Bruno Girolami

Venous thromboses of upper limbs are more frequently associated with occult cancer as compared with those of lower limbs.

Three hundred and forty-three consecutive patients with deep vein thrombosis (DVT) were investigated for the possible presence of occult or undiagnosed cancer, of whom 305 patients had DVT of the lower limbs whereas 38 had DVT of the upper limbs. Cancer was diagnosed during a 12-month follow-up in nine patients with DVT of the upper limbs (23.7%) and in 34 patients with DVT of the lower limbs (11.1%). The difference was statistically significant. Furthermore, it was shown that the majority of cancers (seven of nine) in the case of DVT of the upper limbs were discovered during the first week of hospital admission. In contrast, in the case of DVT of lower limbs, only eight of 34 cancers were discovered during the initial investigation. Lung cancer and lymphomas represented the majority of cancers associated with upper limb venous thrombosis (seven of nine). In the case of DVT of the lower limbs, cancers were heterogeneous; however, 12 of 34 were cancers of the colon or prostate.

Are Antiphospholipid Antibodies an Independent Risk Factor for Atherosclerosis

The purpose of this study was to check whether antiphospholipid antibodies (aPL) could be an independent risk factor for atherosclerosis. Eighty-five subjects were studied: 45 with primitive antiphospholipid antibody syndrome and 40 controls affected by deep vein thrombosis secondary to known causes. The two groups were homogeneous for age, sex, and risk factors for atherosclerosis. All the subjects submitted to echo-color doppler of the carotid arteries, femoral arteries, and abdominal aorta. The cases were then subdivided into three subgroups on the basis of the positivity to the three subpopulations of aPL. Results demonstrate that there is no correlation between aPL and atherosclerosis. The different positivity to aPL does not modify this conclusion.

The role of drugs, Particularly oral contraceptives, in triggering thrombosis in congenital defects of coagulation inhibitors:a study of six patients.

It is well established that pregnancy and puerperium, surgery and trauma may often trigger thrombotic events even in the normal population. On the other hand, patients with congenital deficiency of clotting inhibitors may develop spontaneous thrombotic episodes, although they become often symptomatic when one of the above-mentioned triggering factors is present. We found this to be true in 40 out of 81 symptomatic patients with congenital defects of coagulation inhibitors. In six (15%) of these cases medications (mainly oral contraceptives) triggered the thrombotic event. The incidence of pharmacological factors as a cause of thrombosis is commonly maintained to be low. This study indicates that this is not so and underlines the potential importance of drugs, particularly oral contraceptives, in the pathogenesis of thrombotic events in patients with congenital defects of clotting inhibitors.

Homozygous patients with APC resistance may remain paucisymptomatic or asymptomatic during oral contraception.

The effect of oral contraceptive therapy was studied in five patients with homozygous activated protein C resistance. Patients with this congenital abnormality, in contrast to those with antithrombin, protein C or protein S deficiencies, showed only a mild thrombotic tendency. In fact, only two of six observations (one patient took the pill on two separate occasions many years apart) showed deep vein thrombosis. No patient had pulmonary embolism. Two additional patients had a superficial vein thrombosis of the legs. In two instances, a superficial vein thrombosis and a deep vein thrombosis, concomitant risk factors were present (immobilization and surgery for an ovarian cyst, respectively). However, compared with heterozygous for the same abnormality, the symptomatic homozygous patients with APC resistance appeared to develop thrombosis after a shorter period of oral contraception.

Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

Use of an Algorithm for Administering Subcutaneous Heparin in the Treatment of Deep Venous Thrombosis

Patients with deep venous thrombosis of the lower extremities are usually treated with an initial course of unfractionated or low-molecular-weight heparin, followed by long-term oral anticoagulation [1, 2]. The use of nomograms for the intravenous administration of unfractionated heparin assures that almost all patients will promptly achieve sustained anticoagulation [3-5]. Subcutaneous heparin has been shown to be as effective and safe as intravenous heparin [6]; in addition, low-molecular-weight heparins may facilitate the early discharge of suitable patients from the hospital, with the accompanying advantage of a relatively low cost. However, no accepted guidelines exist with which to achieve adequate anticoagulation with subcutaneous administration of heparin. We implemented a weight-based algorithm for the subcutaneous administration of unfractionated heparin and evaluated the efficacy and safety of this therapy in 70 outpatients with proximal venous thrombosis. Methods Patients Eligible patients were consenting symptomatic outpatients who had a first episode of proximal venous thrombosis, as assessed by compression ultrasonography. Exclusion criteria were contraindications to anticoagulation, ongoing full-dose anticoagulant therapy, pregnancy, and poor life expectancy. The institutional ethical board approved the investigation. Intervention Patients were given an intravenous bolus of sodium heparin (Liquemin, Roche, Basel, Switzerland) and a subcutaneous injection of calcium heparin (Calciparina, Italfarmaco, Milan, Italy) in doses adjusted according to body weight (Table 1). Table 1. Algorithm for the Adjustment of Subcutaneous Heparin Doses* The first activated partial thromboplastin time (aPT) was done after 6 hours, and subsequent dose adjustments during the first 48 hours were scheduled twice daily according to the algorithm shown in Table 1. The aPT was performed in the mid-interval. Adjustments were arranged in steps to be run up or down according to aPT, regardless of body weight. The target aPT range (50 to 90 seconds) was calibrated to correspond to a heparin plasma level (as expressed by antifactor Xa [aXa] activity) of 0.35 to 0.70 U/mL. To avoid unnecessary overanticoagulation [7, 8], an aXa assay was scheduled if the aPT was subtherapeutic 6 hours after the administration of 25 000 U of heparin. If the aXa level exceeded 0.35 U/mL, the heparin dose was not modified. After the first 48 hours, heparin administration was managed on the basis of daily aPT determinations. Sodium warfarin therapy was begun on the first or second day and was continued for 12 weeks, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0. Heparin therapy was discontinued if the international normalized ratio in patients who had received the study drug for at least 5 days was greater than 2.0 for 2 consecutive days. Clinical Evaluation Patients were examined daily for signs and symptoms of recurrent thromboembolism, bleeding, or the occurrence of heparin-induced thrombocytopenia (decrease in platelet count to <109 cells/L or to >50% below the baseline count). Follow-up visits were scheduled after 1 and 3 months. Patients were asked to return to the study center if clinical manifestations of recurrent thromboembolism occurred. Recurrent venous thromboembolism was diagnosed according to standard methods [9, 10]. Bleeding was defined as major if it was intracranial or retroperitoneal or was associated with a decrease in the hemoglobin level of at least 2.0 g/dL. Autopsy was intended for all decedents in whom pulmonary embolism could not be excluded. Study Outcomes and Analysis We determined the proportion of patients who achieved the therapeutic threshold (aPT 50 seconds) within 24 and 48 hours and the time elapsed from initiation of heparin therapy until achievement of the threshold aPT. We calculated the percentage of patients with supratherapeutic aPT that persisted for more than 12 hours. We also evaluated the rate of recurrent thromboembolism during heparin treatment and follow-up and the rate of major bleeding occurring during heparin treatment and during the following 48 hours. Descriptive statistics were calculated according to standard methods; 95% CIs were estimated by using the exact method. The time from initiation of heparin therapy until achievement of the aPT threshold was calculated according to the Kaplan-Meier method. Results Patients Twenty-seven of 97 eligible patients were excluded because of ongoing full-dose anticoagulant therapy (15 patients), contraindications to heparin (4 patients), refusal to participate (4 patients), poor life expectancy (3 patients), and pregnancy (1 patient). Thus, 70 patients were enrolled (25 men; median age, 65 years). Three patients weighed less than 50 kg, 21 weighed 50 to 70 kg, and 46 weighed more than 70 kg. Risk factors for thrombosis were identifiable in 51 patients: cancer (20 patients), prolonged immobilization (14 patients), recent trauma (9 patients), thrombophilia (5 patients), and estrogen therapy (3 patients). Biological Outcomes Eighty-seven percent of patients (61 of 70) achieved the aPT threshold within 24 hours, and 99% (69 of 70) achieved the threshold in 48 hours. Figure 1 shows the Kaplan-Meier curve for the heparin therapeutic threshold. Seven patients (10.0% [95% CI, 4.1% to 19.5%]) had supratherapeutic aPT that persisted for more than 12 hours. In 2 of the 4 patients who had a subtherapeutic aPT despite the administration of 25 000 U of heparin, the aXa assay showed a plasma heparin level greater than 0.35 U/mL. Figure 1. Cumulative proportion of patients reaching the therapeutic threshold (activated partial thromboplastin time 50 seconds) within 48 hours of the initiation of heparin therapy. The mean (SD) heparin doses administered were 39 700 5300 U during the first day and 30 500 10 800 U during the second day. No patient required less than 10 000 U or more than 30 000 U twice daily to prolong the aPT (or aXa) level. The median duration of heparin treatment was 6.5 days (range, 5 to 12 days). Clinical Outcomes During the initial period of heparin treatment and follow-up, thromboembolism recurred in three patients (4.3% [CI, 0.9% to 12%]). One of the three (age, 93 years) died of autopsy-proven pulmonary embolism within 5 days after heparin treatment began. Both the aPT and the international normalized ratio were in the therapeutic range. The two other patients had contralateral thrombosis (one after 8 weeks and one after 10 weeks), as assessed by compression ultrasonography. In all three patients, the aPT threshold had been achieved within 24 hours of initiation of heparin therapy. No major bleeding episodes or heparin-induced thrombocytopenia occurred during heparin treatment (0% [CI, 0.0% to 5.0%]), and no patient was lost to follow-up. Five patients died during the follow-up period: Four died of cancer (one after 65 days, one after 72 days, one after 80 days, and one after 85 days), and one died of pleural hemorrhage that occurred 1 month after heparin therapy began. Discussion Our results suggest that the use of a weight-based algorithm for the subcutaneous injection of unfractionated heparin allows the rapid achievement of correct anticoagulation in almost all patients with deep venous thrombosis while avoiding prolonged periods of excessive anticoagulation. The therapeutic threshold was achieved within 24 hours in 87% of patients and within 48 hours in 99%. In only 10% of patients did supratherapeutic aPT persist for more than 12 hours. No patient had major bleeding or heparin-induced thrombocytopenia, and thromboembolism recurred in only three patients (4.3%). These results are consistent with those reported in recent studies done with either intravenous unfractionated heparin according to standardized guidelines or fixed-dose low-molecular-weight heparins [3-5, 11-13]. An intravenous loading dose was chosen because of the poor bioavailability of subcutaneous heparin [8], and weight-adjusted heparin doses were chosen because body weight is the single best predictor of individual heparin requirements [5, 14, 15]. The combination of an initial intravenous bolus and weight-adjusted heparin doses probably explains the high biological success rates achieved with our protocol, rates that are similar to those recently reported with the use of a weight-based intravenous heparin nomogram [5, 16]. Of interest, the mean daily amount of heparin required to prolong the aPT during the first 24 hours (almost 40 000 U) was greater than the dose (30 000 to 35 000 U) usually required to attain proper anticoagulation with intravenous administration [1, 3-5, 8]. The implication of this finding is that the common practice of injecting as much subcutaneous heparin as is commonly administered intravenously for the initial treatment of patients with thrombotic disorders is likely to produce insufficient anticoagulation, thereby increasing the likelihood of recurrent thromboembolism [17-19]. A few considerations deserve careful analysis. Because of a relatively small sample size and the lack of a control group, our results should be validated in other cohorts of patients to ensure external validity. In addition, because we confined our investigation to symptomatic outpatients with a first episode of venous thrombosis, widespread generalization of this therapeutic regimen requires proper evaluation in patients who develop thrombosis during hospitalization and in those presenting with pulmonary embolism or recurrent thromboembolism. In conclusion, the use of a weight-based algorithm for the subcutaneous administration of unfractionated heparin may greatly simplify the initial treatment of venous thromboembolic disorders. It enables the early mobilization of patients with venous thrombosis and allows the early discharge of suitable patients. The relatively low cost of unfractionated heparin makes this approach attractive in comparison w

Frequent but low titre factor VIII inhibitors in haemophilia A patients treated with high purity concentrates

The development of inhibitor antibodies is one of the more important complications in the management of haemophilia patients. In a previous study, the prevalence of inhibitor varies between 5 and 52%, seems to be different for different types of concentrates, and is less frequent in multitransfused patients. In our prospective study we followed for 3 years 62 multitransfused haemophilia patients without inhibitor or past history of inhibitor. Thirty-seven haemophilia patients were treated with intermediate purity factor VIII concentrates, whereas 25 were given high purity concentrates (from the eighth month of the study five of these patients were treated with recombinant products). Factor VIII inhibitor antibody developed in seven of 25 haemophilia patients treated with high purity concentrates or recombinant products, whereas none of the haemophilia patients treated with intermediate purity concentrates had inhibitors. The difference was statistically significant (P < 0.001; OR = 0.06, 95% CI 0.001-0.3). In all patients, the titre of the inhibitor was low and no problem occurred in their management. Since inhibitors appeared in multitransfused patients when transfused with high purity concentrates and/or when the patients were switched to recombinant FVIII product, the development of inhibitor seems to be due to the administration of a new concentrate. Therefore this potential complication must be considered every time a new concentrate is administered.

Congenital FVII deficiency and pulmonary embolism: a critical appraisal of all reported cases.

Fourteen patients with congenital factor VII (FVII) deficiency were reported to have had pulmonary embolism. All patients were type 2 defects with variably low activity but normal or near-normal antigen. Concomitant deep vein thrombosis was present in 7 instances. The majority of patients had no or only a mild bleeding tendency. Associated prothrombotic risk factors were present in 11 patients (old age, surgery, substitution therapy with prothrombin complex, plasma-derived or activated FVII concentrates). Pulmonary embolism was usually moderate or severe. In 2 cases, it was fatal. Only 4 patients were studied by means of molecular biology techniques. The Arg304Gln mutation was found in 5 of the 8 alleles. Heparin and Coumadin together with adequate substitution therapy were carried out in 5 patients with satisfactory results. The FVII deficiency does not grant a sure protection from venous thromboembolism.

Factor V antigen levels in APC resistance, in factor V deficiency and in combined APC resistance and factor V deficiency (pseudohomozygosis for APC resistance)

Factor V antigen levels were measured in 40 patients with factor V deficiency (11 homozygous and 29 heterozygous), in 38 patients with factor V Leiden mutation (16 homozygous and 22 heterozygous) and in three patients with combined heterozygous factor V deficiency and heterozygous factor V Leiden mutation (so-called pseudohomozygosis for APC resistance). Twenty normal subjects of both sexes served as controls. Factor V antigen levels compared well with factor V activity in normal subjects and in all groups of patients. They were normal both in homozygous and heterozygous APC resistance patients. Factor V antigen determination may be useful for the diagnosis of pseudohomozygosis for APC resistance. These patients have a phenotypic picture similar to homozygous APC resistance, but show a factor V antigen level about half the normal value since they are compound heterozygotes for factor V deficiency and APC resistance. In contrast, homozygous patients for APC resistance show normal factor V activity and antigen levels.

Prevalence of hypertension and its complications in congenital prekallikrein deficiency: analysis of all reported cases and clinical significance.

The extra coagulation effects of prekallikrein and of the other factors of the contact phase of blood clotting have received great attention in the past few years. The clinical observation that hypertension was present in two families with congenital prekallikrein deficiency prompted a survey of all reported cases of this disorder. Altogether, 89 cases of proven prekallikrein deficiency have been described in the literature. Hypertension or vascular complications of it were found in 21 patients (12 men and nine women). If the analysis is limited to patients over 25 years of age, the number becomes 21 out of 64 cases (38.2%). This prevalence is much higher than that seen for other conditions occasionally found in patients with prekallikrein deficiency, namely hyperthyroidism, lupus erythematosus, chronic lymphocytic leukemia, kidney malformation, peptic ulcer, and myelofibrosis (1–2%). These results indicate the need to investigate further the relation between prekallikrein deficiency and hypertension.