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In a retrospective study of 166 patients, all admitted to the University Hospital, Leiden, The Netherlands, between January 1, 1970 and December 31, 1979, we estimated the relative risk of intracerebral hemorrhage from oral anticoagulant therapy. The risk was more than ten times higher for patients over 50 years of age than for similarly aged untreated individuals in the general population. Within this age group the risk was influenced by neither age nor sex. Hypertension, present in 80% of the patients, was the most important predisposing condition; the risk of bleeding rose with increasing intensity of anticoagulation. There was no substantial difference in clinical condition at onset, rate of progression, mortality, or degree of recovery between patients with anticoagulant-associated hemorrhage and those with spontaneous intracranial hemorrhage.

A prospective double-blind trial was performed to investigate the safety of long-term oral anticoagulant control when dosaged adjustment depends on the prothrombin times assessed with one type of thromboplastin being calculated as if assayed by another type. The three main types of thromboplastin, i.e., bovine (Thrombotest), human (British Comparative Thromboplastin), and rabbit (Simplastin Automated) were tested. Before entering the actual trial, patients had been checked with the bovine type of thromboplastin. During the actual comparison study, prothrombin times obtained with the human and the rabbit types of thromboplastin were translated, using the appropriate calibration data, into terms of the bovine type of thromboplastin, which were used for dosage prescription. After six months, all patients returned to bovine-type thromboplastin control. No substantial difference among the three groups was observed in the prothrombin times, the dosage of the anticoagulant, the bleeding complications, and the dropouts. It was concluded that the safety of monitoring patients receiving long-term oral anticoagulation was independent of the type of thromboplastin used.

In thromboplastin calibration, the possibility of replacing fresh individual plasmas by pooled fresh plasmas (used immediately after preparation or after storage at -25 degrees C) or by pooled lyophilized plasmas has been investigated. It was found that the thromboplastin sensitivity ratios (TSR's) assessed with pooled fresh plasmas show no divergence from those obtained with the original Biggs/Denson calibration procedure. With pooled lyophilized plasmas a small divergence can be found in particular with so-called PIVKA-insensitive rabbit-tissue thromboplastins. Since, in contrast to the original procedure, only a limited number of determinations with pooled fresh or lyophilized plasmas are needed to obtain an accurate TSR value, the modification substantially simplifies thromboplastin calibration. Moreover, the technique using lyophilized plasmas can be applied in laboratories where an insufficient number of patients are available or none at all. However, as long as pooled lyophilized plasmas display a more or less pronounced activation, it might be preferable to restrict calibration to qualified expert laboratories, i.e. national reference laboratories. The merits of pooled lyophilized plasma are those of good stability even under the condition of accelerated degradation. They might be just as useful as thromboplastins for use as (long-term) reference material in the standardization and quality control program of manufacturers of thromboplastins, and for laboratorians preparing their own thromboplastin for the anticoagulant control. Conditions for the preparation and use of lyophilized reference plasmas have been worked out and are presented.

For patients on oral anticoagulation controlled with Quick's prothrombin time test using rabbit brain thromboplastin American clinicians proposed in the early 1940s that the lower limit of prolongation be taken at 1.5 and the upper limit at 3, corresponding to 10-30% prothrombin activity on a saline dilution curve. Thromboplastins derived from other tissues and species were later introduced, methods were modified, and adsorbed plasma was used instead of saline in the construction of the dilution curve to obtain percentage prothrombin activity; ratios and percentages lost their initial significance, but too often without the clinicians' awareness. With the detection of PIVKAs, finally, it became clear that transformation of prothrombin times into percentage activity, as obtained from dilution curves, could never be a valid means of standardization. It also became evident that only direct comparison of thromboplastins with (fresh) plasma from patients on stabilized oral anticoagulants could be used to determine equivalent therapeutic ranges for different types of thromboplastins. Reference thromboplastins were established and calibration procedures developed. A series of well-controlled clinical trials has provided sufficient information to define, in terms of these reference thromboplastins, therapeutic ranges for the prophylaxis and treatment of venous as well as arterial thrombosis. Definition of the ranges in terms of the biochemical defect induced by coumarin congeners remains, however, to be established.

In Western countries, hepatic vein thrombosis (Budd-Chiari syndrome) is, as a rule, an uncommon though well-known complication of acquired or hereditary thrombophilia. It may be complicated by overt defibrination when secondary to deep venous thrombosis ascending to the vena cava. To be effective treatment should consist of early initial intensive thrombolysis for up to one week, followed without interruption by an APTT-controlled heparin infusion. Oral anticoagulant therapy is started together with the heparin, which should not be discontinued until the prothrombin times, expressed as international normalized ratios (INR), lie within a therapeutic range of 3-5 INR for 2 days, the target being 4 INR. After this intensity of anticoagulation has been maintained for three weeks, the range may be lowered to 2.5-4 INR, the target being 3 INR. Oral anticoagulation should be continued for as long as thrombophilia persists.

Because of its fibrinolytic action, streptokinase is believed to reduce the severity of the postthrombotic syndrome in patients with deep vein thrombosis. A prospective and a retrospective study have been undertaken in an attempt to determine when this therapy is useful for patients with deep vein thrombosis. The prospective study included 15 patients with deep vein thrombosis: 5 were treated in the hospital with streptokinase and heparin and 5 only with heparin, 5 were treated at home with only phenprocoumon. All the patients received oral anticoagulant therapy for at least 6 months. Three to four months after the acute episode, phlebography and venous pressure measurements were carried out. Streptokinase appeared to give the best results but with more side-effects. In the retrospective study, 51 patients who had had deep vein thrombosis in 1969 were reexamined 31-47 months later. It was found that more than 50% of the patients with a thrombosis in the femoral and/or iliac vein developed a severe postthrombotic syndrome, in contrast to only 9% of those with a thrombosis in the popliteal vein or lower. It is recommended, on the basis of both the prospective and the retrospective study, that patients with a thrombosis in the femoral and/or iliac vein should be treated with either heparin or streptokinase during the early stage. It is probable that streptokinase will significantly decrease the frequency and severity of the postthrombotic syndrome in these patients in particular, although this has not yet been proven.

A number of commercial rabbit tissue thromboplastins used in oral anticoagulant control have been calibrated against the first International Reference Preparation for thromboplastins. This was done in a three-stage procedure by one laboratory, each stage representing a different level of thromboplastin comparability. The calibration model recently recommended by ICTH and ICSH was tested. This model proved to be suitable, although a statistically significant aberration was observed for some of the thromboplastins. The bias introduced by using the model in these non-ideal cases was small compared to the overall variation of the International Normalized Ratio, being the universal scale for reporting the prothrombin time during oral anticoagulant control. Batch-to-batch calibration using lyophilized pooled plasmas could be reliably performed for several commercial thromboplastins.

Appropriate long-term oral anticoagulation prevents cardiogenic thromboembolism to a large extent in patients with artificial heart valves, rheumatic heart disease, myocardiopathy, atrial fibrillation of non-rheumatic origin, sick sinus syndrome, cardiac aneurysm, and in the exceptional cases of mitral valve prolapse with thromboembolic complications. In arterial thrombosis, oral anticoagulation remains a controverted, probably because a much higher intensity would be needed to achieve the same degree of effectiveness. With target prothrombin times between 3.5 and 4 International Normalized Ratios (INRs) and a compliance of the INRs with the range of 2.5-5 INRs for greater than or equal to 80%, cardiogenic thromboemboli can be prevented in approximately 95% whereas only about two thirds of the cases of recurrent coronary thrombosis can be avoided. The intensity and stability of treatment needed in cardiovascular thrombosis involve a considerable risk of bleeding, but--as shown by the results of the Dutch Sixty Plus Reinfarction Study--intracranial haemorrhages are more than compensated for by the prevention of cerebrovascular thromboembolic events. Appropriate administration of oral anticoagulation requires painstaking laboratory and therapeutic control, the former being based on continuous quality assessment and strict standardization of the prothrombin time. Therapeutic control consists of continuous patient education and adequate dosage regulation. Similar to the situation prevailing for hemophilia patients, an organization must be available to which long-term anticoagulated patients can apply for expert advice. In The Netherlands, an organization has been built up on a voluntary basis, called Federation of Thrombosis Centres, meeting this requirement and covering more than 90% of the country.

Two spectrophotometric assays for prothrombin have been developed and compared with a one stage coagulant and an immunological assay. One of these assays (called the XAPC assay) uses a combination of factor Xa, phospholipid, Ca2+ and factor V as activator of prothrombin, and measures only normal prothrombin. The second (the ECAR assay) uses Echis carinatus venom as activator. This assay measures both normal prothrombin and PIVKA II (protein induced by vitamin K antagonists/absence). Combination of the results obtained by the XAPC and ECAR assays provides rapid and reliable information on the degree of "subcarboxylation" of prothrombin (oral anticoagulation, vitamin K deficiency). For patients on long term anticoagulant treatment the prothrombin time (Thrombotest) shows better correlation with the ratio prothrombin/prothrombin plus PIVKA II (XAPC/ECAR) than with the factor II concentration. For patients starting the anticoagulant treatment there is no correlation between the Thrombotest time and the XAPC/ECAR ratio. It seems doubtful that (a) spectrophotometric factor II assay(s) will be as useful as the prothrombin time in the control of oral anticoagulation.