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Semin Thromb Hemost 2011; 37(3): 175-180
DOI: 10.1055/s-0031-1273081
PREFACE

© Thieme Medical Publishers

Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations, Part IV

Giuseppe Lippi1 , Emmanuel J. Favaloro2 , Massimo Franchini3
  • 1Laboratory of Analytical Chemistry and Hematology, Department of Pathology and Laboratory Medicine, University Hospital, Parma, Italy
  • 2Department of Haematology, ICPMR, Westmead Hospital, Westmead, NSW Australia
  • 3Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital, Parma, Italy
Further Information

Publication History

Publication Date:
31 March 2011 (online)

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Welcome to the fourth issue of Seminars in Thrombosis and Hemostasis devoted to the topic “Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations.” In previous issues, we provided several insights into the life-threatening pathologies represented by venous and arterial thrombosis, reviewing common as well as less appreciated relationships between physiological/pathological conditions and their pathogenesis, prevention, diagnosis, and managed care.[1] [2] [3] In this fourth issue, we offer readers additional material of interest to help us understand the pathogenesis and the management of arterial and venous thrombosis.

In the first article in this issue,[4] Hans Zoellner provides a comprehensive overview on the emerging association between dental infection and vascular disease. The burden of gingivitis and periodontal disease (i.e., a successful chronic inflammatory response to the bacterial onslaught characterized by swelling, redness, and susceptibility toward bleeding, which may further progress with damage of soft tissues and bone resulting in tooth mobility and loss) is a growing health-care problem worldwide that can affect as many as 20% of the general population. Several epidemiological investigations have reported a significant association between periodontitis and cardiovascular disease, namely cardiovascular, cerebrovascular, and peripheral artery disease, displaying a notable pooled odds ratio of 2.35 (95% confidence interval, 1.87 to 2.96). Several pathogenic mechanisms might link dental infection and cardiovascular disease, including direct bacterial infection of the arterial wall, the development of an acute phase response, and specific atherogenic properties of oral bacteria that might promote atherogenesis. Although this relationship appears convincing, it remains to be established whether dental infection is a trigger per se or rather only shares traditional risk factors with atherosclerosis (e.g., diabetes mellitus, hypertension, high white blood cell count, elevated total and low-density lipoprotein cholesterol, increased plasma triglyceride levels, as well as reduced plasma high-density lipoprotein cholesterol levels), so that the onset of cardiovascular disease in patients with periodontitis might be sustained by separate positive feedback relationships.

In the second article,[5] Tormene et al explore the debated relationship between gender and the risk of venous thromboembolism (VTE). Although no definitive differences are observed at the time of the first VTE between men and women, the thromboembolic risk seems to be higher in women of childbearing age than in men of the same age group. Transient conditions such as hormonal use or pregnancy are recognized risk factors for VTE in women of childbearing age. Epidemiological findings also suggest that men have a higher risk of first and recurrent VTE than women. Conversely, gender seems to be a less common risk factor in the elderly. The authors conclude, however, that whether gender is an independent risk factor for first and recurrent VTE is not yet fully clarified. Further clinical studies are needed to determine whether gender may influence the natural history of thromboembolic disease in the general population. Nevertheless, the article nicely complements a previous exploration in this journal into gender-related thrombotic risk as potentially linked to platelet activity.[6]

The article by Phang et al[7] offers a comprehensive overview on the role of several nutrients and nonnutrients on hemostasis, platelet aggregation, and the risk of thrombosis. It is now widely acknowledged that diet may be involved in modifying individual risk for the development of thrombotic diseases, although its influence during the treatment of these disorders is probably less clear or significant. Overall, different dietary regimens can modulate several risk factors for cardiovascular and thrombotic diseases. As such, it is conceivable that specific nutritional approaches can facilitate the prevention or the potential management of cardiovascular disease. Several dietary components, such as proteins, carbohydrates, vitamins, allium species, ginger, ginkgo biloba, tomatoes, flavonols, proanthocyanidins, resveratrol, alcohol, and fatty acids, have a substantial influence on platelet activity and/or hemostasis pathways, leading the hypothesis that specific nutritional approaches may provide a useful preventive approach or an adjunct to current pharmacological treatments for thrombotic diseases. Unfortunately, however, the vast majority of current scientific evidence is only supported by experimental and animal studies, so the mechanistic effects in humans can only be speculated or extrapolated from prior studies. Nevertheless, this article also complements a previous exploration in this journal into the potential benefits of dietary components on cardiovascular disease risk that discussed the functional food we call wine.[8]

Multiple myeloma, which is part of a spectrum of conditions ranging from monoclonal gammopathy of unknown significance to plasma cell leukemia, is a disease characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein. The clinical phenotype of this disorder is highly heterogeneous and ranges from asymptomatic to severely symptomatic with serious complications such as bleeding, infections, and renal failure. As reviewed in the article by Zamagni et al,[9] multiple myeloma confers a high risk of developing thrombotic complications among the manifold hematologic malignancies, and VTE may develop in up to 10% of these patients. The pathogenesis of VTE in multiple myeloma is complex and multifaceted, involving an increased blood viscosity, high levels of immunoglobulin, procoagulant activity of monoclonal protein, and inflammatory cytokines. Additional traditional risk factors such as immobility, age, infections, hormone therapy, and a previous history of thrombosis are other important cofactors in the pathogenesis of the thrombotic process. Moreover, following the development and clinical use of immunomodulatory derivatives such as thalidomide and lenalidomide, VTE has emerged as one of the leading complications in patients receiving these therapies, affecting as many as 14 to 26% of the patients, especially when associated with dexamethasone or other forms of chemotherapy. Nevertheless, due to the lack of prospective randomized clinical trials, the most advantageous prophylaxis for multiple myeloma patients receiving antiangiogenic agents is still debated because no prophylactic regimen (e.g., oral anticoagulants at a fixed low or therapeutic dose, low molecular weight heparin [LMWH], and low-dose aspirin) has yet been proven to be significantly superior to another.

Di Fabio et al[10] provide insights into an insidious association requiring a high degree of vigilance: venous and arterial thromboembolism in inflammatory bowel disease (IBD), which comprises a group of inflammatory conditions of the colon and small intestine. The leading conditions are represented by Crohn's disease and ulcerative colitis. Although the former pathology can affect any part of the gastrointestinal tract, the latter is instead limited to the colon and the rectum. Venous thrombotic complications are relatively frequent (i.e., up to 10% in clinical investigations and as high as 41% in postmortem studies) and serious (i.e., mortality rates up to 25%) extraintestinal complications of these gastrointestinal disorders. Arterial thromboembolic events occur less frequently and mostly involve the cerebral, retinal, coronary, carotid, splanchnic, iliac, renal, and upper and lower limb arteries. The current knowledge of the pathogenesis of thrombotic complication in IBD seems to confer a more prominent role to acquired (e.g., local and chronic inflammation, surgery, prolonged immobilization, central venous catheters, fluid depletion, steroid therapy, smoking, oral contraceptives, high levels of antiphospholipid antibodies, and hyperhomocysteinemia) rather than to congenital risk factors. As such, prevention of thrombosis in patients with IBD is principally driven to attenuate the role of acquired and reversible risk factors. Both deep vein thrombosis (DVT) and pulmonary embolism (PE) may be clinically silent or manifest with only few specific symptoms, so the diagnosis is traditionally challenging and requires a high degree of vigilance within the context of IBD. Thrombosis of the portal vein system may also occur, associated with nonspecific symptoms such as abdominal pain, nausea/vomiting, abdominal tenderness, ascites, and fever. Arterial thrombosis of the splanchnic region is traditionally overlooked or misinterpreted, so its diagnosis is typically challenged. A timely diagnosis is essential, however, for optimizing therapeutic interventions and reducing the risk of short-term and long-term venous and arterial thrombosis, although the type and duration of systemic anticoagulation are still undefined because these must be adopted according to individual needs.

Sickle cell disease (SCD), or sickle cell anemia or drepanocytosis, is a genetic blood disorder characterized by mutations in the hemoglobin gene that cause a severe form of hemolytic anemia. The most common form is homozygous hemoglobin S (HbS) (a thymine for adenine mutation in the 6th codon of the β-chain gene, which determines a glutamate to valine substitution in position 6 of the Hb β chain), first described by Herrick in 1910. The resulting Hb molecule has the physical properties of forming polymers under deoxy conditions, and it also displays changes in solubility and molecular stability that contribute to generate gel-like substances containing Hb crystals called tactoids into the red blood cell. As such, deoxygenated HbS causes a distortion of the shape of the red blood cell and a marked decrease in its deformability (a phenomenon also known as “sickling”). The most severe feature of SCD is the episodic and unpredictable occurrence of vaso-occlusive events, which can cause serious injury to the spleen, kidneys, lung as well as pain episodes (arms, legs, chest, and abdomen), stroke, and priapism (painful prolonged erection).

Several studies, reviewed in the article of De Franceschi et al,[11] have recently pointed out that SCD patients might display a hypercoagulable state that strongly contributes to the pathogenesis of vaso-occlusive events in the microcirculation. The leading abnormalities reported include perturbation of the coagulation pathways, platelet hyperactivity and hyperaggregability, increased adherence of neutrophils, increased nonphagocytic iNKT cells, and abnormal red cells that more easily adhere on an abnormally activated vascular endothelial surface. The data concerning antiplatelet or anticoagulant therapy in the treatment of acute or chronic vaso-occlusive events are still limited due to the small number and low-quality design of the clinical studies. Overall, no substantial differences or limited improvement—at best—in the frequency and duration of acute vaso-occlusive events in SCD patients could be observed. Thrombolytic treatment of stroke in SCD patients is instead precluded due to the high risk of possible hemorrhage, especially in patients with moyamoya disease or pseudoxanthoma elasticum tissue abnormalities.

The two articles that follow are devoted to the debated aspect of preventing VTE with either mechanical or pharmacological prophylaxis. In the first article, Lippi et al[12] discuss the current approaches of mechanical prophylaxis, which include early and frequent ambulation, graded compression stockings, intermittent pneumatic compression devices, and venous foot pumps. All these methods have both advantages and limitations. Early ambulation seems inadequate per se and frequently unfeasible as the unique mean of thromboprophylaxis. Overall, mechanical compression methods were proven effective to lower the thromboembolic risk by nearly two thirds when used as the only form of thromboprophylaxis, and by about half when combined with a pharmacological approach. The lack of any risk of bleeding complications also offset the potential complications (e.g., improper use, application, and fitting, iatrogenic thrombosis, neurovascular compressions, compartment syndrome, irritation of the skin, edema of the legs, ulceration), and the cost of these methods can be entirely outweighed by the considerable economic savings achievable from preventing VTE. Although convincing data and clinical recommendations (e.g., those of the American College of Chest Physicians) suggest that graduate compression stockings might be an effective, inexpensive, and comfortable mechanical thromboprophylactic measure, its benefits are outweighed, however, by intermittent pneumatic compression, which seems the more promising approach. But one important question remains unanswered, whether mechanical prophylaxis combined with anticoagulant treatment would improve the effectiveness of preventive measures against VTE while reducing the bleeding risk.

The use of antithrombotic drugs for prevention of VTE is currently supported by solid principles and high-level scientific evidence. In the article by Tufano et al,[13] the current strategies of pharmacological thromboprophylaxis are comprehensively reviewed. Perioperative risk of VTE basically depends on a kaleidoscope of factors, including the type of surgery and the presence of additional risk factors such as elderly age and cancer. It is thereby suggested that early mobilization might be an adequate prophylactic measure in patients undergoing minor general surgery, whereas in patients undergoing major general surgery, thromboprophylaxis with LMWH, low-dose unfractionated heparin, or with the pentasaccharide fondaparinux might be advisable. It is now definitely established that patients undergoing major orthopedic surgery have a particularly increased risk of VTE, so that regular thromboprophylaxis with LMWH, fondaparinux, or a vitamin K antagonist is the standard of care. Two novel oral anticoagulants, rivaroxaban (factor Xa inhibitor) and dabigatran etexilate (direct thrombin inhibitor), have been licensed for thromboprophylaxis after orthopedic surgery in Europe. Mechanical methods of thromboprophylaxis, already reviewed in the article by Lippi et al,[12] should also be considered in patients with a particularly high risk, in association with the pharmacological prophylaxis, or in cases of contraindications to anticoagulants, as in patients or procedures at a high risk of bleeding.

The prevention of VTE in medical patients with thrombocytopenia or with platelet dysfunction is a challenging issue because up to a fourth of patients admitted to medical departments exhibit these conditions, and no specific recommendations or algorithms for pharmacological prophylaxis are available so far. As such, in the next article,[14] Tufano et al provide an overview of the current scientific literature on this topic. It is first suggested that pharmacological prophylaxis should be considered in liver disease patients at high thromboembolic risk with a platelet count ≥ 50,000/μL and should be performed as long as additional risk factors for VTE are present. In patients with very low platelet counts (i.e., < 50,000/μL) and abnormal coagulation tests, prophylaxis should instead be decided on an individual basis. In patients with antiphospholipid antibodies and concomitant thrombocytopenia, prophylaxis during high-risk conditions is suggested because these patients are characterized by a thrombotic tendency rather than by a bleeding risk. Antithrombotic prophylaxis should also be considered in hospitalized cancer patients with thrombocytopenia, especially in those with hematologic malignancies and multiple VTE risk factors, except in those with clear contraindications to anticoagulation. It is also highlighted that antiplatelet agents (e.g., aspirin) might not be as effective as heparins in lowering the VTE risk. Finally, it is suggested that the need for VTE prophylaxis in patients on chronic treatment with aspirin and/or clopidogrel should not be performed before assessing the individual risk-benefit ratio.

Factor V Leiden, first identified by Bertina et al in 1994,[15] is the name given to a common (e.g., present in ~5% of the white population) polymorphism (G1691A → Arg506Gln) in the gene encoding for factor V, which has been consistently associated with a prothrombotic state. Traditionally, heterozygous carriers of factor V Leiden have a ~5-fold increased risk of VTE, whereas homozygous carriers have a 20- to 80-fold increased risk. However, recent insights into the biology of factor V Leiden have led researchers to hypothesize that this common polymorphism might represent a kind of gain-of-function gene mutation. As clearly described in the article by Franchini and Lippi,[16] women carrying this mutation have an increased risk of thromboembolic complications and adverse pregnancy outcomes such as preeclampsia, fetal loss, placental abruption, and fetal growth restriction, especially when associated with acquired prothrombotic conditions (e.g., contraceptive use, hormone replacement therapy, pregnancy, and postpartum). Nevertheless, factor V Leiden might also confer an evolutionary selective advantage because the mutation would represent a gender-related survival advantage, conferring a lower risk of blood loss and profuse hemorrhage in association with delivery, thereby resulting in a reduced rate of maternal fatality. The results of the most important meta-analyses on the relationship between inherited (factor V Leiden) and acquired thrombophilia in women are further analyzed in this article, along with the possible evolutionary role of this mutation.

Obstructive sleep apnea syndrome (OSAS) is a common chronic disease characterized by recurrent episodes of partial or complete upper airway collapse and obstruction during sleep. The prevalence of OSAS in the general adult population is 2 to 7% but increases significantly in the elderly from 5 to 9%. The main complications of this condition include intermittent oxygen desaturation, sleep fragmentation, and symptoms of disruptive snoring and daytime sleepiness. Growing attention has recently focused on the intriguing association between OSAS and all-cause and cardiovascular disease (e.g., coronary artery disease, stroke, metabolic abnormalities, arrhythmias, and heart failure), although it is unclear as yet whether this relationship is causative or rather simply speculative and epidemiological (e.g., patients with OSAS typically have traditional cardiovascular risk factors such as obesity, diabetes, and dyslipidemia). In the article by Fava et al,[17] the reliable clinical evidence supporting the hypothesis that OSAS might be associated with essential and resistant hypertension, as well as with an incremental risk of developing stroke, cardiac rhythm perturbations (e.g., atrial fibrillation, bradyarrhythmias, supraventricular and ventricular arrhythmias), coronary artery disease, acute myocardial infarction, and heart failure are reviewed. In particular, the existence of a plausible biological basis supporting this association is hypothesized because most of the pathogenetic mechanisms involved in OSAS (i.e., hypoxia, hypercapnia, negative intrathoracic pressure, microarousal, sympathetic hyperactivity, metabolic and hormonal changes, oxidative stress, phlogosis, endothelial dysfunction, hypercoagulability, and genetic predisposition) are also hallmarks of the cardiovascular disorders.

Despite the large number of studies investigating several aspects of VTE, only a few have clearly focused on thrombus sidedness, particularly the association of thrombus sidedness with clinical presentation and subsequent complications. In the interesting article by Bikdeli et al,[18] the current knowledge regarding this topic is reviewed according to recent data from a large prospective study (i.e., the prospective National Research Institute of Tuberculosis and Lung Disease DVT registry). From this registry of 100 patients, 45% had left-sided DVT, 41% right-sided DVT, and 14% bilateral DVT. Interestingly, the presenting symptoms and comorbidities were globally similar, except for cancer, which was more common in those with right-sided involvement. Moreover, PE seemed to happen more frequently in right-sided DVT patients, who also had a higher rate of massive PE and a greater mean embolic burden. Although additional investigation is needed to better define both epidemiological and clinical differences of thrombus sidedness, the original findings of Bikdeli et al would suggest that right-sided and left-sided DVT might not be identical, and right-sided DVT might be somehow more “sinister.”

Plasma coagulation factor XIII (FXIII) is a zymogen of tetrameric structure (FXIII-A2B2), consisting of two potentially active A subunits (FXIII-A) and two inhibitory/carrier B subunits (FXIII-B). This factor has at least two essential roles in hemostasis: the mechanical strengthen of the fibrin clot through cross-linking of the fibrin chains and the regulation of fibrinolysis by protecting newly formed fibrin from the fibrinolytic system by binding a2-plasmin inhibitor to the fibrin meshwork.[19] As reported in the article by Bereczky and Muszbek,[20] interest in FXIII has been traditionally focused on its deficiency, which is associated with a life-threatening bleeding diathesis.[19] Nevertheless, emerging clinical evidence seems to support a role for this factor in some thrombotic diseases. In particular, elevated FXIII levels represent a risk of myocardial infarction and peripheral arterial disease, whereas discordant results have been observed in the few studies investigating FXIII levels in patients with VTE. Among the various FXIII polymorphisms, the effect of FXIII-A Val34Leu has been extensively investigated regarding the risk of VTE. Two meta-analyses seem to confer a moderate protective effect of the FXIII-A Leu34 allele against thrombosis, but environmental and genetic differences may have contributed some bias in the overall estimation. Moreover, gender- and age-specific effects have not been sufficiently explored, so further investigation might be warranted because the current scientific knowledge does not justify the inclusion of FXIII-A Val34Leu genotyping into a general thrombophilia screening profile. This article extends the FXIII story, as otherwise recently explored by researchers in this journal.[19] [21]

Paroxysmal nocturnal hemoglobinuria (PNH), also known as Marchiafava-Micheli syndrome, is a rare, acquired, and potentially life-threatening disease characterized by complement-induced hemolytic anemia, pancytopenia, and thrombosis. Ilene Weitz[22] describes that clinically identifiable thrombosis might occur in up to 40% of PNH patients, markedly contributes to organ failure, and is also the leading cause of death in 40 to 67% of these cases. The pathogenesis of thrombosis in PNH is complex and multifactorial. Although hemolysis has been historically considered the major contributor (free hemoglobin in the plasma is a scavenger of nitric oxide, and membrane vesiculation results in the exposure of prothrombotic phosphatidyl serine), several other mechanisms have been advocated, including complement-mediated injury to other cell lines, as well as endothelial cell activation for the loss of CD59. A pathway independent of hemolysis, through the generation of C5a, has also been suggested to contribute to the underlying inflammatory state and the generation of the prothrombotic state. Regarding the prevention and treatment of thrombosis in PNH, anticoagulation with heparin, LMWH, fondaparinux, and warfarin remains the standard of care in these patients, although the opportunity to establish this therapy might need to be balanced with the risk of increased bleeding due to the presence of thrombocytopenia.

In the next article of this issue, Walenga et al[23] raise awareness of the specific problems associated with biosimilar LMWH development that have led to new recommendations from several expert bodies. The article debates several serious implications related to these differences for the production and use of biosimilar LMWHs and provides recommendations to address the limitations of the pending U.S. Congress legislation. An exploration of the chemical, biological, and pharmacological properties of generic versions of LMWH was explored in this journal a few years ago.[24]

In the concluding article of this issue, Lassila and colleagues provide some practical viewpoints on the diagnosis and management of heparin-induced thrombocytopenia (HIT, type II).[25] The topic of HIT is a perennial favorite for readers of Seminars in Thrombosis and Hemostasis, with previous articles[26] [27] entering top-50 listings on several occasions.[28] [29] [30] The current article is somewhat different than previous articles, given its practical focus. It primarily addresses clinicians who do not normally encounter such patients. Prepared by a Nordic expert panel, the article provides clinical and laboratory guidelines along with two practical case scenarios. HIT is an immune-mediated disorder due to antibodies formed against heparin–platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of the 4T's: Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of oTher causes. Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. New anticoagulants and platelet inhibitors may also offer future alternatives in the management of HIT.

The guest editors of this issue of Seminars in Thrombosis and Hemostasis would like sincerely to thank all the contributing authors for their interesting and timely contributions. We hope that you enjoy the collation of articles and the fourth of this series related to the usual and unusual causes and associations of coagulopathies and thrombosis.

REFERENCES