Heparin and low molecular weight heparin for treatment of acute pulmonary embolism.

Pulmonary embolism occurs in more than 175,000 patients each year in the United States. The objectives of treatment are to prevent death from the existing embolus, to prevent death and morbidity from recurrent pulmonary embolism, and to prevent morbidity from recurrent deep-vein thrombosis. For patients with adequate cardiorespiratory reserve, the primary objective is to prevent recurrent pulmonary embolism. Anticoagulant therapy with intravenous unfractionated heparin or subcutaneous low molecular weight heparin followed by oral anticoagulant treatment for at least 3 months is the treatment of choice for most of these patients. Clinical trials indicate that the effectiveness of intravenous heparin depends on achieving an adequate heparin effect (activated partial thromboplastin time above lower limit) during the initial 24 hours. A validated protocol for intravenous heparin should be used to lessen the likelihood of delayed heparinization. Low molecular weight heparin given subcutaneously either once or twice daily is as effective as intravenous heparin for the treatment of patients with deep-vein thrombosis and submassive pulmonary embolism. Low molecular weight heparin enables many patients with uncomplicated deep-vein thrombosis to be treated in an outpatient setting.     

Treatment of thrombophlebitis

Dr. Lawrence W. Hanlon: Some of the problems of treatment of thrombophlebitis were explored this afternoon. There are many varieties of thrombophlebitis differing in their causes, clinical aspects and pathologic changes. The regimen of treatment should be adjusted to the special requirements of the particular patient. The differentiation between phlebothrombosis and thrombophlebitis has limited value, since after a time, the thrombi in the two become pathologically indistinguishable. While thrombophlebitis often makes its appearance with characteristic signs and symptoms, such as pain, tenderness, swelling, fever and elevated sedimentation time in many of these patients the onset is silent and the first indication of the disease is a pulmonary embolus. Emphasis was placed on the desirability of making routine systematic examinations of the legs in surgical and non-surgical patients confined to bed, as a means of uncovering cases of thrombophlebitis sufficiently early to make it possible to prevent pulmonary complications.The discussion covered measures that are useful in the prevention of thrombophlebitis, such as care against traumatization of vessels, prevention of infection, control of epidermophytosis, free movement in bed, early ambulation, deep respiratory exercises and the avoidance of the latter in thrombophlebitis to prevent pulmonary embolism. Attention was called to the highly controversial nature of the measures used in the treatment of thrombophlebitis; the application of heat and cold, the use of leeches, prolonged rest, free exercise, early ambulation, dependent and elevated position of the extremity, lumbosacral sympathetic block, prophylactic venous ligation and the use of anticoagulant agents. It was indicated that the consensus favors hot, moist packs to the affected extremity, the elevated position of the limb to control swelling, a middle course in relation to rest and activity, the patient being allowed up and about after a short period of rest even though the disease is not fully checked provided anticoagulant therapy is employed. There are those who recommend prophylactic ligation of the veins in thrombophlebitis of the lower extremity in order to prevent embolism, although others prefer a more conservative course, ligating only after there is proof that the vein is a source of recurrent embolization. The choice of site for ligation depends on the location of the phlebitis.The use of the anticoagulant agents, heparin and dicumarol, appears to be an advance of the first importance in the treatment of thrombophlebitis. Figures were cited showing most extraordinary results following their use; for example, second thrombosis or embolus was reduced from an incidence of nearly 50 per cent to about 1 per cent, cases of fatal pulmonary embolus with an incidence of nearly 6 per cent completely vanished. The discussion embraced the details of application, dosage, mode of action, dangers and methods of control of anticoagulant therapy.     

Effects of testosterone propionate and dicumarol on plasma prothrombin rate and serum cholesterol level in capons and orchiectomized rats

Capons and orchiectomized rats were used to investigate the effect of testosterone propionate and dicumarol on plasma prothrombin rate and serum cholesterol level. In capons, testosterone increased the prothrombin rate and decreased the cholesterol level. Dicumarol alone decreased the prothrombin rate but had no effect on cholesterol level. However, dicumarol in the presence of testosterone exhibited hypocholesterolemic effect. In rats, testosterone decreased both plasma prothrombin rate and cholesterol level. The effect of dicumarol was to decrease the prothrombin rate and increase the cholesterol level. The results show that the effect of testosterone on serum cholesterol is similar in the chick and the rat, but its effect on prothrombin rate is different, indicating that the coagulation system in the chick responds differently than that of the rat to exogenous testosterone at the level of administration used in this experiment.     

Heterozygous prothrombin gene mutation G20210A and associated diseases

PURPOSE: Prothrombin gene mutation G20210A (factor II) is, in frequency, the second genetic polymorphism involved in venous thrombosis. We report a retrospective studies on 38 patients issued from our medical department, all heterozygous for the factor II mutation and a literature review. METHODS: We have studied 38 patients, all heterozygous for the factor II mutation, selected through a population of 516 tested patients issued from our medical department from 1997 to 2002. The research was performed face with history of thrombotic or obstetrical events, angiopathy or familial screening. RESULTS: Twenty out of thirty-eight patients have at least one episode of venous thrombosis: superficial thromboses, deep thromboses and/or pulmonary embolism. One case of cerebral thrombophlebitis is observed. Venous thrombotic risk factors are associated in 12 cases (60%). Four out of thirty-eight patients have one episode of arterial thrombosis: cardiovascular, peripheral or cerebral. Arterial thrombotic risk factors are associated in all cases. Median age of the first venous thrombosis is earlier than the one of arterial thrombosis (39.11 versus 49.25 years). CONCLUSION: Our studies confirms the interest to search the prothrombin gene mutation when faced with a venous thrombotic event (deep vein thrombosis and/or pulmonary embolism) with or without acquired risk factors. Its involvement in thrombotic arterial disease is still a matter of debate. Data concerning its involvement in systemic diseases and angiopathies (thromboangeitis obliterans, Raynaud's phenomenon and migraine) are still needed. Mechanisms of thromboses could be an increase of prothrombin plasma level with high thrombin synthesis.     

Pulmonary infarction complicating thrombophlebitis of the upper extremity

Five cases of thrombophlebitis of the upper extremity in which pulmonary embolism occurred as a complication are presented. The etiology was secondary to chemical irritation in two cases, was unknown in one case and was probably traumatic in the fifth case. All of the patients having pulmonary emboli received anticoagulant therapy. Pulmonary emboli were controlled satisfactorily in two of the five patients. One patient died from repeated pulmonary emboli originating in the right axillary, brachial and subclavian veins, and multiple pulmonary infarctions were demonstrated at postmortem examination. Venous ligation was necessary in one of the remaining cases, and the fifth patient continued to have hemoptysis for six weeks even though the prothrombin time was maintained at therapeutic levels. This patient subsequently had recurrent thrombophlebitis of the upper extremity with pulmonary embolism, from which he recovered with conservative therapy.     

Hereditary protein C deficiency

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterozygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.     

Current status of anticoagulant therapy

Anticoagulant therapy has stood the test of time. Full-dose heparin and warfarin prevent recurring pulmonary embolism and deep venous thrombosis. Their use is indicated in patients who have experienced venous thromboembolism unless contraindications are compelling. Low-dose heparin is successful in preventing the initial episode of venous thrombosis in most patients at high risk for the development of thrombophlebitis. Warfarin reduces the incidence of systemic embolization in patients with heart disease and atrial fibrillation and in patients with artificial heart valves. Evidence is accumulating to suggest that warfarin may still retain an important role in the management of patients with myocardial infarction. However, bleeding remains an inevitable risk in patients receiving anticoagulant therapy. The risk, however, can be diminished when both the physician and patient understand the mechanism of action of the drugs and the factors that predispose to bleeding.     

Thrombolytic therapy for noncoronary diseases

Thrombolytic therapy has been used fairly extensively in the management of acute proximal deep-vein thrombophlebitis of the extremities, acute pulmonary embolism, and acute peripheral arterial thrombosis and embolism in addition to acute thrombotic coronary events. In the presence of acceptable indications and a favorable benefit to risk ratio, this form of therapy, when successful, has served as a useful adjunct in the management of these disorders. In deep-vein thrombophlebitis, lysis of the thrombus before permanent pathological changes (eg, organization, scarring) have occurred can prevent venous valvular dysfunction and postural venous hypertension and its complications, especially the postphlebitic syndrome. In the more severe forms of acute pulmonary embolism, thrombolytic therapy, when applied early after symptom onset, decreases morbidity and is likely to prevent a chronic increase in pulmonary vascular resistance and persistent pulmonary hypertension. In peripheral arterial thrombo-occlusive events, early restoration of flow through thrombolysis has been shown to limit ischemic damage and serve as a useful supplement to angioplasty or surgery. Thrombolytic therapy has been used less extensively in acute strokes. Here the danger of reperfusion causing bleeding into a softened area of brain undergoing infarction has slowed its evaluation for this disorder; its application to stroke remains experimental.     

Prevention of venous thromboembolism

The aim of prophylaxis in venous thromboembolism is firstly to prevent fatal pulmonary embolism and secondly to reduce the morbidity associated with deep vein thrombosis and the post-phlebitic limb. Particularly high-risk groups are identifiable and include those over 60 years of age undergoing major surgery, patients with malignancy and those undergoing hip operations. Low-dose subcutaneous heparin (5000 U s.c. commenced two hours preoperatively and continued eight to twelve hourly until the patient is fully mobile) is unequivocally effective in preventing deep vein thrombosis in medical and surgical patients and, most importantly, significantly reduces the incidence of fatal postoperative pulmonary embolism and total mortality. Furthermore, in established deep vein thrombosis, low-dose heparin limits proximal clot propagation, which is the prelude to pulmonary embolism. Despite this, surveys have demonstrated an alarming deficiency amongst clinicians in the application of measures to prevent venous thromboembolism. Heparin prophylaxis carries a small risk of increased bleeding complications, mostly evidenced by the frequency of wound haematoma rather than major haemorrhage. Low molecular heparin fragments (e.g. Fragmin, Choay, Enoxaprin) are now emerging as useful alternative agents, having the advantage of once daily administration and yet providing similar efficacy in the prevention of deep vein thrombosis. However, protection against fatal pulmonary embolism has yet to be demonstrated. Mechanical methods of prophylaxis designed to counteract venous stasis, such as graduated elastic compression stockings, are also beneficial in protection against deep vein thrombosis but by themselves do not achieve such consistently good prophylaxis as low-dose heparin. However, clinical trials with combinations of mechanical methods and low-dose heparin indicate that this may be the optimum approach to very high-risk patients. In the presence of established acute deep vein thrombosis, anticoagulant therapy is the mainstay in preventing pulmonary embolism. Vena caval interruption procedures should be reserved for patients in whom anticoagulation is contraindicated or for those who develop recurrent pulmonary embolism despite adequate anticoagulation.     

Despite imperfect sensitivity, ultrasound thrombosis detection following arthroplasty is useful

We sought to determine whether ultrasound may be used to screen for deep venous thrombosis 7 days following arthroplasty (despite its known imperfect sensitivity), to select a population at high risk of pulmonary embolism from day 7 to 90 after surgery. Complete bilateral triplex ultrasound imaging was scheduled for 656 patients one week after primary total hip or knee replacement. Prophylactic low molecular weight heparin administration was replaced by anticoagulant treatment if a thrombosis was detected. Venous thrombosis, pulmonary embolism and haemorrhage were recorded at 3 months, as were deaths. Thrombo-embolic events were observed in 83 of 656 patients at one week (mainly asymptomatic). Age >60 years, knee (versus hip) arthroplasty or a history of varicose veins were associated with a significantly increased risk of thrombosis at day 7 (p<0.0001). Three of these 83 patients (3.6%) suffered from pulmonary embolism (1 fatal) between days 7 and 90, despite efficient anticoagulant treatment. Treatment of venous thrombosis in these 83 patients was associated with one re-admission for haemorrhagic complications (1.2%). In the remaining 573 patients between day 7 and 90, two patients suffered from pulmonary embolism, 12 others developed a venous thrombosis and 6 were re-admitted for haemorrhage (1 fatal). Neither age≥60 years, varicoses veins, nor knee (vs. hip) arthroplasty significantly increased the risk of delayed pulmonary embolism. Ultrasound is useful for the detection of asymptomatic deep venous thrombosis following arthroplasty. A positive echo-doppler (and no other clinical index) increases by 10 times (p<0.01) the risk of delayed pulmonary embolism despite anticoagulant therapy as compared to subjects with no evidence of thrombosis receiving prophylaxis.     

Therapy of deep vein thrombosis

Adequate anticoagulation treatment in patients with deep vein thrombosis reduces the risk of thrombus extension or embolization to less than 5%. Thrombolytic treatment may possibly prevent subsequent postthrombotic syndrome. Heparin is the initial treatment of choice for most patients with deep vein thrombosis. The dose is adjusted according to the results of tests such as the whole blood clotting time, thrombin clotting time, activated partial thromboplastin time or plasma heparin concentration. The most commonly used test is the activated partial thromboplastin time which should be maintained at 1 1/2 to two times the control level. Initially the test should be performed two to three times daily and when optimal adjustment has been established, clotting studies are required only at 24-hour intervals. In general, treatment with intravenous heparin should be continued for seven to ten days. Thereafter, for secondary prophylaxis, treatment with oral anticoagulants is carried out for six to eight weeks for symptomatic lower leg thrombosis, for twelve weeks in the case of proximal venous thrombosis and pulmonary embolism. Oral anticoagulant therapy with warfarin should be given overlapping the last few days of heparin with the dose adjusted to prolong the prothrombin time to 1.3 to 1.5 times control. Initially, the prothrombin time should be monitored weekly, thereafter at intervals of two to three weeks. If oral anticoagulant therapy is contraindicated, secondary prophylaxis with subcutaneous heparin given twice daily in doses sufficient to prolong the activated partial thromboplastin time to 1 1/2 times control is an effective and safe alternative. The major side effect of oral anticoagulant therapy, as well as that of heparin, is bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unexpected high prevalence of silent pulmonary embolism in patients with deep venous thrombosis

In patients presenting with clinically suspected deep vein thrombosis, symptomatic pulmonary embolism is rarely apparent. To assess the prevalence of silent pulmonary embolism in outpatients with proven deep vein thrombosis but without symptoms of pulmonary embolism, perfusion ventilation lung scans were performed in 101 consecutive patients at presentation. Fifty-one percent of these patients had a high probability lung scan at the initiation of treatment. In comparison, in patients referred with suspected venous thrombosis, but who on subsequent objective testing did not have venous thrombosis (n = 44), the prevalence of a high probability-scan for pulmonary embolus was only 5 percent. At repeat lung scanning, performed after one week of anticoagulant treatment, complete to partial improvement was observed in 68 percent of the patients with initially abnormal scans. Lung-scan detected asymptomatic pulmonary embolism occurs frequently in patients presenting with symptomatic deep venous thrombosis, and the majority of these emboli showed significant to complete resolution within one week of anticoagulant treatment.     

Are patients with multiple sclerosis protected from thrombophlebitis and pulmonary embolism?

To study the incidence of deep venous thrombophlebitis (DVT) and pulmonary embolism (PE) in patients with multiple sclerosis (MS), charts of 228 subjects with multiple sclerosis who constituted 1986 hospital admissions to the Milwaukee Regional Medical Center were reviewed, covering a 3 1/2-year period. The records were investigated for any other hospitalization for deep venous thrombophlebitis and pulmonary embolism. No case of pulmonary embolism or deep venous thrombophlebitis was found. There were over 57,416 non-MS-related admissions during the same interval. Among these patients there were 175 with PE and 258 with DVT. The presence of lower extremity spastic disease may have prevented clotting. This statistically low incidence of thromboembolic events in MS is less than expected, and further studies are warranted.     

Disseminated arterial occlusions revealing bilateral venous thrombosis with paradoxical embolisms

Paradoxical embolism is a diagnosis of exclusion. Clinical triad associates deep venous thrombosis with or without pulmonary embolism, arterial embolism, and intracardiac communication with right-to-left shunt. The intracardiac communication is generally related to a patent foramen ovale (PFO). We report a 75-year-old patient, who presented with bilateral deep venous thrombosis of the legs, complicated by massive pulmonary embolism and paradoxical embolisms through a PFO. This resulted in cerebral, mesenteric, splenic and bilateral kidney infarctions. A promptly initiated anticoagulant treatment allowed a favourable outcome.     

When and how to use heparin prophylaxis and treatment.

Heparin is a naturally occurring anticoagulant drug that combines with anti-thrombin III to inhibit many steps of the coagulation pathway. Clinically, heparin is used in small doses to prevent venous thrombosis and pulmonary embolism; in large doses, it is the treatment of choice in acute venous thromboembolism. Heparin also is used to treat some acute arterial thromboembolic episodes. Heparin may be given by intermittent intravenous injection or continuous intravenous infusion, usually in doses of approximately 30,000 units per day. Hemorrhage, the main side effect of heparin, appears to be less frequent when therapeutic doses are given by continuous intravenous infusion rather than by intermittent intravenous injection.     

The noninvasive diagnosis of thrombophlebitis in the lower extremities: clinical value of plethysmography combined with augmentation methods and a new scoring system.

Venous impedance plethysmography and respiratory-compression Doppler augmentation responses have proved to be diagnostically valuable in suspected thrombophlebitis of the lower extremities. These noninvasive methods can provide quantitative and reproducible data on the basis of which the presence of increased deep venous resistance can be confirmed, suspected, or doubted. A new scoring system for the composite evaluation of data from 100 consecutive patients with possible thrombophlebitis, pulmonary embolism, or both, is presented. These procedures assume added importance in view of the diagnostic limitations, and even potential hazards, of other methods. These methods indluce lung scanning, radioactive fibrinogen scanning, venography, and pulmonary angiography. Serial studies can be performed with impunity for following highrisk patients and evaluating various therapeutic or prophylactic measures. The importance of monitoring the femoral-popliteal segment is emphasized, because of the greater propensity for massive pulmonary thromboembolism from thrombi in these veins than in the calf vessels. Clinical observations coupled with these studies underscore the fallacy of several widely-held diagnostic biases pertaining to deep venous thrombosis and pulmonary thromboembolism. The long-term followup of 12 patients in whom inferior vena cava unbrellas has been inserted for life-threatening pulmonary embolism is presented. The possible propensity to deep vein thrombosis from vitamin E therapy is raised.     

Diagnosis of pulmonary embolism.

The patient with suspected pulmonary embolism presents a challenging diagnostic problem. The symptoms and signs are nonspecific, and objective testing is required to establish or exclude the presence of pulmonary embolism. Lung scanning continues to be a first-line test, but in 40% to 70% of all patients, the results do not definitively provide indication for either giving or withholding anticoagulant treatment even when combined with the clinical assessment. Pulmonary angiography is the reference standard, but it is invasive and may not be available in all clinical settings. Pulmonary embolism is strongly associated with proximal deep-vein thrombosis of the legs (popliteal, femoral, or iliac vein thrombosis). Objective testing for proximal deep-vein thrombosis is useful in patients with suspected pulmonary embolism. A positive result from such testing provides an indication for anticoagulant treatment. Serial testing for proximal deep-vein thrombosis is a safe and effective alternative to pulmonary angiography in patients with adequate cardiorespiratory reserve. The assay for plasma D-dimer using either a rapid enzyme-linked immunospecific assay technique or a bedside whole-blood agglutination technique is promising as a test for excluding venous thromboembolism. A positive result by spiral CT imaging is useful for ruling in a diagnosis of pulmonary embolism, but the safety of withholding treatment in patients with negative spiral CT results remains uncertain. Pulmonary angiography continues to have an important role in selected patients in whom it is critical to definitively confirm or exclude the presence of pulmonary embolism.     

Anticoagulant proteins in childhood venous and arterial thrombosis: a review

Thrombotic disease is less frequent in children than in adults, but may result in severe morbidity and mortality. The coagulation system is balanced to provide rapid activation to stop bleeding and appropriate inhibition to prevent unwanted clot extension. It is regulated by fibrinolysis and by three major anticoagulant pathways: the protein C, antithrombin, and tissue factor pathway inhibitor systems. Acquired or inherited abnormalities of coagulation proteins or hemostatic regulatory mechanisms, particularly when combined with dehydration or the presence of indwelling catheters, may pose a high risk for thrombosis. Thrombosis in a child warrants investigation of potential underlying prothrombotic conditions. These include acquired antiphospholipid antibodies or the lupus anticoagulant as well as abnormalities of the inherited anticoagulant factors including protein C, protein S, antithrombin, and Factor V Leiden. Other abnormalities may result in heightened levels of otherwise normal coagulation proteins such as hyperprothrombinemia due to the prothrombin 20210 mutation. A large survey of children with thrombosis indicated that Factor V Leiden, protein C deficiency, and increased lipoprotein(a) were found most commonly. The most severe predisposition occurs with homozygous protein S or protein C deficiency with resultant purpura fulminans in the newborn. The risk of thrombosis in children with heterozygous deficiencies of anticoagulant proteins is not well defined, although it is clear that combined heterozygotes or a combination of an inherited and an acquired defect heightens the risk for thrombosis. Treatment of thrombosis primarily involves a rapidly acting anticoagulant such as heparin or low-molecular-weight heparin to prevent extension, and long-term anticoagulation with warfarin may be instituted to prevent recurrence. Fibrinolytic therapy is infrequently used because of the risk of serious bleeding complications and is reserved for selected cases of arterial thrombosis to initiate rapid reperfusion of ischemic tissue or used in those patients with a large venous thrombosis and pulmonary emboli causing hemodynamic compromise.     

Outpatient treatment of patients with deep-vein thrombosis or pulmonary embolism

There have been a large number of randomized trials comparing standard unfractionated intravenous heparin with low-molecular-weight heparin for the treatment of deep-vein thrombosis, but only two of these have looked at outpatient therapy. There have been only two randomized trials including patients with symptomatic pulmonary embolism, and neither of these provided outpatient therapy. Postmortem and clinical studies have shown a strong association between pulmonary embolism and the presence of venous thrombosis in the lower limbs. Based on similar rates of venous thromboembolic recurrence and death, these studies suggest that initial treatment should be the same for deep-vein thrombosis and pulmonary embolism. The feasibility of providing outpatient care to many patients seeking treatment for deep-vein thrombosis or acute pulmonary embolism at certain tertiary care hospitals has become evident, but the data suggest that the proportion of eligible patients is institution dependent and may vary from 18% to 91%. In the author's institution, approximately 50% of patients with pulmonary embolism could be treated as outpatients, but there have been no other reports on outpatient therapy for patients with pulmonary embolism. If patients with pulmonary embolism meet criteria demonstrated to result in a higher risk of death, it is, of course, reasonable to not treat such patients on an outpatient basis. Low-molecular-weight heparin followed by oral anticoagulant therapy provides adequate therapy in most patients with deep-vein thrombosis or pulmonary embolism, and many patients can be treated as outpatients.     

Syncope in patients with pulmonary embolism: comparison between patients with syncope as the presenting symptom of pulmonary embolism and patients with pulmonary embolism without syncope

Syncope as an initial presentation of pulmonary embolism occurs in 10% of patients. We compared clinical and instrumental parameters in patients with syncope as the presenting symptom of pulmonary embolism and in patients with documented pulmonary embolism without syncope. Seventy patients with the diagnosis of pulmonary embolism and apparently stable clinical conditions were evaluated. They were divided in two groups: 10 patients with syncope as the presenting symptom of pulmonary embolism (group 1) and 60 patients without syncope (group 2). Patients with syncope showed a more pronounced tendency to present with main pulmonary artery embolus than patients without syncope (contingency coefficient = 0.301, p < 0.04; one-tailed). However, despite the evidence that patients with syncope have significant reductions in systolic and/or diastolic blood pressure, shock was not observed in any patient. In no case was thrombolytic treatment given and all patients received standard anticoagulation with unfractioned heparin and oral anticoagulant. We suggest that syncope in the setting of non-massive pulmonary embolism may be due to vaso-vagal mechanism that can lead to a reduction of arterial blood pressure when central artery thrombosis is involved.