Version May 2024
INTRODUCTION — Thrombotic microangiopathy (TMA) describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. TMA is a pathologic diagnosis made by tissue biopsy. However, it is commonly inferred from the observation of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia in the appropriate clinical setting. Immune thrombotic thrombocytopenic purpura (TTP) was the first of the primary TMAs to be described and is perhaps the best understood of the TMAs pathophysiologically. TTP is unique among the primary TMAs for minimal abnormalities of kidney function, despite microthrombi observed throughout the kidney.
The pathophysiology of immune TTP, complement-mediated TMA, Shiga toxin-induced TMA (hemolytic uremic syndrome [ST-HUS]), and some of the rare inherited TMAs will be reviewed here.
The pathophysiologies of hereditary TTP and drug-induced TMA (also called drug-induced TTP) are presented separately. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Genetics' and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Pathophysiology'.)
Separate topic reviews also discuss the general approach to the patient with a suspected TMA (see "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)"), and diagnosis and management of specific conditions:
●Immune TTP – (See "Diagnosis of immune TTP" and "Immune TTP: Initial treatment".)
●Hereditary TTP – (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)
●Drug-induced TMA – (See "Drug-induced thrombotic microangiopathy (DITMA)" and "Kidney disease following hematopoietic cell transplantation".)
●Pregnancy-associated syndromes – (See "Thrombocytopenia in pregnancy".)
●HUS – (See "Overview of hemolytic uremic syndrome in children" and "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
HISTOPATHOLOGY OF TMA
Endothelial changes and microthrombi — The histopathology of TTP and other primary TMAs is distinguished from that of systemic conditions such as systemic infections and malignancies, which may also cause microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and/or disseminated intravascular coagulation (DIC). In the primary TMAs, a heritable (genetic) or acquired abnormality promotes formation of platelet microthrombi in the microvasculature.
TMA is characterized by small vessel changes including swelling of endothelial cells and the subendothelial space, along with vessel wall thickening and platelet microthrombi, typically in small arterioles and capillaries [1]. These changes can obliterate the vessel lumen, especially in smaller vessels, and lead to hyaline occlusion. In some cases, endothelial cell proliferation and/or vessel wall dilatation (eg, microaneurysms) have been seen in the affected arterioles. Large-vessel thrombosis is not typical of TTP or other primary TMAs.
Similar histologic findings of TMA may also be seen in other disorders such as malignant hypertension, systemic lupus erythematosus, scleroderma, antiphospholipid syndrome, and kidney transplant rejection.
Examples of the typical sites of organ involvement include the following:
●Kidney – Kidney involvement by TMA is typical of all primary TMA syndromes. Severe acute kidney injury is a prominent feature of all primary TMA syndromes except TTP, in which it is rare. Pathologic changes in the kidney include thrombi in the arterioles (picture 1) and glomeruli (picture 2). Urinary findings are nonspecific and may include hematuria, hemoglobinuria, and/or proteinuria. (See "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
These pathologic changes are similar for all of the TMAs; however, they may be helpful in distinguishing between a TMA and other causes of renal failure with a nondiagnostic urine sediment [2]. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)
●Central nervous system – Central nervous system involvement may occur in any of the primary TMA syndromes. Clinical features of neurologic involvement may be most common in patients with TTP. Neurologic manifestations, when they occur, may be mild, with headache and transient confusion, or severe, with tonic-clonic seizures, stroke, and/or coma. Focal abnormalities often occur in TTP, including episodes of numbness or weakness localized to an arm or hand or side of the face, or transient aphasia or vision impairment.
Similar TMA lesions of the microvasculature in the heart, skin, and/or gastrointestinal tract are inferred from clinical findings such as acute coronary syndrome, purpuric skin lesions, and gastrointestinal symptoms (eg, abdominal pain, bloody diarrhea). An exception is pulmonary involvement, which is rarely clinically evident despite microvascular thrombi in the lungs [3]. Autopsy of patients who have died with an acute episode of TTP demonstrates microvascular thrombi characteristic of TTP in almost all organs [4].
Hematologic findings — Hematologic findings are the same in TTP and other primary TMA syndromes. The characteristic and constant feature is microangiopathic hemolytic anemia (MAHA). MAHA was first described in 25 patients 60 years ago [5]. The etiologies of MAHA in these patients predicted the etiologies that we recognize today: TTP, malignant hypertension, kidney diseases, systemic lupus erythematosus, and metastatic cancer. Some degree of thrombocytopenia also occurs in almost all primary TMAs.
●MAHA – MAHA is caused by mechanical RBC fragmentation that occurs as RBCs traverse platelet-rich thrombi in the microcirculation. The result of RBC fragmentation is schistocytes, which typically are prominent on the peripheral blood smear (picture 3). The electron micrograph illustrates how schistocytes are formed (picture 4).
●Thrombocytopenia – Thrombocytopenia is due to platelet consumption in microthrombi throughout the microcirculation. Thrombocytopenia may be only mild or moderate in many of the primary TMA syndromes, but in patients with TTP it is typically severe (platelet count almost always <30,000/microL).
Bone marrow evaluation (aspiration/biopsy) typically is not performed in TTP or other primary TMAs. If it is performed, it shows normal trilineage maturation with increased thrombopoiesis and erythropoiesis to compensate for consumption of platelets and RBCs in the peripheral circulation. A bone marrow evaluation is appropriate when the clinical features of a primary TMA are not clear and an alternative diagnosis such as a systemic malignancy is suspected [6]. A systemic malignancy should be considered in all patients who have a history of cancer, as occult systemic cancer can mimic TTP [7].
The white blood cell (WBC) count is normal in primary TMAs; leukocytosis or leukopenia suggests that another disorder such as myelodysplasia, systemic malignancy, or megaloblastic anemia is responsible for abnormalities of RBC morphology and thrombocytopenia.
Abnormalities of coagulation are uncommon in TTP and other primary TMAs. This is a major clinical feature that distinguishes primary TMAs from other causes of MAHA and thrombocytopenia such as systemic infection or malignancy, which are often associated with disseminated intravascular coagulation (DIC). DIC is characterized by prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT), increased D-dimer, and reduced fibrinogen. In occasional patients with TTP, organ ischemia may be severe enough to cause DIC, but this is rare. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
TTP PATHOGENESIS
Deficient ADAMTS13 activity — TTP is caused by severely deficient activity of the ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) protease, clinically defined as an activity level <10 percent [1]. ADAMTS13 is a plasma protease that was initially defined by its function as a von Willebrand factor (VWF)-cleaving protease. It cleaves the ultralarge, string-like molecules of VWF that are synthesized by endothelial cells and secreted into the plasma but remain attached to the endothelial surface. This normal cleavage to smaller sized multimers prevents ultralarge multimers from accumulating, especially in areas of high shear stress (eg, small arterioles and capillaries). Shear stress leads to a conformational change in the large VWF multimers that exposes the ADAMTS13 cleavage site. When protease activity is reduced, ultralarge VWF multimers accumulate on the endothelial surface, where platelets attach and accumulate [8]. (See "Overview of hemostasis", section on 'Platelet adhesion' and "Pathophysiology of von Willebrand disease", section on 'VWF functions'.)
●Metalloprotease refers to the metal-dependent enzymatic domain of the protein, which cleaves VWF. Its catalytic activity is facilitated by the metal zinc (as well as calcium ions).
●Disintegrin refers to the domain of the protein that interferes with cell-cell interactions, which might include interactions between platelets and endothelial cells.
●Thrombospondin refers to the domain of the protein similar to thrombospondins, which have antiangiogenic properties.
●ADAMTS13 is the 13th member of the ADAMTS family to be described.
ADAMTS13 is primarily synthesized in hepatic stellate cells [9]. It may also be synthesized by endothelial cells and megakaryocytes [8].
A severe reduction in ADAMTS13 activity (typically to less than 10 percent of normal, although ADAMTS13 activity ≥10 percent is not rare [10]) is present in almost all patients with acute TTP, although diagnosis is always made using a combination of clinical and laboratory findings. In contrast, modest reductions may occur in a variety of medical conditions such as sepsis or liver disease and are not thought to cause clinical disease. Use of ADAMTS13 activity testing in the diagnosis of TTP is presented separately. (See "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity'.)
However, a severe deficiency of ADAMTS13 activity alone is not sufficient to cause TTP.
●Individuals with hereditary ADAMTS13 deficiency may have no signs or symptoms of TTP until they have a triggering exposure such as an infection or pregnancy [11-14]. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Clinical features'.)
●Some individuals with severe ADAMTS13 deficiency due to an autoantibody continue to have severe deficiency in clinical remission without clinical findings [15,16]. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Natural history of ADAMTS13 activity during remission'.)
These observations suggest that additional factors such as an acute inflammatory or prothrombotic stimulus may be responsible for triggering clinical manifestations.
Causes of ADAMTS13 deficiency — The major cause of severe ADAMTS13 deficiency is an autoantibody; inherited gene mutations account for a small additional number of cases. Additional conditions may reduce ADAMTS13 activity, including sepsis, cardiac surgery, pancreatitis, and liver disease [17-21]. However, these conditions are extremely unlikely to lower ADAMTS13 activity to a level likely to cause TTP. (See "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity'.)
ADAMTS13 activity also appears to decrease during the last two trimesters of pregnancy, declining to the lowest levels at 36 to 40 weeks of gestation and the early puerperium [20,22]. Higher levels of VWF also appear to reduce ADAMTS13 activity, as illustrated by kinetic studies in healthy individuals treated with desmopressin, which causes release of VWF from endothelial cells, with a concomitant reduction of ADAMTS13 activity, likely due to consumption [23]. These further reductions in ADAMTS13 activity and/or inflammatory stimuli in a patient with an underlying anti-ADAMTS13 autoantibody or hereditary ADAMTS13 deficiency may act as triggers for an acute episode of TTP.
High levels of free hemoglobin in the circulation (eg, in severe hemolytic anemia) or hemolysis in the blood sample after collection may interfere with laboratory measurement of ADAMTS13 activity, giving a false impression of severe deficiency [24]. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)
Inhibitory antibodies to ADAMTS13 — The vast majority of cases of TTP (approximately 95 percent) are immune, due to inhibitory autoantibodies against ADAMTS13 [1,25]. Risk factors for development of the autoantibodies are not clearly defined, although immune TTP is more common in young females, and the relative incidence is increased in Black individuals [26]. The incidence of immune TTP also may be increased in individuals with other autoimmune conditions such as systemic lupus erythematosus (SLE) or certain human leukocyte antigen (HLA) types, but most affected patients do not have an underlying rheumatologic or immunologic condition [27,28]. Additional autoimmune disorders occur in 20 percent of patients with immune TTP [10] (See "Diagnosis of immune TTP", section on 'Epidemiology'.)
The titer of the ADAMTS13 autoantibody may have implications for therapy and prognosis. As examples:
●In plasma from patients with immune TTP, the concentration of recombinant ADAMTS13 required to normalize ADAMTS13 activity correlated strongly with the inhibitor titer [29].
●Another study correlated higher initial inhibitor titers with a greater incidence of refractory disease and a greater likelihood of inhibitor "boosting" (ie, increasing inhibitor titer) during initial therapy [30]. (See "Immune TTP: Treatment of clinical relapse", section on 'Refractory disease'.)
●Additional studies have shown correlations between a higher inhibitor titer and a greater likelihood of disease relapse and/or reduced survival [15]. (See "Immune TTP: Treatment of clinical relapse", section on 'Clinical relapse'.)
Analysis of patient autoantibodies to ADAMTS13 has indicated that many of these antibodies react with a cysteine-rich spacer domain in the ADAMTS13 protein, although others react with other domains [31-33]. Some autoantibodies inhibit enzyme activity, while others may increase clearance of the protein; these latter so-called "non-neutralizing" antibodies are not detected in all commercial ADAMTS13 activity assays and may account for the failure to document an inhibitor in some patients [34,35].
ADAMTS13 gene variants — Hereditary TTP caused by biallelic pathogenic variants in the ADAMTS13 gene is much less common than immune TTP. Additional details about the types of pathogenic variants seen, their effects on ADAMTS13 function, and the International Hereditary TTP Registry (www.ttpregistry.net) are presented separately. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Genetics'.)
Consequences of ADAMTS13 deficiency — ADAMTS13 is a protease that cleaves ultra-large, string-like multimers of VWF that are attached to the endothelial surface in areas of high shear stress. These VWF multimers bind to platelets and appear to promote microvascular thrombosis.
The importance of the VWF-platelet interaction in TTP pathogenesis is illustrated by clinical observations in patients treated with caplacizumab, a monoclonal antibody that interferes with VWF-platelet interactions. Caplacizumab treatment can result in prompt, significant clinical improvement despite persistent ADAMTS13 deficiency [36]. (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)
COMPLEMENT-MEDIATED TMA PATHOGENESIS — Defective complement regulation is responsible for complement-mediated TMA (CM-TMA), which can affect children or adults [1]. We avoid using the term "atypical hemolytic uremic syndrome (aHUS)" to describe CM-TMA because it was originally intended as a nonspecific diagnostic term for children with non-diarrheal HUS. The term "aHUS" does not specify a mechanism or an appropriate therapy.
Consequences of excessive complement activity — Complement is a major component of the innate immune system. The complement cascade can cause lysis of target cells by forming a pore in the cell membrane. Any cell can be a target, including micro-organisms and host cells. The alternative pathway (see "Complement pathways", section on 'Alternative pathway') is responsible for protecting self-cells from inappropriate complement-mediated attack, and failure of normal control mechanisms to downregulate the alternative pathway may lead to endothelial damage. Specific complement regulatory proteins responsible for protecting self-cells from inappropriate complement activity include soluble factors such as complement factor H (CFH) and membrane-bound factors such as membrane cofactor protein (MCP), decay accelerating factor (DAF), and thrombomodulin (TM) [37,38]. These factors promote inactivation of membrane attack complex components. CFH and TM act as cofactors in the proteolytic inactivation of C3b by complement factor I (CFI). Loss of these protective factors may cause TMA by a variety of mechanisms.
Examples of the crosstalk between complement and other processes include the following:
●Activation of complement triggers a variety of inflammatory responses. (See "Overview and clinical assessment of the complement system".)
●Endothelial cells express receptors for complement; they are also susceptible to complement attack and injury. (See "The endothelium: A primer", section on 'Complement-mediated endothelial cell injury'.)
●Kidney cells appear to be especially sensitive to complement activation, which may explain the predominance of acute kidney injury in complement-mediated TMA. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Clinical manifestations' and "Overview and clinical assessment of the complement system", section on 'Alternative pathway activation'.)
●von Willebrand factor (VWF) may activate complement. (See 'Interactions between VWF and the alternative complement pathway' below.)
●Hemostatic factors involved in the clotting cascade, especially those with regulatory roles, interact with complement proteins; the specific mechanisms and their importance are less well understood. (See "Overview of hemostasis".)
Synergy and crosstalk among these processes make it challenging to dissect their individual contributions to each TMA syndrome.
Inhibitory antibodies to complement factor H — Acquired complement-mediated TMA can be caused by autoantibodies to complement factor H; in some cases, there is a coexisting complement gene mutation. The relative contribution of these acquired inhibitors to clinical disease is unknown [39]. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Autoantibodies against CFH' and "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies'.)
Complement gene variants — TMA can occur as a result of a pathogenic variant in one of several genes encoding complement factors. Factors H, I, B (also called CFH, CFI, and CFB), C3, and CD46 (also called membrane cofactor protein [MCP]) have been implicated. Heterozygosity for a pathogenic variant may be sufficient to cause clinical manifestations, in contrast to variants in the ADAMTS13 gene in hereditary TTP, which require homozygosity or compound heterozygosity, with biallelic ADAMTS13 variants. Specific complement factor gene variants and their role in causing a TMA are discussed in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Genetic variants' and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Pathogenic sequence variants in complement genes'.)
Interactions between VWF and the alternative complement pathway — Although relatively less well studied, there may be interactions between the von Willebrand factor (VWF) and complement regulators. As an example, endothelial-anchored ultralarge strings of VWF have been shown to serve as an activating surface for the alternative pathway of complement [40-42]. (See "Complement pathways", section on 'Alternative pathway'.)
SHIGA TOXIN-INDUCED TMA (ST-HUS) — Infection with an enteric organism that produces Shiga toxin is responsible for most cases of childhood hemolytic uremic syndrome (HUS). Childhood HUS caused by Shiga toxin is also called ST-HUS.
Most cases of ST-HUS occur in children under five years old, but ST-HUS can also occur in adults. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
In the United States and Europe, the organism responsible for ST-HUS typically is an Escherichia coli such as O157:H7, O111, or O104:H4 [43-46]. Shigella species may be more common as a source of Shiga toxin in Asia.
Although large outbreaks are widely publicized, endemic/sporadic cases of ST-HUS are much more common [47]. A variety of improperly prepared foods, especially beef, have been implicated as the source of infection. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Transmission'.)
Examples of some of the major outbreaks include:
●Europe in 2011, correlated with ingestion of raw bean sprouts [46].
●United States in 2018, correlated with romaine lettuce [48].
Other vegetables and meats, and exposure to livestock at farms, have also been implicated.
The clinical presentation (eg, bloody diarrhea, acute kidney injury, hematologic findings of TMA) and appropriate management, which generally involves supportive care, are presented in detail separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Management'.)
OTHER PRIMARY TMAS — A variety of other gene mutations have been associated with TMA. An understanding of the relative importance of these defects is evolving, facilitated by advances in recognition of these entities and availability of diagnostic testing [1,49].
Regulators of clotting or fibrinolysis — Pathogenic variants in genes that encode regulators of the coagulation cascade have been implicated in inherited TMAs [1]. The implicated factors are generally negative regulators of coagulation or fibrinolysis that also crosstalk with complement factors. The relative contributions of altered coagulation and altered complement activity in the pathogenesis of these TMAs have not been elucidated. Affected individuals generally present in infancy or early childhood.
In contrast, pathogenic variants in genes that encode coagulation factors themselves have not been described in inherited TMA syndromes; rather, these types of variants appear to cause excessive bleeding (hemophilia) or excessive clotting (thrombophilia).
DGKE — Biallelic pathogenic variants in the DGKE gene, encoding diacylglycerol kinase epsilon (DGKE), have been reported in several independent kindreds with a familial TMA [50-52]. Homozygous or compound heterozygous pathogenic variants may be seen.
DGKE is produced by endothelial cells, renal podocytes, and platelets. It is involved in protein kinase C (PKC) signaling, which increases endothelial cell production of several hemostatic factors including von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1), platelet activating factor (PAF), and tissue factor (TF), as well as the antithrombotic factor tissue-type plasminogen activator (TPA) [50]. DGKE also appears to be important for endothelial cell migration and angiogenesis [53]. It is unclear what roles DGKE plays in complement activation, with some research suggesting only a small contribution to the expression of membrane cofactor protein (MCP, also called CD46) on endothelial cell surfaces, and other research showing more dramatic complement dysregulation [53,54].
Thrombomodulin — Pathogenic variants in the THBD gene, encoding thrombomodulin (TM), have been described in cases of inherited TMA [55,56]. Heterozygosity for a pathogenic variant in THBD may be sufficient to cause clinical manifestations, in contrast to hereditary TTP, which requires homozygosity or compound heterozygosity for pathogenic variants in ADAMTS13.
TM is produced by endothelial cells. It regulates both the coagulation and the complement cascades. Its better established role in coagulation is as a membrane surface cofactor for thrombin in the activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). These activities serve to dampen coagulation and fibrinolysis, respectively. Activated TAFI (TAFIa) functions as a basic carboxypeptidase and inactivates both C3a and C5a efficiently. (See "Overview of hemostasis", section on 'Activated protein C and protein S' and "Overview of hemostasis", section on 'CPB2/TAFI'.)
TM also plays a role in inactivating complement. It serves as a cofactor for factor I in C3b inactivation, and it promotes inactivation of C3a and C5a via TAFI [38].
Regulators of vitamin B12 metabolism — TMA has been reported in individuals with pathogenic variants in the MMACHC gene, which encodes an enzyme involved in vitamin B12 (cobalamin) metabolism. Deficiency of this enzyme causes methylmalonic aciduria (MMA) and homocystinuria type C [57-60]. Homozygosity or compound heterozygosity appears to be required for clinical disease. While this TMA has generally been reported in children, this may be because adults have not been evaluated [61].
Infants with cobalamin C disease, a type of MMA, present with a variety of neurologic and developmental findings. Plasma homocysteine levels are markedly elevated, whereas plasma cobalamin levels are normal. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)
Complete responses of this TMA to therapy with high-dose cobalamin, folinic acid (leucovorin), and betaine have been reported [59,60].
Evaluation for these abnormalities in cobalamin metabolism is available by routine laboratory testing (by measuring serum homocysteine and methylmalonic acid levels). These tests are appropriate for individuals with unexplained TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Drug-induced TMA — Drug-induced TMA (DITMA) has been reported following exposure to several types of drugs, illicit substances, and over-the-counter remedies, especially those containing quinine (table 1) [62]. The mechanism can be immune (autoantibody-mediated) mediated or non-immune.
Our approach to the diagnosis and management of DITMA is discussed in detail separately. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
COVID-19-ASSOCIATED MICROTHROMBOSIS — COVID-19, the disease caused by infection with the SARS-CoV-2 virus, may be associated with microvascular thrombosis. Despite this, we do not consider COVID-19 to be a TMA, and there are no data to suggest that TMA-directed therapies are effective. Management of COVID-19 is discussed separately. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management of the intubated adult".)
Observations that distinguish COVID-19 from primary TMAs include the following:
●Autopsy studies have demonstrated microvascular thrombosis of the lungs, and, to a lesser extent, the kidneys [63-65]. However, a hypercoagulable state associated with large vessel thrombosis is also common. (See "COVID-19: Hypercoagulability".)
●COVID-19 is not typically associated with microangiopathic hemolytic anemia (MAHA) or thrombocytopenia, which are the hallmarks of TMA [66].
●In rare cases in which thrombocytopenia is seen, it may be a feature of disseminated intravascular coagulation (DIC), which is also rare in patients with COVID-19, or even immune thrombocytopenia [67]. (See "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)
●ADAMTS13 activity levels do not appear to be severely deficient in patients with COVID-19 [68].
●Complement-mediated endothelial injury has been speculated to play a role in the microvascular thrombosis, and anti-complement agents for treatment of COVID-19 are under investigation [69].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)
SUMMARY
●Histopathology of TMA – The histopathology of thrombotic thrombocytopenic purpura (TTP) and other primary thrombotic microangiopathies (TMAs) is characterized by small vessel changes including swelling of endothelial cells and the subendothelial space, along with vessel wall thickening and platelet microthrombi, typically in small arterioles and capillaries. This causes thrombocytopenia and microangiopathic hemolytic anemia (MAHA). Involvement of the kidney and central nervous system is common. (See 'Histopathology of TMA' above.)
●Pathophysiology of primary TMAs
•TTP – TTP is caused by severely deficient activity of the ADAMTS13 protease, typically with an activity level <10 percent. ADAMTS13 cleaves newly synthesized ultralarge von Willebrand factor (VWF) multimers attached to the endothelial surface that are responsible for formation of platelet microthrombi. Most commonly, ADAMTS13 deficiency is immune, due to autoantibodies against ADAMTS13, although hereditary TTP caused by biallelic pathogenic variants in the ADAMTS13 gene is also seen. (See 'TTP pathogenesis' above.)
•CM-TMA – Dysregulation of complement is responsible for complement-mediated TMA (CM-TMA), which can affect children or adults. Autoantibodies to factors in the alternative complement pathway and heterozygosity for a pathogenic variant in a gene encoding one of these components can be seen. (See 'Complement-mediated TMA pathogenesis' above.)
•ST-HUS – Enteric infection with a Shiga toxin-producing organism such as Escherichia coli 0157:H7 is the cause of Shiga toxin-induced hemolytic uremic syndrome (ST-HUS). Although large outbreaks are widely publicized, most cases are endemic. (See 'Shiga toxin-induced TMA (ST-HUS)' above.)
•Other primary TMAs – The pathogenesis of other primary TMAs, including pathogenic variants in genes encoding coagulation regulators (DGKE and thrombomodulin) and a vitamin B12 metabolic enzyme (MMACHC) is less well understood. (See 'Other primary TMAs' above.)
●Pathophysiology of DITMA – Drug-induced TMA (DITMA) can result from non-immune-mediated drug toxicity (such as with certain opioids) or an immune mechanism involving activation of drug-dependent antibodies (such as with oxaliplatin). (See "Drug-induced thrombotic microangiopathy (DITMA)" and 'Drug-induced TMA' above.)
●COVID-19 – Coronavirus disease 2019 (COVID-19) may be associated with microvascular thrombosis, but we do not consider this to be a primary TMA. (See 'COVID-19-associated microthrombosis' above.)
●Diagnosis – Distinguishing among the TMAs can be challenging. Our approach is discussed in detail separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
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