unclottable thrombin and reptilase times caused by impaired fibrin polymerization presumably due to the paraproteinemia. There was no obvious bleeding tendency. The differential diagnosis of thrombin time prolongation includes inhibition of the added thrombin by exogenous heparin, hirudin or seldom by endogenous heparin-like anticoagulants or by acquired (bovine) thrombin antibodies, qualitative fibrinogen disorders (congenital and acquired dysfibrinogenemia), quantitative fibrinogen disorders (severe hypo- and afibrinogenemia) and delayed fibrin polymerization due to fibrin/fibrinogen degradation products, paraproteins and antibodies against fibrin(ogen). In multiple myeloma, thrombin time prolongation may seldom be due to endogenous heparin-like anticoagulants or antibodies to thrombin and more frequently to impaired fibrin polymerization by paraproteins. Simultaneous reptilase time prolongation as present in this case hints to this latter possibility.

A 68-year-old woman suffered from spontaneous hemarthrosis of the right elbow joint in april 1994. Cutaneous ekchymoses had been noted since summer 1993. Prothrombin time was prolonged (Quick percentage 40-50%) and was not corrected by prolonged administration of vitamin K. Coagulation studies showed isolated factor X (FX) deficiency without circulating FX inhibitor. This suggested the diagnosis of systemic amyloidosis which was retrospectively confirmed in small bowel biopsy specimens obtained one year before. Bilateral femoral head necrosis and femoral neck fracture due to amyloidosis, necessitated orthopedic surgery. The patient died four weeks postoperatively after several episodes of bleeding complications. Isolated FX deficiency may be hereditary but should--in the clinical context--also evoke the diagnosis of systemic amyloidosis. The possible bleeding tendency associated with amyloidosis is not attributable to acquired FX deficiency alone, but may also be caused by amyloid deposition in the microvasculature leading to acquired vascular hemorrhagic diathesis.

We report the history of a 77-year-old man with Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) who suffered from recurrent epistaxis and chronic bleeding anemia for many years. Hereditary hemorrhagic telangiectasia is a rare congenital disease, that is characterized by telangiectases of the nasal and oral mucosa, the gastrointestinal tract and the skin. Arteriovenous malformations of the lung and the brain may be present. The genetic and pathologic features, the clinical manifestations and the differential diagnosis are shortly presented. The management is not validated by controlled studies and is mainly based on clinical experience. It involves supportive therapy with iron supplementation and erythrocyte transfusions, if needed, for chronic bleeding anemia, aminocaproic acid, tranexamic acid or oestrogen-progesterone therapy to prevent mucosal bleeding, cauterisation, photocoagulation, transcatheter embolotherapy or surgery to treat the vascular abnormalities.

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.

A 76-year-old man under long term oral anticoagulant treatment showed unclottable prothrombin time (PT) without overt bleeding. After oral administration of vitamin K1, PT remained severely prolonged and the patient was hospitalized. INR was 8.0 and responded to parenteral vitamin K. Cholestasis resulting in poor intestinal vitamin K resorption was assumed to have caused "overanticoagulation". Quick test is a global clotting test for the extrinsic and common pathways of the coagulation system. Increased PT, i.e. decreased Quick percentage, may be due to different conditions and should--if unexplained--be further analyzed by assaying factors II, V, VII, X and fibrinogen. Preanalytical problems, plasma dilution with clotting factor-free volume replacement, decreased vitamin K-dependent clotting factors (oral anticoagulation, intoxication with certain rodenticides, vitamin K deficiency), impaired liver synthetic capacity, disseminated intravascular coagulation, or massive heparin contamination may cause prolonged PT. Newborns physiologically have longer PT and should receive vitamin K prophylaxis.

Hemorrhagic complications in CLL are most often related to thrombocytopenia either due to decreased megakaryopoiesis caused by diffuse lymphocytic bone marrow infiltration or to increased peripheral platelet consumption by platelet autoantibodies (immune thrombocytopenia), both being typical manifestations of the disease. Disseminated intravascular coagulation (DIC) does not belong to the spectrum of CLL-related complications. In the case here reported with DIC and newly diagnosed CLL the leukoerythroblastic blood changes hinted to bone marrow infiltration by another neoplastic process in addition to CLL. Bone marrow biopsy revealed infiltration by metastatic carcinoma of the prostate in addition to that by CLL, the former being responsible for triggering severe DIC leading to fatal intracranial bleeding.

A 46-year old nurse complaining of multiple hematomas including bleeding into the tongue was referred for hemostasis evaluation. A very low Quick percentage value, i.e. a severely prolonged prothrombin time with severely depressed vitamin K-dependent coagulation factors (FII:C, FVII:C, FX:C) and normal FV:C and fibrinogen level was found. In the absence of cholestasis, malabsorption and broad-spectrum antibiotic therapy, ingestion of vitamin K antagonists was suspected. Three years previously, she had been on oral anticoagulant treatment with phenprocoumon (Marcoumar) for postoperative pulmonary embolism. She denied having voluntarily ingested anticoagulant drugs. A high plasma level of coumarins was found. To exclude accidental ingestion, the patient's son living in the same household was tested as well. Surprisingly, a low level of coumarin was found also in his plasma. We suspect that the patient voluntarily intoxicated herself and gave a low dose of coumarin anticoagulant to her son as well.

Based on the description of a severe bleeding disorder in a young child a short overview on the genetics, the epidemiology, the pathophysiology, the clinical manifestations and the laboratory diagnosis of factor XIII deficiency is presented. The impressive clinical signs with bleeding starting in the neonatal period (prolonged bleeding from the umbilical cord), followed by severe, life-threatening episodes of intracranial hemorrhages should raise the clinical suspicion of FXIII deficiency. Difficulty of laboratory diagnosis is stressed. The importance of repeating initially negative screening tests and of performing a quantitative FXIII assay in the presence of strong clinical suspicion is strengthened. The diagnosis of factor XIII deficiency is difficult but has important therapeutic consequences: patients with documented severe deficiency should be put on regular substitution with factor XIII concentrates. Appropriately timed periodic infusions of such factor XIII concentrates enable patients to live normal lives, free from catastrophic bleeding episodes.

Background: The prothrombin time, also called thromboplastin time ("Quick"), is usually measured by using citrated plasma from venous blood. Recently, portable coagulation monitors have been developed which measure prothrombin time using non-anticoagulated capillary whole blood from a finger-stick. In the present study we evaluated the CoaguChek Plus coagulation monitor in comparison with a standard laboratory method in various patient groups: patients on oral anticoagulation with or without heparinisation, patients receiving heparin without oral anticoagulation, patients with a deficiency of one of the coagulation factors of the extrinsic or common pathway, and patients with liver disease. Furthermore, we studied the influence of the haemoglobin concentration on the test results., Method: Capillary prothrombin time was measured by using the portable coagulation monitor CoaguChek Plus and venous prothrombin time was assessed by using Thromborel S., Results: We found a correlation coefficient of 0.94 between capillary and venous INR values in 216 determinations from 167 patients. The slope of the regression line was 1.03, and the y-intercept 0.05, 93.5% of the results were within 0.9, 90.7% within 0.7, and 83.8% within 0.5 INR units. Similar results were obtained in patients on oral anticoagulation, patients with a deficiency of a factor of the extrinsic system and in patients with liver disease. Correlation and agreement were somewhat lower among patients on oral anticoagulation and simultaneous heparinisation (40 patients): correlation coefficient was 0.83, slope of the regression line was 0.87 and y-intercept was 0.27 INR units. No influence of the haemoglobin concentration on INR results could be demonstrated., Conclusion: Our results show the CoaguChek Plus coagulation monitor to be a valuable tool for measuring prothrombin time in patients on oral anticoagulation, in patients with liver disease to estimate the capacity of protein synthesis, and to screen for possible deficiencies of one of the coagulation factors of the extrinsic or common pathway. However, based on our preliminary data we cannot recommend the use of the CoaguChek Plus coagulation monitor in heparinised patients.

Resistance against the anticoagulatory effect of activated protein C (APC resistance) is the most prevalent hereditary risk factor for venous thromboembolism known today. In this short review, an exemplary casuistic observation from our thrombophilia outpatient ward is presented. The discovery by Dahlbäck et al. in 1993 of hereditary APC resistance as a basis of familial thrombophilia and the molecular characterization of this defect as point mutation in the coagulation factor V gene (FV R506Q- or FV Leiden-mutation) by Bertina and coworkers are discussed. The clinical implications of this thrombophilia and relevant knowledge for daily practice are briefly summarized.

Venography is still the gold standard for objective diagnosis of deep venous thrombosis (DVT). However, this investigation is costly and time-consuming, demands technical expertise and has potential side-effects. To reduce the number of phlebographies a simple, rapid and reliable screening test for exclusion of DVT would be greatly appreciated. In many studies markers of activated coagulation and fibrinolysis such as thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F 1 + 2) and D-dimers, respectively, were investigated with respect to their potential use as screening tests. Especially D-dimers as assessed by ELISA have turned out to have high sensitivity and negative predictive value for DVT and could therefore serve as screening test for exclusion of DVT. However, most of the easier, more rapid D-dimer Latex tests which would be better suited for emergency situations as well as the TAT- and F 1 + 2-ELISA tests are according to most studies not sufficiently sensitive. In the present article the significance of the different activation markers in the diagnostic approach of DVT is discussed based on the literature.

Venous thromboembolic diseases are of major importance with respect to morbidity and mortality. Therefore, efficient prophylaxis is essential. Indication for thromboprophylaxis has to be made individually: In high risk situations, especially in orthopedic surgery, every patient should receive medical prophylaxis, e.g. with heparin, in addition to other preventive measures such as the wearing of elastic stockings or physiotherapy until full mobilization. For high-risk patients having a history of recurrent venous thromboembolism or which are suffering from a thrombogenic disease (e.g. myeloproliferative disorder, especially polycythemia vera, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, homocystinuria) or a hereditary thrombophilia (e.g. deficiency of antithrombin III, protein S, protein C or APC resistance), prophylactic measures should be more generally applied. In these patients, risk factors (e.g. oral contraceptive medication) or risk situations (e.g. long-distance travelling by car or airplane) have to be avoided whenever possible. In inevitable risk situations (e.g. perioperative or peripartal period) prophylaxis is mandatory. It is generally limited to the period of elevated thrombogenic risk and is often effected by application of a low molecular weight heparin. Patients with a history of recurrent thromboembolic events despite elimination of all avoidable risk factors should get a lifelong prophylaxis, usually with oral anticoagulants.

Five selected case reports of patients suffering from rather unusual bleeding complications during oral anticoagulant therapy are presented. The reported frequency of bleeding during oral anticoagulation varies greatly. An unacceptably high incidence of hemorrhages has been reported in North American studies of the early 1980ies. The therapeutic target INR of 2.5-4.9 in these series is comparable to that in European studies where bleeding occurred much less frequently. We suggest that the insensitive thromboplastin reagents used in North America are unsuited to guide coumarin dosage, because too many prothrombin time values were outside the INR target range. In contrast, most prothrombin time values in European studies where a sensitive thromboplastin reagent was used, were within the target range. A recent prospective investigation by 25 Swiss practitioners showed an acceptably low bleeding complication rate (2.1 hemorrhagic complications severe enough to necessitate hospitalization per 100 patient years). Observation of contraindications, regular control of the prothrombin time using a sensitive and correctly calibrated thromboplastin, participation of practitioners and hospital laboratories at quality control exercises and consideration of drug interferences with coumarins help to reduce the incidence of hemorrhagic side effects. In case of either a PT value outside the target range or manifest bleeding, the necessary measures have to be tailored to the individual situation considering the Quick value as well as the severity and localization of hemorrhage.

The thrombin time assay is able to detect abnormalities of the terminal phase of plasmatic coagulation. The differential diagnosis of thrombin time prolongation includes (1) inhibition of the added thrombin by exogenous heparin or endogenous heparin-like anticoagulant, seldom by acquired antibovine thrombin antibodies, (2) qualitative fibrinogen disorders (congenital and acquired dysfibrinogemia, (3) quantitative fibrinogen disorders (hypo- and afibrinogenemia), and (4) delayed fibrin polymerization due to fibrin/fibrinogen degradation products, paraproteins or seldom acquired antibodies against fibrinogen.

The overall incidence per year of deep vein thrombosis is about one per thousand, but may be much higher in the presence of certain clinical risk factors such as advanced age, immobilization, surgical procedures, pregnancy, puerperium, use of oral contraceptive agents and malignancy. Moreover, homocystinuria, nephrotic syndrome, systemic lupus erythematosus and hematological disorders such as paroxysmal nocturnal hemoglobinuria or myeloproliferative syndromes predispose to thrombotic disease. Evaluation of the patient with thromboembolism should include detailed history, clinical examination and laboratory investigation to exclude these secondary thrombophilic states. Primary or hereditary thrombophilia is suspected mainly in patients suffering from (venous) thromboembolism at an early age (< 45 years), especially if recurrent and/or familial thrombosis is present. Hereditary thrombophilia may be due to deficiency of antithrombin III, protein C, protein S or plasminogen, some other defects being less well-established prethrombotic risk factors. These currently recognized primary prethrombotic molecular defects are found in 10 to 30% of patients with idiopathic thromboembolism. In the majority of cases the cause of thrombosis remains unknown.

Numerous patients with a thromboembolic history are referred to our Central Haematology Laboratory for a complete investigation of thrombophilia. Among them, patients with idiopathic thromboembolism represent the largest group. In collaboration with the obstetrician we control pregnant women at increased risk for thromboembolic complications. Individuals with myeloproliferative disorders often suffer from thromboembolism and are investigated at our Laboratory as well. Thirteen illustrative cases are presented, which are of diagnostic and/or therapeutic interest for the practitioner.

A heterozygous hereditary fibrinogen variant, fibrinogen Bern III, has been characterized. The proposita and her daughter showed prolonged thrombin time and reptilase time, as well as a markedly reduced fibrinogen concentration as determined by functional clotting assay. Fibrinogen was purified from the proposita's plasma and subjected to biochemical characterization. The delayed fibrin formation was shown to result from impaired release of fibrinopeptide A. Thrombin was found to cleave an extended fibrinopeptide A (A alpha 1-19) from the reduced polypeptide chains of the abnormal fibrinogen. Amino acid analysis of this fragment indicated that the arginine residue, located at the physiological thrombin cleavage site, was replaced by cysteine. The functional defect of the fibrinogen variant Bern III is due to the amino acid substitution A alpha 16 Arg----Cys.

Factor VIII procoagulant activity, antigen concentration and von Willebrand activity as ristocetin cofactor were determined several times in 10 patients with DIC. These is a significant negative correlation between the DIC-score and the VIII:C/von Willebrand activity ratio.

Between October 1982 and July 1984 systemic thrombolysis was carried out in 10 patients (5 males and 5 females aged 19 to 66 years) with massive pulmonary embolism (PE). Mean thrombolytic treatment duration was 77 hours. The main fibrinolytic agent used (9 cases) was streptokinase. Sequential treatment with streptokinase and urokinase was given to 2 patients and urokinase alone to one. 5 patients received porcine plasmin additionally, and one patient BRL 26921 (streptokinase-plasminogen complex) and human plasminogen. Pulmonary arterial pressures were recorded serially. Pulmonary angiograms were obtained before, occasionally during and after thrombolysis. Pulmonary arterial pressures (systolic: p less than 0.01, diastolic: p less than 0.05, mean: p less than 0.01, paired t-test, two tailed) and pulmonary angiograms (p less than 0.001, paired t-test, two tailed) all showed significant improvement. Thrombolytic treatment had to be discontinued in two patients due to side effects. Patients with the most recent PE showed the best response. Patients with recurrent PE and preexisting pulmonary hypertension showed no improvement. In PE without deep vein thrombosis (DVT), treatment duration of up to three days seems to be appropriate. In PE with concomitant DVT the treatment should be prolonged to achieve complete lysis of thrombi.

Unlabelled: The entire literature up to the present of 119 patients described as having adult Still's disease is reviewed. Clinical, laboratory, radiological and histological findings, treatment, follow-up and outcome are presented. 1., Clinical Findings: All patients had arthralgias and/or myalgias. Seven did not fulfill strict diagnostic criteria as they did not have overt arthritis. All had fever, and 93% had septic fever with temperature peaks of greater than or equal to 39 degrees C. The characteristic maculo-papular rash was present in 89%. Other findings were sore throat, lymphadenopathy, splenomegaly (in about 50% each), weight loss, pericarditis, hepatomegaly, pleuritis (in 1/4 to 1/3 of the cases each). Less frequent were alopecia, pneumonitis and abdominal pain (in less than 10% each). 2., Laboratory Findings: The ESR was uniformly elevated. Over 90% of the patients exhibited neutrophilic leukocytosis. Anemia, hypoalbuminemia and pathologic liver function tests were found in 60-80%. IgM-RF and ANA were both negative in 95% of the patients and hence were not more frequently present than in the normal population. 3. X-ray findings: There were no pathognomonic radiological abnormalities of the joints. Nevertheless, the tendency to ankylosis, especially of the carpus, seems to be typical. A few patients developed severe destructive lesions, especially of the hip and shoulder joints. 4. Biopsies: Many biopsies were performed and did not reveal specific histologic abnormalities. Nonetheless, they sometimes are necessary in order to exclude other disease entities. 5. Treatment, follow-up, prognosis: Therapeutically high-dosage ASA and (if necessary) systemic steroids are recommended for the acute phase. The efficacy of this treatment is controversial. Even after successful control of the acute disease, exacerbations are frequent for many years. Despite the initial optimism, there is significant long-term morbidity due to recurrent disease flare-ups on the one hand, and articular destructions in some patients on the other.

55 consecutive patients (28 males and 27 females) who had suffered from (recurrent) venous and/or arterial thromboembolism were evaluated for laboratory findings of thrombophilia. At the time of investigation, 15 patients were taking oral anticoagulants. In addition to patient and family history and clinical examination, a coagulation profile, euglobulin clot lysis time before and after venous occlusion, assays of plasminogen, antithrombin III, protein C (PC), free protein S (PS[f]), and C4b binding protein bound protein S (PS[b]) were obtained. 2 patients not orally anticoagulated had partial PD deficiency with functional PC activity values of 53% and 57% respectively, as compared to normal human plasma (NHP). Functionally active PS(f) was found to be lower than normal in 14 patients not taking oral anticoagulants and without signs of hepatopathy. In 4 of these 14 patients partial PS deficiency was present (PS[f] between 7 and 37% of NHP, and PS[b] between 51 and 86% of NHP). In one of these 4 subjects the hereditary nature of PS deficiency was proven by investigation of family members. In 3 of the 14 patients a shift from PS(f) (between 34 and 66%) towards PS(b) (124-141%) was found. The remaining 7 patients showed subnormal PS(f) values (56-64%) and normal PS(b) values (78-105%). In the patients receiving oral anticoagulant therapy, PC and PS levels were diminished. Statistically there was no close relationship between PC and PS levels on the one hand and prothrombin time values on the other. In anticoagulated patients, therefore, PC or PS deficiency can only be diagnosed by investigation of members of the propositus's family.(ABSTRACT TRUNCATED AT 250 WORDS)

If blood for monitoring of heparin therapy is collected through indwelling catheters it may be contaminated by exogenous heparin. A prospective study comparing thrombin times in plasma obtained by venipuncture and by collection through heparin perfused catheters showed that 26 out of 77 catheter samples were contaminated. In 16 of these 26 cases, overestimation of the heparin effect would have led to incorrect dosage recommendations. It is concluded that blood for laboratory monitoring of heparin treatment should be collected by venipuncture.

Case report of a 35-year-old female patient who was admitted in Addisonian crisis and in whom primary adrenal, ovarian and thyroid failure was detected. Antibodies against the adrenals and the thyroid were found, together with dinished serum IgA levels. The patient had been treated for 20 years with diphenylhydantoin, a drug known to induce immunological disturbances, e.g. depression of serum IgA levels. The IgA deficiency and pluriglandular failure may be due to prolonged therapy with diphenylhydantoin. The coincidence of IgA deficiency and autoimmune diseases is well known. As far as is known this is the first case of IgA deficiency associated with autoimmune polyendocrinopathy.

The treatment of primary hyperparathyroidism consists in a teamwork between the physician, pathologist and surgeon. The endocrinologist must be able to motivate the surgeon to perform an often tedious exploration of the neck, while the pathologist may influence the tactics of surgery by his analysis of the frozen sections. The surgeon needs much experience, a sound knowledge of anatomy, a good surgical technique and enough time and leisure for the operation.

From 1971-1982 121 patients with arterial occlusions of the lower limbs underwent systemic thrombolysis treatment at the Kantonsspital Basel. During 4 time-periods, 3 different treatment schedules were evaluated consecutively: a) individually titrated high dose streptokinase (SK), b) individually titrated low dose SK and c) p-plasmin, followed by low dose SK-infusion. Thrombolytic success rates did not differ significantly with the 3 treatment schedules. Nevertheless, the p-plasmin-SK scheme tended to the thrombolytically more effective (68%) than high-dose (58%) or low-dose (50%) SK. The most frequent side effects were bleeding complications. In 6 out of the 121 patients, intracranial bleeding occurred and was lethal in 1 of the patients. The incidence of this most serious complication of 4/47 during the sequential p-plasmin-SK schedule led the authors to abandon this scheme for the treatment of arterial occlusions. The intracranial bleeding complications are much less frequent in patients with deep venous thrombosis undergoing systemic thrombolysis, and hence seem to be due in part to the generalized arteriopathy often present in patients with arterial occlusions. The p-plasmin-SK schedule induced the strongest systemic proteolysis in the light of thromboplastin time and factor V values. Comparison of these data with those of other authors is very difficult because of differences in patient selection, treatment schedules and observance of contraindications. The serious prognosis for patients with acute arterial occlusions, with an overall hospital mortality of 26% (experience at the Kantonsspital Basel, 1978-1982) relativizes the importance of the side effects due to systemic thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Two patients with adult Still's disease are presented. Both had high "septic" fever, weight loss, mild pharyngitis, evanescent maculo-papular rash, myalgias, arthralgias, splenomegaly and pericarditis, while one of the two patients also had lymphadenopathy and pleurisy. Arthritis, which is a sine qua non for the diagnosis, developed only 5 months after disease onset in one patient. Both ultimately developed severe destructive joint disease requiring hip arthroplasty. Laboratory findings were neutrophilic leukocytosis, normochromic normocytic anemia, elevated ESR, slightly elevated liver enzyme values, negative IgM-rheumatoid factor and antinuclear antibodies, and normal or slightly elevated complement factors. Several biopsies failed to reveal pathognomonic findings. It is of the utmost importance that the exclusion diagnosis of adult Still's disease be posed in order to avoid repeated hospitalizations with undue investigations and unnecessary therapeutic trials with antibiotics.

1. The extent to which skeletal involvement in hyperparathyroidism can be detected by X-ray remains an unsolved issue. The present investigation, aimed at resolving this problem, was carried out in 44 patients with primary (PHPT) and 57 subjects with secondary hyperparathyroidism (SHPT) due to terminal renal insufficiency. For comparison, 49 age-matched controls were included in this series. Subperiostal resorption of the phalanges of the hand was considered pathognomonic and graded according to a semiquantitative system using a magnifying lens. The data were compared with the serum calcium and alkaline phosphatase values. 2. Pathological subperiostal resorption was detected in 38.5% of the PHPT and in 56% of the SHPT patients while the controls showed 4% (false) positive results. A highly significant correlation between the extent of bone resorption and alkaline phosphatase was found (PHPT: r=0.80, SHPT: r=0.71, p less than 0.001). No correlation of the X-ray findings to the serum calcium could be detected. Compared to the degree of skeletal involvement demonstrated by X-ray, the alkaline phosphatase was significantly lower in SHPT than in PHPT. In PHPT on the other hand, subperiostal resorption was prominent among female patients aged over 40 years, while no prevalence for sex and age was found in the SHPT group. 3. These results demonstrate that a clinically relevant degree of bone involvement in hyperparathyroidism may be easily and reliability assessed by evaluating X-rays of the hands by means of a magnifying lens. Increased bone resorption in hyperparathyroidism appears to be paralleled by an increase of osteoblastic activity as assessed by elevation of alkaline phosphatase. In SHPT due to chronic renal failure, however, a relative osteoblastic insufficiency seems to exist. In PHPT, the prevalence of subperiostal bone resorption in women aged over 40 years may be compatible with a skeletal protecting effect of intact ovarian function (estrogens).

Prothrombin times were measured in 120 orally anticoagulated patients and 122 patients not orally anticoagulated using two different commercial thromboplastin reagents, a rabbit brain thromboplastin (CRB-Thromboplastin, Roche) and a human placenta thromboplastin (Thromborel S, Behring). A good correlation (r = 0.93, slope = 1.089, intercept = 0.014) was found between the International Normalized Ratio (INR) values of the anticoagulated plasmas obtained with both thromboplastins. Defining five degrees of intensity of anticoagulation (between INR less than or equal to 2.0 to INR greater than or equal to 5.1) the intensity of treatment was judged concordantly with both thromboplastins in 67% of the patients and as differing by one degree in 32%. In only one out of 120 patients was a larger discrepancy of INR values found. - A good correlation (r = 0.93) was also found between the prothrombin times expressed as Quick percentage values as assessed with both thromboplastins in 122 patients not orally anticoagulated. In 82 cases a "normal" prothrombin time (Quick greater than or equal to 70%) and in 33 cases a "subnormal/diminished" percentage value (Quick less than 70%) was obtained with both thromboplastins. In only 7 out of 122 plasma samples was the Quick percentage normal with one and subnormal with the other reagent. - The good conformity of the INR values measured with two thromboplastins of differing species but similar sensitivity (International Sensitivity Index [ISI] = 1.14 for CRB-Thromboplastin, and = 1.10 for Thromborel S) supports the recommendation by the World Health Organization that the intensity of oral anticoagulation be expressed in terms of INR. Whether INRs obtained with thromboplastins of largely differing ISIs show sufficient conformity will need to be assessed by further prospective studies.

Studies on one-year function conducted by the European Multicenter Trial showed that, after renal allograft transplantation, bleeding complications were only found in patients treated with cyclosporin as compared with those treated with azathioprin/steroids. To investigate a possible relationship between the bleeding tendency and the cyclosporin treatment, 18 parameters of hemostasis were studied in 11 patients, 6 of whom received cyclosporin A and the other 5 conventional treatment with azathioprin/steroids. Bleeding tendency could not be related to any specific coagulation parameter. Of interest is that clot retraction was significantly lower in the cyclosporin group (88 +/- 9% vs. 125 +/- 10%). Considering the fact that the skin bleeding time according to Ivy was normal in all patients, the clinical significance of the lower levels of the clot retraction appears to be minor. Discriminant analysis showed that these significantly lower clot retraction values could not be related to the lower platelet count levels in platelet rich plasma (205 000 +/- 85 000/mm3 vs. 280 000 +/- 67 000/mm3) but were associated with cyclosporin A treatment. All factor-VIII related activities were elevated in both groups. The main difference between the cyclosporin group and the conventionally treated group was significantly elevated levels of factor VIII procoagulant antigen (VIII: CAg) (cyclosporin A treated group: VIII: CAg 435 +/- 145%, conventionally treated group: VIII: CAg 215 +/- 99%). These results suggest hypercoagulability rather than bleeding tendency under cyclosporin treatment.

Bleeding time measurement and investigation of platelet aggregation in platelet rich plasma (PRP) are routine procedures for the diagnosis of defects in primary hemostasis. These tests are subject to methodological difficulties and should be well standardized in each individual laboratory. - In the present study, bleeding time was measured using the Simplate II device in 40 normal subjects. Furthermore, platelet aggregation in PRP induced by ADP, collagen, arachidonate, and ristocetin was examined. 26 patients referred for investigation of a suspected mild bleeding disorder, who had a normal plasmatic coagulation profile, a normal von Willebrand factor activity, and a normal platelet count, were similarly studied. - Based on the reference values established in the 40 normal subjects, platelet aggregation was found to be pathologic in 7 patients and normal in 12. In 7 patients platelet aggregation was considered to be borderline-pathologic as defined by the range of platelet aggregability found in the 10% of our normal subjects showing the weakest aggregation responses. Bleeding time was prolonged in only 3 patients whereas it was normal in the remaining 23. There was strong evidence of a hemostatic defect as assessed by systematic patient history in 6 out of 7 patients with pathologic platelet aggregation, but in only 3 out of 19 showing normal or borderline-pathologic aggregation. - Pathologic platelet aggregation, therefore, represents not only an abnormal laboratory finding but is likely to be associated with a hemorrhagic diathesis. Platelet aggregation studies do not permit etiologic diagnosis of the thrombocytopathy except for the well-defined membrane glycoprotein deficiencies. The bleeding time appeared to be of low sensitivity for the diagnosis of mild platelet dysfunction.

Since monitoring of oral anticoagulation (OA) by prothrombin time (PT) is a source of standardization difficulties, the authors have tested another approach. 107 patients under long term OA were monitored by both PT and a colorimetric factor X assay (in vitro activation of factor X with RVV and assessment of amidolytic activity towards S-2222). The PT values were between 10 and 34% (therapeutic range 15--25%), and factor X levels were between 10 and 44% (therapeutic range 16--24%). The correlation between the two methods was highly significant (r = 0.65, p less than 0.001). In 68% of the patients the two tests gave the same information (55 subjects were adequately, 16 insufficiently and 2 over-anticoagulated). For a slightly broader therapeutic range (PT 15--30%, corresponding to 16--28% factor X) concordant information was obtained in 82% of the patients. During stable OA, PT and factor X assay gave very similar information. An advantage of the latter method is the possibility of automation, while a disadvantage is its insensitivity to factor VII.