Thrombotic thrombocytopenic purpura (TTP) is one of the few hematologic emergencies. Untreated, most patients die, but prompt and appropriate treatment allows most patients not only to survive but to recover, frequently without long-term sequelae.
TTP is rare. The estimated annual incidence of all TTP syndromes is about 11 cases per million in the general population, and the incidence of severe ADAMTS13 deficiency (see discussion below) is about 2 per million. Therefore, even large medical centers typically see only one or two cases each year. The syndromes are much more common in women, and the incidence among blacks is nine times higher than the incidence among non-blacks. Nevertheless, despite the rarity of this disease, good evidence exists to help guide patient care, thanks to national registries and research organizations, such as the Canadian Apheresis Study Group and the Oklahoma TTP-Hemolytic Uremic Syndrome (HUS) Registry.
This article reviews the physiologic basis of TTP, how to recognize it, and how best to treat it. We also discuss other conditions that clinically resemble TTP but probably have different underlying causes.
A YOUNG WOMAN WITH ARM WEAKNESS
A 24-year-old black woman presents to a community hospital with weakness in her left arm, which began about 30 minutes previously. She has had progressive dyspnea over the last several weeks, but has otherwise been completely well and has had no medical problems in the past other than being obese.
Physical examination reveals weakness in her left arm as well as mild dysarthria, which was not previously noted by the patient or her family. Her laboratory findings:
- White blood cell count 16.7 × 109/L (reference range 4.5–11.0)
- Platelet count 32 × 109/L (150–350)
- Hemoglobin concentration 6.5 g/dL (1.4–17.5)
- Peripheral blood smear: normal white cells, rare platelets, red cells normo-chromic with many fragments
- Lactate dehydrogenase (LDH) concentration 2,300 U/L (100–200).
In view of her symptoms and laboratory values, the physician suspects she may have TTP and refers her to McMaster University Medical Center in Hamilton, Ontario, Canada. Plasma exchange is started immediately; one plasma volume is removed and replaced with fresh frozen plasma. Nevertheless, the patient’s condition deteriorates overnight, she becomes more confused and cannot protect her airway, her LDH concentration rises further, and her hemoglobin concentration falls. She is transferred to the intensive care unit. Her plasma exchange prescription is increased to 1.5 volumes twice daily (although little evidence exists that plasma exchange twice daily is more effective than once daily).
On the third day of her stay, she becomes completely paralyzed on the left side. In addition to her twice-daily plasma exchange procedures, a plasma infusion and corticosteroid therapy are initiated. Her platelet count stabilizes at about 20 × 109/L.
The patient next develops renal insufficiency and requires three acute hemodialysis treatments. (Plasma infusion frequently leads to volume overload in critically ill patients. Some intravascular volume can be removed with plasma exchange; however, significant volume overload with significant renal insufficiency can only be treated with renal replacement therapy.)
The patient undergoes 28 consecutive days of twice-daily plasma exchange and gradually improves, as measured by increasing platelet counts, a gradual fall in the LDH concentration, and stabilization of—and ultimately an increase in—the hemoglobin level. She is weaned off plasma infusions, and then plasma exchange is tapered to once a day and then to alternate days.
She is completely well at the time of discharge 4 weeks after her initial admission, with no residual deficits.
Comment. This case shows that even patients with apparently devastating compromise and neurologic deficits can completely recover with aggressive plasma exchange and other therapies. One child treated at the Hospital for Sick Children, affiliated with the University of Toronto, developed TTP and had 120 consecutive days of plasma exchange: she was unconscious and comatose for much of that time, but she ultimately recovered and is now completely well without residual neurologic deficits.
TTP MAY BE DUE TO ADAMTS13 DEFICIENCY
Twenty-five years ago, little was known about TTP except for its clinical manifestations. Now, it is known to be caused in some patients by an acquired deficiency of a circulating metalloproteinase. In very rare cases a hereditary deficiency of ADAMTS13 causes TTP. In addition, a number of conditions share clinical features with TTP but have other underlying causes.
In acquired TTP, an autoantibody forms against ADAMTS13, a zinc-containing metalloproteinase that is also known as von Willebrand factor-cleaving protease. Normally, von Willebrand factor circulates in plasma as multimers that allow platelets to adhere to vascular surfaces. When von Willebrand factor is initially released from endothelial cells, it exists as large multimers, which are more adhesive for platelets than normal. These large multimers are normally cleaved into smaller units by ADAMTS13. If ADAMTS13 is lacking, the very-high-molecular-weight von Willebrand factor multimers accumulate, causing platelet agglutination and the vascular occlusion that results in the manifestations of TTP.
In 1994, ADAMTS13, the gene of which is on the ninth chromosome, was shown to cleave von Willebrand factor under conditions of high shear stress. In 1996, a congenital homozygous deficiency of ADAMTS13 was found to be associated with platelet microthrombi. Afterwards, some patients with TTP were shown to have low or undetectable levels of ADAMTS13, owing to immunoglobulin G antibodies directed against the enzyme.