Clinical Manifestations
Patients present with various degrees of hemolytic anemia and compensation, with evidence of RBC fragmentation on smear (Fig. 1; see the box on Differential Diagnosis of Extrinsic Nonimmune Hemolytic Anemias). RBC removal is generally extravascular, with minimal or moderately decreased levels of haptoglobin. If RBC damage is sufficiently severe, signs of intravascular hemolysis may be present. Because of the underlying pathology, some of these syndromes show evidence of platelet removal, leading to thrombocytopenia. Occasionally, the underlying cause produces activation and depletion of procoagulant factors with consequent activation of the fibrinolytic system, consistent with disseminated intravascular coagulation (DIC; see the box on Causes of Red Blood Cell Fragmentation Hemolysis).
Fig1. PERIPHERAL BLOOD SMEARS FROM EXAMPLES OF EXTRINSIC NONIMMUNE HEMOLYTIC ANEMIA. (A) Microangiopathic hemolytic anemia. Note the schistocytes, fragmented cells, spherocyte, and polychromasia. More examples of damaged red blood cells (RBCs), including classic “helmet cell” (top), are seen to the immediate right insert. (B) Thermal injury from a burn. Thermally damaged RBCs form numerous microspherocytes and tiny RBC fragments. (C) Malaria infestation. RBCs containing Plasmodium falciparum malaria. Note the high rate of infestation, the presence of only ringed forms, and the multiply infested RBCs (center).
Pathophysiology
Fragmentation hemolysis occurs when mechanical forces disrupt the physical integrity of the RBC membrane. In vitro shear stresses in excess of 3000 dynes/cm2 cause RBC fragmentation. For example, in vivo studies in patients with mitral prosthetic regurgitation and hemolysis show high peak shear stresses of 4500 dynes/cm2, very rapid acceleration or deceleration, or both. Valvular abnormalities or prosthetic vales can thus cause microangiopathic changes.
Research suggests additional mechanisms of producing micro angiopathic hemolysis that involve platelets and small vessel thrombi. The platelet-rich, fibrin-poor microvascular thrombi found in many patients with thrombotic thrombocytopenic purpura (TTP) now are thought to be caused by abnormally decreased ADAMTS 13 activity. This metalloprotease is responsible for converting the highly thrombogenic ultra-large multimers of von Willebrand factor made by platelets and endothelial cells into the smaller forms normally found in circulation. Mutations in or anti bodies against ADAMTS 13 result in unusually large multimers of von Willebrand factor attached to endothelial cell surfaces, where platelets may excessively aggregate, leading to the formation of micro vascular thrombi even in the absence of endothelial damage. In the case of disseminated cancer, the cause of microangiopathy may be microvascular tumor emboli.
Whatever the mechanism of mechanical trauma, the RBC mem brane is viscoelastic and has self-sealing properties so that little hemoglobin leaks out as the cell is being cut. However, pro longed distortion of the membrane produces a plastic change; therefore, the smaller RBC fragments usually do not become microspheres or microdisks but continue to display evidence of the shearing event or distortion in the form of typical irregular shapes. These irregular shapes and the rigidity that they reflect subsequently interfere with the ability of RBCs to fold, elongate, and deform sufficiently to pass through 3-μm capillaries and even smaller slits in the walls of the sinusoids of the reticuloendothelial system. This sequence leads to their destruction.
Differential Diagnosis
Generally, the differential diagnosis of fragmentation hemolysis can be deduced from the clinical findings. The presence of a pros thetic heart valve or a regurgitant jet that fragments or accelerates (i.e., Waring blender syndrome) can be readily discerned. The clinical picture of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP–HUS) is generally dramatic and acute. Atrioventricular malformations may be associated with disseminated intravascular coagulation (DIC) and platelet removal; the diagnosis requires a high index of suspicion and imaging studies. The presence of preeclampsia in a pregnant woman with micro angiopathic hemolysis usually is obvious, but hemolysis plus elevated liver enzymes plus low platelet count (HELLP) syndrome is a serious complication of pregnancy that can occur without other signs of preeclampsia or hypertension. This syndrome can produce hepatic rupture, visual failure, DIC, seizures, and congestive heart failure and requires treatment by prompt delivery of the fetus. Cancer can be an underlying cause of microangiopathy. Vessels supplying malignant tumors are thought to be structurally abnormal. They exhibit the same sort of fibrin stranding that produces fragmentation hemolysis in DIC and TTP–HUS.
Continued use of invasive diagnostic and therapeutic procedures with insertion of foreign bodies into the circulation has been com plicated by microangiopathic hemolysis. A transjugular intrahepatic portosystemic shunt can cause the syndrome in approximately 10% of patients. The hemolysis usually disappears after 12 to 15 weeks. Similarly, the use of coil embolization to seal off a patent ductus arteriosus may also cause significant hemolytic anemia. Vasculitis has also been implicated as a cause.
Multiple drugs are associated with microangiopathic hemolysis, most commonly quinine. A recent review found that in only 22 of 78 drugs reported to produce drug-induced thrombotic microangiopathy was a definite association found. Cyclosporine, tacrolimus, and mitomycin C have been implicated as causing a HUS picture that typically develops within weeks to months of exposure. Total body irradiation and bone marrow transplantation also are associated with microangiopathic hemolysis. Both chemotherapeutic agents and targeted cancer agents, including immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors, are associated with thrombotic micro angiopathy. The thienopyridines ticlodipine and clopidogrel are both capable of producing a significant thrombotic microangiopathy that differs somewhat in presentation. Ticlodipine-associated TTP typically occurs between 2 and 12 weeks after initiation of therapy and presents with severe thrombocytopenia, microangiopathic hemolytic anemia, highly elevated lactate dehydrogenase, and normal renal function and is associated with severe deficiency of plasma ADAMTS13 activity. In contrast, clopidogrel-associated TTP usually presents within 2 weeks of drug initiation and is associated with mild thrombocytopenia, microangiopathic hemolytic anemia, mildly elevated lactate dehydrogenase levels, marked renal insufficiency, and near-normal levels of ADAMTS13 activity. Other reported exposures associated with micro angiopathic hemolytic anemia include the use of cocaine and the herb Echinacea. The mechanisms of drug-induced thrombotic microangiopathy are not well understood but include immune-mediated causes (as in the case of quinine) and direct toxicity to the endothelium.
Thrombotic microangiopathic hemolytic anemia can also be the presenting feature of severe, systemic infection, including viral (cytomegalovirus [CMV], HIV), fungal, and bacterial infections.7 Whether infection “triggers” the development of TTP or instead the presentation remains debatable.
In one large series, 10 of 351 (2.8%) patients diagnosed with TTP were subsequently diagnosed with disseminated malignancy. Symptoms suggesting an underlying malignancy include dyspnea, cough, atypical pain, and poor response to plasma exchange. The diagnosis was made by bone marrow biopsy in six of the 10 patients, and all patients died shortly after the diagnosis of malignancy was made.
A current review highlights four hereditary and four acquired disorders that lead to thrombotic microangiopathy. TTP may be hereditary, due to mutations in ADAMTS13, or acquired, due to autoantibody inhibition of ADAMTS13 activity. In addition, complement mutations causing uncontrolled activation of the alternative pathway, mutations in components of cobalamin metabolism, and mutations in a protein kinase C-associated protein, diacylglycerol kinase, are other hereditary causes of thrombotic microangiopathy. Acquired causes in addition to autoantibodies to ADAMTS13 include shiga toxin (hemolytic uremic syndrome), drug mediated on an immune basis (i.e., quinine), drug mediated on a toxic, dose related basis (i.e., gemcitabine, cyclosporine), and acquired antibodies to complement factor H.
Therapy
Management is primarily directed toward the underlying disease or event. Compensation of RBC production should be optimized by replacing iron or folic acid if the patient is deficient in these nutrients. Occasionally, removal or repair of a damaged native or prosthetic heart valve is necessary when the hemolysis produces a disabling transfusion requirement. Treatment of TTP with plasma exchange is highly effective in classic TTP with very low ADAMTS13 levels but not indicated in other settings of thrombotic microangiopathy such as cancer where plasma exchange may be ineffective. Where autoantibodies to ADAMTS13 are central to pathogenesis, immunosuppressive treatment with steroids and rituximab is important adjuvant therapy.
