Thrombotic Incidence Research Articles

The risk of thrombosis in essential thrombocythemia and polycythemia vera.

Thrombotic events are present in 20% to 50% of patients with polycythemia vera (PV) and essential thrombocythemia (ET) at diagnosis and involve major vessels and the microcirculation. Establishing the precise risk of thrombosis in ET and PV is difficult. However, estimates may be obtained from retrospective and prospective studies, and some risk factors have been defined. In ET, increasing age and previous thrombosis emerge as major factors. The level of the platelet count per se does not correlate with thrombotic incidence. However, there is substantial evidence that adequate control of the platelet count reduces the frequency of thrombosis. While aspirin is usually effective at relieving vasomotor and microvascular occlusive symptoms or signs, there is only limited evidence that its use reduces the risk of larger vessel thrombosis. Other suggested risk factors include apparent clonal hematopoiesis in younger patients, hypercholesterolemia, and cigarette smoking. In PV, the overall impression is that the incidence of thrombosis is greater than in ET. As in ET, increasing age and previous thrombosis are significant risk factors. In addition, adequate reduction of the hematocrit reduces the incidence of thrombosis. Identifying the risk associated with thrombocytosis in PV is confounded by the overall myeloproliferation usually found in these patients and the fact that the thrombocytosis is not usually as marked as in ET. However, by analogy with ET, one could argue that the risk associated with the thrombocytosis in ET is equally applicable to PV. In support of this, there is overwhelming evidence that patients treated with adequate myelosuppression with complete normalization of their blood counts have the lowest thrombotic incidence. Essential thrombocythemia and PV patients presenting with thrombosis should be investigated for other congenital or acquired prothrombotic conditions. Establishment of the presence of one or the other of these may alter the long-term management of these patients with the use of either aspirin or anticoagulation in addition to cytoreduction. Thrombotic risk has emerged as a major factor in stratifying patients with myeloproliferative disease. While some clear thrombotic risk factors have been defined, there is a need to identify further additive risk factors in patients considered to be at low risk of thrombosis.

The risk of thrombosis in essential thrombocythemia and polycythemia vera

Thrombotic events are present in 20% to 50% of patients with polycythemia vera (PV) and essential thrombocythemia (ET) at diagnosis and involve major vessels and the microcirculation. Establishing the precise risk of thrombosis in ET and PV is difficult. However, estimates may be obtained from retrospective and prospective studies, and some risk factors have been defined. In ET, increasing age and previous thrombosis emerge as major factors. The level of the platelet count per se does not correlate with thrombotic incidence. However, there is substantial evidence that adequate control of the platelet count reduces the frequency of thrombosis. While aspirin is usually effective at relieving vasomotor and microvascular occlusive symptoms or signs, there is only limited evidence that its use reduces the risk of larger vessel thrombosis. Other suggested risk factors include apparent clonal hematopoiesis in younger patients, hypercholesterolemia, and cigarette smoking. In PV, the overall impression is that the incidence of thrombosis is greater than in ET. As in ET, increasing age and previous thrombosis are significant risk factors. In addition, adequate reduction of the hematocrit reduces the incidence of thrombosis. Identifying the risk associated with thrombocytosis in PV is confounded by the overall myeloproliferation usually found in these patients and the fact that the thrombocytosis is not usually as marked as in ET. However, by analogy with ET, one could argue that the risk associated with the thrombocytosis in ET is equally applicable to PV. In support of this, there is overwhelming evidence that patients treated with adequate myelosuppression with complete normalization of their blood counts have the lowest thrombotic incidence. Essential thrombocythemia and PV patients presenting with thrombosis should be investigated for other congenital or acquired prothrombotic conditions. Establishment of the presence of one or the other of these may alter the long-term management of these patients with the use of either aspirin or anticoagulation in addition to cytoreduction. Thrombotic risk has emerged as a major factor in stratifying patients with myeloproliferative disease. While some clear thrombotic risk factors have been defined, there is a need to identify further additive risk factors in patients considered to be at low risk of thrombosis. Semin Oncol 29 (suppl 10):16-21. Copyright 2002, Elsevier Science (USA). All rights reserved.

Reduced incidence of thrombosis in mice with hereditary spherocytosis following neonatal treatment with normal hematopoietic cells

Thrombosis is a life-threatening complication of hemolytic anemia in humans. Cardiac thrombi are present in all adult alpha-spectrin-deficient (sph/sph) mice with severe hereditary spherocytosis, providing a model for events preceding thrombosis. The current study evaluated (1) the timing of thrombosis initiation and (2) the effect of postnatal transplantation of normal cells on life span and thrombotic incidence in adult mice. Thrombi are detected histologically following necropsy in untreated sph/sph mice of various ages and are not observed until 6 weeks of age. Thrombotic incidence increases from 50% at 6 to 7 weeks of age to 100% at 9 weeks of age. As a potential therapy, nonablated sph/sph neonates were transfused with either genetically marked normal peripheral blood (PB), bone marrow (BM), or both and assessed for donor cells and thrombosis. A single transfusion of PB, with or without BM, significantly increases the percentage of sph/sph mice that survive to weaning (4 weeks of age). Replacement in all sph/sph recipients is limited to red blood cells (RBCs). RBCs derived from donor PB are lost within 5 weeks. PB plus BM prolongs high-level donor PB cell production better than BM alone. Thrombotic incidence is significantly reduced in all sph/sph mice treated with PB, BM, or both. Hence, the presence of normal blood cells in the peripheral circulation of neonatal and adult sph/sph mice rescues the former and abrogates the development of thrombosis in the latter. (Blood. 2001;97:3972-3975)

Analysis of Nonpenetrating Clips versus Sutures for Arterial Venous Graft Anastomosis

The use of nonpenetrating clips (NPC) for vascular anastomosis is quickly becoming accepted. Studies attest to decreased anastomotic time, comparable patency rates, and decreased blood loss. Few human studies on the use of NPC have been done to date. The purpose of this study was to evaluate primary patency rates, operative time, and complications associated with NPC compared to those with standard sutures for arterial venous graft (AVG). We retrospectively reviewed the clinical course of 82 patients with a mean age of 45 years (range, 22 to 87) from February 1996 to July 1999. All patients underwent upper extremity AVG construction. The procedures were performed at a single institution, by a single, well-experienced surgeon who has extensive experience with NPC. Primary patency rates, operative time, and complications were analyzed. Overall thrombotic incidence of AVG when NPC were used (27/48, 56%) was similar to that of sutures (17/34, 50%). Thrombotic incidence within the first year was similar as well (23/48, 48% and 13/34, 38%). The mean time to primary thrombosis was similar in both groups (6.9 and 6.8 months). The operative time required to construct an AVG with NPC (83 min) was significantly less than that with sutures (96 min) (p = 0.015). There was no significant difference in incidence of graft infection or pseudoaneurysm formation. NPC for AVG reduced operative time and resulted in primary patency and complication rates similar to those associated with use of sutures. The mean time to primary thrombosis was similar for both groups. Our findings suggest an intimal hyperplastic response of a similar nature resulting in thrombosis of both NPC and sutured AVGs.

Antithrombotic Efficacy in a Rat Model of the Low Molecular Weight Heparin, Reviparin Sodium, Administered by the Oral Route

Previous studies in rats show that unfractionated heparin and the low molecular weight heparin logiparin have a dose-dependent antithrombotic effect and are found in endothelium and plasma when administered orally. Objectives of the present study were to determine if similar evidence of absorption could be observed with oral reviparin sodium. Thrombosis incidence was determined 4 h after application of 10% formalin in methanol to the exposed jugular vein. A dose-dependent antithrombotic effect was observed when 0.01 to 7.5 mg/kg (20 rats/group) was administered by stomach tube immediately following thrombus initiation. Thrombotic incidence was also significantly reduced when 0.025 mg/kg was given 4 and 2 h prior to, immediately after, and 2 and 3 h following thrombus initiation. Reviparin was recovered from endothelium and plasma in trace amounts at all doses. At 0.025 mg/kg, peak aortic endothelial reviparin concentrations were found at 1 and 2 h and peak plasma anti-Xa activity was detected at 2 h. Trace amounts of plasma TFPI were found only at 8 h after administration. Dose-dependent antithrombotic activity and recovery from endothelium and plasma support the hypothesis that orally administered reviparin sodium is absorbed.

Factor V Leiden: the venous thrombotic risk in thrombophilic families.

Factor V Leiden (FVL) leads to a sevenfold increased risk of venous thrombosis and is present in 50% of individuals from families referred because of unexplained familial thrombophilia. We assessed the association of FVL with venous thromboembolism (VTE) in 12 thrombophilic families of symptomatic probands with FVL in a retrospective follow-up study. We screened 182 first- and second-degree relatives of the 12 unrelated propositi for the FVL mutation and the occurrence of VTE. The incidence rate of VTE in carriers of FVL (0.56%/year) was about six times the incidence for the Dutch population (0.1%/year). The incidence rate in non-carriers also appeared to be higher (0.15% per year). At the age of 50 years, the probability of not being affected by VTE was reduced to 75% for carriers and to 93% for non-carriers (P = 0.009). Identification of carriers of FV Leiden may be worthwhile in young symptomatic individuals and their relatives with a strong positive family history of venous thromboembolism or a history of recurrent venous thrombosis who may be at risk (e.g. pregnancy, use of oral contraceptives). After adjustment for prothrombin G20210A (present in two families), even higher thrombotic incidence rates were found in carriers and non-carriers of FVL. This makes the presence of other unknown prothrombotic risk factors more probable in these families.

Venous Thrombotic Risk in Family Members of Unselected Individuals with Factor V Leiden

The factor V Leiden mutation (FVL) leads to a seven-fold increased risk of venous thromboembolism (VTE). In thrombophilic families. 25% of carriers have experienced thrombosis before the age of 40 years. Aim of our study was to assess the association of FVL with VTE in first-degree family members of unselected symptomatic and asymptomatic carriers of FVL. We tested 197 relatives of consecutive thrombosis patients with FVL and 36 relatives of asymptomatic carriers on the presence of FVL and the occurrence of VTE. The incidence of VTE in relatives with FVL of symptomatic carriers was 0.34%/year. This was similar to the incidence in relatives with FVL of asymptomatic carriers. Kaplan Meier analysis in relatives of symptomatic propositi showed that at the age of 58 years, thrombosis-free survival was reduced to 75% in carriers and 93% in non-carriers (P <0.05). Carriers of FVL had a three times higher thrombotic risk than non-carriers. In combination with environmental risk factors, FVL clearly adds to the risk of VTE. The thrombotic incidence rate in these unselected relatives with FVL. however, is considerably lower than was seen in carriers of thrombophilic families (1.7%/year). Therefore, special care should be paid to individuals with a positive family history of venous thrombosis while exposed to these risk factors.

Femoral Catheters: Safety and Efficacy in Peripheral Blood Stem Cell Collection

Central venous access is necessary in patients candidate for peripheral blood stem cell (PBSC) collection. We report our experience with a dual lumen femoral catheter (Gamcath, 11 french), initially designed for hemodialysis. We studied 147 patients and performed 488 collections after mobilization with either G-CSF alone or chemotherapy + G-CSF, when the white blood cell count exceeded 1 x 10(9)/L, or when a measurable population of CD34+ cells (20/microL) was detected in peripheral blood. All patients received systemic anticoagulation with a low weight heparin and ultrasound examination was performed after the removal of the catheter. Seven patients developed thrombosis (4.7%), ten experienced hematomas at the site of catheter placement (6.8%) despite prophylactic platelet transfusions, while only one patient (0.6%) had a catheter-related infection. In conclusion, the short-term use of large bore femoral catheters in setting up PBSC collection seems to be associated with minimal risk of infection and low thrombotic incidence.

Aortic thrombosis in a neonate with hereditary antithrombin III deficiency: successful outcome with thrombolytic and replacement treatment

We report the case of a newborn male who presented an aortic thrombosis during the neonatal period and was subsequently diagnosed as having antithrombin III (AT III) hereditary deficiency type I. This hypercoagulable condition is known to predispose young adults to venous thrombosis, but in our patient the primary thrombotic incident affected the arterial vessels within the first few days of life. Combined treatment with thrombolytic agents and AT III concentrates recovered aortic permeability, suggesting that the use of AT III may be beneficial for the treatment of thrombotic complications during the first few days of life.

Gene Mutations in 21 Unrelated Cases of Phenotypic Heterozygous Protein C Deficiency and Thrombosis

SummaryMutations have been identified in the protein C gene in 21 patients with venous thromboembolism and phenotypic heterozygous protein C deficiency. In 20 probands, single mutations were the only abnormalities identified by sequencing all coding regions, intron exon boundaries and the promoter region back to -1540. In one proband 2 mutations were identified and in another family 2 mutations were identified (but not both in the proband). Of the 23 mutations, 18 resulted in predicted amino acid substitutions, 3 were mutations resulting in stop codons, one was a mutation within a consensus splice sequence and another a 9 base pair insertion within exon 5 (this region within exon 5 is proposed as a deletion/insertion hot spot). A novel polymorphism was also, uniquely, identified in the propeptide region of the molecule (Pro-21 Pro; CCT to CCC) in a kindred from Hong Kong. Cosegregation of the protein C gene mutation with protein C deficiency could be determined in 13 families. In a further family, phenotypic protein C deficiency and the genetic mutation cosegregated in only 4/5 members.The first thrombotic incident occurred in the probands between the ages of 11 and 59 years and 12 individuals suffered recurrent thrombosis. Thrombosis occurred in at least one other family member in 9/21 families, but in 2 of these it was inconsistently associated with protein C deficiency. An independent genetic risk factor, factor V Arg506Gln (FV Leiden) was identified in 2 probands (and 3 family members) and in 4 protein C deficient members of a third family but not in the proband. The results suggest that in the majority of probands with thrombosis and phenotypic protein C deficiency, a single protein C gene mutation is associated with thrombosis. However, it is also possible that additional unknown genetic risk factors contribute to the thrombotic risk. An added, acquired, risk factor leads to thrombosis at an early age (&lt; 25 years).

Cutaneous thrombosis in human immunodeficiency virus type 1-positive patients and cytomegalovirus viremia

In a group of over 900 patients infected with human immunodeficiency virus type 1 (HIV-1) who underwent follow-up for cutaneous disease, we have seen 17 patients in whom evidence of thrombotic disease developed ( Table ). The majority of patients have presented with peripheral thrombophlebitis or strokes as their presenting thrombotic incident; however, we have seen two patients whose first sign of a hypercoagulable state was digital infarcts (Table) ( Figure 1 ). The case reports of the two patients with cutaneous infarction illustrate this serious complication of HIV-1 infection. Report of Cases.Case 1. A 28-year-old HIV-1-positive Walter Reed stage 6 (last CD4 count, 0.09 × 10 9 /L 1 year before) black man presented with acute onset of multiple digital infarcts of both upper extremities (Figure 1). The patient had had periodic low-grade fevers for over 4 months. Multiple blood cultures for bacteria, mycobacteria, and fungi were all negative. Coagulation studies included the following

CLINICAL TRIAL OF A NEW ORAL CONTRACEPTIVE PILL CONTAINING THE NATURAL OESTROGEN 17β‐OESTRADIOL

The natural oestrogen, 17 beta-oestradiol, has been shown not to depress fibrinolysis and apparently has less influence on liver function and lipid metabolism than ethinyl oestradiol, the synthetic oestrogen in conventional 'combined' oral contraceptive tablets. A triple-blind study was therefore made of 215 women during 2051 treatment cycles with oral contraceptives containing either (i) 4 mg of micronized 17 beta-oestradiol and 3 mg norethisterone (Netagen 403), (ii) 4 mg 17 beta-oestradiol plus 2 mg of oestriol and 3 mg norethisterone (Netagen 423) or (iii) 50 microgram ethinyl oestradiol and 3 mg norethisterone (Netasyn). There were no pregnancies or thrombotic incidents. The numbers discontinuing treatment were about the same in the three groups, the main reasons being intermenstrual spotting in those on Netagen 423, amenorrhoea and weight gain in those on Netagen 403 and nausea and weight gain in those on Netasyn. The natural oestrogen showed promise as a new and safe component of the 'combined' pill.

Streptokinase treatment of deep venous thrombosis of the lower extremity. Clinical, phlebographic and plethysmographic evaluation of early and late results.

The investigation comprises 19 patients with acute deep vein thrombosis of the leg treated with streptokinase. The acute clinical symptoms rapidly subsided in 15 patients. Phlebography, performed immediately after treatment, revealed complete thrombus regression in 7 cases, restoration of venous flow but remnants of thrombi in 4 and no effect in 7. One woman was not evaluated radiologically due to pregnancy. The phlebographic restoration seemed to be correlated to the duration of the thrombotic symptoms. Follow-up examinations 6-50 months after the thrombotic incident demonstrated normal phlebograms in 8 patients, all of whom were also free from post-thrombotic symptoms. Venous occlusion plethysmography confirmed that these patients had a normal venous outflow capacity and valvular function in the relevant limbs. By contrast, the remaining 11 patients, with more or less extensive remnants of thrombi at the follow-up phlebography, were found to have plethysmographic signs of venous obstruction and sometimes also valvular insufficiency. The results indicate that thrombolytic treatment is able to give a complete and lasting anatomical and functional restitution of the deep veins after an acute thrombosis in the leg, provided that treatment is induced early enough.

Editorial: Outpatient treatment of haemorrhoids.

The estrogenic potency of combined oral contraceptives (OC) is discussed. A dose of 30-50 mcg estrogen was recommended once it was learned that the incidence of thromboembolic disease was related to the estrogen content of OCs. The synthetic progestogens in OCs are usually nortestosterone derivatives, many of which are partly metabolized to estrogen when taken orally. It is difficult, however, to determine whether pills with lowered estrogenicity will reduce the incidence of thromboembolic disorders. Norethynodrel has a purely additive effect on the estrogenicity of estrogens, norgestrel is antagonistic, while norethindrone and ethynodiol diacetate have less estrogenic action at high doses and more action at low doses. It is doubtful that the standard measure for estrogenicity in the mouse uterus is applicable to the association of thromboembolic disease and OC use. The only way to resolve the question is by a more complete epidemiological analysis, which requires greater cooperation in the reporting of thrombotic incidents.

Effect of acetazolamide and magnesium therapy on erythrocyte survival in sickle-cell anaemia and sickle-cell-haemoglobin-C disease

Erythrocyte survival studies, with 51Cr were undertaken in 13 patients with sickle-cell disease, before and during treatment with acetazolamide and magnesium citrate. No significant improvement in erythrocyte life span was observed as a result of the treatment. Simultaneous observations on the number of circulating sickled cells, reticulocytes and haemoglobin level also showed no marked change during treatment. It is clear that acetazolamide and magnesium have no significant therapeutic effect on the haematological picture of these patients, but closely supervised use of magnesium might be valuable in diminishing the effects of thrombotic incidents.

FEMORAL ARTERY INJURY DURING INGUINAL HERNIORRHAPHY.

INJURY to the femoral vessels during inguinal herniorrhaphy is of constant concern to the general surgeon. In most repairs of the floor of the inguinal canal, sutures are placed through the inguinal ligament directly above the femoral artery and vein. The Cooper's ligament repair as described by McVay is particularly apt to endanger these vessels. Because of this unique anatomic arrangement and because of the vast numbers of inguinal hernias which are repaired, one would expect this complication to occur with some frequency. This does not seem to be the case, however, and a review of the literature for the last five years did not yield a single reported case! Marsden1has presented a three-year review of 2,000 inguinal herniorrhaphies with an infection rate of 6%. There were 24 patients who developed thrombotic incidents, including cornary, cerebral, axillary, and calf vessels and three additional patients without leg symptoms who

PROGNOSIS IN DEEP VENOUS THROMBOSIS.

The management of gravitational ulcers and the bottle present many problems. Much time is given over to the treatment of the conditions both in hospital wards and out-patient departments. Recurrence of ulceration is only too common. The pathogenesis of the condition now seems clear. A previous thrombosis in the deep veins of calf or thigh can be incriminated with certainty in the vast majority. Bauer, 1 who has done much work in this field, found that 80% of his patients, attending because of gravitational ulceration, gave a history of such a thrombosis. Dodd and Cockett 6 believe that 75% of patients who have had a thrombotic incident suffer subsequently from edema, induration, ulceration, or bursting leg pain. The time that elapses before the patient has symptoms may be such that the original incident has been forgotten, and, indeed, a deep venous thrombosis may be silent, particularly in the bilateral