How do you differentiate and manage suspected ADAMTS13 (A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13) deficiency versus sepsis?

Differentiating ADAMTS13 Deficiency from Sepsis

In critically ill patients with thrombocytopenia and microangiopathic hemolytic anemia, immediately send ADAMTS13 activity testing while initiating empiric treatment for sepsis, as ADAMTS13 activity <10% confirms TTP requiring plasma exchange, whereas levels >10% indicate sepsis-induced coagulopathy or DIC requiring supportive care and infection control. 1, 2

Key Diagnostic Algorithm

Step 1: Initial Clinical Assessment

When encountering a patient with thrombocytopenia and hemolysis, assess for:

• Fever and infection source: Sepsis typically presents with fever/hypothermia, tachycardia, and identified or suspected infection 3
• Neurological symptoms: TTP causes neurological manifestations in 10-20% (confusion, seizures, encephalopathy), but these can also occur in septic encephalopathy 1
• Rapidity of onset: Severe precipitous platelet drop with concurrent hemolysis suggests TTP, while gradual progression favors sepsis-induced DIC 1
• Schistocytes: >1% on peripheral smear suggests TMA (present in both conditions), though absence doesn't exclude early disease 1

Step 2: Immediate Laboratory Testing

Send ADAMTS13 activity and antibody testing urgently—do not wait for results before treating 1, 2:

• ADAMTS13 <10%: Diagnostic of TTP; initiate plasma exchange immediately 1, 2
• ADAMTS13 10-50%: Moderate deficiency seen in severe sepsis; treat underlying infection 4, 5
• ADAMTS13 >50%: Excludes TTP; focus on sepsis management and alternative TMA causes 2

Apply the PLASMIC score for risk stratification while awaiting ADAMTS13 results (score >5 suggests high TTP likelihood and warrants empiric plasma exchange in adults) 1

Step 3: Distinguish Sepsis-Induced Coagulopathy from TTP

Critical differences:

• Sepsis-induced DIC: ADAMTS13 typically 20-70% (moderate reduction), progressive purpura, prolonged PT/PTT, elevated D-dimer, responds to infection control and supportive care 3, 4, 5
• TTP: ADAMTS13 <10%, normal PT/PTT (key differentiator), minimal D-dimer elevation, requires plasma exchange 1, 2

The 2019 ISTH guidelines recommend a two-step diagnostic approach for septic patients with thrombocytopenia: first assess for Sepsis-Induced Coagulopathy (SIC), then for overt DIC 3

Management Based on ADAMTS13 Results

If ADAMTS13 <10% (Confirmed TTP)

• Initiate plasma exchange immediately—do not delay for antibody results in adults 1
• Continue daily plasma exchange until platelet count normalizes (>150,000) and LDH normalizes 1
• Add corticosteroids and rituximab for immune-mediated TTP 1
• Exception: In children, may defer plasma exchange 24-48 hours until ADAMTS13 confirms diagnosis due to higher procedural morbidity 1

If ADAMTS13 >10% (Sepsis-Induced Coagulopathy/DIC)

Stop plasma exchange if already initiated—patient does not have TTP and continuing exposes to unnecessary procedural risks 2

Primary treatment focuses on infection control and supportive care:

• Aggressive fluid resuscitation and vasopressor support for shock 3
• Source control and appropriate antimicrobials 3
• Fresh frozen plasma infusion for progressive purpura with thrombocytopenia-associated multiple organ failure to replace consumed anticoagulant proteins (protein C, antithrombin III, ADAMTS13) 3
• Target hemoglobin >10 g/dL during active resuscitation with ScvO2 <70% 3

Anticoagulant therapy considerations (regional variation in practice):

• Antithrombin supplementation may be considered in DIC patients with decreased antithrombin activity (common in Japan, not elsewhere) 3
• Recombinant soluble thrombomodulin shows nonsignificant mortality benefit but improved coagulation parameters 3
• Heparin/LMWH for thromboprophylaxis, though efficacy for septic DIC mortality remains unproven 3

Critical Pitfalls to Avoid

Do not wait for ADAMTS13 results to treat suspected TTP in adults—mortality is time-dependent, and plasma exchange must begin immediately in high-probability cases 1

Do not confuse moderate ADAMTS13 reduction (20-70%) in sepsis with severe deficiency (<10%) in TTP—research shows 51% of septic patients with ADAMTS13 <20% develop unusually large VWF multimers and have 41% incidence of acute renal failure versus 15% in those with ADAMTS13 >20% 4. However, this moderate reduction does not indicate TTP and does not require plasma exchange 4, 6, 5

Recognize that ADAMTS13 deficiency in sepsis is transient and secondary—caused by proteolytic cleavage, decreased hepatic synthesis, and consumption, not autoantibodies 4, 6. One pediatric case report documented severe transient ADAMTS13 deficiency in pneumococcal HUS that normalized without plasmatherapy 6

Monitor for symmetrical peripheral gangrene (SPG)—devastating complication of septic DIC with microvascular thrombosis causing acral limb loss, often preceded by acute hepatic dysfunction impairing synthesis of protein C and antithrombin 3

Prognostic Implications

Lower ADAMTS13 levels in sepsis correlate with:

• Higher APACHE II scores and organ dysfunction 5, 7, 8
• Increased mortality (OR 4.5-5.3 for low ADAMTS13) 5, 8
• Development of acute renal failure 4, 7
• Shock and need for vasopressors 7, 8

Serial ADAMTS13 measurements (second sample at 24 hours shows best prognostic value, AUC=0.760) may help risk stratify septic patients, though this doesn't change acute management 8