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Cerebral Sinovenous Thrombosis.

Cranial sinovenous disorders comprise a disparate group of illnesses affecting one or more intracranial venous sinuses and cerebral veins, alone or in combination, due to a variety of causes. As medical knowledge advances, fewer and fewer patients have an "idiopathic" diagnosis, with causes clarified in an ever-increasing number of patients. These not only include the long-known puerperal, marantic, infective, and traumatic causes, but in recent years, also a variety of congenital and acquired coagulation disorders, such as protein S, protein C, and antithrombin III deficiency. Certain sinuses are preferentially involved with certain causative entities; for example, cavernous and lateral sinuses are more frequently occluded in relation to infectious processes, either directly or as a parameningeal focus, whereas the superior sagittal sinus is most often occluded by trauma, tumor, or coagulopathy. The optimal treatment of sinovenous occlusion depends on establishing the cause with alacrity, because delays in diagnosis may lead to life-threatening hyperpyrexia, elevations in intracranial pressure, venous infarctions, seizures, coma, and death. However, because up to a third of patients with nonseptic occlusions may survive untreated, with few residua, controversy persists regarding optimal management. There has been a dearth of randomized, prospective treatment trials in this group of disorders. The little data that exist suggest that rapid control of infection, seizure prophylaxis, and anticoagulation must be achieved early so as to prevent progression of thrombosis and intracranial venous hypertension. In recent years, direct retrograde venous thrombolysis has become increasingly available, and has produced such remarkable results that it is likely soon to become the primary treatment of choice for the nontraumatic or nontumoral occlusions.

Journal Article↗

Placental emboli from a fetus papyraceous.

A syndrome in monozygotic twins that consists of a macerated twin fetus (fetus papyraceous) and a live-born twin with various anatomical defects has been described. The etiology is thought to be placental transfer of emboli or thromboplastic material through vascular shunts. Thromboplastic material precipitates disseminated intravascular coagulation (DIC) in the fetus, with a resultant hypercoagulable state due to relative fetal antithrombin III deficiency. Two cases of this syndrome will be discussed. The case of a live-born twin with intestinal atresia, who developed in utero with a fetus papyraceous, is reported. Emboli were demonstrated in vascular shunts of the diamniotic-monochorionic placenta. The hypothesis of intestinal atresia as a result of a vascular accident is reviewed. Another case involving a live-born twin with congenital skin defects, who developed in utero with a fetus papyraceous, is also reported. The skin defects were a congenital disruption from fetal DIC with resultant hypercoagulable state. Several other manifestations of the placental emboli syndrome will be discussed and the vascular etiology of the disruptions explained.

Adult↗

An abnormal plasma antithrombin with no apparent affinity for heparin.

Congenital antithrombin abnormality was found in several members of a French family. No history of thrombotic episodes was associated with this abnormality. Plasma antithrombin concentration as well as the rate of thrombin inactivation by defibrinated plasma in the absence of heparin were normal. However, the heparin cofactor activity was decreased by about 50% in plasma of affected patients. Accordingly, about half the amount of plasma antithrombin did not bind to gel bound heparin. Moreover the crossed immunoelectrophoretic pattern in the presence of heparin demonstrated two peaks of antithrombin, the slower one migrating as normal antithrombin when heparin was omitted from the first agarose gel. It was concluded that molecular alteration of the antithrombin molecule seemed to affect only the heparin binding site thus preventing from any rate enhancement of thrombin inactivation.

Antithrombin III Deficiency↗

Successful small-bowel/liver transplantation.

A patient with the short-gut syndrome and antithrombin III deficiency underwent small bowel and liver grafting a year ago. Transient, mild graft-versus-host disease and intestinal rejection occurred within 2 months of grafting and were easily managed. Parenteral nutrition was discontinued 8 weeks after surgery. The patient has maintained normal nutritional indices while on an unrestricted oral diet. Small-bowel/liver grafting is feasible for patients with the short-gut syndrome and associated liver disorders. Further experience is needed to determine the specific risks, benefits, and general applicability of this procedure.

Adult↗

Adverse pregnancy outcomes are associated with multiple maternal thrombophilic factors.

OBJECTIVE: To determine to what extent adverse pregnancy outcomes are associated with thrombophilia. STUDY DESIGN: We studied 31 women who had HELLP syndrome, placental abruption, fetal growth restriction or unexplained stillbirth (study group), matched with 12 controls. All women were tested for: Factor V, Prothrombin, methylenetetrahydrofolate reductase gene (MTHFR) mutations; for Protein C, S and Antithrombin III deficiency; for lupus anticoagulant. Correlation with 24h BP monitoring and uterine Doppler velocimetry indexes at 22-24 weeks' gestation was performed. RESULTS: Women with multiple thrombophilic factors had a significant lower birth weight (1568.33+/-146.8 g versus 2546.45+/-438 g), higher 24 h mean diastolic blood pressure at second trimester (76.3+/-12.5 mmHg versus 65.2+/-7.8 mmHg) and higher RI of uterine arteries (0.69+/-0.05 versus 0.50+/-0.15) than women with single thrombophilic factor. CONCLUSION: Multiple thrombophilic factors carry a major additional risk for adverse maternal and fetal outcomes and correlate well with placental maladaptation as indicated by uterine Doppler velocimetry and 24h BP monitoring.

Abruptio Placentae↗

Heparin skin necrosis: delayed occurrence in a patient on hemodialysis.

A case of skin necrosis in a patient receiving intravenous (IV) heparin during routine intermittent hemodialysis is reported. Multiple erythematous, tender lesions developed over the abdomen and thighs and rapidly became necrotic. Biopsies showed fibrin thrombi in the dermal venules and capillaries, but no cellular infiltrate. The patient was in her third month of regular hemodialysis. Skin necrosis associated with the use of heparin usually occurs within 2 weeks of beginning heparin therapy and has not been reported in patients receiving heparin with hemodialysis. Possible mechanisms, including acquired antithrombin III deficiency leading to heparin-induced skin necrosis, are discussed.

Abdomen↗

Epidemiology of venous thromboembolic disease.

From the information presented in this article, it can be concluded that clinical suspicion of VTE should be increased in patients with a history of VTE, recent surgery, spinal cord injury, trauma, or malignancy. A variety of medical illnesses also increase the risk of venous thrombosis, including congestive heart failure, myocardial infarction, stroke with paresis, nephrotic syndrome, cigarette smoking, and obesity. Hypercoagulable states, such as antithrombin III deficiency, protein C deficiency, protein S deficiency, or factor V Leiden mutation should be considered in those patients who develop VTE in the absence of known risk factors. Additionally, the presence of vena caval filters does not exclude the possibility of PE or recurrent DVT. With a careful assessment of risk, physicians can hope to increase the diagnostic yield of VTE and decrease the significant morbidity and mortality of caused by this disease.

Adult↗

Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease.

OBJECTIVES: The purpose of this study was to evaluate the role of endovascular and open surgical reconstructions in patients with superior vena cava (SVC) syndrome caused by nonmalignant disease. METHODS: Clinical data from 32 consecutive patients who underwent endovascular or open surgical reconstruction of central veins because of symptomatic benign SVC syndrome between November 1983 and June 2001 were retrospectively reviewed. RESULTS: The study included 17 male and 15 female patients (mean age, 38 years; range, 5-69 years). Presenting symptoms were head fullness (n = 26), dyspnea or orthopnea (n = 23), headache (n = 17), or dizziness (n = 11); physical signs were head swelling (n = 31), chest wall collateral vessels (n = 29), facial cyanosis (n = 18), or arm swelling (n = 17). Etiologic factors included mediastinal fibrosis (n = 19), indwelling catheter (n = 8), idiopathic thrombosis (n = 4), or post-surgery (n = 1). Two patients were heterozygous for factor V Leiden; 1 patient had antithrombin III deficiency. Twenty-nine patients underwent surgical reconstruction with 31 bypass grafts: spiral saphenous vein (n = 20), superficial femoral vein (n = 4), human allograft (n = 1), or expanded polytetrafluoroethylene (ePTFE, n = 6). Eleven patients underwent percutaneous transluminal angioplasty or stenting; 3 primary and 8 secondary endovascular procedures were performed to treat graft stenosis (n = 7) or occlusion (n = 1). There were no early deaths. Five early graft failures in 3 ePTFE grafts and 2 bifurcated vein grafts (thrombosis, n = 4; stenosis, n = 1) were successfully treated with open surgical revision. Over a mean follow-up of 5.6 years (range, 0.4-16.6 years) in surgical patients, 17 additional secondary interventions were performed in 8 patients, 14 endovascular and 3 surgical. Primary, assisted primary, and secondary patency rates of surgical bypass grafts were 63%, 79%, and 85%, respectively, at 1 year, and 53%, 68%, and 80%, respectively, at 5 years. Graft patency was significantly higher in vein grafts compared with ePTFE grafts (P =.02). Mean follow-up after percutaneous transluminal angioplasty or stenting was 3.1 years (range, 1 day-11.7 years). Twelve secondary endovascular interventions were performed in 6 patients (primary group, 3 of 3; secondary group, 3 of 9 grafts in 8 patients) to maintain patency in 11 of 12 reconstructions. Mean follow-up in the entire patient cohort was 5.3 years (range, 0.4-16.6 years). In 79% of patients symptoms had resolved or were significantly improved at last follow-up. CONCLUSIONS: Surgical treatment of benign SVC syndrome is effective over the long term, with secondary endovascular interventions to maintain graft patency. Straight spiral saphenous vein graft remains the conduit of choice for surgical reconstruction, with results superior to those with bifurcated vein and ePTFE. Endovascular treatment is effective over the short term, with frequent need for repeat interventions. It does not adversely affect future open surgical reconstruction and may prove to be a reasonable primary intervention in selected patients. Patients who are not suitable for or who fail endovascular intervention merit open surgical reconstruction.

Adolescent↗

Reconstruction of the superior vena cava: benefits of postoperative surveillance and secondary endovascular interventions.

PURPOSE: Superior vena cava (SVC) reconstructions are rarely performed; therefore the need for surveillance and the results of secondary interventions are unknown. METHODS: During a 14-year period 19 patients (11 male, 8 female; mean age 41.9 years, range 8 to 69 years) underwent SVC reconstruction for symptomatic nonmalignant disease. Causes included mediastinal fibrosis (n = 12), indwelling foreign bodies (n = 4), idiopathic thrombosis (n = 2), and antithrombin III deficiency (n = 1). Spiral saphenous vein graft (n = 14), polytetrafluoroethylene (n = 4), or human allograft (n = 1) was implanted. RESULTS: No early death or pulmonary embolism occurred. Four early graft stenoses or thromboses (spiral saphenous vein graft, n = 2, polytetrafluoroethylene, n = 2) required thrombectomy, with success in three. During a mean follow-up of 49.5 months (range, 4.7 to 137 months), 95 imaging studies were performed (average, five per patient; range, one to 10 studies). Venography detected mild or moderate graft stenosis in seven patients; two progressed to severe stenosis. Two additional grafts developed early into severe stenosis. Four of 19 grafts occluded during follow-up (two polytetrafluoroethylene, two spiral saphenous vein graft). Computed tomography failed to identify stenosis in two grafts, magnetic resonance imaging failed to confirm one stenosis and one graft occlusion, and duplex scanning was inconclusive on graft patency in 10 patients. Angioplasty was performed in all four patients with severe stenosis, with simultaneous placement of Wallstents in two. One of the Wallstents occluded at 9 months. Repeat percutaneous transluminal angioplasty was necessary in two patients, with placement of Palmaz stents in one. Only one graft occlusion and one severe graft stenosis occurred beyond 1 year. The primary, primary-assisted, and secondary patency rates were 61%, 78%, and 83% at 1 year and 53%, 70%, and 74% at 5 years, respectively. CONCLUSION: Long-term secondary patency rates justify SVC grafting for benign disease. Postoperative surveillance with contrast venography is indicated in the first year to detect graft problems. Endovascular techniques may salvage and improve the patency of SVC grafts.

Adult↗

Management and outcome of pregnancy in women with thrombophylic disorders and past cerebrovascular events.

OBJECTIVE: To evaluate the maternal and fetal outcome in a cohort of women undergoing a subsequent pregnancy after a previous cerebrovascular event in the presence of thrombophilia. PATIENTS: Fifteen pregnancies were followed up in 12 women with past cerebrovascular events and thrombophilic disorders. The cerebrovascular events occurred during a previous pregnancy in five patients. Six patients had a bad obstetric history including intrauterine fetal death in four cases, early onset of severe preeclampsia in two cases and one infant that was small for gestational age. THE THROMBOPHILIC DISORDERS INCLUDED: anti-phospholipid syndrome, protein C, S or antithrombin III deficiencies, mutations of the methyltetrahydrofolate reductase (MTHFR). All patients received prophylactic treatment with low molecular weight heparin and low dose aspirin. RESULTS: Thromboembolic complications occurred in four pregnancies. Postpartum complications occurred in one patient; deep vein thrombosis and pulmonary emboli after stopping anticoagulation treatment. No patient had long-term neurologic damage. All pregnancies except one resulted in live births. (mean gestational age at delivery 36 +/- 3. 7 weeks, mean birth weight 2656 +/- 811 g). The one remaining pregnancy was electively terminated. There was one neonatal death due to the complications of severe prematurity in a woman with severe HELLP syndrome. CONCLUSION: This preliminary data suggests that women with a history of cerebrovascular events and thrombophilic disorders receiving prophylactic treatment, have a relatively favorable pregnancy outcome; however, they remain at significant risk during pregnancy. Further studies are necessary to determine the optimal prophylactic treatment.

Adult↗

Laboratory findings associated with thrombophilia are not more common in inflammatory bowel disease.

Thromboembolic disease (TED) has been recognized as a complication of inflammatory bowel disease (IBD) since the 1930s (Bargen & Barker 1936). The relative contributions of inherited or acquired thrombophilia and the inflammatory response to the mechanism of this tendency is unclear. Thrombotic events are more common in active disease although significant numbers also occur spontaneously, when the disease is in clinical remission (Talbot et al. 1986; Jackson et al. 1997). Studies looking at the prevalence of specific thrombophilic states such as Antithrombin III deficiency (Jackson et al. 1997; Lake, Stauffer & Stuart 1978; Cianco et al. 1996; Ghosh et al. 1983), Factor V Leiden mutation (APC Resistance) (Jackson et al. 1997; Probert et al. 1997; Ardizzone et al. 1998; Liebman et al. 1998), anticardiolipin antibodies (Ciancio et al. 1996), Protein C (Wyshock, Caldwell & Crowley 1988; Korsten & Reis 1992) and Protein S deficiencies (Jorens et al. 1990; Aadland et al. 1992) in IBD have been contradictory or equivocal. We had previously found that IBD patients with a history of TED are not more likely to have a laboratory thrombophilic abnormality than those with uncomplicated disease. We also demonstrated that the prevalence of heterogenous laboratory thrombophilic abnormalities (usually minor) in all IBD patients may be as high as 60%, much higher than the recognized prevalence of TED (Lim, Jones & Gould 1996). We wondered how this would compare with the healthy non-IBD population. We have therefore explored the prevalence of such thrombophilic abnormalities in a group of IBD patients who had no history of TED and compared them with healthy age and sex matched controls.

Adult↗

Clinical use of intrapulmonary heparin.

Of 16 patients treated with intrapulmonary heparin at doses between 10,000 and 20,000 U/week for 1592 patient days, or 4.3 years, only one rethrombosed. This patient has a congenital antithrombin III deficiency. However, the use of intrapulmonary heparin, even in this particular patient, has remarkably decreased her thrombotic events as manifested by studying her history of deep vein thrombosis and pulmonary embolism prior to starting intrapulmonary heparin. This represents a failure rate of 4.2% in the total of 1592 patient days of therapy, or a rethrombosis rate of 1.4% per year. This recurrence rate is far superior to that reported for warfarin-type therapy or for platelet suppressive therapy. From this limited experience, it appears that heparin is an extremely safe and highly effective mode of outpatient prophylaxis for deep vein thrombosis and thromboembolic disease. The ultimate aim of this study is to determine the possibility of calcium heparin being placed into a hand-held aerosol nebulizer that a patient can use at home on a weekly basis. This would provide a highly convenient, safe, and apparently very efficacious mode of therapy for the long-term outpatient prophylaxis of deep vein thrombosis and thromboembolic disease.

Administration, Intranasal↗

Effect of argatroban, a selective thrombin inhibitor, on animal models of cerebral thrombosis.

Argatroban, (2R,4R)-4-methyl-1-(N2 [(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfonyl]-L-arginyl)-2-pi peridinecarboxylic acid, a selective and competitive thrombin inhibitor, was examined for effectiveness in three different experimental models of cerebral thrombosis in rats, namely, the four-vessel occlusion model, the middle cerebral artery occlusion model, and the distal middle cerebral artery occlusion model. Argatroban was demonstrated to be effective in these experimental models of thrombosis. Among these models, the distal middle cerebral artery occlusion model was the most similar to clinical cerebral thrombosis with respect to restriction of the infarction to the cerebral cortex and the accompanying stable neurologic deficits. In this model, the thrombus was generated at the Y-shaped bifurcation of the middle cerebral artery by green light irradiation through a cranial window after administration of rose bengal. Argatroban given after thrombus formation by intraperitoneal implantation of an osmotic pressure pump was shown to reduce infarct size and neurologic deficits on day 3 and microthrombi generation on day 1, and to raise the regional cerebral blood flow on day 1, at a plasma level of 0.2 to 0.6 microM supporting its clinical usefulness in the treatment of acute-phase cerebral thrombosis. Argatroban was considered to exert its effects by salvaging neuronal cells in the ischemic penumbra and suppressing extension of the infarction into the penumbra by keeping blood vessels patent, mainly through the inhibition of microthrombogenesis.

Acute Disease↗

[Percutaneous vascular endoprotheses for occlusions or stenoses of hemodialysis shunts].

In ten patients (four men and six women, mean age 51.7 [26-79] years), with six occlusions and five stenoses of a haemodialysis shunt or shunt-draining subclavian vein, a self-expanding intravascular stent was implanted percutaneously after balloon-dilatation. The implantation was successful in 9 of 11 instances, but the shunt thrombosed in two within 24 hours (in one of the patients, with antithrombin III deficiency, the shunt had to be abandoned). After an average observation period of 7.8 (1-14) months, ten shunts have remained open and suitable for dialysis. A further stent had to be implanted in one of the patients because of stenosis distal to the first stent. In three patients intima hyperplasia within the stent necessitated percutaneous balloon dilatation and/or atherectomy.

Adult↗

Ancrod: a practical alternative to heparin.

To rapidly start systemic anticoagulation there are few alternatives to heparin; those that may be used are often less effective and are impractical substitutes for various reasons. We report the cases of seven patients in whom anticoagulant therapy was begun with ancrod instead of heparin for one or more of the following reasons: (1) failure to achieve systemic anticoagulation in response to heparin (e.g., antithrombin III deficiency), (2) heparin-associated complications (e.g., thrombocytopenia, thrombosis, or both), and (3) combined anticoagulation and improved blood rheology considered to be potentially more beneficial than anticoagulation alone (e.g., massive thrombosis). In the cases reported, ancrod permitted systemic anticoagulation equal to that of heparin; this was achieved without bleeding complications. In contrast to streptokinase or urokinase, ancrod does not degrade preformed, fully cross-linked thrombin fibrin; consequently hemorrhagic complications are uncommon. Ancrod appears to be an appropriate alternative to heparin and may be preferable to it in certain circumstances.

Adult↗

Enhancement of heparin cofactor II anticoagulant activity.

Heparin cofactor II (HCII) is a serpin whose thrombin inhibition activity is accelerated by glycosaminoglycans. We describe the novel properties of a carboxyl-terminal histidine-tagged recombinant HCII (rHCII-CHis(6)). Thrombin inhibition by rHCII-CHis(6) was increased >2-fold at approximately 5 microgram/ml heparin compared with wild-type recombinant HCII (wt-rHCII) at 50-100 microgram/ml heparin. Enhanced activity of rHCII-CHis(6) was reversed by treatment with carboxypeptidase A. We assessed the role of the HCII acidic domain by constructing amino-terminal deletion mutants (Delta1-52, Delta1-68, and Delta1-75) in wt-rHCII and rHCII-CHis(6). Without glycosaminoglycan, unlike wt-rHCII deletion mutants, the rHCII-CHis(6) deletion mutants were less active compared with full-length rHCII-CHis(6). With glycosaminoglycans, Delta1-68 and Delta1-75 rHCIIs were all less active. We assessed the character of the tag by comparing rHCII-CHis(6), rHCII-CAla(6), and rHCII-CLys(6) to wt-rHCII. Only rHCII-CHis(6) had increased activity with heparin, whereas all three mutants have increased heparin binding. We generated a carboxyl-terminal histidine-tagged recombinant antithrombin III to study the tag on another serpin. Interestingly, this mutant antithrombin III had reduced heparin cofactor activity compared with wild-type protein. In a plasma-based assay, the glycosaminoglycan-dependent inhibition of thrombin by rHCII-CHis(6) was significantly greater compared with wt-rHCII. Thus, HCII variants with increased function, such as rHCII-CHis(6), may offer novel reagents for clinical application.

Alanine↗

An evaluation of 200 consecutive patients with spontaneous or recurrent thrombosis for primary hypercoagulable states.

Two hundred consecutive patients who were referred for evaluation of spontaneous or recurrent thrombosis were investigated for possible hypercoagulable states to determine the relative frequencies of these conditions in the Australian population and to identify features that would indicate which patients should be investigated with the expensive battery of tests for hypercoagulable states. Thirty-two percent were found to have prolongation of the postvenous occlusion euglobulin clot lysis time (PVO-ELT), 32% were found to have elevated levels of plasminogen activator inhibitor-1 (PAI) and 66% were found to have reduced release of tissue plasminogen activator (tPA). Antiphospholipid antibodies were found in 12%. Hereditary antithrombin III deficiency was found in 2%. Hereditary deficiency of the naturally-occurring anti-coagulant factors protein C and protein S was found in 2%. Age, sex, site of thrombosis (venous or arterial), or presence of a family history was not helpful in predicting a group more likely to have abnormal investigation results. Reduced fibrinolytic activity and the presence of antiphospholipid antibodies are the most common findings in patients with thromboembolic disease. Further prospective studies are required to assess the natural history and appropriate management of patients with these abnormalities.

Adolescent↗