128 Thrombotic Microangiopathies

Question 1

Refers to thrombotic microangiopathy without another apparent cause and without acute renal injury at presentation, although mild or modest renal insufficiency may be seen.

Answer 1

Thrombotic thrombocytopenic purpura (TTP)

Question 2

TTP is associated with autoantibodies against the plasma metalloprotease ____________ that reduce plasma activity to less than 10% of normal.

Answer 2

ADAMTS13

Question 3

TRUE OR FALSE

TTP is caused by unregulated VWF-dependent platelet thrombosis.

Answer 3

TRUE

TTP is caused by unregulated VWF-dependent platelet thrombosis.

Question 4

ADAMTS13 deficiency in TTP is caused by polyclonal autoantibodies against ADAMTS13, usually immunoglobulin ____

Answer 4

(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

Question 5

TRUE OR FALSE

Autoantibodies associated with increased ADAMTS13 clearance are related to reduced mortality and refractory disease.

Answer 5

FALSE

Autoantibodies associated with increased ADAMTS13 clearance are related to increased mortality and refractory disease.

Question 6

TRUE OR FALSE

The demographics of TTP are similar to those of systemic lupus erythematosus (SLE).

Answer 6

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.

Question 7

Approximately_____ of patients have symptoms of hemolytic anemia.

Answer 7

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.

Question 8

Systemic microvascular thrombosis typically affects the kidney, heart, brain, pancreas, adrenals, skin, spleen, marrow, and most other tissues except the ______, which are spared.

Answer 8

Lungs & liver

Question 9

TRUE OR FALSE

Renal involvement is common, but acute renal failure occurs in fewer than 30% of cases.

Answer 9

FALSE

Renal involvement is common, but acute renal failure occurs in fewer than 10% of cases.

Question 10

Macrovascular venous or arterial thrombosis occurs in up to__________of patients

Answer 10

One-half

Question 11

Approximately _____ of patients have a positive antinuclear antibody test.

Answer 11

50%

The symptoms and signs of TTP are nonspecific.
In most cases of acute TTP, there is no obvious predisposing cause.

Question 12

The characteristic morphologic feature of TTP on the blood film

Answer 12

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.

Question 13

ADAMTS13 activity is characteristically less than ________ and this degree of ADAMTS13 deficiency appears to be specific for TTP.

Answer 13

10% or 10 IU/dL

Question 14

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):

Answer 14

• Myocardium
• Pancreas
• Kidney
• Adrenal gland
• Brain

The liver and lung are relatively spared.

Question 15

Other conditions with decreased ADAMTS13 levels

Answer 15

Newborns, during pregnancy, after surgery, and in chronic liver cirrhosis, chronic renal insufficiency, stroke, coronary disease, acute inflammatory states, sepsis

Question 16

Inherited ADAMTS13 deficiency, with mutations in ADAMTS13

Answer 16

Upshaw-Schulman Syndrome or Congenital Thrombotic Thrombocytopenic Purpura

Question 17

The mainstay of therapy for TTP

Answer 17

Plasma exchange

Aiming to replenish adequate ADAMTS13
Should be started as soon as is feasible

Question 18

The optimal dose of plasma is not known, but a common practice is to perform plasma exchange ________________

Answer 18

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.

Question 19

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.

Answer 19

Plasma
10–20 mL/kg/d

High-dose glucocorticoid, such as methylprednisolone, can also be given if there is a delay.

Question 20

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.

Answer 20

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.

Question 21

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.

Answer 21

Greater than 150 X 109/L

At least 2 days

Question 22

Glucocorticoid options for TTP

Answer 22

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

Question 23

Low-dose aspirin (eg, 80 mg/d orally) has been suggested for thromboprophylaxis, once the platelet count exceeds _______ x 109/L.

Answer 23

50 x 109/L

Question 24

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.

Answer 24

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.

Question 25

Therapy for TTP that is **refractory** to plasma exchange

Answer 25

Rituximab (eg, 375 mg/m2 intravenously weekly for 4 doses) ## Footnote Should be administered immediately **after plasma exchange** to maximize the interval until the next plasma exchange.

Question 26

# 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.

Answer 26

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.

Question 27

Other treatments for TTP

Answer 27

**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**

Question 28

An **anti-VWF** dimeric nanobody, binding to the **GP1b receptor on VWF** licensed for the treatment of acute TTP

Answer 28

Caplacuzimab

Question 29

Trials of Caplacuzimab

Answer 29

TITAN106 and HERCULES

Question 30

Caplacuzimab causes **severe VWF activity deficiency**, the bleeding risk is typically mild to moderate, with __________ symptoms most common

Answer 30

**Epithelia-based symptoms** most common, such as epistaxis and gingival bleeding ## Footnote 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.*

Question 31

A commonly used protocol for the treatment of acute TTP, once confirmed by **severe deficiency of ADAMTS13 (< 10 IU/dL)**

Answer 31

Plasma exchange, caplacuzimab, and immunosuppression (in particular, steroids and rituximab)

Question 32

Frequency of laboratory monitoring: complete blood count with platelet count, LDH, electrolytes, blood urea nitrogen, and creatinine

Answer 32

Daily

Question 33

Prophylaxis for venous thromboembolism may be instituted with **low-molecular-weight heparin and low-dose aspirin** can be started once platelt count

Answer 33

Above 50 x 109/L

Question 34

**Exacerbations** in TTP are defined as

Answer 34

TTP **recurring within 30 days** after a treatment response ## Footnote 25% to 50% of patients have an acute exacerbation within 2 weeks that requires further treatment with plasma exchange

Question 35

**Relapses** in TTP is defined as

Answer 35

**Recurrences more than 30 days** after a complete response ## Footnote 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**.

Question 36

The mortality rate for TTP treated with plasma exchange ranges from ______%

Answer 36

10% to 20% ## Footnote 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.

Question 37

Other name for Congenital TTP

Answer 37

Upshaw-Schulman syndrome

Question 38

Congenital TTP, or Upshaw-Schulman syndrome is autosomal ___________ and affects the genders almost equally

Answer 38

Autosomal recessive

Question 39

Clinical features of Congenital TTP, or Upshaw-Schulman syndrome

Answer 39

* Neonatal jaundice and hemolysis but no evidence of ABO blood group or Rh incompatibility * Severe congenital ADAMTS13 deficiency (<5%) ## Footnote *The clinical features of congenital TTP are similar to those of acquired TTP, except for age of onset.*

Question 40

# TRUE OR FALSE Females often present during their second pregnancy, possibly because VWF levels are decreased late in pregnancy.

Answer 40

FALSE Females often present during their **first pregnancy**, possibly because **VWF levels are increased late in pregnancy**. ## Footnote **TTP** usually occurs in the **third trimester or postpartum**, whereas **fetal loss** is most common in the **second trimester**

Question 41

Treatment for congenital TTP

Answer 41

Periodic infusions of fresh-frozen plasma or an equivalent virucidally treated product ## Footnote 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.

Question 42

Maximum ADAMTS13 activity levels achieved with: 10 to 15 mL/kg of plasma: Recombinant ADAMTS13 :

Answer 42

10 to 15 mL/kg of plasma: **30 IU/dL** Recombinant ADAMTS13 : **100 IU/dL** ## Footnote The activity level of ADAMTS13 that should be attained and maintained is not currently known, but achieving higher ADAMTS13 levels appears preferable.

Question 43

Given to patients with severe allergic reactions to plasma

Answer 43

Plasma-derived factor VIII/VWF concentrates ## Footnote However, ADAMTS13 activity levels are not measurable in these products.

Question 44

# TRUE OR FALSE ADAMTS13 replacement therapy is required throughout pregnancy and the postpartum period

Answer 44

TRUE ADAMTS13 replacement therapy is required throughout pregnancy and the postpartum period ## Footnote 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.**

Question 45

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**.

Answer 45

Less than 2.5% ## Footnote Patients with ADAMTS13 activity of **2.5% to 6.0%** tend to **present in adulthood** and have **infrequent acute episodes** of disease

Question 46

Refers to thrombotic microangiopathy that mainly affects the **kidney** and usually causes oliguric or anuric renal failure

Answer 46

Hemolytic uremic syndrome Diarrhea-associated HUS and “typical” HUS

Question 47

# TRUE OR FALSE HUS was often preceded by a diarrheal illness and, unlike TTP in adults, the prognosis was relatively favorable.

Answer 47

TRUE HUS was often preceded by a diarrheal illness and, unlike TTP in adults, the prognosis was relatively favorable. ## Footnote STEC-HUS can occur at any age but affects mainly children **younger than age 5 years** and is **rare before age 6 months**.

Question 48

Two types of Shiga toxin (Stx)

Answer 48

* **Stx1**: identical to Shigella dysenteriae serotype 1 toxin * **Stx2** is approximately 50% identical in sequence to Stx1 and occurs in several closely related forms ## Footnote 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.**

Question 49

Accounts for at least 80% of cases of STEC-HUS

Answer 49

E coli O157:H7

Question 50

Percentage of patients with bloody diarrhea and E coli O157:H7 infection that will develop STEC-HUS

Answer 50

15% ## Footnote The acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury an average of **seven days (range, 5–13) after the onset of diarrhea.**

Question 51

**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

Answer 51

First 6 days ## Footnote But in less than 30% of patients at later times Fecal leukocytes are not always present and generally are not abundant.

Question 52

**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.

Answer 52

Diagnosis After 2 weeks ## Footnote Titers rise after infection and persist for **8 to 12 weeks.**

Question 53

STEC-HUS mainly affects what area of the kidney

Answer 53

Renal cortex ## Footnote Often shows extensive necrosis

Question 54

# 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.

Answer 54

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** ## Footnote **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.

Question 55

Signals the end of the period of risk for developing HUS

Answer 55

A rising platelet count

Question 56

HUS not associated with Stx-producing organisms

Answer 56

Diarrhea-negative HUS or aHUS

Question 57

Mutation that cause of **familial HUS**

Answer 57

Complement factor H (CFH) or Membrane cofactor protein (MCP, CD46) ## Footnote 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

Question 58

Drives the pathogenesis of aHUS

Answer 58

Alternative complement pathway ## Footnote 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).

Question 59

# 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.

Answer 59

TRUE Approximately 60% of affected children with aHUS have their first episode of aHUS before age 2 years, and 25% before age 6 months. ## Footnote **In contrast, STEC-HUS is rare before age 6 months.**

Question 60

# TRUE OR FALSE Childhood aHUS affects males and females equally, whereas onset in adults disproportionately affects females mainly because of disease triggered by pregnancy.

Answer 60

TRUE **Childhood aHUS affects males and females equally,** whereas onset in **adults** disproportionately affects **females** mainly because of disease **triggered by pregnancy**.

Question 61

Clinical features of aHUS

Answer 61

* 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

Question 62

Most common extrarenal symptom of aHUS

Answer 62

CNS

Question 63

Treatment for aHUS

Answer 63

Plasma Exchange Eculizumab ## Footnote After excluding severe ADAMTS13 deficiency, STEC, and secondary causes of thrombotic microangiopathy, plasma exchange can be stopped and eculizumab started for presumptive aHUS

Question 64

Dosing of Eculizumab

Answer 64

900 mg intravenously every week for four weeks, followed by 1200 mg in week 5 and every other week thereafter ## Footnote Supplementary doses are recommended during plasma exchange or infusion,but concurrent **plasma exchange and eculizumab are not beneficial and should be avoided**.

Question 65

The most significant risk in patients receiving eculuzimab

Answer 65

Meningitis infection ## Footnote 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

Question 66

Can be added to eculizumab for treatment of aHUS caused by **autoantibodies to CFH**

Answer 66

Rituximab and glucocorticoids ## Footnote If the autoantibodies are eradicated, then eculizumab can be discontinued.

Question 67

# TRUE OR FALSE In renal transplantation in aHUS, living related donors generally are used.

Answer 67

FALSE In renal transplantation in aHUS, living related donors generally are not used. ## Footnote Mutation screening should be performed before transplantation to guide subsequent therapy. **HUS has not recurred after renal transplantation in children with DGKE mutations.**

Question 68

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

Answer 68

MCP mutations

Question 69

Mutation that is associated with the development of **nephrotic syndrome**, which is otherwise uncommon in aHUS.

Answer 69

DGKE mutations

Question 70

Causes of secondary thrombotic microangiopathy

Answer 70

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 ## Footnote **Endothelial injury** may be a common cause, although the mechanism of disease varies and in most cases is not understood.

Question 71

# 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.

Answer 71

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.

Question 72

Thrombotic microangiopathy, often with acute renal failure, is a rare complication of invasive infections with _____________ in children.

Answer 72

S. pneumoniae ## Footnote 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).

Question 73

Recipients of **solid-organ transplants** can develop thrombotic microangiopathy, often dominated by renal involvement associated with immunosuppression by _______________

Answer 73

Cyclosporine or tacrolimus ## Footnote ADAMTS13 levels are normal,and plasma therapy is ineffective.

Question 74

Cancer-associated paraneoplastic hypercoagulability and thrombosis

Answer 74

Trousseau syndrome ## Footnote 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.

Question 75

# TRUE OR FALSE The thrombosis of Trousseau syndrome may respond to anticoagulation with warfarin but not heparin

Answer 75

FALSE The thrombosis of Trousseau syndrome may respond to anticoagulation with **heparin but not warfarin**

Question 76

Leukemia associated with abundant schistocytes

Answer 76

Acute erythroleukemia

Question 77

Differential diagnosis of thrombotic microangiopathy in pregnancy

Answer 77

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 ## Footnote Pregnancy also can **trigger** disease in patients with congenital or acquired ADAMTS13 deficiency or defects in the alternative complement pathway

Question 78

How to distinguish Evan syndrome from TTP

Answer 78

Positive Coombs test and the prominence of spherocytes relative to schistocytes in the blood film

Question 79

# 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.

Answer 79

TRUE The thrombotic microangiopathy is **idiosyncratic** and often **preceded by hypertension**, before development of a TMA with primarily renal involvement.

Question 80

Example of drugs that cause drug-induced thrombotic microangiopathy

Answer 80

Quinine* Cyclosporine and tacrolimus Ticlopidine* Emicizumab Mitomycin C Gemcitabine Interferon Sunitinib and bevacizumab ## Footnote 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**.

Question 81

The most common cause of drug-induced thrombotic microangiopathy

Answer 81

Quinine

Question 82

Antiplatelet drug that induces **autoantibody inhibitors of ADAMTS13**, effectively causing TTP that **responds to plasma exchange**.

Answer 82

Ticlopidine ## Footnote 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

Question 83

A rare autosomal recessive condition caused by mutations in the **MMACHC (methylmalonic aciduria and homocystinuria type C protein)** gene

Answer 83

Cobalamin C deficiency ## Footnote Treatment with **high-dose hydroxocobalamin and betaine** may reverse or prevent HUS.