GENERAL NEUROLOGY
Thrombotic thrombocytopenic purpura
David Goldemund M.D.
Updated on 02/05/2024, published on 30/04/2024
- TTP is a severe form of thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multiple organ dysfunction caused by thrombosis in the microcirculation
- it belongs to the group of primary thrombotic microangiopathies (TMA) together with, e.g., hemolytic uremic syndrome (HUS)
- rare disease (incidence 1-6 cases /million population/year) with a high mortality rate caused often due to acquired or inherited deficiency of ADAMTS13 enzyme
- TTP should be considered in patients with severe thrombocytopenia associated with renal and/or neurologic impairment
- initiate plasmapheresis as soon as possible (within 4 hours) – remission can be achieved in almost 90% of patients with early treatment
- before starting treatment, take a blood sample to test ADAMTS13 activity and antibodies
Etiopatogenesis
- the process begins with the formation of platelet-rich microthrombi affecting small vessels; this leads to platelet depletion (thrombocytopenia)
- platelet thrombi in small vessels form a network that mechanically breaks erythrocytes, leading to hemolytic anemia with an increased number of erythrocyte fragments (schistocytes)
⇒ consumptive thrombocytopenia + microangiopathic hemolytic anemia + organ dysfunction
- the cause of microthrombus formation is an excess of von Willebrand factor (vWF) ultra-large multimers caused by a severe absolute or relative deficiency of a proteolytic enzyme from the group of metalloproteases called ADAMTS13, whose function is to cleave vWF multimers
Classification
There are two main causes of severe ADAMTS13 deficiency leading to acute manifestations of TTP
- acquired immune-mediated TTP (iTTP, 95%)
- caused by the presence of autoantibodies (usually IgG) that bind the enzyme and block its activity
- primary or secondary (within another systemic disease)
- congenital (hereditary) form of TTP (cTTP, 5%)
- rare disease, inheritance of AR
- severe absolute deficiency of ADAMTS13 in heterozygous or homozygous mutation of the gene for this enzyme
- genetic variability leads to variable clinical presentation (severity, age); some patients develop symptoms in adulthood (e.g., during pregnancy, causing 25% of all TTPs) [Moatti-Cohem, 2012]
Clinical presentation
- thrombocytopenia (95-100%)a
- a consequence of platelet consumption in microvascular thrombi, moderate to severe (median platelet count in various studies is 10-30 × 109/l)
- ⇒ cutaneous hematomas, epistaxis, petechiae, menorrhagia, hematuria or GIT, life-threatening bleeding is rather rare
- microangiopathic hemolytic anemia (96-100%)
- ↑↑ LDH
- hyperbilirubinemia
- elevation of free hemoglobin in serum and urine
- decreased haptoglobin
- numerous schistocytes in peripheral blood smear
- renal involvement (up to 70%)
- from mild impairment to renal failure requiring hemodialysis
- neurological impairment (70-80%)
- headaches
- qualitative or quantitative impairment of consciousness
- epileptic seizures
- ischemic stroke
- microbleeds/ICH
- fever (~ 25%)
- course:
- isolated attack with complete resolution
- recurrent attacks with normal hematological findings between attacks
- chronic relapsing form with persistent laboratory abnormality
- haptoglobin’s primary function is to bind free hemoglobin released into the plasma during intravascular hemolysis
- the haptoglobin-hemoglobin complex is then rapidly cleared by the reticuloendothelial system, primarily in the spleen and liver
- this prevents the hemoglobin from becoming nephrotoxic and causing renal damage
- additionally, this process aids in iron recycling, as iron from the catabolism of hemoglobin is not lost
- in conditions of intravascular hemolysis, haptoglobin levels decrease significantly due to its consumption in binding to free hemoglobin
- schistocytes are fragmented red blood cells (RBCs/erythrocytes) typically seen in blood smears in various clinical conditions that involve mechanical damage to the erythrocytes
- the presence of schistocytes is an important diagnostic clue in several medical conditions associated with microangiopathic hemolytic anemia (MAHA)
- common conditions in which schistocytes are observed include:
- Thrombotic Thrombocytopenic Purpura (TTP)
- Hemolytic Uremic Syndrome (HUS) – typically following an infectious process, HUS involves endothelial injury predominantly in the kidneys, leading to mechanical fragmentation of RBCs.
- Disseminated Intravascular Coagulation (DIC): DIC can cause widespread formation of microthrombi in the vasculature, mechanically damaging RBCs.
- malignant hypertension: extremely high blood pressure can damage the endothelium, resulting in turbulent blood flow and RBC fragmentation
- mechanical heart valves: artificial heart valves, especially older models, can induce shear stress on RBCs, leading to fragmentation
Diagnostic evaluation
- clinical manifestations (combination of thrombocytopenia + anemia + organ manifestations)
- coagulation is normal or with only non-specific signs of coagulation activation (mild prolongation of baseline coagulation times, mild elevation of D-dimers)
- CT/MRI of the brain (non-specific changes)
- edema
- ischemic lesions
- less frequently microbleeds / ICH
- sometimes findings similar to posterior reversible leukoencephalopathy can be seen [Bakshi, 1999]
- ADAMTS13 testing
- ADAMTS13 enzyme activity
- normal enzyme activity: > 40%
- severe deficit: < 10%
- antibodies against ADAMTS13
- blood samples must be obtained prior to initiation of therapy
- these highly specialized tests have limited availability, and in most cases, the results are not available during the initial management of the patient
- ADAMTS13 enzyme activity
| Basic examination panel for a patient with clinical picture of thrombotic microangiopathy (TMA) |
|
| CBC | CBC + differential count, MCV, schistocytes, reticulocytes |
| coagulation | aPTT, PT, TT, fibrinogen, AT III, D-dimers |
| blood type | |
| serum chemistry panel |
|
| ADAMTS-13 |
|
| additional tests | troponin I, HIV, hepatitis, ANA, anti-dsDNA, APLA, anti-Ro |
| differential diagnosis of HUS | exclude E.coli infection during diarrhea C3/4 |
| ECG, echocardiogram, neurological examination |
|
| Platelet count < 30 x109/L | 1 |
| Creatinine/S < 2 mg/dL (177 umol/L) | 1 |
| Laboratory signs of hemolysis (undetectable haptoglobin, reticulocytes > 2.5%, indirect bilirubin > 2 mg/dL (34.2 μmol/L) |
1 |
| No history of transplantation (stem cell or organ) | 1 |
| INR < 1.5 | 1 |
| MCV < 90 fL | 1 |
| No active malignancy | 1 |
| Probability of severe ADAMTS13 deficiency (defined as ADAMTS13 activity level <15%) score 0-4 = 0% (low risk) score 5 = 5% (intermediate risk) score 6-7 = 62-82% (high risk) |
|
Intermediate risk (PLASMIC Score 5): send ADAMTS-13 testing, keep close observation, obtain expert consultation, consider plasma exchange if no other cause identified.
High risk (PLASMIC Scores ≥6): send for ADAMTS-13 testing, obtain expert consultation, immediate plasma exchange
Differential diagnosis
Thrombotic microangiopathy (TMA) is a histologic diagnosis that manifests clinically and laboratory as a combination of thrombocytopenia + microangiopathic hemolytic anemia (MAHA). In addition to TTP, it is a typical finding in other primary diseases but also occurs in a number of systemic diseases. ADAMTS13 activity may be secondarily reduced in a number of these conditions but usually remains >10%.
| Primary Thrombotic Microangiopathies (TMA) | |
| TTP |
|
| Hemolytic Uremic Syndrome (HUS) |
|
| Drug-Induced TMA |
renal failure
|
| Coagulation-Related TMA | congenital, typically renal failure in childhood |
| Metabolically-Related TMA | congenital, typically renal failure in childhood ↑ concentration of methylmalonic acid and homocysteine |
| Secondary TMA – diseases associated with microangiopathic hemolytic anemia (MAHA) + thrombocytopenia | |
| DIC | coagulation disorder dominates |
| malignancy | especially adenocarcinomas producing mucin, which are often occult |
| systemic infections | inflammatory markers |
| pregnancy-related syndromes (HELLP syndrome, preeclampsia) | elevated hepatic enzymes predominate |
| hypertensive crisis | in combination with renal insufficiency |
| connective tissue diseases (e.g. SLE, AFS) | relevant autoantibodies are found |
Management
- TTP is an urgent condition ⇒ treatment should be initiated once TTP is strongly suspected based on clinic and laboratory findings (within 4-8h)
- sufficient indication is thrombocytopenia and microangiopathic hemolytic anemia concomitant with the absence of other causes of thrombotic microangiopathy
- therapeutic plasma exchange remains the first-line treatment in iTTP
- the goal is to supplement ADAMTS13, to remove both large vWF multimers and circulating anti-ADAMTS13 antibodies [Cataland, 2005]
- ADAMTS13 metalloprotease levels + antibodies should be collected prior to PE !!!
- initiate treatment within 4-8 h of the onset of suspected TTP
- perform daily, with 1-1.5x plasma volume replacement (usually using fresh frozen plasma as replacement)
- V = patient weight * 0.07 m3/kg * (1-Hct)
- PE indicated should continue for at least 3 days after remission is achieved
- at first, the clinical symptoms recede, followed by normalization of LDH
- later normalization of platelet count (>100-150 x 109 /l), anemia, and renal functions occur
- the intensity of plasmapheresis can be gradually reduced until the patient is clinically stable
- remission is achieved in ~ 75% of patients within 14 days
- treatment failure within 7 days is reported in ~20% of patients ⇒ combination with corticosteroids is recommended
- acquired TTP – can be used if PE is not available immediately; administer 30-40 mL/kg until the start of PE
- congenital TTP – administer FFP at an initial dose of 10-15 mL/kg to supplement the missing or faulty ADAMTS13 enzyme
- used in acquired autoimmune forms with the presence of ADAMTS13 inhibitors
- corticosteroids administered concomitantly with PE
- methylprednisolone 5-10 mg/kg/d (divided into 2 doses) for 3-5 days with subsequent dose reduction (taper)
- IV initially, then switch to PO form
- long-term dose of 4 mg per day is used for relapsing forms
- rituximab, cyclosporine A, and IVIG have been tested in relapsing forms
- rituximab 375 mg/m2 once weekly for 4-8 weeks; administered at least 12 h prior to initiation of PE
- in cases of refractory or relapsing TTP, caplacizumab may be considered (Scully, 2019)
- antibody targeting von Willebrand factor (vWF) and inhibiting the interaction between ultra-large vWF multimers and platelets, thus preventing the formation of platelet-rich thrombi which are central to the pathophysiology of TTP
- the indication is questionable (risk of bleeding) [Rock, 2000]
- ASA 100mg can be given when platelets rise to >50 x 109 /L [Allford, 2003]
- do not administer thienopyridines (cases of TTP provoked by them have been reported)
Substitution of platelet concentrates is contraindicated due to the frequent progression of disease manifestations after platelet administration !!!
Prognosis
- after achieving remission of TTP, patients remain in the dispensary of a hematologist with regard to the risk of relapse (about 20-50%)
- definition of relapse: an attack of acute TTP after > 30 days of remission
- risk of relapse depends on ADAMTS13 activity (patients with normal ADAMTS13 activity are unlikely to relapse)
