Prednimustine and mitoxantrone (PmM) in patients with low-grade malignant non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and prolymphocytic leukemia (PLL)

Summary Patients with intracoronary stent implantation are treated with aggressive anticoagulant and antiplatelet therapy consisting of high-dose heparin, phenprocoumon, acetylsalicylic acid, dipyridamole, and the infusion of dextran to prevent a subacute thrombotic occlusion of the stented segment. In an effort to optimize this treatment by reducing both imminent bleeding complications and subacute thrombotic occlusion, the concentrations of prothrombin fragment 1+2 (F1+2) were determined after intracoronary Palmaz-Schatz stent implantation in 19 consecutive patients. The F1+2 concentrations after stent implantation and before the initiation of oral anticoagulant therapy (OAT) were 0.35 nm/l and 0.25–0.53 nm/l (median and 25th–75th percentile), versus 0.74 nm/l and 0.52–0.78 nm/l, in healthy subjects and 0.61 nm/l and 0.30–1.02 nm/l in 15 patients with ongoing proximal DVT. Nine days after initiation of OAT, F1+2 concentrations in both patient groups had not yet reached levels observed in patients with OAT in the stable state (0.16 nm/l, 0.12–0.26 nm/l;n=76;P<0.0001 compared with healthy subjects; INR 2.0–4.5). Despite an INR greater than 2.0, accompanying heparinization was terminated on day 9. In two stented patients a minor bleeding complication arose after the removal of the arterial catheter. Subacute thrombotic occlusions were not observed. Since F1+2 concentrations did not exceed the upper limit of normal range (1.11 nm/l) in any of the 19 patients, the therapeutic regimen was not changed. Monitoring F1+2 may thus be helpful in introducing a more individual treatment if aggressive anticoagulation has to be performed.     

Direct oral anticoagulants for atrial fibrillation in patients with congenital factor VII deficiency

The management of anticoagulant therapy (OAT) in patients with factor VII (FVII) deficiency is a very challenging clinical issue, as warfarin further reduces FVII levels, thus potentially increasing bleeding risk. On the other hand, the International Normalized Ratio test is misleading in such patients, as they do not reflect the actual level of global inhibition of the coagulation system. We report here three cases of patients with a moderate FVII deficiency and receiving direct oral anticoagulants (DOAC) for prevention of cardioembolism in atrial fibrillation. Of note, two of them experienced a treatment failure while on warfarin, while DOAC treatment was not associated with thrombotic or hemorrhagic adverse events. DOAC are very attractive for the management of OAT in FVII deficient patients, because they do not require monitoring by tests affected by the inherited defect, and their mechanism of action is FVII‐independent.     

Pregnancy and oral contraceptives in congenital bleeding disorders of the vitamin K-dependent coagulation factors

Pregnancies and deliveries represent important hemostatic challenges for congenital coagulation disorders. The same is true for the assumption of oral contraceptives. Available information mainly deals with von Willebrand's disease, factor XI (FXI) deficiency and carriers of hemophilia A. Data concerning patients with congenital prothrombin complex factor deficiencies are very scanty. In the present study, data of a total of 27 women are presented, 11 patients with homozygous or double heterozygous deficiencies of FII, FVII and FX, together with 16 cases of hemophilia B carriers. The patients with FII, FVII or FX defects had a total of 14 pregnancies and often needed transfusion therapy. Proper management resulted in a decrease in postpartum bleeding and satisfactory fetal outcome. Elective cesarean delivery seems indicated only in recent years. Carriers of hemophilia B had a total of 19 pregnancies but showed no bleeding and needed no substitutive therapy. Searching the literature, we discovered only 9 additional patients with prothrombin deficiency or FX deficiency, having a total of 16 pregnancies. On the contrary, there were at least 17 additional patients with FVII deficiency, with a total of 21 pregnancies. The management of the diseases has been variable, but in substantial agreement with the personal observations. Oral contraceptive therapy was administered in some of our patients and in a few additional cases described in the literature. Medication was always well tolerated and patients who took it for a long period of time showed a decrease in menometrorrhagia and an improvement in hematocrit levels. This led to a decrease in transfusional needs and to improved general conditions.     

Exaggerated initial response to warfarin following heart valve replacement.

The response to initiation of oral anticoagulants at a usual dose of 5 mg of warfarin has been retrospectively evaluated in patients following heart valve replacement (HVR). Patients starting oral anticoagulants after HVR have a lower target International Normalized Ratio (INR) (1.5 to 2.6) until the pacing wires are removed after operation. The mean daily doses and INR responses after HVR and nonsurgical patients were retrospectively compared during the first 5 days of warfarin treatment. In a subset from both groups, the mean dose of warfarin was correlated with age, body weight, and albumin levels. Eighty-four HVR and 32 nonsurgical patients were studied. The mean daily warfarin dosage was 3.29 +/- 1.29 mg after HVR and 4.96 +/- 1.76 mg in controls (p <0.001), and the mean INRs 2.08 +/- 0.60 and 1.60 +/- 0.54, respectively (p <0.001). Of the HVR patients and controls, 48.8% and 21.8%, respectively, exceeded the upper level of the targeted range (p = 0.014), 86.9% and 40.6% had the dose reduced after the first 5 mg (p <0.001), and 54.7% and 28.1%, respectively, had warfarin withheld for at least 1 day (p = 0.015). Thirty-nine patients were included in the subset analysis. Patients with serum albumin levels <35 g/L required significantly less warfarin (3.84 mg/day) than patients with levels > or =35 g/L (5.37 mg/day; p <0.05). Thus, patients starting oral anticoagulation after HVR are significantly more sensitive to warfarin than nonsurgical patients. Patients with serum albumin levels below the normal values require less warfarin than patients with normal values during the initial phase of treatment.     

Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients

Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease.     

Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency.

BACKGROUND AND OBJECTIVES: Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleedings occurring in hemophiliacs with inhibitors. Very few reports exist on the use of rFVIIa in patients with inherited FVII deficiency. Pharmacokinetic studies on rFVIIa have been performed exclusively in hemophiliacs, patients with cirrhosis or volunteers pretreated with acenocoumarol. The aim of this study was to evaluate the kinetics of rFVIIa in patients naturally deficient of FVII. DESIGN AND METHODS: A single dose kinetic study with rFVIIa was performed in 5 patients affected by severe congenital deficiency of factor VII in order to evaluate the true kinetic parameters of rFVIIa without the interference of FVII. Two dosages, 15 and 30 microg/kg, were used in a crossover schedule. FVII:C and FVIIa concentration/time curves were analyzed by a model-independent method. Antithrombin (AT), prothombin fragment 1+2 (F1+2) and tissue factor pathway inhibitor (TFPI) were assayed. RESULTS: No differences emerged between the dosages with respect to dose-independent parameters [total body clearance (CL), volume of distribution area (VdArea), mean residence time (MRT)]. No significant changes of AT, TFPI, and F1+2 were observed. Comparing the results with those of other studies performed in adult hemophiliacs, in patients affected by cirrhosis or in volunteers on oral anticoagulant therapy (OAT), CL and VdArea of rFVIIa were definitely higher and in vivo recovery was lower. INTERPRETATION AND CONCLUSIONS: These findings suggest that the kinetics of rFVIIa are not dose-dependent. In the absence of FVII, the changes of VdArea and CL may be in agreement with a mechanism of competition between FVII and rFVIIa for tissue factor binding.     

Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels.

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.     

Evaluation of the blood coagulation mechanism and platelet aggregation in individuals with mechanical or biological heart prostheses.

Oral anticoagulants have been widely employed to decrease thrombotic risk by reducing the levels of vitamin K-dependent clotting factors. Paradoxically, the use of oral anticoagulants also decreases the levels of natural anticoagulants (protein C and protein S), which favors the hypercoagulability state. Increased platelet activation has been reported in patients undergoing warfarin treatment. These findings have raised questions about the antagonistic effect of oral anticoagulants and their implications for hemostatic balance. The aim of this study is to determine the relationship between warfarin dosage and prothrombin time [International Normalized Ratio (INR)], platelet aggregation, vitamin K-dependent clotting factors, and protein C and protein S. Blood samples from 27 patients were analyzed, seven with mechanical prostheses and 20 with biological prostheses, and 27 controls. Multiple regression analysis showed that factor II most significantly determines the INR. Results showed that the INR, clotting factors, and protein C and protein S activity did not correlate with warfarin dosage, highlighting the need for accurate laboratory monitoring of those undergoing anticoagulant therapy.     

Anti-Xa and anti-IIa drugs alter international normalized ratio measurements: potential problems in the monitoring of oral anticoagulants.

Several of the newly developed anti-Xa and anti-IIa agents have been shown to influence the International Normalized Ratio (INR) values. During phase I trials with normal healthy volunteers and phase II study patients who were given warfarin and concomitant anti-IIa or anti-Xa agents, it has been reported that INR values were falsely elevated. It is of critical importance to know of the effects of these agents on INR to avoid dosage errors. To study the influence of these agents on INR, we used several anti-IIa agents (argatroban, recombinant hirudin, efegatran, and PEG-hirudin) and anti-Xa drugs (pentasaccharides such as fondaparinux and idraparinux, DX-9065a and JTV-803). The anti-IIa drugs were supplemented in citrated plasma at a concentration of 0 to 1 microg/mL level and anti-Xa drugs in the range of 0 to 25 microg/mL. The IC(50) values for each of these agents were calculated. Four different commercially available prothrombin time (PT) reagents were used to perform the PT assays and to calculate the relative INR values. Direct synthetic factor IIa and Xa inhibitors exhibited a concentration-dependent increase in the INR values. Hirudin, efegatran, and PEG-hirudin showed a weaker effect, whereas argatroban showed a much higher elevation of the INR values. Synthetic indirect anti-Xa agents such as the pentasaccharide did not show any effect on the INR values. Furthermore, prothrombin time reagents with high ISI values exhibited disproportionally higher INR values for both the direct anti-Xa and anti-IIa agents. Elevation of INR values has therapeutic implications when non-oral anticoagulant drugs are used in combination with drugs such as warfarin. Because of the false elevation of INR values with some of the non-oral anticoagulant drugs, patients who are on concomitant warfarin therapy should be carefully evaluated for their corresponding INR values for proper dosing. To avoid dosing errors it is best not to use the INR values in the therapeutic monitoring of anti-Xa and anti-IIa agents either in the monotherapeutic or polytherapeutic modalities. These data also warrant the development clinically relevant methods for the monitoring of the concomitant use of newly developed anti-Xa and anti-IIa drugs with oral anticoagulants.     

Haemostatic Activity in Patients with Atrial Fibrillation Treated with Low-Molecular-Weight Heparin Before and After Electrical Cardioversion

BACKGROUND: Electrical cardioversion of atrial fibrillation (AF) is associated with a thromboembolic risk, and this risk can be reduced by the use of antithrombotic therapy. International guidelines recommend an effective oral anticoagulant therapy (OAT) for at least 3 weeks before, and 4 weeks after cardioversion. We studied whether electrical cardioversion in it self causes changes in the level of activity in the haemostatic system during treatment with either low-molecular-weight heparin (LMWH). METHODS: Thirty-eight patients with AF were randomised consecutively to either LMWH administered subcutaneous in a fixed daily dose, or conventional OAT. Changes in the biochemical markers prothrombin fragment 1+2 (F1+2), D-Dimer, and soluble fibrin, all reflecting the activity in the haemostatic system, were assessed at baseline, before and after electrical cardioversion in patients treated with LMWH for 3 weeks prior to cardioversion. A follow up compared the time spent on anticoagulation prior to cardioversion, and eventual complications in the two group (LMWH vs. OAT). RESULTS AND CONCLUSIONS: No significant differences between the levels of the biochemical markers measured before, and after cardioversion were seen, indicating that during anticoagulant therapy with LMWH, electrical cardioversion in itself, does not cause an increased activity in the haemostatic system. Also the level of F1+2 had declined significantly after cardioversion, when compared to baseline level in patients, whom had a normal sinus rhythm (NSR) re-established. This indicates that even in patients on a stable anticoagulant treatment, restoration of a NSR can cause a further decrease in thrombin generation.The median time spent on antithrombotic treatment prior to cardioversion, was significantly different between the LMWH (27 days) and the OAT group (138 days). Our study indicates that cardioversion in patients on LMWH does not cause a hypercoagulable state and that LMWH significantly shortens the time spent on anticoagulant therapy prior to cardioversion.     

New developments in the treatment of deep venous thrombosis

An initial course of standard heparin (SH) or low-molecular-weight heparins (LMWH) is regarded as the treatment of choice for patients with deep venous thrombosis (DVT). LMWH have better bioavailability after subcutaneous administration, have a longer half-life, and show higher and more predictable anticoagulant activity. As a result they can be given subcutaneously and without laboratory control, using a dose that is determined by bodyweight. Because of these multiple advantages of LMWH they will replace SH in the future and subsequently home treatment with LMWH of selected patients seems feasible. The currently accepted approach is to start with SH or LMWH therapy combined with oral anticoagulant therapy (OAT) at the time of diagnosis. The course of SH or LMWH should continue for at least 5 days, provided that international normalized ratio (INR) is in the therapeutic range on 2 consecutive days. OAT should be continued for at least 3 months to prolong the prothrombin time to an INR of 2–3. When oral anticoagulants are either contraindicated or inconvenient, SH or LMWH can be used at the middosing interval. The role of anti-platelet treatment is not yet established and should be compared with coumarin therapy in the future.     

Management of oral anticoagulant treatment in patients with venous thromboembolism

Oral anticoagulants (OAs) are the drugs of choice for the prevention of recurrence and death in patients with venous thromboembolism (VTE). Oral anticoagulant treatment (OAT) aims to retard blood coagulation to obtain maximum protection against thromboembolic events with the lowest risk of bleeding. The intensity of OAT is ascertained by measuring the prothrombin time (PT), which is expressed as the international normalized ratio (INR). The efficacy and safety of these drugs depends on the ability to maintain the level of anticoagulation as close as possible to the therapeutic target (INR = 2.5) or inside the therapeutic range (INR = 2.0 to 3.0). Given that dosage of oral anticoagulants varies from patient to patient and within the single patient, clinical and laboratory (biological effect of the drug) check-ups must be performed periodically. The management of patients with VTE, as well as that of other patients receiving OAT, includes medical controls and expertise that are better available in specialized centers (anticoagulation clinics).     

Biological monitoring of treatment with antivitamin K. Value of INR and definition of new therapeutic ranges. A study of 73 patients

The prothrombin time test (PT) is the most common method used for monitoring oral anticoagulant therapy. As a consequence of the variability in responsiveness of different thromboplastins, PT results obtained from patients on oral anticoagulant therapy may not be interchangeable between laboratories and as consequence could produce potential problems for anticoagulant control. The conversion of PT in INR (International Normalized Ratio) has been introduced recently to standardise the PT used for anticoagulant control. 127 determinations of prothrombin time and INR with 2 different thromboplastin reagents (Thromboplastin C Dade and Owren reagent) have been performed in 73 patients. This study confirm the usefulness of the INR (INR discrepancy in 10% of the cases) despite the imperfections concerning the choice of the control plasma and the need of a precise measurement of the ISI, International Sensitivity index. In parallel, changes in therapeutic ranges for anticoagulant therapy occurred, based on results of the international literature: less intense anticoagulant treatment (INR 2-3) is effective against recurrent venous thromboembolism with reduced bleeding. Different therapeutic ranges must be recommended for oral anticoagulant therapy according to the indication of the treatment.     

Prolonged prothrombin time, Factor VII and activated FVII levels in chronic liver disease are partly dependent on Factor VII gene polymorphisms

BACKGROUND: Prothrombin time is a benchmark for functional assessment in cirrhosis and Factor VII levels (FVII), crucial in determining the prothrombin time, are genetically determined. METHODS: We have evaluated the prothrombin time, a number of haemostatic variables synthesised by the liver (FII, FV, FVII and activated FVII, AT and fibrinogen) and two polymorphisms of the FVII gene (5'F7 and 353R/Q) in: (a) patients with liver cirrhosis (n=118), (b) patients with chronic hepatitis (n=102) and (c) controls (n=100). RESULTS: By one-way analyses of variance, the prothrombin time and the mean levels of the FII, FV, FVIIc, FVIIa, and AT were statistically different between cirrhotics, chronic hepatitis patients and controls. The allele frequency of the FVII polymorphisms did not differ between the three groups. Those rare patients (4.6%) who were homozygous for the type 2 alleles had markedly reduced FVIIc and FVIIa levels. The analysis carried out taking into account Child class versus FVII genotype showed that the mean FVIIc levels were comparable for different genotypes within each Child's class, with the exception of the patients homozygous for the type 1 allele. CONCLUSION: Our findings help to explain the not infrequent finding of a severely prolonged prothrombin time in patients who are otherwise in a good functional class.     

Withdrawal of warfarin after deep vein thrombosis: effects of a low fixed dose on rebound thrombin generation.

The optimal procedure for withdrawal of warfarin in patients with deep vein thrombosis (DVT) is still not defined. Rebound thrombin generation, which occurs after the withdrawal of warfarin, has been said to be associated with early recurrence of DVT. The aim of this study was to compare two procedures for warfarin withdrawal after the first episode of DVT with respect to rebound thrombin generation. Forty-one consecutive patients were randomly assigned to abrupt withdrawal of warfarin (group A), or to an additional month of warfarin, at the fixed dose of 1.25 mg/day (group B). Plasma samples were withdrawn for the assay of prothrombin fragment F1+2 (F1+2), protein C, factor VII and International Normalized Ratio (INR), before any anticoagulant treatment (I), during initial heparin (II) and full dose warfarin (III), at the end of full dose warfarin (IV) and then 1 (V), 4 (VI), 5 (VII) and 9 (VIII) weeks after randomization. The mean duration of full-dose warfarin treatment, the mean warfarin dose and the mean INR during full-dose warfarin treatment were similar in the two groups. A decrease in F1+2 was observed during heparin and warfarin treatment (II, 1.7 nmol/ml; III, 1.0 nmol/ml; IV, 0.7 nmol/ml; versus I, 3.5 nmol/ml; P<0.01). After the withdrawal of warfarin, an increase in F1+2 was observed in both groups, but without significant statistical differences (group A: V, 1.2 nmol/ml; VI, 1.5 nmol/ml; VII, 1.6 nmol/ml; VIII, 1.1 nmol/ml; group B: V, 1.3 nmol/ml; IV, 1.5 nmol/ml; VII, 1.4 nmol/ml; VIII, 1.4 nmol/ml). No significant difference between the two groups was observed in the recovery of protein C and factor VII. Four patients experienced a recurrence of DVT, three in group B and one in group A. Our findings confirm that rebound thrombin generation occurs in patients with DVT after the withdrawal of warfarin. Rebound thrombin generation is not reduced by a low, fixed dose of warfarin.     

Evaluation of protein C and protein S levels during oral anticoagulant therapy

A number of workers have examined protein C in relation to other vitamin K dependent factors during warfarin therapy and successfully identified protein C deficient patients by ratio calculation. However, protein S deficiency has not been addressed in this manner. This study compares protein C and protein S by functional and antigenic determination with procoagulant factors of similar half life (Factors VII and II) in an attempt to identify protein C and protein S deficient patients whilst on oral anticoagulant therapy. Procoagulant and anticoagulant factors were compared by linear regression in a population of normal blood donors and patients on stabilized warfarin therapy to obtain expected values for protein C and protein S dependent upon FVII and FII levels, respectively. Observed over expected values for protein C and protein S were calculated for individual patients and normal ranges derived. Comparison of similarly calculated observed over expected protein C and protein S ratios with these normal ranges successfully identified known protein C and protein S deficient patients who were taking warfarin at time of testing.     

Clotting activation after oral anticoagulant therapy discontinuation: a risk factor for recurrent venous thromboembolism.

A hypercoagulable state has been reported in some patients treated for venous thromboembolism (VTE) after oral anticoagulant treatment (OAT) discontinuation. It is unclear whether this is a risk factor for thrombosis recurrence. We investigated 139 patients with VTE and followed them up for a median of 20.5 months (6-90 months) to evaluate whether fragment 1 + 2 (F1 + 2) plasma levels are prognostic for VTE recurrence and to confirm clotting activation after OAT withdrawal. Fourteen patients had recurrences during the follow-up. F1 + 2 was measured the day before OAT withdrawal (T0) and 4 weeks later (T1) and its levels were similar in patients with spontaneous VTE versus those with transient risk factors for VTE. F1 + 2 levels increased from T0 to T1 (P < 0.0005). At T1, F1 + 2 values were significantly higher in patients with recurrence than in those without (P < 0.005). The negative predictive value of normal levels of F1 + 2 at T1 was 95%. In carriers of thrombophilic conditions no correlation was found between F1 + 2 levels and VTE recurrence. The results of this study confirm clotting activation after OAT discontinuation and suggest that higher F1 + 2 plasma levels are an independent risk factor for VTE recurrence.     

Determination of markers of coagulation activation and reactive fibrinolysis in patients with mechanical heart valve prosthesis at different intensities of oral anticoagulation.

In a group of 60 patients with mechanical heart valve prosthesis prothrombin fragment 1 + 2, thrombin-antithrombin III complexes and D-dimer have been determined in order to assess the residual coagulation activation and the extent of the reactive fibrinolysis. The patients were divided into three subgroups of 20 patients each with different intensities of oral anticoagulation as indicated by International Normalized Ratio (INR) values in the ranges 4.8-3.6, 3.5-2.5 and 2.4-2.1. From the two markers of coagulation activation studied (prothrombin fragment 1 + 2 and thrombin-antithrombin III (TAT)) the prothrombin fragment 1 + 2 was dependent on the INR level in all groups, although the median values were still significantly beneath the lower limit of the reference range. The D-dimer concentrations were unexpectedly high with respect to the low coagulation activation levels, as indicated by the D-dimer/TAT and D-dimer/F 1 + 2 ratios. This demonstrates the enhanced presence of fibrin degradation products as a scarcely described side-effect of oral anticoagulation. The anticoagulant properties of fibrin degradation products might contribute partly to the in vivo haemorrhagic risk in high-intensity oral anticoagulation. These results show, inasmuch as the prothrombin fragment 1 + 2 is concerned, that from the laboratory point of view the residual thrombin activity is low enough to be adequate under the therapeutical regimen followed in this study. However, the question of the efficacy of anticoagulation intensities can only be finally answered by clinical trials.     

Congenital hypersensitivity to vitamin K antagonists due to FIX propeptide mutation at locus -10: a (not so) rare cause of bleeding under oral anticoagulant therapy in Switzerland

QUESTION UNDER STUDY: In most countries hypersensitivity to vitamin K antagonists (VKA) is considered to be a rare congenital bleeding diathesis. It occurs in patients with FIX propeptide mutations at locus -10. We present a Swiss family with two patients who suffered major bleedings under oral anticoagulant treatment in the presence of therapeutic or subtherapeutic INR levels and abnormally prolonged aPTT. In both patients a mutation in the propeptide of FIX at locus -10 with substitution of alanine by threonine (Ala-10Thr) was found. In one patient FIX clotting activity was found to be severely reduced (2%). The observed bleeding tendency is related to this--compared to the other vitamin K dependent factors (FII, FVII, FX)--excessively and disproportionately low level of FIX. Three generations of this family were tested for propeptide mutations, which are transmitted in an X-chromosomal recessive mode of inheritance. Apart from the two symptomatic male patients we found another male with the mutation who has not been exposed to VKA, six female carriers and four potential male carriers in the fourth generation who have not been tested. A founder effect for this mutation has been previously described for cases in Switzerland and Germany. CONCLUSION: FIX propeptide mutation-associated hypersensitivity to VKA is a rare occurrence in Switzerland. The severity of associated bleeding complications and the reversible nature of the bleeding diathesis may nonetheless warrant increased awareness on the part of primary care physicians in Switzerland.     

Effects of high-dose methylprednisolone therapy on coagulation factors in patients with acute immune thrombocytopenic purpura.

Autoimmune thrombocytopenic purpura (ITP) is a disease that presents with skin and mucous membrane bleeding due to thrombocytopenia. In the literature, there are a few studies about the effect of high-dose steroid therapy on coagulation tests in different diseases, but their results are still controversial. In this study, coagulation parameters were investigated that might have a role in hemostatic compensation in childhood acute ITP before and after high-dose methylprednisolone (HDMP) treatment. The study includes 21 children age 1.5 to 14 years with acute ITP and 21 healthy age-matched control subjects. All patients with acute ITP received HDMP for 7 days. Before and after HDMP treatment (0 and 8 days) prothrombin time, partial thromboplastin time, fibrinogen, Protein C, Protein S, antithrombin III, and the levels of factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, and FXII were studied in all subjects. The results were compared with those of the control group. Pre-treatment Protein C and Protein S levels in the patient group were significantly lower than those in the control groups (p<0.05). Protein S and Protein C levels were significantly improved after HDMP treatment in patient group. There were lower FV, FVII, FX values in the patient group compared to the control groups on admission. There was no difference in AT III and fibrinogen levels before and after treatment. As a result, some changes in the coagulation system associated with thrombocytopenia were observed in patients with acute ITP. These changes may be accepted as compensatory mechanisms to maintain hemostasis.