1. Description of the problem
What every clinician needs to know
Patients who develop new-onset thrombocytopenia (unexplained by bone marrow suppression) and multiple organ failure commonly have a thrombotic microangiopathy, which, if unrecognized and not treated, leads to higher mortality than if recognized and treated. These microangiopathies are mediated in part by platelet thrombi due to endotheliitis and release of very thrombogenic ultra-large vWF multimers in the presence of decreased ADAMTS 13 (the enzyme that cleaves ultra-large vWF multimers) activity caused by ADAMTS13 antibodies, or ADAMTS13 inhibitors including free hemoglobin and cytokines.
Clinical features of the condition
New-onset unexplained thrombocytopenia < 100,000 / mm3 ( not caused by bone marrow suppression and usually associated with bone marrow megakaryocytes), multiple organ failure, increased LDH, greater than or equal to 1% schistocytes, and renal dysfunction. Other features commonly present include abnormal mental status and fever.
Key management points
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Remove the source of endotheliitis.
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Remove nidus of infection.
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Start appropriate antibiotics within one hour if infected.
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Reverse shock within one hour if present.
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Hold immune suppressants or drugs thought to be inciting factors of endotheliitis.
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Begin activated Protein C for straightforward sepsis.
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Begin hydrocortisone (if not considered straight orward sepsis).
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If thrombocytopenia and multiple organ failure have not resolved by 24 hours, then begin 1-1/2 volume plasma exchange by 30 hours and then daily 1 volume plasma exchange thereafter in cycles of 7 days until resolution of thrombocytopenia and multiple organ failure.
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Restart plasma exchange if thrombocytopenia and multiple organ failure recrudesce after stopping. The number of days needed ranges from 1-3 days for disseminated intravascular coagulation to 18 days or longer for thrombotic thrombocytopenic purpura. Secondary thrombotic microangiopathies generally respond after a median of 9 days.
2. Emergency Management
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Plasma exchange therapy should not be performed until hemodynamic stability is attained. Attain hemodynamic stability using the ACCM guidelines for hemodynamic support.
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Plasma exchange therapy should not be performed in hypernatremic patients > 160 mg/dL because an abrupt drop in serum sodium can result in increased intracranial pressure. Slowly restore serum eunatremia in these patients by dropping serum [Na] by no more than 1 per hour in these patients.
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Plasma exchange therapy should not be started in patients with increased intracranial pressure. As with all extracorporeal therapies, fluid shifts may cause changes in blood pressure that may not be tolerated in patients with intracranial hypertension. Reverse intracranial hypertension according to ACCM guidelines in these patients.
Management points not to be missed
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Plasma exchange therapy exchanges citrated plasma for patient plasma. Citrate chelates calcium. Therefore, patients can become hypocalcemic during this procedure. Patients should be given bolus CaCl2 on beginning and then an infusion during the procedure. A good rule of thumb in adults is 10 mg/kg bolus then 10 mg/kg/h infusion during the procedure (20 mg/kg in children, and 30 mg/kg in infants). Keep ionized [Ca] at 1.0 or greater during the procedure.
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Plasma exchange will remove sedatives and result in awakening. If awakening is considered an untoward side effect, then sedatives will require titration during the procedure.
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Plasma exchange will remove hydrocortisone and inotropes/vasopressors and result in hypotension in patients dependent upon these infusions. When present, inotrope, vasopressor, and hydrocortisone infusions will require titration during the procedure.
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Patients will develop alkalosis over time with repeated treatments as citrate is converted from an acid to a base by the liver. There is rarely any need to address this degree of alkalosis.
3. Diagnosis
Clinical criteria Include:
1) New-onset thrombocytopenia
2) Multiple organ failure
3) Elevated LDH
4) Greater than or equal to 1% schistocytes on peripheral blood smear
5) Renal dysfunction
6) Abnormal mental status, +/- seizures
7) Bone marrow with megakaryocytes
8) Fever
Confirming laboratory (1 and 2) and autopsy (3 and 4) criteria include:
1) Elevated vWF antigen > 100% normal
2) Reduced ADAMTS 13 activity < 10% of normal in thrombotic thrombocytopenic purpura, < 57% of normal in disseminated intravascular coagulation, < 57% of normal in secondary thrombotic microangiopathy
3) vWF multimer microvascular thrombi in brain, lung, or kidney. The microvessels of these three organs are most prone to shear stress and activation of ultra-large vWF multimers.
4) +/- Fibrin microvascular thrombi
Normal lab values
Platelet count > 150,000
LDH < 200
No schistocytes
vWF antigen 100% of control
ADAMTS 13 > 57% of control
How can I be sure this is what the patient has?
Certainty in this diagnosis depends directy upon the number of diagnostic tests performed.
Differential diagnosis
If one does not attain the confirmatory tests, then the differential is wide and most notably related to disorders of:
1) Platelet production depression: eg, related to bone marrow suppression
2) Platelet destruction: eg, related to autoimmune disease, or mechanical shear stress disease
3) Platelet consumption that is not related to endotheliitis, increased vWF multimer release, and reduced ADAMTS 13 activity: eg, heparin-induced thrombocytopenia, splenomegaly
Confirmatory tests
Diagnostic certainty can be attained by performing the following three tests available in clinical laboratories:
ADAMTS13 levels
vWF antigen levels
Bone marrow – megakaryocytes present
4. Specific Treatment
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Activated protein C for straightforward severe sepsis
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24 hours of hydrocortisone 100 mg q 6 hours if not straightforward sepsis
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If not resolving, then begin 1 1/2 volume plasma exchange by 30 hours and follow with daily 1 volume plasma exchange until resolution. Restart if recrudescence occurs.
Drugs and dosages
Activated protein C
Hydrocortisone – in adults, 100 mg IV q 6 hours
Plasma exchange – The first treatment is 1 1/2 volume plasma exchange followed daily by 1 volume plasma exchange
Calcium – In adults 10 mg/kg CaCl2 bolus, followed by 10 mg/kg/h during infusion
Refractory cases
In refractory cases it is prudent to measure ADAMTS13 activity inhibitor levels and antibody levels using a modified Bethesda method.
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Consider plasma exchange with cryoprecipitate-poor plasma to reduce vWF multimer length in replenished plasma.
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If inhibitors continue to persist and they are not antibodies, then revisit removing the source of endotheliitis (eg, infection, drugs, or toxins).
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If the inhibitors are antibodies, then consider, in the following order, steroids, rituximab (B cell monoclonal antibody) + IVIG, and/or vincristine in consultation with hematology/transfusion medicine.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Without therapy, mortality is expected to be 80% or greater. With therapy, mortality is expected to be reduced to 20% or less.
Response is expected according to the degree of ADAMTS 13 reduction, severity of endotheliitis (vWF antigen levels), degree of multiple organ failure, and ability to remove the inciting cause of endotheliitis.
According to the literature, a median number of 1-3 treatments are sufficient for disseminated intravascular coagulation, 9 or more treatments are sufficient for secondary thrombotic microangiopathy, and 18 or more treatments are sufficient for thrombotic thrombocytopenic purpura.
Incorrect diagnosis
If one has confirmatory testing (ADAMTS 13 levels, vWF antigen levels, bone marrow megakaryocytes), then the diagnosis is correct. If the patient is not improving in a timely manner, then it is more likely that the source of endotheliitis has not been removed than that the diagnosis is incorrect.
Follow-up
After recovery, a normal ADAMTS 13 level > 57% of control should be documented. If it remains < 57% but > 10%, then this may be a sign of chronic liver insufficiency, since ADAMTS 13 is produced by the liver. If it remains < 10% of control, then the patient may have congenital thrombotic thrombocytopenic purpura and an absence of ADAMTS13. These patients will need to be followed by a hematologist/transfusion medicine specialist to consider long-term management, which could include routine plasma infusions, steroids, rituximab + IVIG , and/or vincristine.
Pathophysiology
Endotheliitis is caused by many triggers, including infection, drugs, autoimmune disorders, and toxins. Patients at particular risk include those who receive certain drugs (eg, ticlopidine), chemotherapy, radiation, and certain immune suppressants (eg, calcineurin inhibitors) known to induce direct endothelial injury or indirect hapten-mediated endothelial injury. When endothelium is activated or injured it releases ultra-large vWF multimers, which unfold in an accordion-like fashion in the presence of shear stress in susceptible microvessels (particularly brain and kidney) and attract platelets, causing platelet thrombi.
Formerly known as the vWF cleaving protease, ADAMTS13 is the circulating enzyme that is responsible for cleaving these ultra-large vWF multimers into smaller, less thrombogenic multimers, leading to both reduction and reversal of microvascular platelet thrombosis. ADAMTS13 activity can be decreased from several causes. Patients with liver dysfunction have low ADAMTS13 levels because the enzyme is produced in the liver. Infants under 6 months have low ADAMTS13 levels. ADAMTS13 activity is inhibited by several cytokines, most notably TNF-alpha and interleukin-6, which are often present in systemic inflammation syndromes in critically ill patients. ADAMTS13 activity is also inhibited by free hemoglobin. This inhibitor is common in patients with hemolytic disorders as well as in those who receive cardiopulmonary bypass therapies.
When patients have both endotheliitis and diminished ADAMTS13 activity they are at high risk for developing thrombocytopenia-associated multiple organ failure, also known as TTP-HUS. In truth, this syndrome is a spectrum of systemic inflammation and thrombosis that spans from disseminated intravascular coagulation to secondary thrombotic microangiopathy to thrombotic thrombocytopenic purpura. Disseminated intravascular coagulation is the most fulminant side of the spectrum, with rapid consumption of both platelets and fibrin. These patients have reduced ADAMTS13 activity with increased ultra-large vWF multimers, tissue factor activity, and plasminogen activator inhibitor type 1 activity. This consumptive process kills quickly but can also respond quickly to therapy, usually with 1-3 plasma exchange treatments.
Thrombotic thrombocytopenic purpura is the most insidious side of the spectrum, with slow consumption of platelets and high rather than low fibrinogen and factor VIII levels. Tissue factor activity is not increased in this disorder as it represents increased inflammation and platelet consumption. Activity of both ADAMTS13 and plasminogen activator inhibitor type 1 is decreased. These patients recover with a more prolonged course of therapy, requiring as many as 18 or more plasma exchange treatments. This syndrome can be acquired or congenital. Secondary thrombotic microangiopathy has normal tissue factor activity but low ADAMTS13 and plasminogen activator inhibitor type 1 activity. Compared to TTP patients, this population has higher circulating vWF antigen levels and ultra-large vWF multimers, with reduced but not absent ADAMTS13 activity. This population requires a median of 9 or more plasma exchange sessions to improve.
Epidemiology
Little is known about the epidemiology of TTP/HUS in the critical care population. Now that the role of ADAMTS 13 has been elucidated, it is expected that more studies will be performed to address this issue.
Prognosis
The prognosis of TTP-HUS is very poor in the absence of recognition and treatment. Mortality rates reported prior to use of plasma exchange therapy ranged from 80-90%. Remarkably, the mortality ratio has been completely reversed with use of plasma exchange therapies. Survival rates of 80-90% are now observed with use of plasma exchange therapies. Survival rates using plasma infusion alone without plasma exchange are lower, at 50-60%, but still higher than no treatment at all. Plasma infusion provides ADAMTS13. Plasma exchange removes the thrombogenic ultra-large vWF multimers and ADAMTS13 inhibitors.
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