Recent Clinical Advances in Coagulopathies

To write a dissertation on coagulopathies in the era of biotechnology, protein mapping, and recombinant technology would require more space than allotted. Therefore, we confine ourselves to several areas: hemophilia, von Willebrand’s disease (VWD), immune thrombocytopenic purpura (ITP), and heparin-induced thrombocytopenia (HIT), all bleeding disorders. We will focus on the unresolved issues facing the field.

Hemophilia

To write a dissertation on coagulopathies in the era of biotechnology, protein mapping, and recombinant technology would require more space than allotted. Therefore, we confine ourselves to several areas: hemophilia, von Willebrand’s disease (VWD), immune thrombocytopenic purpura (ITP), and heparin-induced thrombocytopenia (HIT), all bleeding disorders. We will focus on the unresolved issues facing the field.

Hemophilia

The earliest descriptions of this disease were the Egyptian papyrus and Talmudic writings. Specific diagnosis and therapy did not occur until the 1940s. With blood banking advances, the field of therapy went from plasma to cryoprecipitate to concentrate. These therapies led to changes in the healthcare system with comprehensive care clinics and self-infusion. These human-derived products carried both hepatitis and HIV viruses, devastating the recipients. This led to techniques of successful viral inactivation. Biotechnology then allowed for defining the factor VIII and IX molecules, leading to the manufacture of recombinant factors. The clinical observation that changing on-demand replacement therapy with prophylaxis markedly altered the long-term outlook of patients, particularly as human and recombinant products have been safe from viral transmission since 1985.

Inhibitor Induction

What we are left with, however, is the transfusion-transmitted disease, antibody production (inhibitor). This has led to a variety of as yet unresolved issues around the question of relative risk of these two classes of therapies (human-derived versus recombinant) vis-à-vis immunogenicity and inhibitor induction. No head-to-head study has been carried out to provide an answer. Several studies demonstrate that recombinant factors produce more inhibitors than human-derived factors. Within the armamentarium of human-derived products, there are those that have highly purified factor VIII and others with substantially large amounts of von Willebrand factor (VWF), believed by many to be even less immunogenic. Thus, making an initial therapeutic choice is an issue. Those who believe that there are no differences in immunogenicity between human-derived and recombinant therapies are convinced that differences in inhibitor incidence are attributable to study design. Compounding factors are differences in genetic and familial propensity for antibody production. Ethnic background also plays a role, as African-Americans and Hispanics have higher prevalence rates. The point in life at which therapy is initiated—very early in infancy or later—remains controversial. The relevance of prophylactic versus on-demand therapy in terms of whether one prophylaxis reduces the likelihood of inhibitors has not been adequately tested. Most of the data surrounding these unresolved issues are derived from small prospective—but mainly retrospective—analyses that do not stand up to high evidence-based conclusions.
As inhibitors are a serious life-threatening complication for which hemostasis cannot be guaranteed for the patient, its eradication, as well as means to prevent it (above), remain high-priority concerns. Inhibitors to factor VIII also appear de novo (called acquired hemophilia), offering the same challenges. Immune tolerance, known in immunology for years, has been applied to these patients using antigen overload. There is now a consensus as to what successful tolerance is, but what regimen and what type of factor should be used is not known. An international study is ongoing to evaluate regimens, and a new study has recently been initiated to evaluate different types of product. There is increasing evidence in vitro using neutralizing data, applying thrombin generation, and in vivo that vW-containing products may be more successful at modulating the immune response and achieving tolerance where prior attempts with non-vW-containing products have failed. More recently, immunologists showed that using the dendritic cell as the antigen receptor is more susceptible to incorporating factor VIII without vW content and can be interrupted when vW factor is presented with factor VIII. This area continues to confound treaters, but data are evolving to address them.

Joint Disease

As factor coagulopathies lead to spontaneous joint bleeds, which lead to significant morbidity and reduce quality of life, finding preventive techniques to ensure as normal a joint as possible has led to multiple techniques to measure progression of joint damage. Physical examination and X-ray scores have been the gold standard for years. With the introduction of magnetic resonance imaging (MRI), it has been possible to demonstrate very early damage with Fe deposition, and synovial as well as cartilage damage. Its role in predicting long-term outcome and progression has not been established; this needs to be done. Whether undetected bleeding can cause damage and understand damage seen on MRI without bleeding is undetermined. This area may well help to unravel the predictability of clinical outcome of varied regimens.
Many adults with pre-existing joint damage have been shown in a prospective study to decrease the rate of joint destruction on prophylactic treatment. No formal study since then has been performed to either corroborate or encourage adult prophylactic programs. Hopefully, this will come to pass.^1,2

Heparin-induced Thrombocytopenia

HIT is an immune-mediated prothrombotic disease caused by the development of an immunoglobulin G (IgG) antibody that recognizes complexes of platelet factor 4 and heparin. Binding and activation of these complexes causes an acquired hypercoagulability.³ HIT can cause significant morbidity and mortality. An estimated 600,000 cases of HIT occur yearly in the US.⁴ The thrombotic risk in patients with HIT is estimated to be more than 30 times that of control.

Diagnosis

HIT is a clinical pathological syndrome that requires a clinical manifestation (thrombosis or thrombocytopenia) as well as a laboratory confirmation of antibody detection. In classic HIT, patients present with a platelet count less than 150,000 or a decrease of 50% or more from baseline. Immunoassays detect circulating IgG, IgA, and IgM antibodies, with a high negative predictive value but a low positive predictive value. The serotonin release assay is considered the gold standard, although it is not widely available.

Management

All heparin should be discontinued when HIT is suspected. Treatment of HIT requires anticoagulation with a direct thrombin inhibitor (DTI). Three DTIs are avaible for use in the setting of HIT: argatroban, lepiriduin, and bivalirudin. These inhibitors bind directly to thrombin and do not require antithrombin. All three have short half-lives. Argatrobran must be dose-adjusted for hepatic failure, while lepirudin and bivalirudin must be adjusted in renal failure. The development of antibodies to lepirudin has been reported, and a patient should not be treated with lepirudin more than once. Bivalirudin is currently approved for use only in patients with HIT who must undergo percutaneous coronary intervention. There is a bleeding risk associated with these agents, and there are no randomized, controlled clinical trials comparing these agents with one another.⁵
The risk for thrombosis remains elevated for weeks after the discontinuation of heparin.⁶ In a patient with a documented thrombosis, treatment with a DTI should be followed by treatment with warfarin for at least two to four weeks. Data are lacking regarding the exact length of anticoagulation, as well as the duration of anticoagulation in an HIT patient without evidence of thromboses.

Controversies

It is unclear why certain patients with HIT develop thrombosis and some do not. The approach to patients with HIT with only isolated thrombocytopenia varies. Routine testing for the HIT antibody is not recommended, as the clinical significance of a positive test without clinical symptoms is unclear. A newly recognized issue is the high rate of antibody positivity post-cardiac surgery. It is unclear whether this is true HIT or an epiphenomenon. Prospective epidemiological studies are ongoing to determine in what setting HIT-antibody positivity requires alternative therapy. Data are also still needed regarding the management of HIT patients without thromboses, length of anticoagulant therapy, and management of an HIT-antibody-positive patient and re-exposure to heparin.

Immune Thrombocytopenic Purpura

ITP is an autoimmune disorder in which platelet destruction is seen due to antiplatetelet antibodies causing thrombocytopenia. This can cause a range of bleeding symptoms, from epistaxis, petechiae, and bruising to intracranial hemorrhage, hemoptysis, and gastrointestinal bleeding. Historically, efforts to control the disease have relied on interfering with the destruction of antibody-coated platelets or the use of immunomodulatory agents to suppress the production of antiplatelet antibodies. Relapse is common, and patients are often intolerant of the side effects of treatment. Recent exploration into the pathogenesis of ITP has demonstrated that platelet production is suboptimal in patients with ITP.^7–9 This has spurred the development of exciting new treatments.

Thrombopoeitin Receptor Agonists

Thrombopoetin (TPO) is the main cytokine involved in thrombopoiesis. TPO agonists are a focus of treatments for ITP that aim to enhance platelet production. First-generation TPO agonists were found to cause the development of autoantibodies that cross-reacted with endogenous TPO, causing thrombocytopenia.^10–12 Non-immunogenic second-generation TPO agents have been developed. The furthest along in clinical study is AMG 531. A large clinical study of weekly subcutaneous injections of AMG 531 in patients with ITP demonstrated a platelet response in 85% of patients, and the drug was well tolerated.¹³ Long-term clinical studies are ongoing. Eltrombopag (GSK), a first-in-class non-peptide oral TPO receptor agonist, was found to increase platelet counts to greater than 50,000 in 70 and 81% of patients treated with 50 and 75mg daily doses, respectively.¹⁴ AKR-501 (AkaRx), another oral TPO mimetic, has been tested as single and multiple doses in healthy subjects, with promising results. Prospective, randomized, placebo-controlled studies in ITP are ongoing.
Unresolved issues with these new agents include long-term safety and efficacy, use in combination with other agents, and use in splenectomized patients.

Rituximab

Rituximab, a monoclonal anti-CD20 antibody that targets B cells, is being used more frequently in patients with ITP. Currently, rituximab is US Food and Drug Administration (FDA)-approved only for CD-20+ lymphoma. A recent systematic retrospective review of the use of Rituxan demonstrated a platelet count response in over 60% of patients, but with marked toxicities. Death was documented in 2.9% of cases.¹⁵ To date, there have been no randomized, controlled clinical trials involving the use of Rituxan in ITP patients. The indiscriminate use of Rituxan in this patient group should be avoided. These are exciting new approaches to the treatment of ITP. These agents may serve to change the way in which patients with chronic ITP are treated. Long-term studies will aid us in clarifying their role in the life-long care of patients with ITP.

Von Willebrand Disease

VWD was originally described many years ago in a family from Aland, an island off the coast of Sweden. It is the most common inherited bleeding disorder. It is clinically characterized by mucocutaneous bleeding, while patients with severe VWD suffer from hemarthrosis and soft-tissue bleeding. The disease, caused by the inheritance of a mutated VWF, results in a quantitative or qualitative abnormality of VWF.¹⁶ Over time, recognition of the complex relationship of VWF as the carrier for factor VII has led to an increased understanding of the disease and its treatment. Extensive sub-typing has been carried out through multimer analysis. More recently, the role of increased proteolysis of VWF by a disintegrin-like and metalloprotease with thrombospondin type 1 motifs-13 (ADAMTS-13) has been established for VWF type 2A, and is also being investigated in other VWD subtypes.^17,18

Diagnosis

The diagnosis of VWD can be difficult due to various factors. The diagnosis requires characterization of the VWF multimer. The phenotype versus the genotype can be disparate in a large number of cases. The assays are complex and many variables can affect testing, making consistent, reproducible results difficult to obtain. O+ blood has been associated with lower levels of VWF, while high estrogen states can increase VWF.^19,20 How plasma is stored can also affect VWF activity, leading to erroneous screening values. This variability has led to efforts to increase diagnostic sensitivity and specificity. Laboratory panels testing for VWD often now include collagen-binding assays and use of a platelet function analyzer. The true additional benefit of these tests in accurately diagnosing VWD remains to be seen.
Desmopressin (DDAVP), which stimulates the release of VWF from vascular endothelial cells, is an effective treatment, particularly in patients with type I VWD, although not all patients will respond. VWF/FVIII concentrates are a mainstay of treatment and prophylaxis for VWD patients, and the safety of these products continues to improve. Optimal prophylaxis scheduling and dosing is an issue under continued investigation. VWD continues to pose a clinical challenge. Improved classification of the disease, based on correlations between specific mutations as well as clinical characteristics, will allow us to further understand associated diseases and target therapeutic interventions.
The management of these bleeding disorders has sparked the imagination of clinicians, and requires us to integrate the basic science relating to these disorders into the clinical presenting picture and existing therapeutic options. The care of patients with these bleeding disorders truly takes us from bench to bedside. Much remains to be done. ■