128 Thrombotic Microangiopathies Flashcards
Refers to thrombotic microangiopathy without another apparent cause and without acute renal injury at presentation, although mild or modest renal insufficiency may be seen.
Thrombotic thrombocytopenic purpura (TTP)
TTP is associated with autoantibodies against the plasma metalloprotease ____________ that reduce plasma activity to less than 10% of normal.
ADAMTS13
TRUE OR FALSE
TTP is caused by unregulated VWF-dependent platelet thrombosis.
TRUE
TTP is caused by unregulated VWF-dependent platelet thrombosis.
ADAMTS13 deficiency in TTP is caused by polyclonal autoantibodies against ADAMTS13, usually immunoglobulin ____
(Ig) G
Occasionally IgA or IgM
These antibodies almost always bind the ADAMTS13 spacer domain, and often bind to the CUB domains and first thrombospondin-1 repeat; they bind less frequently to other thrombospondin-1 repeats, the metalloprotease domain, or the propeptide
TRUE OR FALSE
Autoantibodies associated with increased ADAMTS13 clearance are related to reduced mortality and refractory disease.
FALSE
Autoantibodies associated with increased ADAMTS13 clearance are related to increased mortality and refractory disease.
TRUE OR FALSE
The demographics of TTP are similar to those of systemic lupus erythematosus (SLE).
TRUE
The demographics of TTP are similar to those of systemic lupus erythematosus (SLE).
- TTP is relatively uncommon before age 20 years, with a peak incidence between ages 30 and 50 years.
- Across many reports, the female-to-male ratio averages approximately 2:1, but female preponderance is more pronounced below age 50 years, and the ratio approaches equality above age 60 years.
- Other risk factors for TTP include African ancestry and obesity.
- HLA-DRB1*11 is overrepresented severalfold in whites with TTP.
Approximately_____ of patients have symptoms of hemolytic anemia.
One-third
Anemia is almost universal, with a mean hemoglobin of approximately 80 g/L.
Thrombocytopenia typically is severe, with a mean platelet count of approximately 20 x109/L.
Systemic microvascular thrombosis typically affects the kidney, heart, brain, pancreas, adrenals, skin, spleen, marrow, and most other tissues except the ______, which are spared.
Lungs & liver
TRUE OR FALSE
Renal involvement is common, but acute renal failure occurs in fewer than 30% of cases.
FALSE
Renal involvement is common, but acute renal failure occurs in fewer than 10% of cases.
Macrovascular venous or arterial thrombosis occurs in up to__________of patients
One-half
Approximately _____ of patients have a positive antinuclear antibody test.
50%
The symptoms and signs of TTP are nonspecific.
In most cases of acute TTP, there is no obvious predisposing cause.
The characteristic morphologic feature of TTP on the blood film
Marked increase in schistocytes
Schistocytes are helmet cells, or small irregular triangular or crescent-shaped cells with pointed projections, that lack central pallor
Schistocytes occur in a variety of conditions besides TTP, although the level seldom enters the 1% to 18% range typical of TTP.
ADAMTS13 activity is characteristically less than ________ and this degree of ADAMTS13 deficiency appears to be specific for TTP.
10% or 10 IU/dL
The histologic appearance of microvascular lesions in TTP is consistent with a pathophysiologic role of VWF-dependent platelet thrombosis
Amorphous thrombi and subendothelial hyaline deposits may be found in the small arterioles and capillaries of any organ, but they are particularly common (in order of decreasing severity):
- Myocardium
- Pancreas
- Kidney
- Adrenal gland
- Brain
The liver and lung are relatively spared.
Other conditions with decreased ADAMTS13 levels
Newborns, during pregnancy, after surgery, and in chronic liver cirrhosis, chronic renal insufficiency, stroke, coronary disease, acute inflammatory states, sepsis
Inherited ADAMTS13 deficiency, with mutations in ADAMTS13
Upshaw-Schulman Syndrome or Congenital Thrombotic Thrombocytopenic Purpura
The mainstay of therapy for TTP
Plasma exchange
Aiming to replenish adequate ADAMTS13
Should be started as soon as is feasible
The optimal dose of plasma is not known, but a common practice is to perform plasma exchange ________________
Once daily at a volume of 40 or 60 mL/kg, equivalent to 1.0- or 1.5-times plasma volumes
For refractory disease, the intensity of plasma exchange can be increased to twice daily.
Prompt treatment is important, and if plasma exchange must be delayed more than a few hours,_________ infusion should be given by simple infusion at _________mL/kg total dose per day, consistent with the patient’s ability to tolerate the fluid load.
Plasma
10–20 mL/kg/d
High-dose glucocorticoid, such as methylprednisolone, can also be given if there is a delay.
TRUE OR FALSE
Cryosupernatant is depleted in the largest VWF multimers but has normal ADAMTS13 levels, which could make cryosupernatant particularly suitable for the treatment of TTP.
TRUE
Cryosupernatant is depleted in the largest VWF multimers but has normal ADAMTS13 levels, which could make cryosupernatant particularly suitable for the treatment of TTP.
Nevertheless, small randomized trials suggest that cryosupernatant is not superior to fresh-frozen plasma for the initial treatment of TTP.
Plasma exchange should be continued daily until the patient has a treatment response as shown by a platelet count greater than __________X 109/L for at least _______ days.
Greater than 150 X 109/L
At least 2 days
Glucocorticoid options for TTP
Prednisone 1 mg/kg orally, in one or two doses, for the duration of plasma exchange, followed by tapering
Methylprednisolone 1 g intravenously daily for 3 days
High-dose methylprednisolone (10 mg/kg/d for 3 days followed by 2.5 mg/kg/d) was more effective than standard-dose methylprednisolone (1 mg/kg/d) in a small randomized trial
Low-dose aspirin (eg, 80 mg/d orally) has been suggested for thromboprophylaxis, once the platelet count exceeds _______ x 109/L.
50 x 109/L
TRUE OR FALSE
Platelet transfusions are given outright in TTP for the treatment of life-threatening hemorrhage, preferably after plasma exchange treatment has been initiated.
FALSE
Platelet transfusions are relatively contraindicated and should be reserved for the treatment of life-threatening hemorrhage, preferably after plasma exchange treatment has been initiated.
Transfusion of platelets may correlate with acute deterioration and death in TTP.
Therapy for TTP that is refractory to plasma exchange
Rituximab (eg, 375 mg/m2 intravenously weekly for 4 doses)
Should be administered immediately after plasma exchange to maximize the interval until the next plasma exchange.
TRUE OR FALSE
Splenectomy can result in lasting remissions or reduce the frequency of relapses for some patients with TTP that is refractory to plasma exchange or immunosuppressive therapy, presumably by removing a major site of anti-ADAMTS13 antibody production.
TRUE
Splenectomy can result in lasting remissions or reduce the frequency of relapses for some patients with TTP that is refractory to plasma exchange or immunosuppressive therapy, presumably by removing a major site of anti-ADAMTS13 antibody production.
Other treatments for TTP
Vincristine : 2 mg intravenously on day 1 followed by 1 mg on days 4 and 7, or 2 mg intravenously per week for 2 to 14 weeks
Oral cyclosporine 2 to 3 mg/kg daily in two divided doses as an adjunct to plasma exchange
Oral or IV cyclophosphamide; oral azathioprine; bortezomib, mycophenolate,100 N-acetylcysteine, combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, and autologous stem cell transplantation
An anti-VWF dimeric nanobody, binding to the GP1b receptor on VWF licensed for the treatment of acute TTP
Caplacuzimab
Trials of Caplacuzimab
TITAN106 and HERCULES
Caplacuzimab causes severe VWF activity deficiency, the bleeding risk is typically mild to moderate, with __________ symptoms most common
Epithelia-based symptoms most common, such as epistaxis and gingival bleeding
The greatest risk to patients who initiate therapy for TTP is between 7 and 10 days.
Caplacuzimab acts as an adjunctive therapy to normalize platelets and prevent further microvascular damage, but it has no impact on the underlying pathology, in relation to ADAMTS13.
A commonly used protocol for the treatment of acute TTP, once confirmed by severe deficiency of ADAMTS13 (< 10 IU/dL)
Plasma exchange, caplacuzimab, and immunosuppression (in particular, steroids and rituximab)
Frequency of laboratory monitoring: complete blood count with platelet count, LDH, electrolytes, blood urea nitrogen, and creatinine
Daily
Prophylaxis for venous thromboembolism may be instituted with low-molecular-weight heparin and low-dose aspirin can be started once platelt count
Above 50 x 109/L
Exacerbations in TTP are defined as
TTP recurring within 30 days after a treatment response
25% to 50% of patients have an acute exacerbation within 2 weeks that requires further treatment with plasma exchange
Relapses in TTP is defined as
Recurrences more than 30 days after a complete response
Occur in up to one-third of patients within 2 years after treatment with plasma exchange and glucocorticoids alone
There may be an associated trigger, such as infection, surgery, or pregnancy.
Relapses in TTP are associated with severe ADAMTS13 deficiency and detectable ADAMTS13 autoantibody inhibitors.
The mortality rate for TTP treated with plasma exchange ranges from ______%
10% to 20%
Most deaths occur within a few days after presentation, and almost all occur within the first month.
However, the early use of caplacuzimab will reduce the mortality rate acutely, when initiated as soon as a diagnosis of acute TTP is confirmed.
Other name for Congenital TTP
Upshaw-Schulman syndrome
Congenital TTP, or Upshaw-Schulman syndrome is autosomal ___________ and affects the genders almost equally
Autosomal recessive
Clinical features of Congenital TTP, or Upshaw-Schulman syndrome
- Neonatal jaundice and hemolysis but no evidence of ABO blood group or Rh incompatibility
- Severe congenital ADAMTS13 deficiency (<5%)
The clinical features of congenital TTP are similar to those of acquired TTP, except for age of onset.
TRUE OR FALSE
Females often present during their second pregnancy, possibly because VWF levels are decreased late in pregnancy.
FALSE
Females often present during their first pregnancy, possibly because VWF levels are increased late in pregnancy.
TTP usually occurs in the third trimester or postpartum, whereas fetal loss is most common in the second trimester
Treatment for congenital TTP
Periodic infusions of fresh-frozen plasma or an equivalent virucidally treated product
The half-life of ADAMTS13 is 2 to 3 days; 5 to 20 mL/kg of plasma every 2 to 3 weeks was considered sufficient to maintain ADAMTS13 at a greater than 5% level and prevent symptoms.
Maximum ADAMTS13 activity levels achieved with:
10 to 15 mL/kg of plasma:
Recombinant ADAMTS13 :
10 to 15 mL/kg of plasma: 30 IU/dL
Recombinant ADAMTS13 : 100 IU/dL
The activity level of ADAMTS13 that should be attained and maintained is not currently known, but achieving higher ADAMTS13 levels appears preferable.
Given to patients with severe allergic reactions to plasma
Plasma-derived factor VIII/VWF concentrates
However, ADAMTS13 activity levels are not measurable in these products.
TRUE OR FALSE
ADAMTS13 replacement therapy is required throughout pregnancy and the postpartum period
TRUE
ADAMTS13 replacement therapy is required throughout pregnancy and the postpartum period
Fetal loss and premature birth can be prevented by plasma infusions of 10 mL/kg every 2 weeks beginning at 8 weeks of gestation, increasing to weekly in the second trimester.
Patients with ADAMTS13 activity of less than ____ % of normal tend to have their first TTP episode in childhood, have more than one episode of TTP per year, and require regular plasma prophylaxis.
Less than 2.5%
Patients with ADAMTS13 activity of 2.5% to 6.0% tend to present in adulthood and have infrequent acute episodes of disease
Refers to thrombotic microangiopathy that mainly affects the kidney and usually causes oliguric or anuric renal failure
Hemolytic uremic syndrome
Diarrhea-associated HUS and “typical” HUS
TRUE OR FALSE
HUS was often preceded by a diarrheal illness and, unlike TTP in adults, the prognosis was relatively favorable.
TRUE
HUS was often preceded by a diarrheal illness and, unlike TTP in adults, the prognosis was relatively favorable.
STEC-HUS can occur at any age but affects mainly children younger than age 5 years and is rare before age 6 months.
Two types of Shiga toxin (Stx)
- Stx1: identical to Shigella dysenteriae serotype 1 toxin
- Stx2 is approximately 50% identical in sequence to Stx1 and occurs in several closely related forms
Both toxins consist of pentameric B subunits that bind globotriaosylceramide (Gb3) on cell surfaces and a single A subunit that is responsible for cytotoxicity.
The observed predilection for renal injury is a result of the relatively high expression of Gb3 on renal tubular epithelial, mesangial, and glomerular endothelial cells.
Accounts for at least 80% of cases of STEC-HUS
E coli O157:H7
Percentage of patients with bloody diarrhea and E coli O157:H7 infection that will develop STEC-HUS
15%
The acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury an average of seven days (range, 5–13) after the onset of diarrhea.
Stool should be cultured on selective media for E coli O157:H7 and tested for Stxs to detect non-O157 strains.
STEC in the stool are found in at least 90% of patients during the
First 6 days
But in less than 30% of patients at later times
Fecal leukocytes are not always present and generally are not abundant.
Serologic testing for antibodies to STEC surface antigens at ________ and after _______ weeks can facilitate the diagnosis of STEC-HUS if stool cultures are not informative.
Diagnosis
After 2 weeks
Titers rise after infection and persist for 8 to 12 weeks.
STEC-HUS mainly affects what area of the kidney
Renal cortex
Often shows extensive necrosis
TRUE OR FALSE
Antibiotics should not be used early in the course of acute diarrheal illness caused by E. coli O157:H7 because antibiotics increase the risk of HUS.
TRUE
Antibiotics should not be used early in the course of acute diarrheal illness caused by E. coli O157:H7 because antibiotics increase the risk of HUS
Antimotility agents and narcotics increase the risk of HUS and neurologic complications.
Nonsteroidal antiinflammatory drugs and antihypertensives that reduce renal perfusion such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided.
Signals the end of the period of risk for developing HUS
A rising platelet count
HUS not associated with Stx-producing organisms
Diarrhea-negative HUS or aHUS
Mutation that cause of familial HUS
Complement factor H (CFH) or Membrane cofactor protein (MCP, CD46)
These cofactors are structurally and functionally similar, but factor H is a plasma protein, whereas MCP is a transmembrane protein found on the surface of almost all cells.
Another mutation is DGKE mutations
Drives the pathogenesis of aHUS
Alternative complement pathway
Complement component C3 is spontaneously converted to C3b at a low rate and deposited on cell surfaces.
Under normal circumstances, this C3b is promptly cleaved and inactivated by the serine protease factor I, and this reaction is accelerated by factor H or membrane cofactor protein (MCP, CD46).
TRUE OR FALSE
Approximately 60% of affected children with aHUS have their first episode of aHUS before age 2 years, and 25% before age 6 months.
TRUE
Approximately 60% of affected children with aHUS have their first episode of aHUS before age 2 years, and 25% before age 6 months.
In contrast, STEC-HUS is rare before age 6 months.
TRUE OR FALSE
Childhood aHUS affects males and females equally, whereas onset in adults disproportionately affects females mainly because of disease triggered by pregnancy.
TRUE
Childhood aHUS affects males and females equally, whereas onset in adults disproportionately affects females mainly because of disease triggered by pregnancy.
Clinical features of aHUS
- Present acutely with thrombotic microangiopathy and renal failure, sometimes with progressive hypertension
- Not classically preceded by bloody or painful diarrhea
- Women with pregnancy-associated aHUS usually present postpartum
Most common extrarenal symptom of aHUS
CNS
Treatment for aHUS
Plasma Exchange
Eculizumab
After excluding severe ADAMTS13 deficiency, STEC, and secondary causes of thrombotic microangiopathy, plasma exchange can be stopped and eculizumab started for presumptive aHUS
Dosing of Eculizumab
900 mg intravenously every week for four weeks, followed by 1200 mg in week 5 and every other week thereafter
Supplementary doses are recommended during plasma exchange or infusion,but concurrent plasma exchange and eculizumab are not beneficial and should be avoided.
The most significant risk in patients receiving eculuzimab
Meningitis infection
Therefore, patients need to receive the tetravalent and serotype type B meningitis vaccines.
Children also should be vaccinated for S. pneumoniae and Haemophilus influenzae type b.
Concomitant antibiotic prophylaxis is also recommended throughout the period of eculizumab therapy
Can be added to eculizumab for treatment of aHUS caused by autoantibodies to CFH
Rituximab and glucocorticoids
If the autoantibodies are eradicated, then eculizumab can be discontinued.
TRUE OR FALSE
In renal transplantation in aHUS, living related donors generally are used.
FALSE
In renal transplantation in aHUS, living related donors generally are not used.
Mutation screening should be performed before transplantation to guide subsequent therapy.
HUS has not recurred after renal transplantation in children with DGKE mutations.
Mutation that is associated with a less aggressive clinical course: patients may improve during plasma exchange but have similar outcomes without plasma exchange, with 90% alive and free of dialysis after several years
MCP mutations
Mutation that is associated with the development of nephrotic syndrome, which is otherwise uncommon in aHUS.
DGKE mutations
Causes of secondary thrombotic microangiopathy
Metastatic cancer, malignant hypertension, systemic infection, solid-organ or hematopoietic stem cell transplantation, vasculitis, catastrophic APS, radiation exposure, chemotherapy, certain other drugs, inherited or acquired metabolic disorders, and various causes of disseminated intravascular coagulation
Endothelial injury may be a common cause, although the mechanism of disease varies and in most cases is not understood.
TRUE OR FALSE
Severe ADAMTS13 deficiency almost never occurs in secondary thrombotic microangiopathy, and treatment with plasma exchange, rituximab, or eculizumab is not known to be beneficial.
TRUE
Severe ADAMTS13 deficiency almost never occurs in secondary thrombotic microangiopathy, and treatment with plasma exchange, rituximab, or eculizumab is not known to be beneficial.
Thrombotic microangiopathy, often with acute renal failure, is a rare complication of invasive infections with _____________ in children.
S. pneumoniae
The pathophysiology is thought to involve bacterial neuraminidase, made by S pneumoniae and some other organisms, which removes sialic acid residues from cell surface glycoproteins and exposes Thomsen-Friedenreich antigen (T antigen).
Recipients of solid-organ transplants can develop thrombotic microangiopathy, often dominated by renal involvement associated with immunosuppression by _______________
Cyclosporine or tacrolimus
ADAMTS13 levels are normal,and plasma therapy is ineffective.
Cancer-associated paraneoplastic hypercoagulability and thrombosis
Trousseau syndrome
Thrombotic microangiopathy occurs in a small fraction of patients with cancer, most commonly with adenocarcinoma of the pancreas, lung, prostate, stomach, colon, ovary, breast, or unknown primary site that usually is widely metastatic.
Plasma exchange is ineffective.
TRUE OR FALSE
The thrombosis of Trousseau syndrome may respond to anticoagulation with warfarin but not heparin
FALSE
The thrombosis of Trousseau syndrome may respond to anticoagulation with heparin but not warfarin
Leukemia associated with abundant schistocytes
Acute erythroleukemia
Differential diagnosis of thrombotic microangiopathy in pregnancy
Preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), acute fatty liver of pregnancy, abruptio placentae, amniotic fluid embolism, and retained products of conception
Pregnancy also can trigger disease in patients with congenital or acquired ADAMTS13 deficiency or defects in the alternative complement pathway
How to distinguish Evan syndrome from TTP
Positive Coombs test and the prominence of spherocytes relative to schistocytes in the blood film
TRUE OR FALSE: DRUG-INDUCED THROMBOTIC MICROANGIOPATHY
The thrombotic microangiopathy is idiosyncratic and often preceded by hypertension, before development of a TMA with primarily renal involvement.
TRUE
The thrombotic microangiopathy is idiosyncratic and often preceded by hypertension, before development of a TMA with primarily renal involvement.
Example of drugs that cause drug-induced thrombotic microangiopathy
Quinine*
Cyclosporine and tacrolimus
Ticlopidine*
Emicizumab
Mitomycin C
Gemcitabine
Interferon
Sunitinib and bevacizumab
Some agents cause disease by an immune (*) mechanism and others by direct toxicity; a few drugs reportedly act by either mechanism.
In all these therapies, the thrombotic microangiopathy is idiosyncratic and often preceded by hypertension, before development of a TMA with primarily renal involvement.
The most common cause of drug-induced thrombotic microangiopathy
Quinine
Antiplatelet drug that induces autoantibody inhibitors of ADAMTS13, effectively causing TTP that responds to plasma exchange.
Ticlopidine
The related thienopyridine drugs clopidogrel, prasugrel, and ticagrelor do not appear to cause thrombotic microangiopathy by this mechanism.
Plasma exchange appears to be ineffective or possibly harmful for other drug-induced thrombotic microangiopathy
A rare autosomal recessive condition caused by mutations in the MMACHC (methylmalonic aciduria and homocystinuria type C protein) gene
Cobalamin C deficiency
Treatment with high-dose hydroxocobalamin and betaine may reverse or prevent HUS.
