Unmasking thrombotic thrombocytopenic purpura: A case study and brief review

Because the clinical presentation is variable, this rare and potentially fatal condition is difficult to diagnose. Recognizing the two classic clues of microangiopathic anemia and thrombocytopenia can speed life-saving treatment.

Audrey Griffin, MPAS, PA-C

Ms. Griffin is Assistant Professor, Physician Assistant Department, Wichita State University, Wichita, Kan.

Case study

A 30-year-old white woman arrived by ambulance at the emergency department (ED) with dehydration and syncope after her husband found her unresponsive. He reported that she had been vomiting and had had diarrhea for the past 5 days. Her medical history was unremarkable, and she had never been pregnant. The use of OTC dimenhydrinate, suggested by her physician during a phone consultation 2 days earlier, had done little to relieve the vomiting.

The patient’s skin and sclera were notably icteric, her lips appeared dry, and she had poor skin turgor. She was tachycardic, hypotensive, and afebrile. She was disoriented and aphasic, reacting to her name by looking at the speaker but unable to answer questions. She was mildly combative and became uncooperative during attempts at an oropharyngeal exam. Heart and lung sounds were normal, and she was not in respiratory distress. Her abdomen was soft, and she appeared to have right upper quadrant tenderness to palpation. No petechiae or ecchymoses were noted. IV fluids, oxygen, and cardiac monitoring were initiated.

An ECG showed sinus tachycardia but was otherwise normal. The CBC revealed anemia with a markedly low platelet count of 16 X 10⁹/L (normal range is 150-450 X 10⁹/L). The prothrombin time (PT) and partial thromboplastin time (PTT) were normal. Hemoccult results were negative. Direct and indirect bilirubin were elevated. BUN was elevated at 34 mg/dL (normal, 7-19 mg/dL). Serum creatinine was normal. Serum lactate dehydrogenase (LDH) was elevated at 1,940 IU/L (normal, 313-618 IU/L). Urinalysis revealed 3+ protein, 2+ bilirubin, positive nitrite, trace leukocyte esterase, and few bacteria. Pregnancy test and serum toxicology results were both negative. CT scans of the brain and abdomen were normal. The peripheral smear contained schistocytes.

Based on the presence of thrombocytopenia and hemolytic anemia, a tentative diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and the patient was admitted to the ICU where plasma exchange was initiated and a corticosteroid administered. Despite treatment, her condition deteriorated and she died within 24 hours after presentation to the ED.

HIV test results received after her death were negative, as were results of a hepatitis panel and antinuclear antibody tests. Blood, urine, and stool cultures were negative for bacterial growth.

Discussion Young women have a higher incidence of TTP,¹ and this patient’s acute onset of acquired TTP without any identifiable risk factor or cause is a common presentation of this syndrome. Her neurologic impairment complicated the initial assessment. Although some TTP patients develop a rash, this patient had no visible purpura or bruising. Her symptoms of fever, nausea, and vomiting were similar to those of viral gastroenteritis. The patient’s husband noted that she did not exhibit any neurologic symptoms until the fifth day of her illness, when he called for an ambulance. Unfortunately, this type of late clinical presentation is associated with a poor prognosis.

Overview of TTP

Fever, thrombocytopenia, neurologic symptoms, microangiopathic hemolytic anemia, and renal dysfunction–the pentad associated with TTP–are caused by microthrombi of platelets and fibrin in the capillaries and arterioles of the kidney, liver, brain, heart, pancreas, and adrenal glands. All five diagnostic clues are rarely seen together until very late in the illness. Because the condition is usually fatal if not treated, treatment should be initiated as soon as a diagnosis of TTP is suspected. However, the multiplicity of organ involvement and the variety of possible presentations make TTP difficult to diagnose quickly.

The annual incidence of TTP is 4 to 7 cases per million; estimated mortality is 1.1 per million,^1,2 a 250% increase since 1972. Actual mortality may be even higher.³ The increase is disturbing because effective treatments are available. Approximately 70% of patients who have TTP are women in their 20s, but when the condition occurs in patients aged 70 years or older, men and women are affected equally. Hundreds of cases of TTP have been reported since it was first described in1924.⁴ It was almost always fatal until blood transfusions, splenectomy, and corticosteroids improved survival in the 1960s. The use of plasma exchange–the current mainstay of treatment–began in the 1970s.

TTP had been linked with hemolytic-uremic syndrome (HUS) because of their common symptoms of CNS changes and microangiopathic hemolysis, with HUS occurring primarily in children and affecting the kidneys. TTP is rare in children, and children with HUS typically recover without plasma exchange. Both disorders are thrombotic microangiopathies (see Table 1).

The most common presentation of TTP is a single, acute episode in a healthy young adult that has no identifiable cause, as in the case described. Episodes of TTP have been associated with the use of drugs, including ticlopidine (Ticlid), clopidogrel (Plavix), cyclosporin, quinine, and oral contraceptives. TTP can also be initiated by viral infections such as HIV disease; pregnancy and systemic lupus erythematosus (SLE) have also been associated with the syndrome. (SLE is usually associated more with the childhood form of TTP.)

Pathophysiology of TTP

Microthrombi formation in TTP is caused by von Willebrand’s factor (vWF), which attracts platelets. vWF is a very large multimeric protein secreted by blood vessel endothelium. Its function is to facilitate platelet adhesion, aggregation, and thrombosis formation at the site of vessel injury. The structure of vWF may have a role in TTP; it is theorized that its large size allows it to have flexibility in smaller vessels. When exposed to fluid stress caused by blood flowing in smaller vessels such as arterioles and capillaries, the globular molecule undergoes a conformation change,⁵ unfolding into an elongated form and exposing platelet-binding sites⁶ and cleavage sites in the molecule.⁷ In a healthy person, a proteolyzing agent cleaves the vWF into smaller proteins. Patients who have TTP, however, have large amounts of this uncleaved, unfolded form--or "ultralarge" vWF--in their serum. These large, filamentous, unfolded multimers have multiple platelet-binding sites that cause platelet-platelet attraction, enhancing the formation of microthrombi in the capillaries and arterioles.⁶

Patients with TTP lack a proteolyzing agent, or protease, which cleaves the vWF. One reason identified for this deficiency is a genetic mutation of the ADAMTS zinc metalloproteinase family: a disintegrin and metalloproteinase with thrombospondin type 1 repeat.⁶ In cases of congenital TTP, this protease deficiency causes lifelong episodes of thrombocytopenia requiring plasma exchanges every 2 to 3 weeks.

No mutations have been found in the ADAMTS-13 gene in acquired TTP.⁶ IgG antibody is, however, known to inhibit the ADAMTS-13 protease activity. Patients with acquired TTP, including the form associated with ticlopidine, have IgG antibody, indicating an autoimmune response. Patients with HIV-related TTP also have a deficiency of this protease with the presence of the IgG protease inhibitor,⁸ which explains why plasma exchange is beneficial in patients with TTP. This protease deficiency is not found in HUS. In some patients, the immune response persists despite successful treatment, and further episodes of TTP may occur.

Making the diagnosis

CBC results that reveal thrombocytopenia and anemia (decreased hemoglobin and hematocrit) should prompt additional diagnostic tests (see Table 2). The differential diagnosis includes disseminated intravascular coagulation (DIC), a coagulation disorder. It is important to distinguish TTP from DIC because giving platelets is helpful in DIC but potentially harmful in TTP. TTP is not a problem of coagulation, and fibrinogen levels remain normal in TTP. Both PT and PTT are prolonged in DIC but are within the normal range in TTP.

Because TTP can have cardiac manifestations such as myocardial infarction, cardiac monitoring and oxygen administration are warranted. An ECG should be obtained and serum cardiac isoenzymes should be measured. Urinalysis can be performed quickly and may reveal signs of renal involvement. The LDH level is markedly increased in TTP as a result of hemolysis and tissue damage. Schistocytosis is found in the peripheral smear in many but not all patients with TTP. Additional tests for pregnancy, HIV infection, and SLE should be performed to detect potential underlying causes. Depending on the clinical presentation, other tests may be indicated--such as CT of the brain when neurologic deficits are present. A patient who has neurologic symptoms warrants periodic evaluation for mental status fluctuations.

Because fever, thrombocytopenia, neurologic symptoms, microangiopathic hemolytic anemia, and renal dysfunction of TTP are rarely seen together until very late in the illness, patients who present with only microangiopathic anemia and thrombocytopenia should be presumed to have TTP, and treatment should be initiated immediately.^3,9-11

Treatment

Plasma exchange with fresh frozen plasma (FFP), cryosupernatant plasma, or solvent/detergent plasma is performed once a day until the platelet count remains above 150 X 10⁹/L for 2 to 3 days and the LDH approaches normal levels. Several weeks or more of daily plasma exchanges are typically required. A hematologist should be consulted when planning treatment for TTP patients.

Approximately 14% of patients with TTP do not respond to plasma exchange.¹² In these cases, the usual treatment is splenectomy, which has also been shown to be beneficial in some patients with relapsing TTP.¹⁰ Although platelet transfusion is generally not recommended because it can increase platelet aggregation and cause more microthrombi to form, some experts have been suggested that platelet transfusions may be safe in patients already receiving plasma exchange.¹³ Platelet transfusion, however, is reserved for patients who are hemorrhaging or who require an invasive procedure.³

Other adjunct medications that have been used to treat TTP include vincristine (Oncovin, Vincasar, Vincrex) and corticosteroids to modulate a possible immune response,¹⁰ and antiplatelet drugs such as aspirin and dipyridamole (Persantine) to decrease platelet activity. Because the effectiveness of adjunctive treatments is unknown, clinicians may rely solely on plasma exchange as the initial treatment, adding adjunctive therapies only in the event of failure of plasma exchange.

The monoclonal antibody rituximab (Rituxan), an immunosuppressive agent, has been used successfully in patients with TTP refractory to plasma exchange.¹² Further studies are needed, however, before this agent can be generally recommended.

Conclusion

Whether this patient would have survived with earlier clinical evaluation and intervention is unknown. Anemia and a low platelet count should alert the clinician to the possibility of TTP.

Today, patients presenting with the microangiopathic anemia and thrombocytopenia without any other cause should be presumed to have TTP, and plasma exchange should be initiated. Plasma exchange can be discontinued if TTP is not found to be the accurate diagnosis. It is hoped that increased awareness of the diagnostic dyad will assist clinicians with prompt recognition and timely treatment of this deadly syndrome.

REFERENCES

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