CONTENTS

TMA (thrombotic microangiopathy)

• Diagnosis of thrombotic microangiopathy
• Causes of TMA
• Laboratory investigation of TMA
• Initial empiric therapy for TMA
• TMA in pregnancy or postpartum

TTP (thrombotic thrombocytopenic purpura)

• Epidemiology of acquired TTP
• Clinical presentation of TTP
• Empiric therapy (PLASMIC score)
• Treatment of acquired TTP

C-HUS (complement-mediated hemolytic uremic syndrome)

• Clinical presentation of C-HUS
• Evaluation of C-HUS
• Empiric eculizumab for C-HUS
• Treatment of C-HUS

ST-HUS (Shiga-Toxin mediated hemolytic uremic syndrome)

• Epidemiology & presentation of ST-HUS
• Diagnosis of ST-HUS
• Treatment of ST-HUS

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thrombotic microangiopathy (TMA)

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diagnosis of TMA (thrombotic microangiopathy)

Thrombotic microangiopathy involves tiny clots forming within the microvasculature. This leads to erythrocyte fragmentation (which is termed MAHA: microangiopathic hemolytic anemia). Occlusion of the microvasculature also leads to tissue damage. There is no official set of criteria used to define the presence of TMA, but the following might be useful.

key diagnostic findings in acute TMA

• [1] Schistocytes within the peripheral blood at a pathological level (>0.5-1%).
• [2] Absence of an obvious alternative explanation for schistocytes (e.g., Impella pump, ECMO, LVAD, mechanical valve leak).
• [3] LDH >1.5 times the upper limit of normal (roughly >420 IU/L) (39156177)
  • LDH is elevated by both hemolysis and also TMA-mediated end-organ tissue damage, so this may function as a global indicator of disease severity in TMA.
  • LDH elevation is nonspecific, so an LDH >420 IU/L doesn't mean much.
  • If LDH is <420 IU/L, this casts doubt on whether there is an acute thrombotic microangiopathy. Note that LDH <420 IU/L is a criterion for stopping plasma exchange therapy for patients with TTP. This would imply that if LDH is <420 IU/L to begin with, there is little rationale for initiating plasma exchange.
• [3] Thrombocytopenia, either:
  • Absolute platelet count <150,000 (or <100,000 in pregnancy).
  • 25% reduction from baseline. (31935318)
• [4] Ischemic tissue damage due to microvascular occlusion. Organs involved may include the kidney, brain, heart, lungs, gut, or skin. Different microangiopathies tend to involve different organs.
  • AKI may also result from plasma-free hemoglobin.

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causes of thrombotic microangiopathy & differential diagnosis

Causes of thrombotic microangiopathy are listed below, with additional details about more common etiologies. 

[1] TTP

• Distinguishing lab abnormalities:
  • Low ADAMTS13.
  • Thrombocytopenia is more severe (usually <30).
  • Schistocytes are profuse.
  • PT/PTT is often normal.
• Size of vessel involvement: Small.
• Organ system involvement:
  • Kidneys (typically mild, Cr <2.5).
  • CNS.
  • Heart.
  • Alimentary tract (n/v, diarrhea).

[2] complement-mediated HUS

• Medical history and/or preceding trigger:
  • Pregnancy.
  • Malignant HTN.
  • Stem cell transplant.
• Distinguishing lab abnormalities:
  • Schistocytes.
  • Thrombocytopenia usually isn't severe (platelets >30).
  • PT/PTT is often normal.
• Size of vessel involvement: Small.
• Organ system involvement:
  • Kidney.
  • Alimentary tract (n/v, diarrhea).

[3] CAPS (catastrophic antiphospholipid syndrome)

• Medical history and/or preceding trigger:
  • ~50% have a known diagnosis of antiphospholipid syndrome or lupus.
  • Triggers:
    • Pregnancy.
    • Sepsis.
    • Trauma/surgery.
    • D/C anticoagulation.
    • Lupus flare.
    • Malignancy.
• Distinguishing lab abnormalities:
  • Antiphospholipid antibodies.
  • Schistocytes may be seen (often scanty however).
  • DIC can occur; PTT may also be prolonged due to lupus anticoagulant.
  • Cytokine storm (e.g., ferritin >1,000 ng/ml).
• Size of vessel involvement: Small +/- large.
• Organ system involvement:
  • Renal failure.
  • CNS.
  • Heart.
  • Lungs.
  • Prominent skin necrosis may occur.

[4] Shiga toxin-mediated HUS

• Medical history and/or preceding trigger:
  • Diarrhea due to Shigella or E. coli 0157:H7 infection.
  • ⚠️ Note that complement-mediated HUS may cause diarrhea due to GI involvement, so the presence of diarrhea alone doesn't secure the diagnosis of classic HUS.
• Distinguishing lab abnormalities:
  • Schistocytes.
  • PT/PTT often normal.
• Size of vessel involvement: Small.
• Organ system involvement:
  • Kidney only.

[5] drug-induced TMA

• [5a] Drug-induced TTP
  • Thienopyridines (ticlopidine, clopidogrel, prasugrel).
  • Quetiapine.
• [5b] Antibody/immune mechanism (more clinically acute) (33841853)
  • Quinine (including tonic water 🍸).
  • Antimicrobial agents:
    • Trimethoprim-sulfamethoxazole.
    • Famciclovir.
    • Fluoroquinolones.
    • Metronidazole.
    • Nitrofurantoin.
    • Penicillin.
    • Vancomycin. (36509342)
  • Some chemotherapies (gemcitabine, oxaliplatin).
  • Some immunosuppressants (adalimumab, OKT3).
• [5c] Non-immune mechanism (e.g., endothelial toxicity; usually gradual onset)
  • Immunosuppressive/immunomodulating therapies:
    • Calcineurin inhibitors (cyclosporine, tacrolimus).
    • m-TOR inhibitors (sirolimus, everolimus).
    • Interferon alpha/beta.
    • Intravenous immunoglobulin.
  • Substance use:
    • Cocaine
    • Intravenous oxycodone.
    • MDMA (ecstasy).
  • Cancer therapies:
    • Alemtuzumab.
    • Checkpoint inhibitors. (36509342)
    • Doxorubicin.
    • Gemcitabine.
    • Mitomycin C.
    • Pentostatin.
    • Proteasome inhibitors (bortezomib, carfilzomib, ixazomib).
    • Tyrosine kinase inhibitors (e.g., ponatinib).
    • VEGF inhibitors (bevacizumab, sunitinib).
    • Vincristine.
  • Miscellaneous:
    • Emicizumab (treatment for hemophilia).
    • Oxymorphone. (32259874)
    • Simvastatin.
    • Valproic acid.
• Treatment of drug-induced TMA: Drug-induced TTP should be treated based on therapies for acquired TTP discussed below (including plasma exchange). In non-TTP cases, treatment is supportive. Complement blockade might be beneficial in some cases, but evidence is scarce. (35615754)

[6] transplant-associated TMA

• Transplantation may be related to thrombotic microangiopathy via numerous mechanisms, including the following: 
• Recurrence of C-HUS in renal transplant patients (if renal failure was initially due to occult C-HUS).
• Acute rejection of a transplanted kidney (antibody-mediated).
• GVHD (graft-versus-host disease):
  • GVHD itself might cause thrombotic microangiopathy.
  • Treatment regimens for GVHD may also be implicated in causing thrombotic microangiopathy.
• Medication-related, including:
  • Calcineurin toxicity in solid-organ transplant recipients.
  • Myeloablative chemotherapy prior to bone marrow transplantation.
• Opportunistic infections associated with transplantation (e.g., CMV). (38018789)

[7] infection-associated TMA

• Infection may be related to TMA in various ways (e.g., infections may trigger CAPS, DIC, TTP, or C-HUS). Any identified infection should certainly be treated. However, diagnosing an infection doesn't exclude the presence of another etiology of TMA. 
• Streptococcus pneumoniae:
  • It usually follows pneumonia/empyema but may also follow meningitis or sinus/ear infection. (36074708)
  • Neuraminidase exposes antigens interacting with preformed circulating IgM antibodies, causing platelet aggregation. The DAT test is positive, unlike most thrombotic microangiopathies. (37610060)
• Klebsiella pneumonia.
• Rocky Mountain Spotted Fever (RMSF).
• Erythrocyte parasites (malaria, babesia).
• Histoplasmosis.
• Viral infections:
  • HIV (with antiretroviral therapy, this has become rare). (36074708)
  • Herpesviruses (CMV, EBV).
  • HCV.
  • Influenza.
  • COVID.

[8] malignancy-associated TMA

• Malignancy may be related to thrombotic microangiopathy via numerous mechanisms, including the following: 
• Systemic malignancy with microvascular obstruction by tumor cells (mostly gastric, breast, prostate, lung, ovarian, urothelial). (32950988, 36509342)
• Hematologic malignancies (including monoclonal gammopathies). (36509342)
• Due to chemotherapy (see drug-induced TMA above).
• Malignancy can be a trigger for CAPS.
• Opportunistic infection following chemotherapy.

[9] HIT (heparin-induced thrombocytopenia)

• Medical history and/or preceding trigger:
  • Heparin exposure.
  • UFH > LMWH.
  • Surgery > Medical patient.
• Distinguishing lab abnormalities:
  • +/- schistocytes.
  • Anti-PF4 antibodies.
• Size of vessel involvement: Small +/- large.

[10] scleroderma renal crisis

• Medical history and/or preceding trigger:
  • Scleroderma, often with cutaneous findings.
  • Renal crisis may be the presenting feature of scleroderma in ~20% of patients. (37610060)
• Distinguishing lab abnormalities:
  • +/- schistocytes.
• Size of vessel involvement: Small.

[11] malignant hypertension

• 💡 Hypertension can cause TMA, or alternatively, hypertension may result from various TMAs (e.g., C-HUS or scleroderma renal crisis). (32539032) 
• Clinical features supporting primary malignant hypertension:
  • Epidemiologically, this is often seen in men >45 years old.
  • There is usually a longstanding history of chronic hypertension with left ventricular hypertrophy. There may be a history of prior episodes of hypertensive emergency.
  • A trigger for a hypertensive emergency is strongly supportive of this diagnosis (e.g., recent cessation of antihypertensive medications).
  • The exam shows severe hypertension (MAP usually >135 mm).
  • 🔑 Clinical improvement occurs with blood pressure control (if blood pressure control doesn't control the thrombotic microangiopathy, an alternative diagnosis should be sought). (37610060)
• Distinguishing laboratory abnormalities:
  • Schistocytes may be seen, but they usually aren't profuse.
  • Severe thrombocytopenia suggests an alternative diagnosis (not solely hypertension). (32539032)
• Size of vessel involvement: small.
• Organ system involvement:
  • Kidney.
  • Brain.

[12] DIC (including purpura fulminans)

• ⚠️ DIC may coexist with other disorders:
  • Severe TTP may cause tissue damage, leading to DIC.
  • DIC may be a component of CAPS.
• Medical history and/or preceding trigger:
  • Sepsis.
  • Malignancy.
  • Trauma.
  • Obstetric catastrophe.
• Distinguishing lab abnormalities:
  • +/- schistocytes.
  • PT and PTT are abnormal.
  • D-dimer markedly elevated.
  • Fibrinogen may be low.
• Size of vessel involvement: Small +/- large.
• Organ system involvement:
  • Prominent skin necrosis may occur.
  • Renal failure.
  • Adrenal infarction.
  • ARDS.

[13] non-TMA entities to consider on the differential diagnosis

• Severe B12 deficiency:
  • May rarely cause thrombocytopenia and microangiopathic hemolytic anemia, often leading to empiric plasma exchange. (38018789)
  • Distinguishing features include elevated MCV and low reticulocyte production index.
• Mechanical erythrocyte fragmentation by prosthetic valve, cardiac assist devices, or transjugular intrahepatic portosystemic shunts (TIPS).

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investigation of TMA

test panel to evaluate the cause of a thrombotic microangiopathy

• CBC with differential.
• Hemolysis labs:
  • Manual blood smear.
  • LDH (lactate dehydrogenase). (LDH elevation reflects a combination of hemolysis and also end-organ tissue damage)
  • Haptoglobin.
  • Direct antiglobulin test (direct Coombs). (Generally negative for thrombotic microangiopathies; can be positive 2/2 TMA from pneumococcus)
• DIC labs:
  • INR.
  • PTT.
  • Fibrinogen.
  • D-dimer.
• Organ damage evaluation:
  • Liver function tests (including indirect bilirubin).
  • Troponin and ECG.
  • Urinalysis & microscopic examination of the urine sediment.
• Pregnancy testing as appropriate.
• Infectious workup:
  • Blood cultures.
  • Other relevant infectious evaluation (e.g., HIV testing, urine pneumococcus antigen).
• ADAMTS13 antigen level & anti-ADAMTS13 antibodies or inhibitor (depending on which tests are available).
• Antinuclear antibodies (ANA).
• Stool PCR analysis for Shiga-toxin genes, stool culture, and/or bioassay of stool for Shiga toxin (depending on the local availability of these tests). 5% of ST-HUS lack diarrheal symptoms, whereas C-HUS may cause diarrhea. Therefore, stool analysis is indicated for any patients with TMA and renal failure (i.e., hemolytic uremic syndrome). (36074708)
• Other studies to consider:
  • Skin biopsy if there are worrisome skin lesions.
  • Renal biopsy may help confirm the diagnosis of TMA and exclude other causes of renal failure.
  • B12 deficiency is suspected: B12 level.
  • CAPS is suspected: anticardiolipin antibody (IgG & IgM), anti-beta-2-glycoprotein type I (IgG & IgM), and dilute Russell viper venom time (more on evaluation of CAPS here).

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interpretation of labs to elucidate the etiology of TMA

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platelet count 

• In TTP, ~95% of patients will have a platelet count <30,000. (29296701) TMA with platelet counts  <30,000 favors TTP.
• In C-HUS, platelets are usually >30,000. (38018789)

coagulation labs

• In most thrombotic microangiopathies, INR, PTT, and fibrinogen are generally normal (e.g., INR <1.5).
• If DIC 📖 is present, this suggests the presence of another underlying process (e.g., sepsis, CAPS).  However, TTP can occasionally cause DIC due to extensive tissue necrosis.
• Isolated elevation of PTT suggests lupus anticoagulant.

creatinine level & renal failure

• Minimal/no renal failure suggests TTP:
  • TTP causes acute kidney injury in 50% of patients, but this is generally mild.
  • Mild or absent renal involvement would favor TTP (as opposed to other thrombotic microangiopathies).
  • Severe acute kidney injury argues against TTP, but this can be seen in some patients with TTP. (35207375)
• Severe renal failure is suggestive of: (37610060)
  • C-HUS often causes severe renal injury that is out of proportion to the degree of anemia or thrombocytopenia. (38018789)
  • ST-HUS.
  • CAPS.
  • Scleroderma renal crisis.
  • Drug-induced TMA may cause extremely rapid renal failure with abrupt-onset anuria.

urinalysis

• Muddy brown casts may suggest acute tubular necrosis, which would tend to imply a non-TMA cause of renal failure.
• Red blood cell casts would imply the presence of glomerulonephritis, which could focus the differential diagnosis on TMA due to glomerulonephritis (listed above).

ADAMTS13 tests

• ADAMTS13 activity:
  • Undetectable levels (<10% normal levels) are seen in almost all TTP patients. However, this isn't always 100% specific for TTP, as it can also be caused by some infections or malignancies.
  • 10-20% normal level: Suspicious for TTP, especially if patients received plasma prior to measurement of the ADAMTS13 level.
  • 10-60% of normal level: is commonly seen among ill patients with systemic inflammation (e.g., malignancy or sepsis) or hemolytic uremic syndrome. (33841853)
  • Normal levels (>60% of normal) exclude TTP.
• ADAMTS13 inhibitor:
  • Most acquired TTP is due to antibodies that block the activity of ADAMTS13. Such antibodies may be detected as the presence of an ADAMTS13 inhibitor in mixing studies (i.e., mixing the patient's plasma with normal plasma causes an inhibition of ADAMTS13 activity in the normal plasma).
  • Acquired TTP may not reveal measurable inhibitor activity in some situations (e.g., an antibody that doesn't inhibit ADAMTS13 enzymatic activity directly but rather causes accelerated clearance of ADAMTS13 from the blood).
  • Hereditary TTP is due to inadequate synthesis of ADAMTS13, so patients with hereditary TTP won't have an ADAMTS13 inhibitor.
• ELISA assay for antibodies that bind to ADAMTS13:
  • This tests for any antibodies binding to ADAMTS13 (whether or not they are neutralizing).
  • This test increases the sensitivity for detection of acquired TTP at the cost of some reduction in specificity.

antinuclear antibodies (ANA) & TMA

• Positive ANA in a patient with TMA may suggest a variety of possibilities:
• TTP:  A positive ANA is generally interpreted to favor a diagnosis of TTP in the context of thrombotic microangiopathy since roughly half of TTP patients will have a positive ANA. (30294946) Some scoring systems have formally incorporated the use of ANA as an indicator of TTP.(30504354) 
• CAPS: ANA is often positive in patients with catastrophic antiphospholipid antibody syndrome (CAPS) 📖, so this should also be considered.
• Lupus nephritis & lupus-associated TMA: Thrombotic microangiopathy is noted in about ~10% of kidney biopsies that reveal lupus nephritis. Lupus is associated with C-HUS, TTP, CAPS, and hypertensive emergency. (37610060) Treatment is complex and may include empiric plasma exchange or eculizumab, depending on the clinical context. (36509342)

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initial empiric therapy for TMA

Empiric therapy must often precede definitive diagnosis due to the slow turn-around time of many labs. Clinical judgment is required to assess the likelihood of TTP or C-HUS rapidly. As laboratory data returns, the diagnosis and treatment may change (e.g., an initial empiric diagnosis of TTP may be changed to a diagnosis of probable C-HUS after a normal ADAMTS13 level is reported).

• Empiric therapy of TTP with plasma exchange: ⚡️
• Empiric therapy for C-HUS with eculizumab: ⚡️

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TMA in pregnancy or postpartum 

There is a broad differential, as explored above ⚡️. Within this differential diagnosis, five entities require close consideration: 

[#1] HELLP syndrome 📖

• Definition: HELLP syndrome usually occurs as a subset of patients with preeclampsia. However, ~20% of patients with HELLP may lack hypertension.
• Epidemiology:
  • HELLP is the most common cause of thrombotic microangiopathy in pregnancy, with a rate of ~1/150 pregnancies. (39156177)
  • HELLP may occur between 20 weeks gestation and the early postpartum period.
• Clinical features of HELLP syndrome:
  • Hypertension is generally seen (~80%), defined as:
    • SBP >160 or DBP >110 (persistent over >15 minutes).
    • SBP >140 and/or DBP >90 (persistent over >4 hours).
  • Microangiopathic hemolytic anemia (e.g., low haptoglobin, schistocytes on blood smear).
  • LDH should be >600 IU/L. (39156177)
  • Elevated AST and ALT (above twice the normal upper limit).
  • Platelets <100,000/mm3.
  • Severe kidney injury is generally uncommon. (39156177)
  • (Further discussion of the diagnosis of preeclampsia: 📖)
• Management: 📖

[#2] C-HUS (aka, pregnancy-associated atypical HUS)

• Epidemiology:
  • 80% of C-HUS occurs in the postpartum period. C-HUS is the only form of TMA that occurs most often in the postpartum period (up to three months after delivery). TMA beginning in the postpartum period after an uneventful pregnancy is very suggestive of C-HUS. (32808006)
  • C-HUS may also be triggered by pregnancy complications (e.g., preeclampsia, placental abruption, fetal demise, or postpartum hemorrhage). (38018789)
  • C-HUS occurs in ~1/25,000 pregnancies and accounts for ~7% of TMA cases. (39156177)
• Clinical features of C-HUS:
  • If encountered, the combination of creatinine >1.9 mg/dL plus LDH >600 U/L at 72 hours postpartum is >90% sensitive and specific for C-HUS in one study. (34275337) 
  • Renal involvement is almost always seen and generally more severe than in TTP. (38018789)
• Management:
  • Eculizumab is the treatment of choice for C-HUS in pregnancy. Higher doses may be required than usual due to higher volume of distribution and/or urinary loss in patients with heavy proteinuria. (32808006)
  • In some patients with TMA, which occurs several weeks postpartum and primarily involves the kidney, empiric initiation of eculizumab may be reasonable (since this presentation strongly suggests C-HUS).

[#3] TTP

• Epidemiology:
  • TTP tends to occur in the second or third trimester. However, if thrombotic microangiopathy occurs in the first trimester, TTP is the most likely diagnosis (because other etiologies of TMA don't tend to occur in the first trimester). (39156177)
  • Pregnant women account for ~20% of adults presenting with TTP. (36074708, 39156177) Congenital TTP may tend to present during pregnancy (whereas otherwise, it is rare among adults). 
  • The absolute risk of TTP might be ~1/50,000 pregnancies. (39156177)
• Clinical features of TTP:
  • Neurological or cardiac symptoms.
  • Platelet count <30,000.
  • Kidney involvement is often mild.
  • Onset before 20 weeks gestation.
• Management: Consider empiric plasma exchange and steroid, discussed below: ⚡️

[4] CAPS (catastrophic antiphospholipid antibody syndrome) 📖

• Clinical history may include:
  • History of fetal loss.
  • History of rheumatologic disease (especially lupus or rheumatoid arthritis).
• Features of current illness:
  • Timing: may occur from the first trimester to postpartum. (37610060)
  • Multi-organ failure (kidney > lung > neuro > cardiac).
  • Skin manifestations (~45%): Livedo reticularis, cutaneous necrosis, digital gangrene.
  • Venous thromboembolism.
  • Arterial thrombosis.
  • Cardiac valve thickening or vegetation.
  • Obstetric complications (e.g., preeclampsia, recurrent fetal loss, fetal demise, premature birth with intrauterine growth restriction). (39156177)
• Laboratory features may include:
  • Thrombocytopenia (~60%).
  • Mild microangiopathic hemolytic anemia (20%).
  • Disseminated intravascular coagulation (25%).
  • Ferritin is often >1,000 ng/ml.

[5] DIC

• DIC may be caused by a variety of obstetric catastrophes.
• Clues to the presence of DIC include:
  • Presence of an overt DIC trigger.
  • Laboratory evidence of DIC. 📖

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TTP (thrombotic thrombocytopenic purpura)

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epidemiology of acquired TTP

• Primarily seen in young adults (~20-50 years old).
• Two-fold female predominance.
• Eight-fold increased rate among African Americans. (33540569)
• TTP may be caused by certain conditions (“secondary TTP”):
  • Pregnancy (more on this below).
  • Rheumatologic disease (mostly SLE).
  • Less often: Malignancy, HIV, ticlopidine.

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clinical manifestations of TTP

the classic pentad of TTP:

• ⬟ Thrombocytopenia (100%).
  • Often with purpura.
  • However, patients usually don't have severe bleeding.
• ⬟ Microangiopathic hemolytic anemia (100%).
• ⬟ Neurologic manifestations (~70% initially).
• ⬟ Kidney injury (~50% initially).
• ⬟ Fever (~20% initially).
• 💡 The classic pentad is present only in ~5% of patients, so this is not useful as a diagnostic criterion.

neurological manifestations (~70%)

• Symptoms:
  • Symptoms often rapidly wax and wane.
  • A wide variety of symptoms may occur: headache, seizure, stroke or transient focal abnormalities, delirium, and coma.
• Neuroradiology:
  • Infarction may be seen.
  • PRES (posterior reversible encephalopathy syndrome) may be seen.
• Prognosis: With aggressive therapy, complete neurologic recovery is generally seen.  Therefore, profound neurologic impairment shouldn't dissuade aggressive therapy.

renal involvement (~50%)

• Renal failure is generally milder in TTP than in other types of TMA. However, ~15% of patients may require dialysis. (35207375)
• Hypertension may occur.
• Hemoglobinuria may manifest as gross hematuria.
• With current management strategies, it's highly unusual for patients to progress to fulminant renal failure.

gastrointestinal symptoms (~50%)

• Common symptoms include pain, nausea/vomiting, and diarrhea.
• Pancreatitis can occur.
• Bloody diarrhea can occur due to mesenteric microthrombosis, causing colitis.  This may cause some diagnostic confusion with regard to Shiga toxin-mediated HUS. Unlike in ST-HUS, patients with TTP experience GI symptoms simultaneously with microangiopathic hemolytic anemia.

cardiac involvement

• Myocardial infarction may range from small areas of microvascular occlusion to transmural infarction.
• Acute heart failure.
• Arrhythmias.
• Pericardial effusion.

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laboratory abnormalities in TTP

• Discussed in the section above on laboratory investigation of TMA: ⚡️

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initial empiric therapy of TTP & PLASMIC score 🧮

TTP is a medical emergency for which prompt plasma exchange reduces mortality. Therefore, plasma exchange is often empirically initiated before the diagnosis of TTP is definite. The decision to initiate plasma exchange is often based largely on the PLASMIC score and the LDH: 

entry criteria: PLASMIC score is applicable to patients with:

• The PLASMIC score is designed as an investigative tool for patients who have been diagnosed with thrombotic microangiopathy. The diagnosis of thrombotic microangiopathy is discussed further above. ⚡️  In short, the following findings are expected in thrombotic microangiopathy:
• [1] Schistocytes.
• [2] Thrombocytopenia, either:
  • Absolute platelet count <150,000 (or <100,000 in pregnancy).
  • 25% reduction from baseline. (31935318)
• [3] LDH >420 IU/L. LDH is elevated by both hemolysis and also TMA-mediated end-organ tissue damage, so thrombocytopenia functions as a global indicator of disease severity in TMA. If LDH is <420 IU/L, this casts doubt on whether there is acute TTP. Note that LDH <420 IU/L is a criterion for stopping plasma exchange therapy for patients with TTP. This would imply that if LDH is <420 IU/L to begin with, there is little rationale for initiating plasma exchange.
• [4] Clinical concern of possible TTP.

scoring: one point is assigned for each of the following (based on the earliest available labs)

• [1] Platelet count <30,000.
• [2] Hemolysis based on one of the following:
  • Reticulocyte count >2.5%.
  • Undetectable haptoglobin.
  • Indirect bilirubin >2 mg/dL (>34 uM/L).
• [3] No active malignancy within one year.
• [4] No history of transplantation.
• [5] MCV <90 fL.
• [6] INR <1.5 (trying to exclude DIC).
• [7] Creatinine <2 mg/dL (<177 uM).  However, if the baseline creatinine is elevated, this criterion may not be valid. The real key is the absence of severe acute kidney injury.

interpretation of the PLASMIC score

• Low risk (scores of 0-4) suggests that TTP is unlikely and that further evaluation for TTP is generally unnecessary.
• Intermediate risk (score of 5) indicates a 6% likelihood of severe ADAMTS13 deficiency. Nonetheless, it is generally suggested that patients with a PLASMIC score of 5-7 should receive empiric plasma exchange unless there is an obvious alternative explanation for the clinical presentation. (37331965)
• High risk (score of 6-7) is 90% sensitive and 92% specific for severe ADAMTS13 deficiency. This carries a 72% positive predictive value and a 98% negative predictive value for TTP (given the low pre-test probability for the disease). (37331965)

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treatment of acquired TTP

[#1] Fresh frozen plasma infusion while waiting for plasma exchange

• Fresh frozen plasma contains ADAMTS13, so this may be beneficial.
• If plasma exchange is going to be delayed (e.g., >6-8 hours), consider giving two units of fresh frozen plasma, followed by ~1 unit every four hours. Consider administration of a diuretic along with plasma to avoid volume overload.

[#2] Plasma exchange

• This is the cornerstone of initial therapy. Plasma exchange works by removing vWF multimers, removing anti-ADAMSTS13 antibodies, and adding ADAMTS13 enzymes.
• Plasma exchange should be initiated promptly, ideally within <6 hours after the diagnosis of thrombotic microangiopathy.
• Technical details of plasma exchange:
  • [1] DO NOT give platelets to “facilitate” the placement of a hemodialysis catheter for plasma exchange. Dialysis catheter placement in TTP appears to be safe regardless of the platelet count. (31588978) The catheter should be inserted carefully, using ultrasound guidance, by an expert operator.
  • [2] Meticulous sterility is critical when placing these catheters, as they will often remain in place for over a week.
  • [3] Hypocalcemia may arise during plasma exchange. (more on hypocalcemia here).
  • [4] Consider scheduling the administration of medications after plasma exchange sessions to avoid excessive medication clearance. (31588978)
  • [5] Make sure to send all pertinent labs ⚡️ prior to plasma exchange, as many labs may be altered by the procedure.
• Patients should receive daily exchanges of 60 ml/kg (1.5 plasma volumes). Plasma exchange may be performed twice daily for patients with life-threatening neurological/cardiac involvement or refractory disease. (26418759)
• Clinical response to plasma exchange is gauged based on:
  • Platelet count >150,000/mm3.
  • LDH <1.5 times the upper limit of normal (i.e., roughly <420 U/L). LDH elevation reflects a combination of hemolysis and also end-organ tissue damage. 
  • There is no clinical evidence of new or worsening organ ischemia. (36074708)
• Plasma exchange usually continues until a clinical response has been achieved for two consecutive days. Subsequently, plasma exchange may be discontinued (with close clinical and laboratory monitoring). (31588978)

[#3] Caplacizumab

• Clinical practice:
  • Caplacizumab should be started before plasma exchange and continued daily until 30 days after completion of plasma exchange. (36074708) Caplacizumab may be given as a 10 mg IV loading dose, followed by daily 10 mg subcutaneous dosing. (35207375)
  • The primary drawback of caplacizumab is an increased risk of mild bleeding. Caplacizumab is contraindicated among patients with severe or life-threatening bleeding. (35207375)
• Evidence & guidelines: The HERCULES RCT found that caplacizumab reduced the mean number of ICU days from ten to three. Consequently, the ISTH guidelines recommend the use of caplacizumab. (32914526)
• Physiology:
  • Caplacizumab is an antibody fragment that binds to von Willebrand factor (vWF). It blocks the interaction between von Willebrand factor and platelets, thereby preventing the formation of microthrombi. This offers the ability to immediately reduce thrombus formation (even before the level of ADAMTS13 can be restored).
  • Caplacizumab may cause clinical improvement even despite a low level of ADAMTS13. This creates a risk of disease relapse after caplacizumab is discontinued if the underlying ADAMTS13 deficiency hasn't been adequately addressed.

[#4] Immunosuppressive therapy

• Steroid:
  • In adults, TTP is generally due to an acquired antibody against ADAMTS13, which may respond to steroids.
  • One RCT suggested that starting with a high-dose steroid could improve remission. (20033409) This study used 10 mg/kg/day methylprednisolone for three days, then 2.5 mg/kg/day. This trial was performed prior to the use of rituximab, so it's possible that such a high dose of steroid might not be necessary among patients being treated with rituximab. (35207375)
  • An alternative regimen is 1 mg/kg/day of oral prednisone. (29582550) This may be a more sensible dose for patients whose diagnosis of TTP is not definite or for patients with milder disease. (31588978)
• Rituximab has been suggested to be utilized as part of first-line therapy for severe TTP (ADAMTS13 level <10%). (37331965) It must be given immediately after a plasma exchange to minimize the removal of rituximab during plasma exchange.

[#5] Blood pressure control

• Correlational studies suggest that hypertension may aggravate erythrocyte fragmentation and worsen the disease process.
• Hypertension should probably be controlled, with a target systolic blood pressure of perhaps <140 mm. (22292070)

[#6] Avoid blood products (other than fresh frozen plasma)

• Platelets:
  • Giving platelets may worsen thrombosis and tissue ischemia. Therefore, platelet administration should be avoided unless there is a clinically significant hemorrhage.
  • 🛑 Don't give platelets prior to placement of a plasma exchange catheter (as discussed above).
• Red blood cell transfusion:
  • Avoid overtransfusion, which may simply aggravate hemolysis.
  • Consider transfusion only if hemoglobin is <7 mg/dL and this is causing symptoms.
• Folate should be supplemented to promote endogenous hematopoiesis. (31588978)

[#7] Venous thromboembolism prophylaxis

• Patients are at high risk of venous thromboembolism (with a risk of ~30% among TTP patients admitted to ICU). (35207375) The presence of thrombocytopenia is not protective against this.
• Prophylactic heparin should be started early (e.g. when platelet count rises above ~30,000/mm3).

[#8] Antiplatelet therapy

• One small RCT found benefit from a combination of aspirin and ticlodipine. (9299856) Providing low-dose aspirin to patients with a platelet count >50 billion/L appears safe and reasonable. (29582550; 9299856). Aspirin may be especially reasonable among patients with myocardial infarction (see below).
• ⚠️ Among patients who are receiving caplacizumab, the safety of aspirin is unknown.

[#9] Myocardial infarction

• Pathophysiology: This is a common manifestation of TTP due to microvascular disease. Epicardial coronary artery occlusion is extremely rare.
• Potentially useful treatments:
  • [1] Aggressive treatment for TTP (e.g., twice daily plasma exchange).
  • [2] Aspirin is indicated for patients with a platelet count >50, as it generally is (see #7 above). (26418759)
  • [3] Blood pressure control with beta-blockers may reduce myocardial workload (assuming that the patient isn't in acute heart failure). (30622684)
• Treatments that are not generally helpful:
  • Usually, these patients don't have a plaque rupture, so typical treatment for MI may not work well.
  • Cardiac catheterization is generally inadvisable for several reasons: Catheterization may worsen kidney injury, the stent may clot off, and placing a stent commits the patient to dual antiplatelet therapy (which may be problematic in the context of fluctuating platelet counts). (30622684)
  • Vasopressin should be avoided, as this may cause secretion of von Willebrand factor, thereby exacerbating TTP.

[#10] Stress ulcer prophylaxis

• Stress ulcer prophylaxis should be utilized, consistent with the most recent guidelines. 📖 Additional rationale for this includes:
  • TTP may affect the gastrointestinal tract and cause bleeding.
  • Hemorrhage is especially problematic in the context of TTP since it may interfere with the ability to provide antithrombotic therapies (e.g., DVT prophylaxis, caplacizumab).

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pathophysiology of TTP

TTP results from the following sequence of events

• (#1) The underlying problem is a deficiency of ADAMTS13, the enzyme that degrades multimers of von Willebrand factor.
  • a) Usually this deficiency is due to an autoantibody against ADAMTS13 (acquired TTP).
  • b) Rarely this is due to a congenital deficiency in ADAMTS13 production (congenital TTP).
• (#2) Huge multimers of von Willebrand factor accumulate.
• (#3) Multimers cause platelet agglutination in small blood vessels, causing microthrombus formation.
• (#4) Microvascular occlusion from platelet agglutination causes shearing of erythrocytes, leading to microangiopathic hemolytic anemia. Vascular occlusion may also cause tissue damage.

congenital TTP (a.k.a., Upshaw-Schulman syndrome)

• Congenital TTP is an autosomal recessive disorder caused by inadequate ADAMTS13 activity.
• Congenital TTP can present in adulthood, especially in the context of pregnancy. Among adults, congenital TTP accounts for ~10% of TTP cases.
• Treatment of congenital TTP is generally similar to the treatment of acquired TTP. However, there is no role for immunosuppression (since patients do not have pathological autoantibodies). Since these patients lack anti-ADAMTS13 antibodies, simple administration of plasma may be more effective (without necessarily requiring plasma exchange).
• The remainder of the discussion below will focus on acquired TTP, as this accounts for 90% of cases among adults.(33540569)

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C-HUS (complement-mediated hemolytic uremic syndrome)

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clinical presentation of C-HUS

[#0] rarely, a history of C-HUS

• A family or a personal history of a complement abnormality might occasionally be present.
• However, most cases are sporadic rather than familial, so family history will usually be absent. (29582550)

[#1] preceding trigger

• Infection causes ~50% of adult cases (including gastroenteritis, viral illnesses, and sepsis).
• Pregnancy is a classic trigger for C-HUS. ⚡️
• Medication or substance exposure (e.g., bleomycin, cisplatin, mitomycin-C, quinine, cocaine).
• Surgery.
• Autoimmune diseases (including SLE).
• Malignancy.

[#2] thrombotic microangiopathy

• Renal dysfunction is often present.
  • This is the hallmark organ failure, potentially requiring hemodialysis.
  • Hematuria and proteinuria are common, with proteinuria occasionally increasing into the nephrotic range. (30294946)
• Hypertension
  • Obstruction of preglomerular arterioles may stimulate renin release, causing hypertension.
  • Fluctuations in obstruction may lead to labile hypertension. (30145224)
  • Severe hypertension may lead to an incorrect diagnosis of thrombotic microangiopathy secondary to malignant hypertension. (32539032)
• CNS involvement is the most common extrarenal manifestation.
  • Clinical features may include headache, confusion, focal neurological abnormalities, seizure, or coma.
  • Imaging may show symmetric involvement resembling posterior reversible encephalopathy syndrome (PRES), edema, or herniation.
• Visual changes may occur, reflective of exudative or ischemic retinopathy.
• Cardiac involvement occurs in ~10% of patients. This may include myocardial ischemia, arrhythmias, myocarditis, pericardial effusion, and reduced ejection fraction. (30031798)
• Respiratory failure may result from alveolar edema, pleural effusions, or pulmonary hemorrhage.
• Gastrointestinal manifestations may include pancreatitis, hepatitis, ascites (serositis), and/or colitis (including intestinal bleeding, obstruction, and perforation).
• Soft tissue involvement may cause anasarca with edema of the face, body, and extremities.  (30145224; 30294946)

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evaluation of C-HUS

laboratory diagnostics are inadequate

• Currently, most hospitals lack any complement testing capable of diagnosing C-HUS in a timely and accurate fashion.
• C3, C4, and CH50 may be measured rapidly, but these tests lack adequate sensitivity and specificity.
• More sophisticated assays (e.g., soluble C5b-9 levels) might be useful, but these are not widely available. Mayo Clinic offers a C-HUS screening panel, which requires up to 21 days to return results. Sending this test prior to initiation of eculizumab may be considered, but the test won't return rapidly enough to affect ICU management.
• Genetic testing for C-HUS takes weeks. Roughly half of patients with C-HUS lack detectable genetic abnormalities. To complicate matters further, detectable genetic anomalies often have unclear clinical significance.

diagnostic approach to C-HUS

• Currently, C-HUS diagnosis in the context of critical illness remains a matter of clinical judgment. Key considerations include:
  • The presence of a thrombotic microangiopathy predominantly involving the kidneys.
  • Lack of an alternative explanation for the patient's thrombotic microangiopathy.
  • Clinical scenario suggestive of C-HUS (especially postpartum renal failure).
• In some situations, it may be reasonable to reach a presumed diagnosis of C-HUS and initiate eculizumab before the results of all diagnostic and genetic testing are returned.

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empiric eculizumab for C-HUS

The criteria to initiate empiric eculizumab for C-HUS are undefined. Factors that might favor the initiation of eculizumab might include the following:

• Lack of any alternative explanation for TMA (other than C-HUS).
• Severe renal involvement, often with hypertension (the rationale for early eculizumab is to salvage renal function).
• A compatible clinical context is suggestive of C-HUS (e.g., postpartum TMA).
• Family history of C-HUS.
• Failure to clinically improve despite treatment of a coexisting condition/trigger. (37610060)

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treatment of C-HUS

general supportive care

• Treat causative factors if possible.
• Platelet transfusion should be avoided unless truly necessary (e.g., clinically significant bleeding), since platelet transfusion may exacerbate microthrombosis.

plasma exchange is usually ineffective

• Theory:
  • Potential benefit: For rare patients (<10%) with anti-complement factor H or factor I autoantibodies, plasma exchange and immunosuppression may be considered in conjunction with anti-C5 monoclonal antibodies. (35615754)
  • Potential harms: Plasma exchange may activate complement due to contact between blood and the extracorporeal circuit, potentially exacerbating C-HUS. Plasma exchange may also cause the elimination of eculizumab (which is beneficial for C-HUS and incredibly expensive).
• Plasma exchange is not generally recommended for C-HUS, given that eculizumab should be uniformly effective (regardless of the precise mechanism underlying the patient's C-HUS). However, a few sources do state that plasma exchange may be considered for patients with life-threatening end-organ injury. (36509342)

anti-C5 monoclonal antibody

• Anti-C5 antibody usually consists of eculizumab. However, a second-generation anti-C5 antibody is increasingly available (ravulizumab, with a similar clinical effect but a longer half-life).
• These antibodies inhibit C5 convertase, thereby blocking the terminal complement pathway.
• Eculizumab may cause renal recovery even in patients who have progressed to hemodialysis.
• The standard initial adult dosing is 900 mg weekly for four weeks. Higher doses may be needed in transplant-associated C-HUS (e.g., targeting eculizumab drug levels >100 ug/mL, CH50 values <10%, and/or normalization of sC5b-9 to <244 ng/mL). (38018789)
• Eculizumab increases the risk of infection by encapsulated bacteria (especially Meningococcus spp.), so patients should be vaccinated against encapsulated pathogens. Until immunity develops, empiric antibiotic coverage might be a consideration (e.g., penicillin V potassium). (30031798)
• Eculizumab is thought to be safe in pregnancy. (36074708)

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pathophysiology of C-HUS

basics

• Complement-related Hemolytic Uremic Syndrome (C-HUS) is due to hyperactivity of the atypical complement system.
• C-HUS is commonly referred to as “atypical HUS” (aHUS). The term C-HUS is used here because it is more pathophysiologically accurate and because C-HUS might actually be more common than we realize.

pathophysiology

• C-HUS results from uncontrolled activation of the alternative complement system. Causes of this dysregulation may include:
  • Genetic deficiency of the inhibitory proteins (e.g., complement factor H, membrane cofactor protein). Although these abnormalities are hereditary, C-HUS commonly presents in adulthood.
  • Acquired deficiency of complement factor H or complement factor I, caused by autoantibodies.
• Following a trigger, inadequate complement regulation may lead to rampant alternative complement activation that damages the vascular endothelium. Endothelial damage causes microvascular thrombosis, leading to thrombotic microangiopathy.
• Systemic release of anaphylatoxins C3a and C5a generated in the kidney may lead to histamine release, causing interstitial edema. (30145224)

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ST-HUS (Shiga toxin-related hemolytic uremic syndrome)

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• ST-HUS is caused by Shiga toxins that are produced by infection with Shigella or certain strains of E. coli (E. coli 0157:H7 and O104:H4). Toxins enter the body and damage endothelial cells, leading to the formation of microthrombi.
• ST-HUS is often called “typical” HUS since it is more common (especially in children). The terminology “ST-HUS” is more pathophysiologically accurate.

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epidemiology and presentation of ST-HUS

[#1] exposure

• Patients may report exposure to raw meat, animals, contaminated water, or unpasteurized milk. Exposure occurs several days before any symptoms occur.
• Occasional outbreaks occur, but most cases are sporadic.

[#2] gastroenteritis

• The initial clinical presentation is with a diarrheal illness (e.g., abdominal pain, nausea/vomiting, and diarrhea). However, clinical colitis may be absent in 5% of patients, so absence of a diarrheal illness doesn't exclude ST-HUS.(32539032)
• Diarrhea often becomes bloody, which may trigger inappropriate concerns regarding gastrointestinal hemorrhage.
• Differential diagnosis: gastrointestinal symptoms can also be caused by bowel ischemia as a result of TMA. The key to sorting this out may be timing: ST-HUS is suggested if gastrointestinal symptoms precede renal dysfunction by some days.

[#3] thrombotic microangiopathy

• Several days after gastrointestinal symptoms, TMA occurs with thrombocytopenia.
• The primary organ involved is the kidney. Acute kidney injury is often severe.
• Neurologic involvement may occur as well (with symptoms including altered mental status, focal abnormalities, seizure, or coma). (32172817)

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diagnosis of ST-HUS

assays for ST-HUS

• Roughly three types of assays are available:
  • Traditional stool cultures.
  • PCR analysis of the stool for the Shiga-toxin gene.
  • Bioassays of stool for the presence of Shiga toxin.
• The availability of various assays will vary across hospitals.  Confer with your laboratory to determine the optimal approach.
• There is no specific therapy for ST-HUS.  However, a definitive diagnosis is useful since it allows for the confident avoidance of plasma exchange or eculizumab.

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treatment of ST-HUS

• Plasma exchange is generally not recommended for ST-HUS.
• Treatment is supportive.
• In patients with volume depletion due to diarrhea, this should be corrected with crystalloid resuscitation.
• Hypertension may require management with antihypertensives.
• Hemodialysis is frequently required in the acute disease phase, but renal recovery often occurs such that long-term hemodialysis may not be required.
• 🛑 Platelet transfusion should be avoided unless truly necessary (e.g., clinically significant bleeding) since platelet transfusion may exacerbate microthrombosis.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• TTP is a medical emergency which often requires aggressive empiric therapy before definitive diagnosis. If you're considering this diagnosis, consult hematology immediately to determine if urgent plasma exchange is needed.
• Platelet transfusion is contraindicated (may worsen thrombosis).
• Standard therapies for myocardial infarction will generally fail in patients with thrombotic microangiopathy, and may actually exacerbate matters (myocardial ischemia is due to micro-thrombosis, not plaque rupture).
• Make sure to send all hematologic labs before starting plasma exchange.

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