HEME/ONC
1. . TTP: (FATRN) lady with neurodeficits and low platelets. ( classic pentad : low platelets,
microangiopathic hemolytic anemia, fever, renal impairment (HUS), neuro
impairment).
------->>>TTP and adult HUS appear to be clinically similar disorders that each present with some of the elements of the classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction. In TTP, neurologic abnormalities predominate, and renal dysfunction is seen less often; the opposite is characteristic of HUS. These syndromes occur twice as often in women and peak in the fourth and fifth decades of life (15).
The pathophysiology TTP involves the formation of occlusive small-vessel thrombi made up of platelets held together by unusually large von Willebrand factor (ULvWF) multimers with little or no fibrin. These large multimers are produced by and released from endothelial cells. In healthy people, they are immediately cleaved into the smaller vWF molecules normally found in the circulation by a metalloprotease enzyme referred to as ADAMTS 13. This enzyme is synthesized in the liver and has a binding site on endothelial cells. During an episode of TTP, ADAMTS 13 activity is undetectable in the plasma, probably owing to the action of IgG inhibitory antibodies. The ULvWF multimers are not cleaved, and their large size and configuration induce active adhesion and aggregation of platelets, leading to thrombus formation. Smaller, cleaved vWF molecules do not bind platelets under conditions of normal blood flow. Patients with familial TTP do not have inhibitors. Instead, genetic mutations interfere with the synthesis or activity of the metalloprotease enzyme .
When the diagnosis of TTP-HUS is suspected on clinical and laboratory grounds, a hematologist should be consulted.
- ****The emergency physician should be aware that despite significant thrombocytopenia and clinical bleeding, platelet transfusions are contraindicated in TTP
- Several case reports note clinical deterioration after platelet administration, and it is assumed that more thrombi are formed in the tissues when additional platelets are supplied.
The mainstay of current therapy for TTP is plasma exchange that removes metalloprotease inhibitors and ULvWF and provides active ADAMTS 13 (12,17).
Response to plasma therapy generally follows a predictable pattern in TTP. Neurologic abnormalities are the first to resolve, usually within 3 days. LDH levels normalize in about 5 days, and platelet counts in 10 days. Renal function is the last to normalize, typically requiring about 2 weeks to return to baseline. It usually takes about nine plasmapheresis treatments to produce sustained improvement (20). Exchange therapy is generally continued for a minimum of 2 days after the platelet count returns to normal (9).
Prednisone in doses of 1 mg/kg/d or greater is often given on the basis of historic precedent (9). Additional immunosuppressive therapy with rituximab, cyclophosphamide, vincristine, and cyclosporine has been given, but has not been evaluated in clinical trials (9). Splenectomy may be performed in those who do not respond to plasmapheresis and immunosuppressive therapy.
Relapse is rare in TTP. However, those patients with very low levels of ADAMTS 13 have a 50% incidence of relapse, most within 1 year of the initial episode (9). A small percentage of relapses occur years after the initial episode.
Since the advent of plasma therapy, overall survival in patients with TTP has been about 90% (14). Recovery from neurologic, hematologic, and renal abnormalities is usually complete.
MC cause if pregnancy(check UPT). Due to deficiency of ADAMTS-13 which nl cleaves
vWF. Tx: plasma exchange (NO PLATLETS). Congenital (give plasma)
and Acquired (plasma exchange).
9.ITP: autoimmune, low platelets. Acute (kids after viral infection). Chronic (adult
women) Tx: steroids, IVIG, spleenectomy, platelets,
PRBC (if anemia)
(I= II, Steroid, TTP= exchange Tof P)
Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS) is a very serious and potentially life-threatening complication of cancer therapy.
- defined as a constellation of metabolic abnormalities that results from spontaneous or treatment-related tumor necrosis. The metabolic abnormalities observed in patients with tumor lysis syndrome include hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These can lead to acute renal failure (ARF).
- Most commonly associated with lymphoma and T-cell acute lymphoblastic leukemia
- Tumor lysis syndrome has also been observed in association with solid tumors, such as hepatoblastoma and stage IV neuroblastoma
- ARF: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes ARF. This often is oliguric (<400 mL/d) in nature, leading to volume overload and complications of hypertension and pulmonary edema.
- Renal dysfunction can be severe enough to require dialysis, but with prompt supportive measures it usually is reversible.
- Cardiac arrhythmia: Hyperkalemia can lead to ECG changes and life-threatening cardiac arrhythmia, including asystole.
- Hypocalcemia can lead to QT interval lengthening, which predisposes patients to ventricular arrhythmia.
- Metabolic acidosis: ARF and liberation of large amounts of endogenous intracellular acids from cellular catabolism result in acidemia. This acidemia causes a decrease in serum bicarbonate concentration and a high anion gap acidosis. Acidemic states can worsen the many electrolyte imbalances already present in tumor lysis syndrome; Proper fluid management, correction of acidosis, and attention to infections are the mainstays of therapy.
Symptoms reflect the severity of underlying metabolic abnormalities.
- Hyperkalemia can cause paresthesia, weakness, and fatal cardiac arrhythmias.
- Uremia can manifest as fatigue, weakness, malaise, nausea, vomiting, anorexia, metallic taste, hiccups, neuromuscular irritability, difficulty concentrating, pruritus, restless legs, and ecchymoses. As uremia progresses, paresthesia and evidence of pericarditis may develop
- Features of volume overload, such as dyspnea, pulmonary rales, edema, and hypertension, may develop.
- Elevated uric acid levels may present with lethargy, nausea, and vomiting.
- Patients with hypocalcemia may present with carpopedal spasms, tetany with positive Chvostek and Trousseau signs, seizures, anxiety, bronchospasm, and cardiac arrest in extreme cases.
TREATMENT --
- Control of hyperuricemia
- Allopurinol is a competitive inhibitor of xanthine oxidase and is given to reduce the conversion of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and subsequent oliguric renal failure.
- Rasburicase (recombinant urate oxidase) is a newer therapy that can be used when the uric acid levels cannot be sufficiently lowered by standard approaches. It has been shown to be both safe and effective in pediatric patients, as well as in adults.
- Rasburicase has emerged as the preferred choice for treatment of hyperuricemia in tumor lysis syndrome.
- Hydration
- Volume depletion is a major risk factor for tumor lysis syndrome and must be vigorously corrected. Aggressive intravenous hydration not only helps correct electrolyte disturbances by diluting extracellular fluid but also increases intravascular volume. Increased volume enhances renal blood flow, glomerular filtration rate, and urine volume to decrease the concentration of solutes in the distal nephron and medullary microcirculation.
- Urinary alkalinization
- Use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The goal is to increase urinary pH levels to 7 to maximize uric acid solubility in renal tubules and vessels.
