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TMA
Overview of TMA
| Question | Answer |
|---|---|
| What are the 3 essential components of a TMA | Thrombocytopenia (<150K platelets or >25% drop), Microangiopathic hemolytic anemia (MAHA)-anemia (Hb<10), Elevated LDH (>200), Low Haptoglobin (<30), Elevated indirect Bilirubin (>1), Schistocytes (>1%) and END Organ Damage (typically renal) |
| The classification of TMAs are evolving, What are some examples of an acquired TMA, inherited TMA, a secondary TMA and an infectious TMA? | Acquired: CFH and ADAMTS13 autoantibodies, Inherited: CFH, CFI, MCP and ADAMTS13 mutations, Secondary: Pregnancy, Drugs, Rheumatoid, TXP (SOT/HSCT), HTN, Malignancy, Surgery, Infectious causes: STEC-HUS (EHEC), Pneumococcal, HIV, CMV etc |
| The 3 key diseases for TMA that overlap are | TTP, aHUS and STEC-HUS |
| The hallmark of TTP is | TTP is characterized by unusually large multimers of vWf- and platelet-rich thrombi in capillaries and arterioles. Also low platelets (typically <20K), mildly elevated Scr (normal up to 1.6) and low ADAMTS13 activity (<5 or 10% depending upon assay). |
| The hallmark of aHUS (complement mediated) | aHUS (complement mediated) is characterized by ADAMTS13 activity >5 or 10% depending upon assay, Low platelet count but greater than TTP (>30-40K), elevated Scr (typically worse renal function than TTP, Scr >1.7). |
| Can you determine the cause of TMA from histologic morphology? | Not currently. In aHUS you see endothelial swelling and mesangiolysis in active lesions, and double contours of the basement membrane in chronic lesions. Overt Fibrin platelet thromobsis may be absent from renal biopsy. |
| Why is LDH elevated in TMA? | Cell Lysis and tissue ischemia. Elevated LDH is largely derived from ischemic or necrotic tissue cells rather than from lysed red cells. |
| Why is haptoglobin low in TMA? | Haptoglobin (an acute phase reactant) normally will bind free hemoglobin and thus levels will fall in the presence of hemolytic anemia. Decreased or undetectable serum haptoglobin levels are classic for any hemolytic anemia. (normal range 30-200mg/dl) |
| Why is indirect bilirubin elevated in TMA? | Bilirubin is a yellow compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. Increased unconjugated bilirubin is characteristic of an active hemolysis |
| What are schistocytes and why are they elevated in TMA? | The formation of the fibrin strands in the vessels occurs as part of the clot formation process. The red blood cells get trapped in the fibrin strands and the sheer force of the blood flow causes the red blood cell to break. |
| What are the normal levels of creatinine (male and female)? | Male: 0.6-1.2 mg/dL Female: 0.5-1.1 mg/dL |
| Is aHUS a Coombs positive or negative hemolytic anemia? | aHUS is a coombs negative hemolytic anemia. The coombs test looks for antibodies against red blood cells, so if coombs is positive then your anemia is likely due to anti-RBC autoantibodies |
| How might LDH behave in TTP vs aHUS, especially in the face of in the institution of PE? | With PE, LDH levels may decline in both TTP and aHUS, yet usually wont normalize in aHUS with PE alone. LDH increase are largely due to TISSUE ISCHEMIA vs RBC hemolysis. Increase may be disproportionately high vs indirect bili or hemoglobin levels in aHUS |
| How do the actual levels of SCr and Platelets potentially help to differentiate TTP vs aHUS initially? | TTP will usually have lower platelet counts <20,000 along with SCr that is only mildly elevated <1.7. The adjusted odds ratio for aHUS vs TTP is 9.1 for serum creatinine values exceeding 1.7 mg/dL to 2.3 mg/dL |
| What is ADAMTS13? | ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) or von Willebrand factor-cleaving protease (VWFCP), is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf). |
| What is von Willebrand Factor? | A large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue. VWF binds platelets etc |
| What is the innate immune system? | The most basic part of the IS. Includes physical barriers like skin and chemical mediators like complement, Mast cells, macrophages, Neutrophils, dendtritic cells, basophils, eosinophils, NK cells and other mechanisms |
| What is the adaptive immune system? | The more specific part of the IS. Lymphocytes: B and T cells. B cells secrete antibodies, highly specific protein molecules that bind to a specific pathogen. B cells or plasma cells (ADEGM), T helper or effector cells. |
| In TTP how do you define a complete response to plasma exchange? | normalization of the hemoglobin, LDH, and platelet count, and a decrease of at least 25% from baseline in serum creatinine after plasma therapy has been completed. |
| What happens to ADAMTS13 in aHUS or STEC-HUS? | Plasma ADAMTS13 activity may be reduced from the normal range of 67% to 120% in aHUS or STEC-HUS, but should still remain greater than 5% to 10%, with the exact cut-off value dependent upon the assay used. |
| How do you rule out STEC-HUS? | STEC-HUS can be ruled out using both culture and PCR-based assays of stool samples or rectal swabs for Shiga toxin–producing E. coli. |
| How do you acquire shiga-toxin producing e coli such as H157:07 and H104:04? | These bacteria have a bovine reservoir. Transmitted via food or water contaminated with cow manure, as in the outbreaks and sporadic cases that typically occur after ingestion of undercooked beef (especially ground beef) or unpasteurized milk. |
| What other infections besides E Coli can result in TMAs? | Encapsulated bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis and Salmonella typhi), HIV, other viral, bacterial, fungal and parasitic infections |
| Are adults or children more commonly affected by STEC-HUS? | Children, most commonly <5 years of age with around 15% of children developing HUS. In all, around 90% of STEC-HUS cases occur in children. |
| How common is diarrhea in STEC-HUS cases vs aHUS cases? If diarrhea develops is it clearly STEC-HUS? | 5% of STEC cases WON'T have diarrhea, while 30% of aHUS cases WILL have diarrehea. You cannot consider every patient presenting with TMA and diarrhea to have STEC-HUS. |
| What is the one clinical TMA senario where the Coombs test is positive? | The direct antiglobin (Coombs) test is negative except in the case of pneumococcal HUS. |
| What are the 6 core organ systems that are effected by TMAs and should be included in the differential? | Kidney, Gastrointestinal tract, Neurological system, Cardiovascular system, Lung (rarely impacted in TTP), Eye (additional organs can include the skin, liver and pancreas). |
| What are the most common organ systems impacted in TMAs involving STEC-HUS? | Renal, Neurologic involvement: including seizures and altered consciousness, Pancreatitis, Cardiac involvement/myocardial infarction, Gastrointestinal involvement (including diarrhea, vomiting, abdominal pain), and Cerebral artery thrombosis/stenosis |
| What is considered to be the first line therapy for TMA in adults? | Plasma exchange (PE) still remains the initial treatment of choice until ADAMTS13 activity is available to exclude TTP as a diagnosis. It should be initiated in adults as soon as the diagnosis of TMA is suspected. |
| How does Plasma Exchange work in patients experiencing TTP? | In addition to removing ADAMTS13 autoantibodies and replacing ADAMTS13 in TTP, PE will also replace faulty complement regulators and remove FH autoantibodies and hyperfunctional complement components in complement-mediated aHUS. |
| What is considered the first line therapy in TMA in children? | PE is associated with a high rate of complications and TTP is rare, therefore eculizumab 1st line when available. Due to the cost of eculizumab PE remains the only treatment for complement-mediated aHUS in parts of the world. |
| What is the classic pentad of TTP? | Thrombocytopenia, MAHA, neurological involvement, renal impairment and fever. |
| In DIC vs TMA, what blood parameters are evaluated and how are they different (DIC value first and TMA listed second). | Platelet (low/low), fibrinogen (low/norm), Fibrinogen degredat (high/norm), D Dimer (high/norm), antithrombin (low/norm), schistocytes (+/+), haptoglobin (norm/low), coag time (high/norm), Blood Press (low/high) |
| TTP caused by deficiency or defect by innate or acquired autoantibodies is known as what and what? | Uphshaw-Schulman Syndrome (innate) and Moschcowitz disease (acquired auto-antibodies) |
| What is the plastic score? | Predicts ADAMTS13 deficiency in suspected TTP with high discrimination. |
| What are the components of the plasmic score and how do they read? | Platelet ct <30k, Scr <2mg/dL, hemolysis (Retic >2.5%, negligible hapto, indirect Bili >2mg/dL), INR <1.5, MCV <9x10^14L, No recent cancer or txt within 12Mo, no BMT or SOT |
Created by:
bradleyjward