The rheological changes after cesarean section: The influence of low molecular weight or unfractionated heparin on the rheological properties of blood.

Thromboembolic complications remain an important cause of maternal mortality. The present recommendations favour for prophylaxis unfractionated (UFH) and low molecular weight heparin (LMWH). We investigated 150 pregnant women before and after cesarean section in three randomized groups. Fifty women received no prophylaxis (group I), 50 women UFH two times 5000 IU/day (group III) and 50 women Dalteparin 5000 U/day (group II). We determined the blood count, the rheological parameters and cholesterol, triglycerides, D-dimer, fibrinogen and the anti-Xa-level. We found a classical hemodilution, with increase of erythrocyte aggregation and plasma viscosity postoperatively. The fibrinogen turnover and D-dimer concentration were elevated. The patients with Dalteparin prophylaxis showed lower thrombin activation, minor changes in the cholesterol and triglycerides level and an improvement of red cell deformability in low shear regions. Our results demonstrated an influence of Dalteparin on the rheological parameters post surgery. The DVT incidence was 1.33% generally and occurred only in the Control group and in women with unfractionated heparin. We observed no side effects such as major bleeding, osteopenia or allergy.

Antiphospholipid thrombosis syndromes.

Antiphospholipid antibodies are strongly associated with thrombosis and are the most common of the acquired blood protein defects causing thrombosis. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagutable state remain unclear, numerous theories, as previously discussed, have been advanced. The most common thrombotic events associated with anticardiolipin antibodies are deep vein thrombosis and pulmonary embolus (type I syndrome), coronary or peripheral artery thrombosis (type II syndrome), or cerebrovascular/retinal vessel thrombosis (type II syndrome); occasionally, patients present with mixtures of these types (type IV syndrome). Type V patients are those with antiphospholipid antibodies and RMS. It is as yet unclear how many seemingly normal individuals who may never develop manifestations of antiphospholipid syndrome (type VI) harbor asymptomatic antiphospholipid antibodies. The relative frequency of anticardiolipin antibodies in association with arterial and venous thrombosis strongly suggests that these should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed. Also, the type of syndrome (I through VI) should be defined if possible, as this may dictate both type and duration of both immediate and long-term anticoagulant therapy. Unlike those with anticardiolipin antibodies, patients with primary lupus anticoagulant thrombosis syndrome usually experience venous thrombosis. Because the aPTT is unreliable inpatients with lupus anticoagulant (prolonged in only about 40 to 50% of patients) and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, including ELISA for anticardiolipin antibodies, the dRVVT for lupus anticoagulant, hexagonal phospholipid neutralization procedure, and beta-2-GP-I (IgG, IgA, and IgM) should be immediately ordered when suspecting antiphospholipid syndrome or in individuals with otherwise unexplained thrombotic or thromboembolic events. If results of these tests are negative, in the appropriate clinical setting, subgroups should also be assessed. Finally, most patients with antiphospholipid thrombosis syndrome will fail warfarin therapy and, except for retinal vascular thrombosis, may fail some types of antiplatelet therapy; thus it is of major importance to make this diagnosis so that patients can be treated with the most effective therapy for secondary prevention--LMWH or UH in most instances, and clopidogrel in some instances.

Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.

Stasis ulcers are commonly the result of chronic venous insufficiency. We have recently assessed 15 patients with stasis ulcers that failed to heal after one year of routine wound care. All patients demonstrated a defect in hemostasis, and a biopsy revealed livido vasculitis. Eleven of fifteen patients were treated with clopidogrel and dalteparin, and 4 of 15 patients were treated with clopidogrel alone. Thirteen of fifteen patients (86.6%) completely healed within three months of starting antithrombotic therapy. Patients with stasis ulcers and chronic venous insufficiency who fail to heal with routine wound care should be subjected to biopsy, a procoagulant defect evaluation, and initiation of clopidogrel and dalteparin therapy if a defect is found.

Proficient and cost-effective approaches for the prevention and treatment of venous thrombosis and thromboembolism.

Thrombosis is clearly a common cause of death in the US. It is obviously of major importance to define the aetiology of deep vein thrombosis (DVT) as (i) many of these events are preventable if appropriate therapy, dependent upon the risk factors known is utilised; (ii) appropriate antithrombotic therapy will decrease risks of recurrence; (iii) the type of defect(s) and risk(s) will determine length of time the patient should remain on therapy for secondary prevention and (iv) if the defect is hereditary appropriate family members can be assessed. Aside from mortality, significant additional morbidity occurs from DVT including, but not limited to, stasis ulcers and other sequelae of post-phlebitic syndrome. Numerous studies have provided evidence that medical patients and patients undergoing surgery or trauma are at significant risk for developing DVT, including pulmonary embolism (PE). Thus, an important task for the clinician is to prevent DVT and its complications. It is important to define risk groups where prophylaxis must be considered. The attitudes and beliefs towards prophylaxis show great regional variations. This is true for the definition of risk groups, the proportion of patients receiving prophylaxis and prophylactic modalities used. For this reason, various 'consensus conference' groups have attempted to alleviate these problems; the primary mission of consensus guidelines is to provide optimal direction to the clinician in the setting of clinical practice. If the practice guidelines generated are successful they will assist clinicians in decision-making for their patients, and they will also provide protection against unjustified malpractice actions. Therapy may be complex, as clinical studies continue to identify more effective treatments. This review includes currently accepted approaches to the treatment of DVT. The clinical course of DVT is highly dynamic. When the response to therapy is not as expected, more than one cause of DVT may be present in a patient. Treatment must address the primary coagulopathy as well as any precipitating factors. The risk of pharmacological intervention must be balanced against potential benefit. If the incidence of DVT in a given disorder is low and if the mortality rate is similarly low, therapy with an agent known to be associated with a high risk for complications, such as warfarin, would not be indicated. If DVT is seen primarily after surgery or in other high-risk situations, therapy might be limited to a fixed time period. However, if the ongoing risk of DVT remains high or if a history of recurrent DVT dictates, lifelong therapy might be indicated. The recommendations presented are based upon published controlled trials; however, indications for therapy and therapeutic agents of choice will continually evolve. By applying the principles outlined in this review, substantial cost savings, reduction in morbidity and reductions in mortality should occur.

An update on heparins at the beginning of the new millennium.

Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a century. Besides an effective anticoagulant, this drug has been used in several additional indications. Despite the development of newer anticoagulant drugs, unfractionated heparin has remained the drug of choice for surgical anticoagulation and interventional cardiology. In the area of hematology and transfusion medicine, unfractionated heparin has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent a class of depolymerized heparin derivatives with a distinct pharmacologic profile that is largely determined by their composition. These drugs produce their major effects by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic mediators from the blood vessels. The cumulative effects of each of the different LMWHs differ and each product exhibits a distinct profile. Initially these agents were developed for the prophylaxis of postsurgical deep-vein thrombosis. However, at this time these drugs are used not only for prophylaxis, but also for the treatment of thrombotic disorders of both the venous and arterial type. To a large extent, the LMWHs have replaced unfractionated heparin in most subcutaneous indications. With the use of these refined heparins, outpatient anticoagulant management has gone through a dramatic evolution. For the first time, patients with thrombotic disorders can be treated in an outpatient setting. Thus, the introduction of LMWHs represents a major advance in improving the use of heparin. The development of the oral formulation of heparin and LMWHs also provides an important area that may impact on the use of heparin and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated the development of newer methods to identify patients at risk of developing this catastrophic syndrome. Furthermore, a strong interest has developed in alternate drugs or the management of patients with this syndrome. Despite the development of alternate anticoagulants that are mostly antithrombin derived (hirudins, hirulog), these agents have failed to provide similar clinical outcome as heparin in many indications. However, antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. The FDA has approved a recombinant hirudin (Refludan) and a synthetic antithrombin agent, argatroban (Novastan), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa agents may have an impact on the prophylaxis of thrombotic disorders. However, these monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore, these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting not only factor Xa and thrombin, but other serine proteases in the coagulation network. The only way the newer drugs can mimic the actions of heparin is in combination modalities (polytherapeutic approaches). It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions. While these drugs may exhibit weak effects on thrombin generation, none of the currently available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely that heparins synergize or augment the effects of the new antiplatelet drugs. Currently, combination approaches are used to anticoagulate patients in these studies. The dosage of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional clinical studies are needed to study these combinations where the alterations of these drugs are compared. Such combinations will require newer monitoring approaches. The development of oral thrombin agents, GP IIb

Syndromes of disseminated intravascular coagulation in obstetrics, pregnancy, and gynecology. Objective criteria for diagnosis and management.

This article presents current understanding of the causes, pathophysiology, clinical, and laboratory diagnosis, and management of fulminant and low-grade DIC, as they apply to obstetric, pregnant, and gynecologic patients. General medical complications leading to DIC, which may often be seen in these patients, are also discussed. Considerable attention has been given to interrelationships within the hemostasis system. Only by clearly understanding these pathophysiologic interrelationships can the obstetrician/gynecologist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Objective clinical and laboratory criteria for diagnosis of DIC have been outlined to eliminate unnecessary confusion and the need to make empiric decisions regarding the diagnosis. Particularly in the obstetric patient, if a condition is observed that is associated with DIC, or if any suspicion of DIC arises from either clinical or laboratory findings, it is imperative to monitor the patient carefully with clinical and laboratory tools to assess any progression to a catastrophic event. In most instances of DIC in obstetric patients, the disease can be ameliorated easily at early stages. Many therapeutic decisions are straightforward, particularly in obstetric and gynecologic patients. For more serious and complicated cases of DIC in these patients, however, efficacy and choices of therapy will remain unclear until more information is published regarding response rates and survival patterns. Also, therapy must be highly individualized according to the nature of DIC, patient's age, origin of DIC, site and severity of hemorrhage or thrombosis, and hemodynamic and other clinical parameters. Finally, many syndromes that are often categorized as organ-specific disorders and are sometimes identified as independent disease entities, such as AFE syndrome, HELLP syndrome, adult shock lung syndrome, eclampsia, and many others, either share common pathophysiology with DIC or are simply a form of DIC. These entities represent the varied modes of clinical expression of DIC and illustrate the diverse clinical and anatomic manifestations of this syndrome.

Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects.

Recurrent miscarriage syndrome and infertility are common problems in the United States. Recurrent miscarriage affects more than 500,000 women annually. If properly screened through a cost-effective protocol, the cause will be found in almost all women. The most common singular defect in women with RMS is a hemostasis defect, and if a thorough APLS evaluation is performed, the most common of these is found to be APLS. Other hereditary and acquired procoagulant defects are also commonly found, if looked for. It is important to evaluate women with RMS appropriately, because if a cause for the RMS is found, most women will achieve normal-term delivery. Hemorrhagic defects are rare hemostasis causes of RMS, but these defects also are treatable in many instances and should be considered in appropriate women. Treatment of the common procoagulant defects consists of preconception low-dose ASA at 81 mg/day followed by immediate postconception low-dose unfractionated porcine heparin. LMWH may be a suitable alternative.

Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Miscarriage Syndrome Cooperative Group.

Although first-time miscarriages are usually caused by chromosomal defects, about 55% of recurrent miscarriages are caused by procoagulant defects that induce thrombosis and infarction of placental vessels. Of recurrent miscarriages, about 7% are caused by chromosome defects, 15% to hormonal defects, and 10% to 15% to anatomical defects. Recurrent miscarriage involves more than 500,000 women in the United States each year. During the past 4 years, 179 patients, prescreened for chromosomal, hormonal, and anatomical defects, and found to harbor none, underwent hemostasis defect evaluation. A total of 160 of these have been analyzed. A hemostasis defect was found in 150 of 160 women (n = 94% of screened women). The mean age was 33 years; the mean number of miscarriages before referral was three. All women with a procoagulant defect (149) were treated with preconception ASA at 81 mg/d, and unfractionated porcine heparin at 5000 U every 12 hours was added immediately postconception; both agents were used to term delivery. Only two of 149 patients failed therapy. The defects found were as follows: antiphospholipid syndrome, 67%; sticky platelet syndrome, 21%; tissue plasminogen activator (TPA) deficiency, 9%; factor V Leiden, 7%; high PAI-1, 6%; protein S, 5%; high LP(a), 3%; AT, 2%; protein C, 1%. Thirty-eight patients had more than one defect. In the group with antiphospholipid syndrome, 24% only had a subgroup antibody (antiphosphatidyl-serine, -inositol, -ethanolamine, -choline, -glycerol) or antiphosphatidic acid antibody, in the absence of anticardiolipin antibody or lupus anticoagulant. This finding is similar to that recently reported in early age ischemic stroke patients (<50 years old). In summary, about 55% of patients with recurrent miscarriage harbor a procoagulant defect to account for placental vascular occlusion. More than 98% will have a normal term delivery with preconception aspirin (ASA) and addition of postconception heparin to term. Patients should be screened by an obstetrician or by reproductive specialists for hormonal and anatomic defects before initiating a procoagulant evaluation; if such prescreening is done, the yield of a defect is high and appropriate therapy leads to an excellent outcome.

Acquired defects of fibrinolysis associated with thrombosis.

Physiologic regulation of fibrinolysis plays an important role in the control of hypercoagulable states and thrombogenesis. Both the hereditary and acquired conditions leading to fibrinolytic deficit result in thrombotic complications leading to arterial and venous occlusive disorders. Several changes in physiologic states such as pregnancy, old age, stress, obesity, and temperature alterations lead to the modulation of the fibrinolytic system. Various disease states, surgery, radiation, and diet can also trigger mechanisms leading to impaired fibrinolytic states. Several drugs, including anticancer agents, oral contraceptives, cytokines, and blood components can also produce transitory fibrinolytic deficit which can predispose patients to thrombotic complications. The identification of the patient populations with an impaired fibrinolytic state is an important step toward the prevention of thrombotic complications which may lead to such catastrophic events as myocardial infarction and thrombotic strokes. Both functional and immunologic methods have currently become available for the rapid diagnosis of fibrinolytic deficit. Thus, it is important to evaluate patients who are at risk of thrombotic complications due to fibrinolytic deficit. Currently, specific guidelines are developed to identify high risk groups and propose methods to manage these groups of patients.

Prothrombin G20210A gene mutation, heparin cofactor II defects, primary (essential) thrombocythemia, and thrombohemorrhagic manifestations.

This article addresses the issue of thromboembolic disorders associated with the prothrombin G20210A gene mutation, with heparin cofactor II (HC-II) defects and with primary (essential) thrombocythemia. The prothrombin gene mutation is of recent discovery, is inherited as an autosomal dominant disorder, and seems to be highly prevalent in the general white population. The incidence is almost as high as that known for factor V Leiden. Both venous and arterial thromboses are noted, especially deep venous thrombosis, including cerebral venous events and myocardial infarction. As with other congenital thrombophilic states, additional risk factors or multiple defects seem to precipitate the events. Although initially elevated plasma prothrombin levels were described in these patients, this is no longer valid for all patients. At this time there is no easy screening test to detect this defect, but, because of the high prevalence, prothrombin G20210A gene mutation should routinely be assayed for in thrombophilic patients. The association between HC-II defects and thromboembolism is more controversial, and reports both confirming and denying this association have been described. The congenital form of HC-II defect is autosomal dominant. HC-II can be determined by its activity and immunologically. HC-II defects very likely play a role in conjunction with other congenital or acquired defects. Acquired HC-II defects are found in association with systemic disseminated intravascular coagulation (DIC) but not with local activation of the hemostasis system. HC-II levels are also decreased in preeclamptic women, and newborns have physiologically low levels. HC-II defects in thrombophilic patients should be considered after the more common disorders have been ruled out. Primary (essential) thrombocythemia can be associated with both thromboembolic events and bleeding. Typical thrombotic manifestations are erythromelalgia and microvascular thrombosis. Also, pregnant females suffer high rates of complications, such as spontaneous abortion. A number of treatment modalities are at present available to not only decrease platelet counts but also manage thromboembolic events.

Treatment of hereditary and acquired thrombophilic disorders.

The treatment of hereditary and acquired thrombophilic disorders is based on an understanding of the disease pathophysiology, prevalence, associated morbidity and mortality, and available therapeutic options. Genetic mutations are identified that result in activated protein C (APC) resistance and hyperhomocyst(e)inemia. The underlying etiologies are less well-defined; however, the disorders of factor XII deficiency, dysfibrinogenemia, Wien-Penzing platelet defect, and sticky platelet syndrome (SPS) are treatable inherited thrombophilias. Antithrombin deficiency, protein C and protein S deficiencies, and plasminogen deficiency are disorders both inherited and acquired. Antiphospholipid antibodies, myeloproliferative syndromes, and Trousseau's syndrome are acquired. Treatment for acute arterial thrombosis or venous thromboembolism is the same or similar for all thrombophilic disorders. Long-term management is based on the risk of a primary or recurrent acute thrombotic event, compared with the risk of the proposed therapy. Few blinded, controlled studies are available to validate treatment recommendations. When long-term anticoagulation is advised, careful consideration should be given to the risk associated with therapy. Bleeding risk, variable efficacy, and the risk of cutaneous necrosis limit the use of warfarin. Fixed low-dose unfractionated porcine heparin and low-molecular-weight heparins (LMWH) offer significant advantages for long-term management. These recommendations are derived from an analysis of the pertinent medical literature and are expected to change with the progress of clinical and laboratory investigation.

Low molecular weight heparins in the outpatient management of venous thromboembolism.

Low molecular weight heparin (LMWH) has challenged the position of unfractionated heparin (UFH) as the treatment of choice in preventing progression, recurrence, and complications of venous thromboembolism (VTE). A meta-analysis of 13 randomized trials has shown that subcutaneous LMWH is associated with lower rates of recurrence, bleeding, and mortality than is intravenous UFH. The use of subcutaneous LMWH yields substantial savings in pharmacy and nursing costs. Recent trials have demonstrated that home treatment with enoxaparin and dalteparin is at least as safe and effective as inpatient treatment with UFH, is feasible in more than 70% of patients with VTE, and is associated with improved quality of life. Home treatment saves as much as $6000 per patient relative to inpatient treatment with UFH and nearly $3000 per patient relative to inpatient treatment with LMWH. Of the three LMWH preparations available in the United States, enoxaparin, dalteparin, and ardeparin, only enoxaparin is approved for the treatment of deep-vein thrombosis. These LMWHs differ substantially in molecular weight and molecular size distribution, bleeding indices in animal models, anti-Xa activity, anti-Xa/anti-IIa ratio, and release of tissue factor pathway inhibitor. Although the clinical relevance of these differences remains uncertain, the United States Food and Drug Administration recognizes LMWHs as distinct noninterchangeable drugs.

Antiphospholipid syndrome and thrombosis.

Antiphospholipid antibodies [such as anticardiolipin antibodies (ACLA)] are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagulable state remain unclear, several theories have been advanced. The most common thrombotic events associated with ACLA are deep vein thrombosis and pulmonary embolus (type I syndrome), coronary or peripheral artery thrombosis (type II syndrome) or cerebrovascular/retinal vessel thrombosis (type III syndrome), and occasionally patients present with mixtures (type IV syndrome). Type V patients are those with antiphospholipid antibodies and fetal wastage syndrome. It is as yet unclear how many seemingly normal individuals who may never develop manifestations of antiphospholipid syndrome (type VI) harbor asymptomatic antiphospholipid antibodies. The relative frequency of ACLA in association with arterial and venous thrombosis strongly suggests that these should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed. Also, the type of syndrome (I through VI) should be defined, if possible, as this may dictate both type and duration of both immediate and long-term anticoagulant therapy. Unlike those with ACLA, patients with primary lupus anticoagulant thrombosis syndrome usually suffer venous thrombosis. Because the activated partial thromboplastin time (aPTT) is unreliable in patients with lupus anticoagulant (prolonged in only about 40 to 50% of patients) and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests including ELISA for ACLA, the dRVVT for lupus anticoagulant, hexagonal phospholipid neutralization procedure, and B-2-GP-I (IgG, IgA, and IgM) should be immediately ordered when suspecting antiphospholipid syndrome or in individuals with otherwise unexplained thrombotic or thromboembolic events. If these are negative, in the appropriate clinical setting, subgroups should also be assessed. Finally, most patients with antiphospholipid thrombosis syndrome will fail warfarin therapy and, except for retinal vascular thrombosis, most will fail antiplatelet therapy, thus it is of major importance to make this diagnosis in order that patients can be treated with the most effective therapy for secondary prevention, low-molecular weight heparin (LMWH) or unfractionated heparin (UHF) in most instances.

Antithrombin agents as anticoagulants and antithrombotics: implications in drug development.

The development of direct thrombin inhibitors goes back nearly four decades. Organic synthetic benzamidine derivatives were initially developed as direct antithrombin agents. Later, the structural analysis of fibrinogen, leading to the identification of thrombin cleavage sites, resulted in the recognition of specific peptide sequences where thrombin cleaved fibrinogen. These observations led to the development of synthetic peptide derivatives as inhibitors of thrombin. The leech salivary extract contained natural hirudin, the structural elucidation of which led to the development of a recombinant equivalent protein (r-hirudin). Understanding the biochemical actions of thrombin and the structure of various inhibitors prompted the development of hirulogs, a class of hybrid molecules with two sites of action. Currently, several of these thrombin inhibitors are being developed for various indications in both intravenous and subcutaneous protocols. The increased interest in thrombin inhibitors is also prompted by reports of heparin-induced thrombocytopenia (HIT) with heparin and the need to anticoagulate patients with alternate drugs. These agents produce a direct anticoagulant response by targeting thrombin. In addition, the amplification of the coagulation cascade by thrombin activation of factors V and VIII, stabilization of fibrin by activated factor XHI, and platelet activation is also inhibited by these thrombin inhibitors. Some of the synthetic thrombin inhibitors are also capable of inhibiting other enzymes in the coagulation cascade. Thrombin inhibitors therefore exert a complex effect on the coagulation network and should be carefully evaluated in clinical trials. These drugs can be used for prophylactic and therapeutic and surgical indications. However, the different thrombin inhibitors have shown distinct pharmacologic differences. There is now an interest in developing oral antithrombin inhibitors. Such issues as antagonism, laboratory monitoring, drug interactions, and long-term safety remain unresolved. Current research is focused on addressing these issues.

Antiphospholipid-thrombosis syndromes.

Antiphospholipid antibodies are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Based upon our experience, approximately 25% of patients with unexplained venous thrombosis, approximately 60% of patients with cerebrovascular thrombosis, approximately 37% of patients with transient ischemic attacks, approximately 18% with premature coronary artery thrombosis and approximately 60% of patients with recurrent fetal loss (recurrent miscarriage syndrome) harbor antiphospholipid antibodies. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagulable state remain unclear, several theories have been advanced. Since the aPTT is unreliable in patients with lupus anticoagulant and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, ELISA for IgG, IgA and IgM anticardiolipin antibodies and the dilute Russel's viper venom time (followed by cephalin correction for confirmation) for lupus anticoagulant should be immediately ordered when suspecting the antiphospholipid syndrome in individuals with otherwise unexplained thrombotic or thromboembolic events or recurrent fetal loss. However, if one strongly suspects antiphospholipid thrombosis syndrome clinically and assays for lupus anticoagulants and anticardiolipin antibodies are negative, specific assays for all three idiotypes of phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol are available and should be considered. These may clearly be indicated for difficult diagnostic cases of fetal wastage syndrome, and cerebrovascular events, but their significance in other types of thrombosis, particularly venous, remains unclear at present. Since about 65% of patients with antiphospholipid antibodies will fail warfarin therapy (rethrombose), it is important to define this common defect and institute appropriate antithrombotic therapy for appropriate time periods.

Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations.

Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters.

Thrombogenesis in myocardial infarction and related syndromes: the role of molecular markers in diagnosis and management.

Anticoagulant therapy has undergone some major developments in recent years. Conventional drugs that produce anticoagulant effects such as heparin and oral anticoagulants are no longer considered the only candidates for the anticoagulant/antithrombotic management of patients. Recombinant hirudin, glycoproteins IIb/IIIa targeting antibodies, synthetic peptides such as Hirulog and efegatran are being tested for their efficacy. These drugs produce their effects at different sites. To monitor their overall effects on the hemostatic system, molecular markers offer a practical and reliable approach. Markers of thrombin generation are useful for the monitoring of antithrombin drugs whereas, the efficacy of antiplatelet drugs can be assessed by monitoring the platelet release products. Furthermore, polytherapy using several anticoagulant and antithrombotic drugs in combination has been considered. In these situations, the use of molecular markers may also prove to be invaluable. The introduction of simple technology such as the test strip or particle agglutination methods may be available for the measurement of many of these markers in the near future. This will be useful for ready availability and reduced cost for individual marker testing. Furthermore, this type of technology can be used at bedside, off-site, and in doctor's offices. It is clear that the molecular marker profiling provides useful information on the nature of pathophysiology of a given thrombotic disorder. However, for practical use, a cost-effective and simpler assay-based approach will enhance their use, and these tests will be readily accepted at the laboratory and clinical levels.