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.

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.

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.

The antiphospholipid-thrombosis syndromes. Fact, fiction, confusion, and controversy.

Anticardiolipin antibodies and the lupus anticoagulant 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. Because the aPTT is unreliable in patients with lupus anticoagulant and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, such as ELISA for IgG, IgA, and IgM anticardiolipin antibodies and the dRVVT (followed by cephalin correction for confirmation) for lupus anticoagulant, should be immediately ordered when suspecting antiphospholipid syndrome in persons with otherwise unexplained thrombotic or thromboembolic events or fetal wastage syndrome. The laboratory diagnosis of APL-T syndrome is summarized in Figure 1.

Fully automated antithrombin-III assays by synthetic substrate on the Multistat III.

Antithrombin-III assays are performed to assess response to heparin therapy and efficacy of antithrombin concentrate therapy and in diagnosing hereditary thrombophilia, deep venous thrombosis, pulmonary embolus, and disseminated intravascular coagulation. Synthetic substrate assays for antithrombin-III are the methods of choice; however, most existing assay systems are semiautomated. A fully automated, antithrombin-III assay using the Kabi Chromogenic Synthetic Substrate S-2238 COATEST on the MULTISTAT III has been developed. This assay was compared with the Dade Protopath fluorometric assay. The correlation (r-sq) between the two assay systems was 0.82. Additionally, a three-way assay comparison was also performed, incorporating a new fluorometric substrate for antithrombin-III. The three-way comparative assays revealed correlation as follows: MULTISTAT III fluorometric assay and the MULTISTAT III/Kabi COATEST assay r-sq = 0.90; MULTISTAT III fluorometric assay and the Dade fluorometric assay r-sq = 0.86; and the MULTISTAT III/Kabi COATEST assay and the Dade Protopath fluorometric assay r-sq = 0.95. These automated assays were extremely cost effective and were a fraction of the cost of performing other types of antithrombin-III assays.

Antithrombins and coronary artery disease.

The role of antithrombin-III with respect to atherogenesis and myocardial infarction remains unclear; however, it has been reported that antithrombin-III levels are decreased in many individuals with coronary artery disease and in those at high risk for coronary artery occlusion. However, the several reports available do not agree and remain inconclusive. Antithrombin-III levels were determined in 86 individuals undergoing coronary artery angiography. Results of these determinations reveal that the majority of patients with angiographically documented coronary artery disease have normal antithrombin-III levels. Additionally, there was found to be no correlation between antithrombin-III levels and severity or site of coronary artery involvement. The results of this study would suggest that plasma antithrombin-III determinations are of no particular significance in determining the presence, absence, or severity of coronary artery disease.

A comparative study of the DuPont antithrombin III and fibrinogen assay systems.

Antithrombin III (AT-III) levels are useful for diagnosing thrombosis and for assessing antithrombotic therapy. Fibrinogen levels also are useful in numerous thrombohemorrhagic disorders and for noting cessation of fibrinolysis after thrombolytic therapy. With the availability of these assays on the DuPont aca, a comparative study of AT-III and fibrinogen assays was performed. DuPont assays were compared to Dade Protopath (AT-III) and Auto-Fi (fibrinogen) assays. In 38 instances a third comparative AT-III assay also was used, namely the Kabi S-2238 method (COATEST). Poor correlation existed between the DuPont AT-III and Protopath AT-III, r - sq = 0.53 to 0.61. There also was poor correlation between the DuPont and S-2238 AT-III assay, r - sq = 0.59. Excellent correlation was noted with the Protopath and Kabi AT-III assays, r - sq = 0.90. There was poor correlation between DuPont and Dade fibrinogen levels, r - sq = 0.55. When comparing AT-III values, the DuPont level was consistently higher. DuPont fibrinogen levels also were consistently higher. The DuPont AT-III and fibrinogen levels correlate poorly with existing assays, and higher results than those noted with the other methods appear common. Spuriously high values noted with the DuPont system could misguide clinicians caring for patients with thrombohemorrhagic diseases where they would expect low levels of AT-III or fibrinogen.

Bleeding times, platelet adhesion, and aspirin.

The effects of aspirin on well-standardized commercially produced platelet adhesiveness devices and template bleeding times were simultaneously studied in 19 normal volunteers. As expected, there was significant prolongation of the bleeding time after aspirin, but there was no change in platelet adhesion. Reason for the different effects of aspirin on the two tests are discussed. In addition, the normal range of platelet adhesion was further defined utilizing commercially prepared glass-bead columns.

Antithrombin III patterns in disseminated intravascular coagulation.

Antithrombin III-heparin cofactor has now been recognized as a major inhibitor of thrombin and other serine proteases in the blood coagulation system. Since the reaction between antithrombin III and serine proteases is irreversible, one would expect antithrombin III consumption in the face of pathologic intravascular coagulation and attendant generation of thrombin, IXa, Xa, XIa, XIIa, and plasmin. Using a new assay system for antithrombin III that is unaffected by heparin or fibrino (geno) lytic degradation products, antithrombin III was monitored before and during therapy in 38 patients who had acute or chronic disseminated intravascular coagulation. It was found that early and significant decreases in anththrombin III occur in disseminated intravascular coagulation and thus may serve as a useful diagnostic tool. It was further found that monitoring antithrombin III during therapy reflected a cessation of antithrombin III consumption and, thus, served as an indicator of the efficacy of therapy in stopping the clotting process. Since the assay system is unaffected by fibrino(geno)lytic degradation products and heparin, it proved useful in monitoring the efficacy of heparin therapy for disseminated intravascular coagulation. In addition for this group of patients, it appeared that mini-heparin therapy and large doses of heparin were equally efficacious in correcting other laboratory abnormalities of disseminated intravascular coagulation, and in controlling clinical hemorrhage in disseminated intravascular coagulation.

Disseminated intravascular coagulation: a clinical/laboratory study of 48 patients.

In summary, this series of 48 patients with acute and chronic DIC demonstrates the reliability of laboratory tests in both aiding a diagnosis of DIC and in offering reasonable predictability of efficacy of therapy, as noted by the correction of abnormalities after delivery of antiprocoagulant therapy for this syndrome. It appears that the diagnostic tests most likely to aid in diagnosis and to reliably inform the clinician when the intravascular clotting process has been stopped are those that determine the antithrombin-III level, the presence of soluble fibrin monomer, and the finding of elevated fibrin(ogen) degradation products, thrombocytopenia and a prolonged thrombin time in the face of the appropriate type of bleeding in the appropriate clinical setting. In addition, it would appear that mini-dose heparin therapy is highly effective in controlling the intravascular clotting process in acute DIC, whereas antiplatelet therapy utilizing two agents is effective in chronic DIC. In addition, in this population, patients with acute disease demonstrated a 74 percent survival rate and those with chronic disease had a 100 percent survival rate from the disseminated intravascular clotting process.

Hereditary hemorrhagic telangiectasia and disseminated intravascular coagulation: a new clinical syndrome.

In summary, 47 patients with documented HHT and a bleeding problem were referred to San Joaquin Hematology Oncology Medical Group over a 2-year period. Fifty-one percent of patients were noted to have an associated DIC syndrome and of these 24 patients, 19 had acute DIC episodes, six had chronic DIC, six presented with diffuse, recurrent deep venous thrombosis and of these six, three suffered pulmonary emboli. Other defects were also noted and were thought to be coincidental defects. This syndrome should be readily considered and searched for when seeing patients with HHT, especially if significant hemorrhage or thrombosis is present. It should further be appreciated that many patients with HHT and bleeding are candidates for the development of acute or chronic DIC and thus a "mini" Kasabach-Merritt syndrome. When patients with HHT present with undue bleeding, this syndrome should be appreciated, searched for from the clinical and laboratory standpoint and, when found, treated in the appropriate manner with supportive therapy, mini-heparin or antiplatelet therapy as the clinical situation dictates.

Antiphospholipid thrombosis syndromes: etiology, pathophysiology, diagnosis and management.

Antiphospholipid antibodies are increasingly being identified as a cause of both arterial and venous thrombosis as well as fetal wastage syndrome via placental vascular thrombosis. The antiphospholipid thrombosis syndromes should be considered and searched for when suggestive clinical findings are present or when unexplained arterial or venous thrombosis occurs. Noting the presence and type of antiphospholipid antibody thrombosis syndrome assumes major importance with respect to not only making an accurate diagnosis of cause of thrombosis but also in selecting effective antithrombotic therapy.

Disseminated intravascular coagulation syndromes.

Current concepts of the etiology, pathophysiology, diagnosis and management of fulminant as well as low-grade disseminated intravascular coagulation have been presented. Considerable attention has been devoted to interrelationship within the hemostasis system. Only by clearly understanding these pathophysiological interrelationships can the clinician and laboratory scientists appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with disseminated intravascular coagulation. Many therapeutic decisions to be made in these patients are controversial and will remain so until more series of patients are published about specific therapeutic modalities and survival patterns. Also, therapy must be highly individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamic and other clinical parameters. Many syndromes which are organ specific share common pathophysiology with disseminated intravascular coagulation but are typically identified as an independent disease entity, such as hemolytic uremic syndrome, adult shock lung syndrome, eclampsia, and many other isolated "organ-specific" disorders. Many of these similar disorders, some systemic and some organ specific or multi-organ specific are listed in Table 8.

Hodgkin's disease in association with hexavalent chromium exposure.

During an epidemiological study assessing cancer risk in a small isolated population exposed to excessive amounts of hexavalent chromium, we noted two patients with Hodgkin's disease after exposure for many years and after a long latency period. The study population demonstrated an observed risk between 65 and 92 times that of reported risks for non-exposed US populations. Although malignant lymphoma, as well as many other malignancies, has clearly been associated with hexavalent chromium exposure, no reports have yet specifically mentioned Hodgkin's disease. We herein report Hodgkin's disease specifically in two individuals so exposed. Although this may be a chance occurrence, clinicians should be aware of the potential association between hexavalent chromium exposure and Hodgkin's lymphoma.

Hydroxyethyl starch versus albumin in cardiopulmonary bypass prime solutions.

To compare hydroxyethyl starch (HES) with 25% albumin, 20 patients undergoing aortocoronary bypass were randomized into two groups: 10 received 1,000 ml of HES and 10 received 200 ml of 25% albumin in a bloodless priming solution for cardiopulmonary bypass (CPB). Platelet aggregation, antithrombin III, reptilase time, fibrinogen, plasminogen, fluid requirements, and hemodynamics were monitored. Platelet aggregation was abnormal in both groups, being relatively poorer in the albumin group. Both groups exhibited below normal antithrombin III and plasminogen levels, with significantly lower antithrombin III levels noted in the HES group postoperatively (41.9 +/- 11.8% versus 56.6 +/- 9.9%; p = 0.006). Compared with the albumin group, the HES group had slightly, but not significantly, elevated liver function test results, total volume replacement (9,173 +/- 2,046 ml versus 8,522 +/- 1,192 ml; p = 0.057), packed red blood cell usage (227 +/- 284 ml versus 75 +/- 168 ml; p = 0.066), and chest tube drainage (599 +/- 253 ml versus 454 +/- 174 ml; p = 0.144). In the HES group, 5% albumin requirement was greater (386 +/- 466 ml versus 50 +/- 158 ml; p = 0.002) and percent increase of body weight was higher (5.2 +/- 0.8% versus 2.3 +/- 0.6%; p = 0.05) postoperatively. Postoperative weight increase and colloid requirements plus trends toward larger blood loss and blood transfusions indicate possible further evaluation. However, results suggest that HES is a safe additive to priming solutions. Compared with albumin, HES has comparable changes in coagulation variables and slightly less severe derangements in platelet aggregation.

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.

Acquired platelet function defects.

Platelet dysfunctions, especially acquired forms, are common causes of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally quite rare, hereditary storage-pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are very common and should promptly be suspected in patients developing easy and spontaneous bruising, mild to moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in the patient frankly bleeding, is not reliable, and platelet aggregation or lumi-aggregation should be done in appropriate clinical situations. Also, prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for essentially all these defects, if bleeding is significant, is the liberal infusion of appropriate numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.

Disseminated intravascular coagulation.

Current concepts of the etiology, pathophysiology, clinical and laboratory diagnosis, and management of fulminant and low-grade DIC have been presented. Considerable attention has been devoted to interrelationships within the hemostasis system. Only by clearly understanding these pathophysiologic 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 will remain so until more is published about specific therapeutic modalities and survival patterns. Also, therapy must be highly individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis, and hemodynamic and other clinical parameters. Many syndromes that are organ-specific share common pathophysiology with DIC but are typically identified as an independent disease entity, such as hemolytic uremic syndrome, adult shock-lung syndrome, eclampsia, and many other isolated "organ-specific" disorders.

Anticardiolipin antibodies and thrombosis.

Anticardiolipin antibodies (ACLAs) 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 ACLAs alter hemostasis to induce a hypercoagulable state remain unclear, several theories, as previously discussed, have been advanced. The most common thrombotic events associated with ACLAs 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). The relative frequency of ACLAs 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 IV) should be defined if possible, because this may dictate both type and duration of both immediate and long-term anticoagulant therapy.