Immune Thrombocytopenic Purpura/Abnormal Bleeding Case File

Immune Thrombocytopenic Purpura/Abnormal Bleeding Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 56

A 26-year-old woman presents to the emergency department complaining of bleeding from her nose and mouth that started last night. She also noticed small, reddish spots on her lower extremities when she got out of the bed this morning. She denies fever, chills, nausea, vomiting, abdominal pain, or joint pain. The patient reports she had developed an upper respiratory infection 2 weeks prior to the emergency department visit, but the infection resolved. She has no current medical problems. Her menses have been normal, and her last menstrual period was approximately 2 weeks ago. She denies excessive bleeding in the past. Prior to this episode, she never had epistaxis, easy bruising, or bleeding into her joints. There is no family history of abnormal bleeding. The patient does not take any medications.

On examination, she is alert, oriented, and somewhat anxious. Her blood pressure (BP) is 110/70 mm Hg, her heart rate (HR) is 90 beats per minute (bpm), and she is afebrile. No pallor or jaundice is noted. There is bright red blood oozing from the nose and the gingiva. Skin examination reveals multiple 1-mm flat reddish spots on her lower extremities. The rest of the examination is normal. No lymphadenopathy or hepatosplenomegaly is noted. Her complete blood count (CBC) is normal, with the exception of a platelet count of 18,000/mm3. Prothrombin time (PT) and partial thromboplastin time (PTT) are normal.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the best initial treatment?

ANSWERS TO CASE 56:

Immune Thrombocytopenic Purpura/Abnormal Bleeding

Summary: A 26-year-old woman presents with

• Persistent epistaxis
• Petechiae on legs
• No past medical history and no personal or family history of excessive bleeding or easy bruising
• No lymphadenopathy or hepatosplenomegaly
• Other than thrombocytopenia (18,000/μL), CBC normal
• Prothrombin time and PTT normal

Most likely diagnosis: Immune thrombocytopenic purpura (ITP).

Next diagnostic step: Peripheral smear to rule out other causes of thrombocytopenia.

Best initial treatment: Oral corticosteroids.

ANALYSIS

Objectives

1. Recognize causes of bleeding disorders, including those affecting platelets and coagulation factors. (EPA 1, 2)
2. Differentiate causes of thrombocytopenia, specifically thrombocytopenic purpura versus other platelet disorders, such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC). (EPA 2, 3)
3. Describe the treatment of ITP. (EPA 4)

Considerations

This patient presents with mucosal bleeding, petechiae, and thrombocytopenia. She has no other history, symptoms, or physical examination findings of any systemic disease; thus, her problem appears to an isolated hematologic problem. A CBC is important to ensure that other cell lines are normal; if abnormal, conditions such as acute leukemia or a bone marrow infiltrative process must be considered and cannot be ruled out. A peripheral smear would also be helpful in teasing out the etiology of her thrombocytopenia. Her coagulation studies (PT and PTT) are also normal; if they were deranged, we would suspect a consumptive coagulopathy causing the thrombocytopenia and a serious underlying disorder. Her current platelet count does not pose a risk for spontaneous hemorrhage, but counts lower than 10,000/μL might place her at risk for serious or life-threatening bleeding.

APPROACH TO:

Abnormal Bleeding

DEFINITIONS

HEMOLYTIC UREMIC SYNDROME: A clinical complex consisting of progressive renal failure that is associated with microangiopathic hemolytic anemia and thrombocytopenia.

IMMUNE THROMBOCYTOPENIC PURPURA: A hematologic disorder characterized by the destruction of blood platelets due to the presence of antiplatelet autoantibodies.

THROMBOCYTOPENIA: Platelet count of less than 150,000/μL.

THROMBOTIC THROMBOCYTOPENIC PURPURA: A life-threatening syndrome characterized by a pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction.

CLINICAL APPROACH

Pathophysiology

Background. For a patient with abnormal bleeding, it is important to screen for previous episodes of bleeding, even if it affected other bodily areas. It is necessary to ask about a history of recurrent epistaxis, menorrhagia, excessive prolonged bleeding from minor cuts, dental extraction, major surgery, obstetric delivery, or trauma. Excessive mucosal bleeding (eg, gum and nose bleeding) and petechiae are suggestive of thrombocytopenia or abnormal platelet function such as von Willebrand disease (vWD). On the other hand, more severe bleeds such as hemarthrosis, deep hematomas, and retroperitoneal bleeding are more likely signs of a severe coagulation abnormality, such as hemophilia due to factor VIII or IX deficiencies.

Definition and Causes. Thrombocytopenia is defined as a platelet count of less than 150,000/μL, although spontaneous bleeding usually occurs at much lower platelet counts. The causes of thrombocytopenia can be divided into (1) decreased platelet production, (2) decreased platelet survival, (3) sequestration (hypersplenism), and (4) dilutional.

Impaired platelet production is caused by bone marrow abnormalities. Examples include marrow infiltration by malignancy or myelofibrosis and marrow suppression resulting from exposure to chemicals, drugs, radiation, or viruses. In bone marrow diseases, thrombocytopenia is often accompanied by abnormalities in the other cell lines.

Decreased platelet survival is another cause of thrombocytopenia. Hemolytic reactions represent a prime example. They can be caused by infection, medications, autoimmune diseases (eg, systemic lupus erythematosus), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and other etiologies. Decreased platelet survival can also be due to splenic sequestration in patients with splenomegaly due to various reasons (eg, portal hypertension, myelofibrosis).

When a patient presents with thrombocytopenia, any drug that the patient is using should be considered a possible cause. Common drugs known to cause thrombocytopenia include H2 blockers, quinine, and sulfonamides. In general, the diagnosis is made by clinical observation of the response to drug withdrawal. Discontinuation of the offending medication should lead to improvement in the platelet count within a time frame consistent with the drug’s metabolism, almost always within 7 to 10 days.

Immune Thrombocytopenic Purpura

Acute ITP is most common in early childhood, often following an upper respiratory infection; it is usually self-limiting. ITP in children has a higher likelihood of spontaneous remission. ITP in adults, commonly presenting in women ages 20 to 40, is more likely to have an insidious or subacute presentation that can persist for months to years, with uncommon spontaneous remission. The patient presents with the clinical manifestations of thrombocytopenia (petechiae and mucosal bleeding) without systemic toxicity, lymphadenopathy, or splenomegaly.

Laboratory values show normal white and red blood cell counts, and normal peripheral blood smear except for thrombocytopenia. Laboratory testing is usually focused on a search for secondary causes of thrombocytopenia such as human immunodeficiency virus (HIV), hepatitis C, antinuclear antibody (ANA), and a direct Coombs test to evaluate for autoimmune hemolytic anemia with ITP (Evans syndrome). Bone marrow biopsy, although seldom recommended, reveals increased megakaryocytes but otherwise normal findings. In patients older than 60 years, bone marrow examination may be needed in order to exclude myelodysplastic syndrome.

Adults with ITP and platelet count > 30,000/μL and no bleeding may be observed without treatment. Those with lower platelet counts or bleeding can be treated with oral glucocorticoids, such as prednisone. Platelet transfusions are usually unnecessary and should be reserved for rare life-threatening situations. The survival of transfused platelets in ITP may be as short as a few minutes. Intravenous immunoglobulin (IVIg) is often used when platelet counts are less than 10,000/mm3 and can raise platelet counts rapidly. Anti-D is an anti-Rh(D) immune globulin for patients who have an Rh+ blood type, but it may be ineffective in patients who have had a splenectomy. Rituximab is an anti-CD20 monoclonal antibody that targets autoantibody-producing lymphocytes and is a second-line therapy for patients with chronic ITP.

Because the spleen removes the antibody-bound platelets, patients with chronic ITP who do not respond to medical therapy may be candidates for splenectomy. Patients being considered for splenectomy should receive immunizations for encapsulated organisms such as Pneumococcus prior to surgery.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the formation of antibodies against the heparin-platelet factor 4 complex, with the fall in platelet count usually occurring 5 to 10 days after heparin begins or sooner if the patient had been sensitized by prior heparin use. HIT can cause serious consequences. HIT differs from other drug-induced causes of thrombocytopenia in that it is not associated with bleeding, but rather with increased risk of thrombosis. The four Ts are a useful mnemonic of the diagnostic criteria for HIT:

• Thrombocytopenia (nadir rarely < 20,000/μL).
• Timing of platelet count drop (usually 5–10 days).
• New Thrombosis of skin necrosis.
• Other causes of Thrombocytopenia are not likely.

Diagnosis depends on clinical suspicion and utilization of an enzyme-linked immunosorbent assay (ELISA) for the HIT antibodies. Treatment includes discontinuing heparin (one cannot switch from unfractionated heparin to low-molecular-weight heparin because HIT antibodies will cross-react), and using a nonheparin anticoagulant with a different mechanism of action such as argatroban, fondaparinux, or bivalirudin to treat thrombosis.

Disseminated Intravascular Coagulation

Thrombocytopenia may also be caused by consumptive coagulopathy, the most common of which is DIC. DIC usually is triggered by serious underlying conditions, such as bacterial sepsis; malignancy, such as acute promyelocytic leukemia; or obstetric catastrophes, such as abruptio placentae. Any of these disease processes can produce pathologic levels of tissue factor, triggering uncontrolled thrombin generation with systemic fibrin deposition in the microcirculation. This uncontrolled activation of coagulation results in consumption of platelets and clotting factors, leading to secondary bleeding. Laboratory findings include thrombocytopenia, elevated PT and PTT (consumptive coagulopathy), decreased fibrinogen, and elevated fibrin-split products and D-dimer (uncontrolled fibrin deposition). Treatment should be directed toward correcting the underlying cause, as well as replacement of platelets and coagulation factors if there is clinically significant bleeding.

Thrombotic Thrombocytopenic Purpura

TTP may be triggered by infection such as HIV or medications such as clopidogrel, or it may be idiopathic. TTP is caused by autoantibody-mediated deficiency of the ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) protease, which cleaves ultra-large von Willebrand factor (vWF) multimers on the endothelial surface. TTP is remembered by a pentad of findings: (1) thrombocytopenia, (2) microangiopathic hemolytic anemia with elevated lactate dehydrogenase (LDH) level and schistocytosis in the peripheral blood smear, (3) fever, (4) fluctuating central nervous system (CNS) deficits with altered mental status, and (5) renal failure. Patients may be acutely ill, and differentiation from DIC may be challenging except that the PT and PTT are typically normal in TTP, but elevated in DIC. Plasma exchange is the standard treatment and has reduced the mortality of this condition greatly. Table 56–1 compares DIC, TTP, and ITP.

Hemolytic Uremic Syndrome

HUS presents very similarly to TTP, with acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Clinically, it may appear to be “TTP limited to the kidney,” but the mechanism and treatment differ from TTP. HUS occurs most often in children after a diarrheal illness, often with the hemorrhagic strain of Escherichia coli O157:H7. Treatment is supportive, and plasma exchange for HUS has not been shown to be useful.

von Willebrand Disease

Patients with vWD present clinically with impaired primary hemostasis (ie, petechiae, easy bruising, mucosal bleeding, menorrhagia) with normal platelet counts but impaired platelet function. vWD is the most common inherited bleeding disorder. It may occur as often as 1 in 1000 individuals. It may be acquired, or it may be inherited as an autosomal dominant disorder; however, it is often not recognized because of relatively mild bleeding symptoms. von Willebrand factor is a large, complex multimeric protein that has two major functions: It allows for platelet adhesion to endothelium at sites of vascular injury, and it is the carrier protein for coagulation factor VIII, which stabilizes the molecule. vWD is a heterogeneous group of disorders, but a common feature is deficiency in the amount or function of vWF. Clinical features are those of primary hemostatic defects as discussed. Typical laboratory features are reduced levels of vWF, reduced vWF activity as measured by ristocetin cofactor assay, and reduced factor VIII activity. The platelet count is usually normal, bleeding time is increased, and PTT may or may not be prolonged. Treatment is desmopressin acetate, which causes release of vWF from endothelial stores, or use of factor VIII concentrate, which contains a large amount of vWF.

CASE CORRELATION

• See also Case 54 (Iron-Deficiency Anemia) and Case 58 (Sickle Cell Crisis).

COMPREHENSION QUESTIONS

56.1 A 28-year-old woman presents to the emergency department with complaints of excessive bleeding from her gums and petechiae. She is otherwise healthy and takes no medications. She smokes half a pack of cigarettes daily and occasionally drinks beer. Her temperature is 99.1 °F, BP is 110/81 mm Hg, HR is 85 bpm, and respiratory rate (RR) is 12 breaths/min. On physical examination, she has bleeding from her gums and petechiae on her bilateral lower extremities. Her CBC shows a white blood cell (WBC) count of 87,000/mm3, a hemoglobin of 8.9 g/dL, and a platelet count of 22,000/mm3. Which of the following is the most likely etiology of her low platelet count?

A. Acute leukemia

B. Drug-induced thrombocytopenia

C. Immune thrombocytopenia purpura

D. Systemic lupus erythematosus

56.2 A 50-year-old man has been treated for rheumatoid arthritis for many years. He currently is taking corticosteroids for the disease. On examination, he has stigmata of rheumatoid arthritis and some fullness on his left upper abdomen. His platelet count is slightly low at 105,000/mm3. His WBC count is 3100/mm3 with neutropenia, and hemoglobin level is 9 g/dL. Which of the following is the most likely etiology of the thrombocytopenia?

A. Autoimmune destruction

B. Prior gold therapy

C. Splenic sequestration

D. Steroid induced

56.3 A 30-year-old woman with ITP comes to her outpatient hematology office for a routine follow-up. She reports that despite taking maximum corticosteroid doses, she still has a platelet count of 20,000/mm3 and frequent bleeding episodes. Which of the following should she receive before her splenectomy?

A. Bone marrow radiotherapy

B. Intravenous interferon therapy

C. Pneumococcal vaccine

D. Washed leukocyte transfusion

56.4 A 65-year-old man with a history of prosthetic aortic valve, hypertension, and osteoarthritis is hospitalized for an elective knee replacement surgery. The patient is a nonsmoker but drinks one or two glasses of wine on the weekends. His admission CBC shows a WBC count of 8000/mm3, hemoglobin of 9.2 g/dL, and a platelet count of 250,000/mm3. Medications started on admission include acetaminophen, heparin prophylaxis, lisinopril, and pantoprazole. The patient’s hospital course was complicated by acute kidney injury and postsurgery ileus. Five days after his knee surgery, laboratory tests are significant for a platelet count of 62,000/mm3. Which of the following is the most likely cause of the thrombocytopenia?

A. Acetaminophen

B. Alcohol intake

C. Heparin

D. Prosthetic heart valve

ANSWERS

56.1 A. The thrombocytopenia is seen with other hematologic abnormalities, the most abnormal of which is a markedly elevated WBC count, suggesting

acute leukemia, which should be further worked up with a peripheral smear. The patient is not on any known medication to cause thrombocytopenia (answer B). ITP is often a diagnosis of exclusion in the setting of low platelets without additional hematologic abnormalities (answer C). The patient is not showing any additional symptoms pointing to lupus, such as discoid or malar rashes, oral ulcers, arthralgia, glomerulonephritis, and hypocomplementemia (answer D).

56.2 C. This patient is likely suffering from Felty syndrome, characterized by rheumatoid arthritis, neutropenia, and splenomegaly. Splenomegaly from any etiology may cause sequestration of platelets, leading to thrombocytopenia. An acronym for Felty syndrome is SANTA: splenomegaly, anemia, neutropenia, thrombocytopenia, and arthritis (rheumatoid). The other answer choices (answer A, autoimmune destruction; answer B, prior gold therapy; and answer D, steroid induced) can also cause thrombocytopenia, but splenic sequestration is the most likely with this patient’s constellation of symptoms.

56.3 C. This patient should undergo splenectomy for refractory ITP. Thus, she will be at risk for infections by encapsulated organisms such as Streptococcus pneumoniae and will benefit from the pneumococcal vaccine. Usually, it is given at least 2 weeks prior to splenectomy so that the spleen can help in forming a better immune response. The other choices (answer A, bone marrow radiotherapy; answer B, intravenous interferon therapy; and answer D, washed leukocyte transfusion) would not provide the protective immune response prior to splenectomy like the pneumococcal vaccine would.

56.4 C. The patient likely has HIT, which may be confirmed by assay for HIT antibodies, including immunoglobulin G against platelet factor 4. The timing after the exposure to heparin, the new platelet count, and the absence of a possible alternative cause support the suspicion. Treatment consists of stopping the heparin and starting a direct Xa inhibitor such as argatroban or bivalirudin. Acetaminophen is more commonly associated with hepatotoxicity than thrombocytopenia (answer A). Chronic alcohol intake (answer B) may lead to thrombocytopenia through toxicity to the bone marrow, though we would not likely see such an acute manifestation in the hospital setting. Prosthetic heart valves (answer D) can lead to an increased risk of thrombosis and embolization, especially in the setting of HIT.

CLINICAL PEARLS

▶ Disorders of primary hemostasis are characterized by mucosal bleeding and the appearance of petechiae or superficial ecchymoses.

▶ Disorders of secondary hemostasis are characterized by the development of superficial ecchymoses as well as deep hematomas and hemarthroses.

▶ Immune thrombocytopenic purpura is a diagnosis of exclusion.

▶ Spontaneous hemorrhage may occur with platelet counts of less than 10,000/mm3.

▶ Platelet transfusion in ITP is often ineffective.

▶ Corticosteroids are the initial treatment of ITP. Patients with more severe disease can be treated with IVIg; chronic refractory cases are treated with rituximab or splenectomy.

REFERENCES

Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008. 

George JN, Arnold DM. Approach to the adult with unexplained thrombocytopenia. Timauer JS, eds. UpToDate. Waltham, MA: UpToDate 2019. https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-thrombocytopenia. Accessed June 10, 2019. 

George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med. 1998;129:886-890. 

Konkle BA. Bleeding and thrombosis. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:400-407. 

Konkle BA. Disorders of platelets and vessel wall. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:725-732.

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