Thrombotic Thrombocytopenic Purpura

The prototypic disease for nonimmune platelet destruction is thrombotic thrombocytopenic purpura (TTP) (see Chapter 63). TTP is caused either by a congenital deficiency of von Willebrand factor cleaving protease or by auto-antibodies directed against the protease. The protease is encoded by the gene designated as ADAMTS 13. Patients with TTP present with the clinical pentad of fever, renal abnormalities, central nervous system disorders, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA). MAHA is characterized by the presence of fragmented red cells, or schistocytes (Figure 45.1), caused by erythrocyte destruction in the microvasculature. Hemolytic uremic syndrome (HUS) shares pathologic features with TTP, but in HUS renal abnormalities are more pronounced. HUS is most often secondary to infection with Shiga toxin, producing organisms such as Escherichia coli O157:H7. The primary treatment for TTP is plasmapheresis (also known as apheresis) accompanied by glucocorticoids. The treatment of HUS is usually supportive. Patients with TTP become thrombocytopenic from activation of platelets caused by the presence of large von Willebrand factor multimers. This leads to intravascular platelet aggregation and ultimate clearance of circulating platelets from the circulation. Platelet transfusions in TTP have been associated with fatal outcomes, presumably from microthrombosis, and are therefore contraindicated except for life-threatening bleeding. Fortunately, patients with TTP rarely bleed. Thrombocytopenia resulting from MAHA in conditions other than TTP usually responds to treatment of the underlying condition or removal of the offending drug (Box 45.2; see also Chapter 63). Again, as with classic TTP, there should be a reluctance to transfuse platelets in all but the most serious bleeding episodes.

Disseminated Intravascular Coagulation

Thrombocytopenia in disseminated intravascular coagulation (DIC) is also secondary to platelet destruction. Much like TTP, in DIC, platelets become activated, clump, and are cleared from the circulation. Unlike TTP, ADAMTS13 is not responsible for platelet activation. Rather, thrombin deposition and the conversion of fibrinogen to fibrin lead to thrombocytopenia. In a large prospective, multicenter study, 8.5% of ICU patients were diagnosed with DIC, and the 28-day mortality rate was 21.9%.

DIC results from various causes, including gram-negative and gram-positive bacterial infections, trauma, snakebites, brain injury, and burns. In DIC, the generation of thrombin occurs without its subsequent neutralization, which is normally carried out by coagulation pathway inhibitors. Because thrombin promotes the conversion of fibrinogen to fibrin, microvascular thrombosis occurs. This results in tissue ischemia along with consumption of coagulation components such as platelets, fibrinogen, and prothrombin. DIC is often identified clinically by skin hemorrhage in the form of petechiae and ecchymoses. Alternatively, DIC can present as thrombosis of digits. Shock, organ dysfunction, and frank hemorrhage may occur as well. Other laboratory findings in DIC include prolongation of the prothrombin time, partial thromboplastin time, and thrombin time, a decrease in the fibrinogen level, and an increased level of fibrin degradation products (FDPs), also known as fibrin split products (FSPs). d-Dimers result from the degradation of cross-linked fibrin by plasmin, and their levels also increase in DIC. Primary fibrinogenolysis, a rare condition that results when plasmin is generated in the absence of DIC, is characterized by normal levels of d-dimers despite a low fibrinogen level.

One common clinical problem is differentiating DIC from the coagulopathy resulting from liver disease. In both conditions, fibrinogen is low, clotting times are prolonged, and fibrin degradation products are increased. Measuring levels of factors VIII and IX can help in distinguishing one from the other. Patients with DIC have consumption of all clotting factors and decreased levels of both factors VIII and IX. In contrast, because factor VIII is stored in endothelial cells, patients with liver failure have low factor IX levels but may have normal levels of factor VIII. Although schistocytes can be seen on the peripheral smear in patients with DIC, this finding is inconsistent.

The treatment of DIC is more an art than a science because of the paucity of randomized, controlled trials in the medical literature. The primary therapy remains treatment of the underlying disorder. Platelet transfusions should be reserved for the acutely bleeding patient with a platelet count of < 50,000/μL or for prophylaxis when invasive procedures are planned. Although concern exists about worsening DIC by transfusing blood components, there is little evidence from controlled clinical trials that blood components “fuel the fire” in DIC. Therefore, in actively bleeding patients with DIC, 8 units of cryoprecipitate should be infused to replace fibrinogen in patients whose levels are less than 100 mg/dL. Similarly, fresh frozen plasma can be administered to correct a prolonged prothrombin time (e.g., international normalized ratio [INR] > 1.5). The use of heparin can partially reduce the coagulopathy in DIC, and a large trial in patients with severe sepsis suggests a benefit of low-dose heparin on 28-day mortality. The use of tissue factor pathway inhibitors and antithrombin III has not shown survival benefit. Likewise, the survival benefit that was observed in the first clinical trial of activated protein C in patients with DIC and severe sepsis could not be reproduced 10 years later in a second pivotal clinical trial in the same patient population with the resulting withdrawal of that product from the market. Other therapies, such as recombinant factor VIIa, have been used to treat DIC anecdotally, but insufficient data exist to recommend their routine use.