Chapter 60 Coagulopathies
A variety of hereditary as well as acquired diseases belong to the group of coagulopathies – diseases that affect the blood clotting system, causing hypercoagulability and susceptibility to bleeding. Important coagulopathies include disseminated intravascular coagulation, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and the HELLP syndrome (hemolytic anemia, elevated liver enzymes, and low platelet count). Since coagulopathies are multiorgan disease processes, ocular involvement may occur and show characteristic changes that should be recognized by ophthalmologists and retina specialists.
Disseminated intravascular coagulation (DIC) is often described as a secondary disease process typically associated with other disease entities.1 The presence of DIC increases the risk of mortality beyond that associated with the primary disease.2 A cascading activation of both procoagulants and fibrinolysis leads to simultaneous, uncontrolled hemorrhages and diffuse thrombosis of small and large vessels affecting virtually all mucocutaneous tissues and various organs, ultimately resulting in end-organ failure (see Box 60.1). As such, DIC is regarded as one of the most common causes of death. But not all presentations of DIC are lethal; it may also manifest as low-grade disease with a chronic or compensated course.
Clinical manifestations of DIC
Triggering events for DIC are manifold and range from trauma to malignancies, septicemia, obstetric complications, cardiovascular disease, inflammatory disorders, and renal disease, only to name a few. Whether DIC will pursue a fulminant or compensated course is loosely related to the disease entity with which it is associated. Chronic conditions such as cardiovascular disease, autoimmune diseases or hematologic disorders tend to be associated with a low-grade DIC, whereas more acutely presenting entities such as crush injuries are more likely to trigger a fulminant DIC. Furthermore, DIC is not restricted to a particular age range and may occur in neonates as well as elderly individuals.
The currently established theory of pathogenesis is an initial activation of the coagulation cascade following inflammation or damage to tissue and vascular endothelial cells.3 Fibrin formation leads to microvascular or macrovascular thrombosis. Soon thereafter, fibrinolysis is upregulated and the consumption of platelets in the obstructed microcirculation causes a systemic thrombocytopenia (cell count <100 000/mm3), thereby generating an environment of simultaneous clotting and extrusion of hemorrhages. Despite a common pathophysiologic pathway, clinical manifestations of the disease may vary widely (see Box 60.1), complicating diagnosis and treatment management.
The onset of DIC is usually marked by fever, shock, acidosis and, more specifically, widespread hemorrhaging, acral cyanosis, gangrene and end-organ failure. Bleeding from more than three unrelated sites at once and a recent medical history compatible with known causes of DIC can direct the clinician towards the diagnosis. Definite diagnosis is heavily based on positive laboratory test results for platelet count, D-dimer (fibrin degradation product or FDP), antithrombin-III, protein C, prothrombin time, partial thromboplastin time, and fibrinogen.4
Treatment of DIC is difficult and should primarily address the underlying cause, however, removal of its cause does not necessarily alleviate the process in all cases and prognosis of a fulminant DIC is very poor. Replacement treatment such as frozen plasma transfusion or infusion of antithrombin-III, fibrinogen, and platelet-concentrates can help to limit hemorrhages. In some cases, anticoagulant treatment may be required. Further, activated protein C has been suggested to treat this condition,5 however, the efficacy of this approach for clinically relevant outcome parameters remains unclear.6
Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy caused by platelet adhesion and aggregation mediated by endothelial cell-attached ultra-large von Willebrand factor multimers (ULVWF). The underlying cause is a congenital or acquired (autoimmune) deficiency of von Willebrand factor-cleaving proteases such as ADAMTS-13.7 TTP is more frequent in young female adults than in males or older individuals. Most presentations of the disease are idiopathic, although familial and secondary TTP have been described. Pregnancy, treatment with certain drugs (clopidogrel, cyclosporine, tacrolimus), and malignancies are associated with a higher incidence of TTP. TTP is accompanied by profound thrombocytopenia, erythrocyte fragmentation, and increased serum levels of lactatdehydrogenase (LDH).8 Clinically it manifests with fever, renal failure, neurological symptoms, purpura, and signs of hemolytic anemia. There is often a prodromal phase that may consist of headache, dizziness, nausea, and abdominal pain, presumably caused by microinfarction of the viscera. Though there are chronic smoldering patterns of the disease, an acute and fulminant course is not uncommon and, if left untreated, can be lethal. In some cases, ocular manifestations as described below may present as the first signs of the disease; thus, prompt referral to a hematologist may be life-saving.9 Plasmapheresis is the principal treatment for this condition and can be supplemented by immunosuppressive therapy (cyclosporine A, rituximab) in refractory cases, although relapses are generally the rule.10 Of note, systemic treatment with bevacizumab, a monoclonal antibody to VEGF which is increasingly used via intravitreal delivery for ocular neovascular disorders, can induce a TTP-like microangiopathy.11
Although idiopathic thrombocytopenic purpura (ITP) also features thrombocytopenia and purpura, the underlying pathophysiology is distinctly different from TTP. In many cases, ITP is the manifestation of an autoimmune process targeting the circulating platelets, thereby causing thrombocytopenia and widespread hemorrhages. Fortunately, ITP is self-limiting in most cases and responds well to treatment with corticosteroids or other immunosuppressants. Rarely, the extremely low platelet counts seen in ITP can cause severe, live-threatening complications.