A 38-year-old woman presents with a 3-day history of fever and confusion. She was previously healthy and is taking no medications. She has not had diarrhea or rectal bleeding. She has a temperature of 38°C (100.4°F) and a blood pressure of 145/85. Splenomegaly is absent. She has no petechiae but does have evidence of early digital gangrene of the right second finger. Except for confusion the neurological examination is normal. Her laboratory studies reveal the following:
What is the most likely pathogenesis of her condition?
This patient has thrombotic thrombocytopenic purpura (TTP). TTP is an acute life-threatening disorder that is characterized by the pentad of microangiopathic hemolytic anemia, nonimmune thrombocytopenia, fever, renal insufficiency, and CNS involvement (confusion or multifocal encephalopathy). Not all patients have the full pentad; the essential features are the red blood cell fragmentation (schistocytes and helmet cells) and the thrombocytopenia. TTP may be triggered by endothelial damage and is associated with deficiency of a plasma protein (ADAMTS 13) that breaks down multimers of von Willebrand factor. Plasma exchange (with the infusion of fresh frozen plasma to provide the missing ADAMTS 13 protein) can be lifesaving. The hemolytic uremic syndrome (HUS), often associated with Shigatoxin-producing strains of E coli O157:H7), is similar but is usually not accompanied by CNS changes. The renal failure is usually more severe in HUS. Disseminated intravascular coagulation (DIC) associated with sepsis can resemble TTP, but the coagulation pathway is usually activated in DIC. In TTP the prothrombin time, PTT, and fibrinogen level are normal. Antiplatelet antibodies are associated with idiopathic thrombocytopenic purpura (ITP), but this patient has multiple abnormalities, not just thrombocytopenia. Hypersplenism can cause thrombocytopenia but rarely with a platelet count of below 50,000; it is not associated with red cell fragmentation.
A 60-year-old man develops numbness of the feet. On physical examination he has lost proprioception in the lower extremities and is noticed to have a wide based gait with a positive Romberg sign. His past medical history includes hypertension, hypothyroidism, and previous gastrectomy for gastric cancer. The peripheral blood smear is shown below.
What is the most likely cause of his symptoms?
This is a classic presentation of a patient with vitamin B12 deficiency. This is commonly seen in patients with gastric resection and malabsorption. Patients with gastric resection lose intrinsic factor production from parietal cells. Loss of intrinsic factor leads to decreased absorption of vitamin B12 . Megaloblastic anemia with hypersegmented neutrophils (as seen on this patient’s peripheral blood smear) can be found in both folic acid and vitamin B12 deficiency. Folic acid deficiency does not produce neurologic findings. B12 deficiency may cause a bilateral peripheral neuropathy or degeneration (demyelination) of the posterior and pyramidal tracts of the spinal cord and, less frequently, optic atrophy or cerebral symptoms. Iron deficiency anemia would show micro-cytic and hypochromic red blood cells on peripheral blood smear. Vitamin K deficiency results in a coagulopathy but does not cause neurologic symptoms or hypersegmented neutrophils on peripheral blood smear. Thiamine deficiency causes beriberi; this vitamin does not depend on gastric factors for absorption.
A 60-year-old man presents with vague left upper quadrant abdominal fullness. He also has fatigue, malaise, and weight loss described as loosening of his pants. CBC shows:
Bone marrow biopsy shows hypercellular marrow. Chromosomal study is shown:
Which of the following is the most likely diagnosis?
This patient has chronic myelogenous leukemia (CML). Patients may be asymptomatic and diagnosed by abnormal CBC found incidentally, or patients may present with symptoms of fatigue, malaise, weight loss, early satiety or left upper quadrant pain due to splenomegaly. Patients with CML typically have a normocytic anemia, leukocytosis with mature cells more than immature cells, and thrombocytosis. Diagnosis can be confirmed with bone marrow biopsy and cytogenetic analysis. The cytogenetic hallmark is reciprocal translocation between chromosome 9 (Abl gene) and 22 (BCR gene) - t(9;22)(q34;q11.2), known as the Philadelphia chromosome. This translocation results in an oncogenic gene (BCR-ABL gene). Treatment with the tyrosine kinase inhibitor imatinib has been shown to be effective in this condition. The Philadelphia chromosome is not specific to CML. Some patients, with acute lymphocytic leukemia (ALL) also have the BCR-ABL gene, but these patients do not have thrombocytosis. Acute myeloid leukemia and the lymphocytic leukemias are not associated with this chromosomal abnormality. None of the other choices are associated with thrombocytosis and the cytogenetic pattern shown.
A 25-year-old woman complains of persistent bleeding for 5 days after a dental extraction. She has noticed easy bruisability since childhood, and was given a blood transfusion at age 17 because of prolonged bleeding after an apparently minor cut. She denies ecchymoses or bleeding into joints. Her father has noticed similar symptoms but has not sought medical care. Physical examination is normal except for mild oozing from the dental site. She does not have splenomegaly or enlarged lymph nodes. Her CBC is normal, with a platelet count of 230,000. Her prothrombin time is normal, but the partial thromboplastin time is mildly prolonged. The bleeding time is 12 minutes (normal 3-9 minutes).
What is most appropriate way to control her bleeding?
This woman’s lifelong history of excessive bleeding suggests an inherited bleeding problem, as does the positive family history. The prolonged PTT indicates a deficiency of factors VIII, IX, XI, or XII, but the commonest of these deficiencies (classic hemophilia A and Christmas disease, or hemophilia B) are vanishingly rare in women. Furthermore, the continued oozing from dental sites and the absence of ecchymoses or hemarthroses suggest a platelet function disorder, as does the prolonged bleeding time. Von Willebrand disease is an autosomal dominant condition that leads to both platelet and factor VIII dysfunction and is the likeliest diagnosis in this patient. Although factor VIII concentrates can be used for life-threatening bleeding, most will respond to desmopressin, which raises the von Willebrand factor level in the most common form (the so-called type 1 form) of this disease. Mild von Willebrand disease is fairly common (1 in 250 individuals). Freshfrozen plasma and whole blood are much less effective ways to deliver factor VIII. Platelet transfusion would not be as effective as correction of the von Willebrand factor level.
A 67-year-old man complains of progressive shortness of breath. He has a history of smoking 2 packs of cigarettes per day for 50 years and has been unable to quit despite nicotine replacement and bupropion. He has mild chronic obstructive lung disease for which he is using ipratropium. He is still able to work as a part-time store manager and play golf with his friends. Chest x-ray shows a moderate-sized left-sided effusion. Thoracentesis reveals bloody pleural fluid. Cytologic examination is consistent with bronchioalveolar adenocarcinoma.
What is the best next step in management?
This patient has a non-small cell lung cancer (NSCLC). NSCLC includes squamous cell carcinoma, adenocarcinoma, large cell carcinoma, bronchoalveolar carcinoma, and other mixed versions. In patients with NSCLC, surgery alone is not appropriate for patients with advanced disease. Advanced disease is defined as the presence of any of the following: extrathoracic metastases; superior vena cava syndrome; vocal cord paralysis (which implies phrenic nerve involvement); malignant pleural effusion; cardiac tamponade; tumor within 2 cm of the carina; metastasis to the contralateral lung; bilateral endobronchial tumor; metastasis to the supraclavicular lymph nodes; contralateral mediastinal node metastases; or tumor involvement of the main pulmonary artery. Radiotherapy also has limited usefulness in advanced NSCLC, but is an option for patients with tumors within 2 cm of the carina, bilateral endobronchial tumors, or contralateral mediastinal node involvement. This patient has advanced disease because of the presence of a malignant pleural effusion. In these patients, chemotherapy has been shown to improve progression-free survival and overall survival compared to supportive therapy alone. The role of chest tube placement in malignant pleural effusion is for symptomatic relief only. This patient has good functional status and no comorbidities that would preclude chemotherapy; hence hospice is not the best option at this time.
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