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D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits unique properties as a biological marker of hemostatic abnormalities as well as an indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this, the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly, D-dimer has been extensively investigated for excluding the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and for monitoring other conditions in which the patient is at high risk of bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization., (© 2019 Wiley Periodicals, Inc.)

Cancer-related anemia (CRA) is due to multiple etiologies, including chemotherapy-induced myelosuppression, blood loss, functional iron deficiency, erythropoietin deficiency due to renal disease, marrow involvement with tumor as well as other factors. The most common treatment options for CRA include iron therapy, erythropoietic-stimulating agents (ESAs), and red cell transfusion. Safety concerns as well as restrictions and reimbursement issues surrounding ESA therapy for CRA have resulted in suboptimal treatment. Similarly, many clinicians are not familiar or comfortable using intravenous iron products to treat functional iron deficiency associated with CRA. This article summarizes our approach to treating CRA and discusses commonly encountered clinical scenarios for which current clinical guidelines do not apply., (Copyright © 2013 Wiley Periodicals, Inc.)

Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. There exists great potential for morbidity and mortality related to acute and recurrent bleeding episodes, making prompt diagnosis and treatment necessary. The two primary goals of treatment focus on cessation of bleeding and eradication of the acquired factor VIII inhibitor. No randomized clinical trials have been conducted regarding treatment, so expert clinical opinion guides therapeutic intervention. This current report provides a profile of patient characteristics, an algorithm for diagnosis, and outlines treatment recommendations based upon current guidelines and clinical experience. As first-line interventions for acute bleeding and inhibitor eradication are generally accepted, we will emphasize discussion of second-line therapeutic options., (© 2013 Blackwell Publishing Ltd.)

The use of prothrombin complex concentrates (PCCs), a heterogeneous combination of coagulation factors and counterbalancing inhibitor components, has broadened in recent years beyond single-factor replacement in conditions such as hemophilia B, to encompass emergency reversal of anticoagulation secondary to oral vitamin K antagonists, ie, warfarin therapy. PCCs also have been studied in other bleeding disorders, such as surgery-related and trauma-related bleeding. This review provides an updated examination of the differences among PCC formulations, their potential role in the management of bleeding disorders, and the primary safety issues affecting their use. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered., (Copyright © 2012 Wiley Periodicals, Inc.)

Clopidogrel is a widely used antiplatelet agent that irreversibly inhibits platelet P2Y12 ADP receptors after conversion to an active metabolite. There are a number of laboratory tests capable of detecting clopidogrel-induced platelet inhibition and published literature correlates suboptimal clopidogrel response to adverse cardiovascular outcomes. Genetic polymorphisms are thought to affect conversion of the prodrug to the active metabolite, and the FDA has recently added a black-box warning to clopidogrel to highlight the effects of these polymorphisms on drug bioavailability and to inform prescribers about the availability of genetic testing. For these reasons, there is growing interest in the use of laboratory tests to monitor patients treated with clopidogrel. This article summarizes the currently available laboratory testing, including platelet function tests and genotyping for CYP2C19 variants., (Copyright © 2011 Wiley-Liss, Inc.)

Aspirin is the most commonly used antiplatelet medication. Laboratory monitoring of aspirin response has recently become a topic of interest due to potential impacts on patient management and clinical outcomes. This article summarizes available laboratory testing of aspirin response with focus on technical issues, limitations, and current opinion on the utility of routine patient testing., ((c) 2010 Wiley-Liss, Inc.)

Lupus anticoagulants (LA) are acquired autoantibodies that can cause antiphospholipid syndrome. LAs prolong phospholipid-dependent coagulation tests, acting as nonspecific inhibitors that are neutralized in the presence of excess phospholipid. However, there is no gold standard test and the testing is influenced by a number of variables. This article summarizes laboratory testing for LAs, with particular focus on technical issues and limitations of testing. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

We performed a retrospective review of patients with immune-mediated thrombocytopenia (ITP) treated with prolonged infusions of intravenous immunoglobulin (IVIg) (1 g/kg by continuous infusion over 24 hr) and concurrent platelets (1 pheresis unit every 8 hr), to determine the response rate of this therapy. Patient inclusion criteria included clinically significant thrombocytopenia, with either active bleeding, need for anticoagulation, or a needed surgical procedure. The average pretreatment platelet count was 10,000/microl, which increased to 55,000/microl after 24 hr and 69,000/microl after 48 hr. After 24 hr, 62.7% of patients had a platelet count >50,000/microl. Bleeding was controlled initially in all patients, and those requiring a procedure experienced no bleeding complications. Over half of the patients (52.5%) required additional treatments for recurrent or refractory ITP. Six of the 21 patients requiring retreatment (29%) received IVIg and platelets again in a similar fashion, with similar results. No side effects of the combined treatment were noted. There is limited literature on the optimal dose and schedule for administration of IVIg and platelets. Our approach for administration of IVIg and platelets concurrently was associated with minimal side effects, resolution of bleeding, ability to safely undergo procedures, and rapid restoration of adequate platelet counts.

The peripherally-inserted central catheter (PICC) is used commonly in hospitalized patients. The presence of heparin within the PICC lumen, however, may affect the results of coagulation indices when measured on blood drawn through it. In 41 patients with a PICC inserted as part of their medical care, we compared activated partial thromboplastin times (aPTTs) measured on blood drawn through the PICC to blood drawn through a peripheral venipuncture (VP). There were no clinically significant differences between aPTT values from the two samples. Using the PICC to obtain blood for the measurement of aPTT is accurate and may reduce the need for peripheral VPs.

Superwarfarins are anticoagulant rodenticides similar to warfarin, but which have various substituted phenyl groups replacing the terminal methyl group, resulting in a fat-soluble, long-acting anticoagulant that is nearly 100 times more potent than the parent compound. Since their development, many accidental and intentional cases of consumption have been reported. We describe two cases of consumption, one related to unknown etiology, and the other related to utilization of the superwarfarin to potentiate a drug of abuse. The clinical manifestations including bleeding symptoms and abnormal coagulation assays are discussed. The differential diagnosis is quite broad, and includes all causes of vitamin K deficiency, factor deficiency or inhibitor, disseminated intravascular coagulation (DIC), and liver disease. Differentiating superwarfarin ingestion from the other causes can be quite difficult, but extremely important, as management requires prolonged administration of vitamin K. Other treatment options are discussed as well including, fresh frozen plasma (FFP), and recombinant factor VIIa. Finally, the significance of "lacing" drugs of abuse with superwarfarin to potentiate their effect is discussed, as well as the complications that could develop from such a habit.

Prothrombin deficiency is a very rare autosomal recessive bleeding disorder associated with mild to severe bleeding symptoms. We identified this bleeding disorder in a US-born patient as due to prothrombin Puerto Rico I. Unlike other prothrombin deficiencies, prothrombin Puerto Rico I is a series of concordant polymorphisms found in people of Puerto Rican descent with a much higher frequency than those prothrombin deficiencies found in the general population. This case underscores the importance of family history in identifying rare bleeding disorders.

A 49-year-old Caucasian woman presented with features suggestive of thrombotic microangiopathy (TMA). She did not respond to treatment with repeated plasma exchange and corticosteroids. A bone marrow biopsy revealed presence of metastatic carcinoma. A limited autopsy revealed presence of breast cancer with rib metastases. Though severe deficiency of von Willebrand factor-cleaving protease was initially proposed as a key pathogenetic factor for thrombotic thrombocytopenic purpura, subsequent studies involving patients with cancer-associated TMA did not find as severe a deficiency of von Willebrand factor-cleaving protease as is seen in idiopathic cases of thrombotic thrombocytopenic purpura. Here we address one approach of management of these patients with cancer-associated TMA.

Acquired amegakaryocytic thrombocytopenia is an unusual hematologic disorder characterized by thrombocytopenia in association with markedly diminished bone marrow megakaryocytes. We report a case that responded to treatment with cyclosporine but not to IL-11. The bone marrow biopsy, repeated after resolution of thrombocytopenia, showed normal number of megakaryocytes., (2006 Wiley-Liss, Inc.)

Venous thromboembolism (VTE) is common but often unrecognized in medically ill patients. Over the past 5 years, three large-scale placebo-controlled trials enrolling a total of 5500 medically ill patients have highlighted the risk of VTE in this group. These trials have helped to define a specific at-risk patient profile, including those admitted to the hospital with severe congestive heart failure, respiratory illness, acute infection, and inflammatory bowel disease. We performed a retrospective review of patients admitted to the medical service at our tertiary care center to define how common the at-risk medical patient is and to evaluate and improve prophylaxis rates in this patient group. The study was conducted in two phases. Based on admission characteristics, patients were stratified into high-risk or low-risk groups for the development of VTE. During the pre-intervention phase, 75% of patients admitted to the medical service were characterized as increased risk for VTE, yet only 43% of these high-risk patients received prophylaxis of any sort. After interventions designed to increase awareness of VTE, we conducted a second review period. In this post-intervention phase, where 79% of patients were at risk for VTE, prophylaxis rates improved to 72%. Based on these results, we conclude that the majority of patients admitted to the medical service at our tertiary care center constitute a high-risk population that warrants consideration for VTE prophylaxis. Implementation of strategies to improve prophylaxis rates, including educational sessions and risk stratification guidelines, can be successful and improve identification and prophylaxis of this population.

The anticoagulant activity of warfarin sodium is monitored by the prothrombin time (PT) using the international normalized ratio (INR). Standard oral anticoagulant therapy monitoring requires frequent patient visits to physicians' offices and/or laboratories to optimize warfarin dosage. Home PT monitoring by patients can increase testing frequency and may thus decrease complications associated with oral anticoagulant therapy. Clinical studies suggest that home PT monitoring is more effective than uncoordinated management and is as effective as care through specialized anticoagulation clinics for keeping INRs within a therapeutic range. There are accurate and reliable instruments available, but paramount to the success of home PT monitoring is sound patient selection, appropriate patient training, and consistent quality control., (Copyright 2004 Wiley-Liss, Inc.)

Parenteral iron therapy is occasionally necessary for patients intolerant or unresponsive to oral iron therapy, for receiving recombinant erythropoietin therapy, or for use in treating functional iron deficiency. There are now three parenteral iron products available: iron dextran, ferric gluconate, and iron sucrose. We summarize the advantages and disadvantages of each product, including risk of anaphylaxis and hypersensitivity, dosage regimens, and costs. The increased availability of multiple parenteral iron preparations should decrease the need to use red cell transfusions in patients with iron-deficiency anemia., (Copyright 2004 Wiley-Liss, Inc.)

Normally, human erythrocytes display several responses to elevated intracellular calcium levels. These include a shape transition from discocyte to spherocyte, shedding of microvesicles into the extracellular fluid, and enhanced susceptibility to the hydrolytic action of secretory phospholipase A(2). These responses to elevated intracellular calcium were all blunted in erythrocytes containing hemoglobin S. The reduction of both the shape transition and the shedding of microvesicles were greater than the impairment of phospholipase susceptibility, and both correlated strongly with the intracellular content of hemoglobin S. In contrast to the response to elevated intracellular calcium, erythrocytes containing hemoglobin S displayed a 2.5-fold increase in basal susceptibility to phospholipase A(2) compared to control erythrocytes in the absence of ionophore. The effect was more prominent among samples from patients heterozygous for hemoglobin S than in samples from homozygous individuals. These results reveal additional abnormalities in the membranes of sickle cell erythrocytes beyond those described previously and demonstrate that red blood cells from both heterozygous and homozygous are affected. Furthermore, they suggest a possible means by which sickle cell disease and trait patients may display enhanced vulnerability to inflammatory stimuli., (Copyright 2003 Wiley-Liss, Inc.)

The inherited thrombophilias are a group of inherited conditions that predispose to thrombotic events. Most of the inherited thrombotic disorders are associated with venous thromboembolism rather than arterial thrombosis. Frequently, one or more predisposing genetic factors and/or environmental risk factor are identified in thrombosis patients. Significant advances in the identification of etiologies of inherited thrombosis have recently been reported. The most common inherited thrombotic disorders include activated protein C (APC) resistance (factor V Leiden), hyperhomocysteinemia, the prothrombin gene variant G20210A, elevated factor VIII levels, and deficiencies of thrombomodulin, protein C, protein S, and antithrombin. Less well characterized disorders include elevated factor IX, X, and XI levels. Recognition of these disorders now permits a laboratory diagnosis in approximately 70% of patients being evaluated for inherited thrombosis. This review focuses on the clinical and laboratory aspects of some of the most common inherited venous thrombotic disorders, including APC resistance, hyperhomocysteinemia, the prothrombin G20210A mutation, and elevated coagulation factor levels., (Copyright 2001 Wiley-Liss, Inc.)

Low-molecular-weight heparins, such as enoxaparin, are increasingly being used for treatment of venous thromboembolism. We describe two patients who received therapeutic enoxaparin for several months. Although their serum creatinine values were normal, both had mild renal insufficiency (creatinine clearance 60-70 ml/min), and both accumulated the drug abnormally and experienced clinical bleeding. These results suggest that patients receiving enoxaparin (or other low-molecular-weight heparins) in therapeutic doses for periods of more than 4 weeks should be considered for laboratory monitoring to avoid bleeding., (Copyright 2001 Wiley-Liss, Inc.)

The availability of a low-molecular-weight heparin, enoxaparin, to treat deep-vein thrombosis (DVT) offers the option for outpatient therapy for certain DVT patients. We monitored the utilization and outcomes of enoxaparin treatment for DVT in our tertiary-care hospital. A retrospective chart survey was performed for all DVT patients treated at our facility between October 1998 and September 1999. We tracked treatment received (unfractionated heparin or enoxaparin), clinical outcomes (recurrent thromboembolism or bleeding), and whether the patient would have met practice guideline criteria for outpatient enoxaparin therapy. A total of 266 patients were either admitted to the hospital for DVT or experienced DVT during their hospitalization. Of 266 DVT patients, 73 (27%) received enoxaparin. Sixty-four (88%) patients receiving enoxaparin met practice guideline criteria. Nine patients (12%) who did not meet criteria also received the drug. Major bleeding occurred in 3 patients (4%) receiving enoxaparin; one patient had a life-threatening hemorrhage. Two of the three patients with major bleeding had contraindications to enoxaparin use. Only 45% of our DVT patients were appropriate candidates for outpatient enoxaparin therapy. We conclude that in tertiary-care hospitals with acutely ill patients, most DVT patients will not be candidates for outpatient therapy with enoxaparin. Limitations to enoxaparin use are not widely appreciated., (Copyright 2000 Wiley-Liss, Inc.)

We present a case of cobalamin deficiency in an elderly woman who presented with peripheral neuropathy without evidence of anemia or macrocytosis; her diagnosis was suspected with cervical magnetic resonance imaging. This imaging modality may identify patients with cobalamin deficiency who have neurologic abnormalities with normal hematologic parameters., (Copyright 2000 Wiley-Liss, Inc.)

Immune thrombocytopenia (ITP) may be associated with serious hemorrhage. We describe 2 patients who received intravenous immunoglobulin given as a 24-hr continuous infusion with a concomitant continuous infusion of platelets. This regimen was rapidly effective in increasing platelet counts in both patients., (Copyright 2000 Wiley-Liss, Inc.)

Disseminated intravascular coagulation (DIC) is a complex acquired coagulopathy resulting from excessive thrombin formation. Abnormal tissue factor (TF) expression is a major mechanism initiating DIC in many disorders, including obstetrical complications, sepsis, cancer, and trauma. Numerous laboratory tests are available to monitor DIC, but most patients are adequately managed using only routine hemostasis screening tests, and assays for fibrinogen and D-dimer. Treatment of DIC should focus on reversing the underlying disorder initiating the coagulopathy. Novel treatments are being investigated for treating DIC; many of these experimental modalities target the excessive TF activity that characterizes DIC.

Significant advances in identification of etiologies of inherited thrombosis have been recently reported. A point mutation in coagulation factor V (factor V Leiden) results in resistance to activated protein C and probably represents the most common genetic risk factor for venous thrombosis. A metabolic disorder, homocysteinemia, is now known to be an important risk factor for both arterial and venous thrombosis. Many patients with recurrent thrombosis will have more than one genetic risk factor identified. Recognition of these new disorders should permit a diagnosis to be achieved in at least half of patients evaluated for inherited thrombosis.

Patients who require oral anticoagulation usually receive warfarin. We used an indanedione drug, anisindione, in two patients who were intolerant of warfarin but who needed long-term oral anticoagulation. The use of this alternative oral anticoagulant is reviewed.

Accurate laboratory monitoring of oral anticoagulation has been emphasized as an important factor in providing safe and effective therapy for patients with thromboembolism. However, recent reports indicate that coagulation laboratories may not be providing optimal clinical information to clinicians who treat these patients. We surveyed all hospital coagulation laboratories in Utah to determine their format for reporting prothrombin time results in patients receiving oral anticoagulants. We found that less than 50% of laboratories used the reliable reporting format, i.e., the International Normalized Ratio (INR), and that many of the laboratories using the INR format may be reporting incorrect values. Our survey also found a significant lack of interest by physicians in requesting that their laboratories adopt reliable reporting methods. These results indicate a substantial lack of understanding by laboratories and clinicians of the importance of using reliable methods to monitor oral anticoagulation. Significant educational efforts will be required to correct this problem.

The laboratory evaluation of patients with recurrent thrombosis is frequently frustrating, with a low diagnostic yield obtained despite extensive testing. The likelihood of reaching a diagnosis in these patients can be increased by considering diagnostic possibilities usually overlooked and by using assays optimal for their detection. This review summarizes clinical and laboratory issues important in inherited thrombotic disease and discusses practical aspects and a strategy for laboratory testing. New information is provided on the fibrinolytic disorders that may be a common cause of recurrent thrombosis.

Monolayer cultures of human endothelial cells were incubated with pre- and postdelivery sera from five women with preeclampsia and four matched, normal pregnancies. Conditioned media collected from endothelial cells pretreated in vitro with prepartum sera from preeclamptic women contained greater mitogenic activity and elevated levels of platelet-derived growth factor (PDGF)-like peptides than cells exposed to normal pregnancy sera or postpartum preeclamptic sera. Under the same experimental conditions, predelivery preeclamptic sera stimulated greater expression of endothelial cell PDGF-B-chain mRNA than that accumulated in the presence of matched postdelivery sera. By contrast, no differences in endothelial cell PDGF-B mRNA levels were noted when pre- and postdelivery sera from normal parturients were tested. The results suggest that a factor(s) in the blood of preeclamptic women can stimulate the synthesis and release of a potent growth factor and vasoconstrictor from human endothelial cells.

The investigation of kindreds with recurrent thrombotic disease has advanced the understanding of the mechanisms of coagulation and fibrinolysis. In those cases where an etiology has been established, congenital thrombotic disorders are associated either with deficiencies or qualitative abnormalities in inhibitors of activated coagulation factors, qualitative abnormalities of fibrinogen, fibrinolytic defects that impair clot lysis, or an inborn error of metabolism, homocystinuria. The etiologies of congenital thrombotic disorders, their clinical features, and an approach to their laboratory diagnosis are summarized in this review.

A previously healthy woman developed severe, periodic neutropenia after ingestion of phenylbutazone. Oscillations in the monocyte count and hemoglobin concentrations also occurred. The neutropenic episodes were associated with severe bacterial infections requiring hospitalization. Lithium induced a transient interruption in the neutropenia, but continued use was ineffective. Prednisone in a dosage of 100 mg daily successfully interrupted the neutrophil cycling and prevented infection. The patient has remained in remission on 10 mg of prednisone on alternate days.

Hematologic abnormalities are common in patients with HIV infection. This review will focus on HIV-associated cytopenias and coagulation abnormalities. Their occurrence, laboratory evaluation, and clinical significance and the mechanisms underlying their development are discussed. Therapeutic modalities are presented, with an emphasis on treatment strategies for HIV-associated thrombocytopenia.