Pediatric Thrombosis and Hemostasis

This issue of Seminars in Thrombosis and Hemostasis is part 2 of the Maureen Andrew Memorial Edition. As with the first issue, problems with thrombosis in childhood, bleeding disorders, anticoagulants, and special problems related to pregnancy are reviewed. Again, most authors either worked with Dr. Andrew for some time, or had a special working relationship with her.

In the first contribution, Monagle discusses the problems of thrombosis in pediatric cardiac patients. Although myocardial infarction (MI) is rare in children, it does occur in conjunction with diseases that cause coronary artery disease, such as congenital hyperlipidemia or Kawasaki's disease. Much more frequent is iatrogenic arterial thrombosis in cardiac pediatric patients, usually in conjunction with cardiac catheterization or similar procedures. In each instance, pathophysiology, clinical presentation, prevention, and treatment are comprehensively discussed. Many surgical procedures are associated with a high risk of thrombosis in children with cardiac diseases. Methods of preventing these serious complications are presented, including the long-term management of children with artificial heart valves.

In the next article Price and Massicotte review arterial thromboembolism in general in the pediatric population. The majority of events are encountered in children with indwelling catheters, and any vessel that has a catheter can thrombose. These serious complications are associated with a high degree of morbidity and even mortality. Length and time of the catheter placement, catheter material, solutions infused, and dose of heparin used to flush catheters are important predictors of thrombosis. Treatment modalities are discussed. Non-catheter-related arterial thromboses are usually due to underlying diseases, such as in Takayasu's arteritis, Kawasaki's disease, and other forms of acquired endothelial disturbances. Of the congenital disorders that are associated with these complications, hyperlipidemia and hyperhomocysteinemia are discussed. Treatment options for arterial thromboses are heparins and thrombolytic therapy.

deVeber next reviews strokes in children. Once thought to be rare, strokes are increasingly recognized, but are often difficult to diagnose. The clinical features may vary greatly and often disappear rather quickly. Vascular disorders are underlying causes, and many intravascular problems, from dehydration to prothrombotic states, are associated with strokes. The radiographic features are reviewed; they often differ from those of adults. Treatment of strokes in children differs as well; it is primarily directed toward management of underlying disorders and prevention of recurrence. Several standardized guidelines for treatment of children with strokes are available and include the entire spectrum of anticoagulants and thrombolytic therapy.

Knoefler and colleagues investigated the impact of single nucleotide polymorphisms of the thrombin activatable fibrinolysis inhibitor (TAFI) on antigen levels in healthy children and in children with malignancies. TAFI is a relatively new discovery of a carboxypeptidase B-like proenzyme, which, in its active form (TAFIa) cleaves lysine and arginine residues from the C-terminal end of fibrin. This impairs lysis of fibrin-mediated plasminogen activation. TAFI levels have been reported in plasma of adults, but so far nothing has been described about levels in children. In addition, little is known about the association of TAFI with bleeding or thromboembolic episodes. The investigators found that TAFI antigen levels in children were similar to those of adults, with the same large variability and no gender differences. No differences were found between healthy children of various age groups and children of similar age with oncologic diseases. The high degree if variability in TAFI levels appears to be genetically determined. This was also found in children, and the gene polymorphism was similar to that of adults. No correlation was observed between the common gene polymorphisms and increased risk of thrombosis in children with oncologic disorders.

In the next contribution, Manco-Johnson and colleagues describe the advances made in the treatment of hemophilic children. Considerable progress has been made-the once rather dismal prognosis of hemophilia has completely changed so that today hemophiliacs can anticipate a normal life expectancy. Many discoveries have made this possible. The development of factor concentrates from cryoprecipitate, virus-safe concentrates from plasma, and genetically engineered products have allowed prompt arrest of bleeding so that the once devastating hemophilic arthropathies have practically been abolished. Specialized centers for the care of hemophiliacs have brought specialists from all areas of medicine together to optimize treatment. Self-administration of factor concentrates by the patients has reduced hospital stays and thus reduced costs for insurers. Adjunct treatment modalities have been developed, especially the use of antifibrinolytic agents, to combat minor hemorrhages. Prophylaxis has reduced the frequency and the severity of bleeding episodes, and protocols have been designed to induce immune tolerance in patients with antibodies. First attempts at using gene therapy to ultimately cure the disease are underway and may potentially eradicate this dreadful disorder.

The next article by Buchanan and colleagues reviews chronic idiopathic thrombocytopenic purpura (ITP) in children. They define the various forms of ITP and discuss in detail the use or abuse of platelet counts in these patients and stress that the clinical manifestations are more important that repeated platelet counts. The clinical presentations of children with mild, moderate, and severe chronic ITP are reviewed and the bleeding risks assessed. Treatment options are delineated from general principles to specific drugs, including splenectomy and its consequences. This review should give the reader an excellent overview of the problems associated with chronic ITP in children.

Blanchette and Carcao review acute ITP, especially from the viewpoint of “to treat” or “not to treat.” This type of thrombocytopenia is typically benign and self-limiting, yet there is the risk for intracranial hemorrhage, which can be fatal. The authors comprehensively discuss this issue. If treatment is necessary, there are several options: corticosteroids, intravenous immunoglobulin, intravenous anti-D, and even splenectomy in emergency situations. These options are comprehensively reviewed and recommendations made, where possible. In addition, the problem of bone marrow biopsy prior to initiation of treatment and the need for hospitalization are discussed. Although many aspects of acute ITP and its management are well understood, others are not, and the need for extensive clinical trials is stressed to answer some of these outstanding questions.

Linkins and Weitz comprehensively review new anticoagulants for the management of arterial and venous thromboembolic disorders. After briefly discussing the pathogenesis of thrombosis and the physiological regulator mechanisms, the authors present the rational for developing new anticoagulants. The presently used compounds, heparins and oral anticoagulants, have several limitations that have prompted the search for new anticoagulants. Of the many new agents under development, few have as yet reached phase II or higher levels of clinical testing. Most new drugs target certain specific steps in the coagulation cascade that the authors divide into initiation of coagulation, propagation, and fibrin formation. Examples of inhibitors of the initiation phase of coagulation are recombinant tissue factor pathway inhibitor (rTFPI), the nematode anticoagulant peptide (NAPc2), and active-site blocked factor VIIa (FVIIai). Of these, NAPc2 is still being further developed and clinically tested. Inhibitors of propagation of coagulation are direct and indirect FXa inhibitors. At present, the most widely studied indirect FXa inhibitor is fondaparinux, a pentasaccharide that binds to antithrombin. Idraparinux is a sulfated derivative of fondaparinux that has a much longer half-life than its parent compound. A nonpeptidic arginine derivative, DX-9065a, is a new direct FXa inhibitor with some promise of potential clinical use. Other inhibitors reviewed are activated protein C, protein C itself, and soluble thrombomodulin. Newly developed inhibitors of fibrin formation are direct blockers of thrombin activity. These are hirudin, bivalirudin, argatroban, and ximelagatran. The latter is of considerable clinical interest. This review contains a wealth of information regarding attempts to develop safer and more specific anticoagulants.

Next, Pabinger and Grafenhofer discuss the use of anticoagulants during pregnancy. Pregnant women have a five-fold higher risk of venous thromboembolism (VTE) than nonpregnant women of similar age. Most of these events occur during the postpartum period. This risk increases markedly when women have a thrombophilic condition, such as congenital inhibitor defects, FV and prothrombin gene mutations, and antiphospholipid antibodies. The presence of two of these abnormalities increases the risk even further. Because coumarin derivatives pass the placenta and cause embryopathies, especially when used during early pregnancy, heparins are the drugs of choice when anticoagulation is needed. Low-molecular-weight heparins (LMWHs) are given preference because of their greater safety profile. Because hypercoagulable states are associated with recurrent abortions, stillbirths, and with preeclampsia, heparins are not only used to manage VTE during pregnancy, but also to reduce the risks of pregnancy complications. LMWH prophylaxis for pregnant women with additional risk factors is widely exercised, especially during the third trimester. Anticoagulant-related problems during delivery are reviewed and special attention is given to anticoagulation of pregnant women with artificial heart valves.

Yamada and colleagues describe the results of a retrospective study of 289 pregnant women in whom they measured anticardiolipin β2-glycoprotein I to study its relationship to pregnancy complications. Thirteen women tested positive and 6 of these had complications. The titer varied greatly among the patients. The other 7 women had immune diseases as well. Most women were managed with aspirin plus unfractionated or low-molecular-weight heparins, and steroids. In women receiving treatment, the titers of the anticardiolipin β2-glycoprotein I tended to decrease. The authors suggest that women who test positive, should be properly treated to minimize pregnancy complications.

The next article by Kobayashi and coworkers describes the results of a prospective randomized feasibility study in which patients with severe preeclampsia were treated with antithrombin (AT) concentrate. There is considerable evidence that preeclampsia is associated with hypercoagulability, which, in turn, influences maternal and fetal morbidity. Because AT plays a key role, not only in clotting, but also in other biological processes, and given that AT levels are markedly decreased in preeclamptic patients, substitution with AT concentrate is a reasonable hypothesis. The authors observed that maternal symptoms (measured by a Gestosis index) improved significantly with AT substitution. Fetal well-being was gauged by a biophysical profile score and this also improved significantly with treatment. Various coagulation parameters also improved. Both the AT and non-AT groups received low-dose heparin (5000 U/day) as standard baseline management. The authors conclude that AT supplementation in preeclamptic women benefits maternal and fetal well-being.

Ohta et al report on the association between a variant of the glutathione S-transferase P1 gene and hypertension in pregnancy. On the basis of a report from The Netherlands, in which a variant of this gene was associated with preeclampsia, the authors analyzed this variant in a large number of pregnant Japanese women with severe hypertension induced by pregnancy and appropriate controls. Glutathione S-transferase is involved in the metabolism of xenobiotics and endogenous toxins. Although the frequency of the genotype was not different between the two groups, the authors found significant differences in elderly primiparous women and some subgroups. The authors conclude that the glutathione S-transferase gene may play a role in pregnancy-induced hypertension, possibly in association with other factors.

In the last article, Sissi and colleagues describe their experience with modifications of heparins to improve their potency and their specificity. Heparins inactivate clotting enzymes, especially thrombin and FXa, by forming complexes with AT. Heparins activate AT by inducing structural modifications that greatly enhance the binding of the enzymes to AT. It is well recognized that the length of the polysaccharide chains that make up heparins is an important factor. LMWHs, for example, are too short to bind thrombin into the tertiary complex and are thus poor inhibitors of thrombin. This is not the case with FXa. The authors used several test heparins, modified from a LMWH, to study the formation and stability of these compounds by further altering the degree of sulfation, the position of the sulfation, carboxylation, hydrogen bonding, and associated charge densities. The data clearly show that the actions of heparins can be improved by selective changes in the molecular structure.

Thanks and appreciation are expressed to all authors for their excellent and informative contributions. It is hoped that the readers will gain appreciation of the problems related to hemostasis disturbances in children. Special thanks go to Ms. Lesley Mitchell and to Dr. Suzuki for assembling this issue.