Critical Care Medicine
Microangiopathic hemolytic anemia
- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
Special considerations for nursing and allied health professionals.
What's the evidence?
Microangiopathic hemolytic anemia
Fragmentation hemolytic anemia
Disease categories/Common causes of MAHA
|Disease categories||Common causes of MAHA|
|Primary thrombotic microangiopathies||Thrombotic thrombocytopenic purpura (TTP, idiopathic or secondary), hemolytic uremic syndrome (HUS, typical or atypical). These are considered variant manifestations of a similar pathologic process and therefore referred to as TTP-HUS.|
|Malignancy||Acute myeloid leukemia (promyelocytic or monocytic subtypes), mucinous adenocarcinomas.|
|Pregnancy||HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, pre-eclampsia, disseminated intravascular coagulation (DIC), placental abruption, acute fatty liver of pregnancy.|
|Rheumatologic||Systemic lupus erythematosus, antiphospholipid syndrome, scleroderma renal crisis.|
|Cardiovascular||Malignant hypertension, heart valve hemolysis, Kasabach-Merritt phenomenon.|
1. Description of the problem
What every clinician needs to know
Hemolysis is defined as red blood cell destruction. Anemia occurs when the rate of destruction exceeds the rate of production of additional red blood cells by the bone marrow. There are various sub-classifications of hemolytic anemia:
Chronic congenital hemolysis is the result of intrinsic developmental defects in red blood cells, and includes disorders such as:
Membrane defects (hereditary spherocytosis, hereditary elliptocytosis).
Enzymatic defects (G6PD deficiency, pyruvate kinase deficiency).
Hemoglobin disorders (sickle cell anemia, thalassemia).
Abnormal red blood cells are selectively destroyed by the reticuloendothelial system. The hemolysis is longstanding, frequently allowing for adequate compensation.
2. Autoimmune hemolytic anemia (AIHA), is the result of antibody-mediated or complement-targeted red blood cell destruction.
Warm autoantibodies are usually of the IgG isotype.
Cold agglutinin disease, as seen in Mycoplasma pneumoniae infection.
3. "Microangiopathic" is defined as the presence of a physical blockage (usually fibrin thromboses).
Red blood cells passing through small capillaries break apart as they pass through this obstruction. The pathognomonic finding is the presence of schistocytes on the peripheral blood smear. Red blood cells have the ability to reseal their damaged cell membrane, but their shape remains forever distorted. Schistocyte fragments can no longer navigate through splenic sinusoids. Thus, they are cleared from circulation by macrophages in the reticuloendothelial system.
Features common to ALL forms of hemolysis(see also Diagnosis section for clinicopathologic features specific to MAHA):
Yellowing of the skin or eyes.
Increased lactate dehydrogenase.
Increased indirect bilirubin.
Increased urine urobilinogen.
Increased reticulocyte count.
Initial management for a patient in the ICU with suspected MAHA
Confirm that the anemia is due to hemolysis.
Avoid empiric red blood cell and platelet transfusion unless the etiology of hemolysis is definitively known, or if life-threatening bleeding or anemia is present.
Confirm that the hemolytic anemia is due to microangiopathy by identification of schistocytes on the peripheral blood smear.
Promptly identify the underlying disease process that is causing MAHA, by recognizing common syndromes associated with MAHA.
2. Emergency Management
Stabilizing the patient
MAHA represents a potential hematologic emergency until the etiology is clarified and appropriate treatment is initiated.
MAHA is considered to be TTP unless a more likely alternative diagnosis is readily apparent.
The immediate treatment for TTP is emergent plasma exchange. In TTP, platelet transfusions can worsen the disease and should not be administered, unless life-threatening anemia or bleeding is present.
Untreated TTP is fatal in 90% of cases.
Management points not to be missed
Reason for MAHA/Emergency management goals
|Reason for MAHA||Emergency management goals|
|TTP-HUS||Immediate plasma exchange is initial therapy. Supportive care as needed (intravenous fluids, correction of electrolyte abnormalities, hemodynamic stabilization, hemodialysis if required).|
|DIC||Rapid identification and treatment of the underlying cause (i.e. infection, malignancy, pregnancy, trauma, surgery). Blood products are often not necessary to correct the coagulopathy once the inciting cause is controlled but may be used to support the patient as needed. Anticoagulation has no clear benefit but may be considered if thrombotic complications are present.|
|Acute promyelocytic leukemia||Correction of coagulopathy with blood products is usually required to prevent severe bleeding complications. Standard treatment includes all-trans retinoic acid, followed by induction chemotherapy.|
|Solid tumor||Treatment directed toward the underlying malignancy.|
|Pregnancy-related complication||Immediate delivery of the fetus. Steroid administration if gestational age is under 34 weeks.|
|Cardiovascular complication||Control of hypertension. Evaluation of prosthetic heart valves.|
|Primary rheumatologic disease||Treatment directed toward the underlying disease. TTP may occur secondarily to SLE or scleroderma, and plasma exchange should be similarly initiated.|
|Medication-induced||Cessation of the offending medication. Plasma exchange is controversial in medication-induced TTP.|
Diagnostic criteria and tests
MAHA must be differentiated from all other forms of hemolysis.
Pathognomonic Findings in MAHA
Clinicopathologic features of hemolysis (as described in Clinical Features section)
A negative Coombs test (also called a direct antiglobulin test)
Schistocytes on microscopic examination of the peripheral blood smear (usually more than two per high power field [100x])
Normal lab values
Normal MAHA lab values
|Laboratory test||Normal range||Abnormality in MAHA||Comments|
|Hemoglobin||12.0-16.0 g/dL||Decreased||Severity is a function of the underlying cause.|
|Indirect Bilirubin||0.2-0.7 mg/dL||Increased||Maximum is usually 4.0 mg/dL in MAHA.|
|LDH||98-192 U/L||Increased||High sensitivity, low specificity for MAHA.LDH will decrease due to plasmapheresis and may not be reliably used for disease monitoring.|
|Haptoglobin||36-195 mg/dL||Decreased||Minimum is usually less than 25 mg/dL in MAHA.Haptoglobin can increase as an acute phase reactant.Haptoglobin can decrease in liver injury.|
|Platelet count||150,000-400,000 per microliter||Decreased||Nadir is usually 20,000-30,000 in MAHA but may decrease to under 10,000 in TTP-HUS.|
|Reticulocyte count||0.5-2.0%||Increased||Increase is inversely proportional to the degree of anemia.A normal bone marrow response to anemia is required for an increased reticulocyte count.|
The peripheral smear will contain schistocytes, which are fragments of red blood cells (Black arrows). Occasionally they are referred to as "helmet cells" due to their shape.
Confirming the diagnosis
Response to therapy implies that the correct diagnosis has been made and the treatment plan is appropriate.
Microangiopathy and thrombocytopenia are sufficient to make the diagnosis; the classic "pentad" of clinical signs and symptoms including fever, neurologic abnormalities, and renal failure are no longer necessary.
Plasma exchange is the mainstay of treatment.
TTP and HUS are considered to be similar diseases along the same spectrum.
Renal failure is often considered the predominant feature in HUS.
Typical HUS is characterized by an antecedent diarrheal illness (E. coli O157:H7) and more commonly presents in children; atypical HUS is characterized by neurologic symptoms and severe hypertension.
Coagulation studies (aPTT and PT) are normal.
ADAMTS13 activity is low and/or antibodies to ADAMTS13 are present.
An underlying cause is usually identifiable (sepsis, pregnancy, malignancy, trauma, surgery, etc).
Patients can present with bleeding and/or thrombosis.
Coagulation studies (aPTT and PT) are prolonged.
Fibrinogen is decreased and fibrin degradation products (such as D-dimer) are increased.
Clinical findings may be indistinguishable from severe liver disease. A normal coagulation factor VIII level may help distinguish liver disease from DIC.
Patients with HELLP can present with epigastric and right upper quadrant pain, nausea, vomiting and malaise.
TTP-HUS may present at any time during pregnancy, but usually near term or postpartum.
Pre-eclampsia, eclampsia, HELLP, and TTP-HUS may be difficult to distinguish in pregnancy.
Consider malignant hypertension if the blood pressure is greater than 180/120 mm Hg with acute kidney injury (including hematuria or proteinuria), papilledema, retinal hemorrhage, headaches, vomiting or intracranial hemorrhage.
Consider dysfunctional prosthetic valves. Longstanding heart valve hemolysis can also result in iron deficiency anemia through renal losses.
Consider aneurysmal dilation or Kasabach-Merritt syndrome as a cause of chronic DIC.
Consider scleroderma renal crisis, SLE or antiphospholipid syndrome (rare) in patients with a diagnosis of or clinical findings consistent with a connective tissue disorder.
Occult cancer is often overlooked as a cause of TTP or DIC.
Other possible diagnoses
Other causes of hemolysis can often be misdiagnosed as MAHA:
March hemoglobinuria/runner's anemia
Patients have a history of repetitive, physical trauma to their hands and feet (i.e military soldiers, bongo percussionists, jackhammer operators).
The anemia is usually mild and self-limited.
There is often no associated systemic illness.
Immune-mediated destruction of red blood cells (including complement activation)
Autoimmune hemolytic anemia.
Cold agglutinin disease.
Paroxysmal nocturnal hemoglobinuria.
Coombs test will be positive.
Schistocytes will be absent.
Microspherocytes will be present on the peripheral blood smear.
Direct infection of red blood cells
Exacerbated by G6PD deficiency.
Erythrocyte sequestration or extravascular destruction
Intrinsic red blood cell defects (see Introduction).
Anemia is often chronic and well-compensated.
Assays for ADAMTS13 activity are available commercially.
Decreased ADAMTS13 activity is associated with idiopathic TTP-HUS.
Antibodies directed against ADAMTS13 is associated with non-idiopathic (secondary) TTP-HUS.
Definitive treatment with plasma exchange should not be delayed due to pending ADAMTS13 testing.
Stool culture for shiga toxin-producing E. coli
This test must be performed on sorbitol MacConkey agar.
Blood cultures are usually negative for E. coli bacteremia, as the toxin (not the bacteria) is implicated in the development of HUS
Although this is the gold standard for diagnosis of malignant hypertension-induced MAHA, it is often not required.
In the absence of alternative diagnoses, imaging may reveal an occult malignancy that is responsible for MAHA.
A pathologic tissue diagnosis is required to confirm the suspicion of cancer.
In the presence of an abnormal CBC: bone marrow aspirate, biopsy and molecular testing is required to make the diagnosis and appropriate classification of an acute leukemia.
Evaluation of the pressure gradients and structural integrity of prosthetic heart valves using echocardiography may be necessary in patients with a mechanical valve.
Angiography or ultrasound procedures can diagnose aneurysms or hemangiomas.
4. Specific Treatment
If the etiology of MAHA is not readily apparent, plasma exchange therapy should be instituted to treat for TTP-HUS.
Emergent plasma exchange is first-line therapy for TTP-HUS. Plasma exchange can replete levels of ADAMTS13 (if deficient in the patient), remove the unusually large von Willebrand factor multimers that are initiating the microangiopathic process and remove autoantibodies directed against ADAMTS13.
Therapy for typical HUS is supportive, and includes hemodialysis for severe acute kidney injury and hypertension management.
Antibiotics are administered if there is concern for sepsis.
Platelet transfusions are reserved for bleeding or in preparation for an invasive procedure, if necessary.
Antiplatelet therapy is recommended for all patients and used with caution in severe thrombocytopenia.
Plasma exchange can be increased in frequency from once a day to twice a day.
Corticosteroids are given concomitantly with the increase in plasma exchange frequency.
Rituximab with or without cyclophosphamide.
Treatment is directed at the underlying cause (infectious, surgical, trauma, malignancy-related, obstetric).
Supportive care includes hemodynamic support, fluid and electrolyte management, and antimicrobial therapy as indicated.
It is often not necessary to administer blood products, as the coagulopathy corrects with management of the underlying cause.
Activated Protein C is FDA approved for use in DIC complicated by sepsis.
First Line therapy:
If the patient is at more than 34 weeks gestation, emergent delivery of the fetus is the first-line therapy. Vaginal delivery is preferred.
If the patient is at less than 34 weeks gestation, corticosteroids are recommended for fetal lung maturation but do not have benefit for the mother.
The goal of therapy is to control the blood pressure and heart failure symptoms with medical therapy.
Diastolic pressure should be lowered to 105 mm Hg or less.
The initial antihypertensive therapy should lower the systolic blood pressure by 25%. More rapid lowering can lead to ischemia or hyperperfusion.
Transfusion of red blood cells can correct an iron-deficiency anemia due to ongoing valve hemolysis.
Drugs and dosages
Aspirin: 81 mg by mouth daily.
Activated Protein C: 24 micrograms/kg/hour in an intravenous infusion over 96 hours.
All-trans retinoic acid: 45 mg/m2 in two divided doses every day until hematologic recovery is observed. This is followed by induction chemotherapy with daunorubicin 50 mg/m2 per day for three doses and cytarabine 200 mg/m2/day continuous infusion for 7 days.
Dipyridamole: 100 mg/day by continuous intravenous infusion.
Methylprednisolone: 1 gram intravenously per day for 1-3 days.
Any refractory case of MAHA in which plasma exchange was not part of initial management should receive plasma exchange therapy to treat for TTP-HUS.
There are no randomized, controlled trials of these strategies, but their use has been reported.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Expected response to treatment of TTP-HUS
Normalization of LDH in 1-3 days.
Neurologic improvement in 1-3 days.
Platelet recovery (to baseline) in 5-7 days.
Full recovery of renal function, in typical HUS.
Resolution of diarrhea, in typical HUS.
Disease monitoring of TTP-HUS
Consideration is given to discontinuation of plasma exchange therapy once the platelet count is greater than 150,000 (or returned to baseline) for 2-3 days.
By convention, plasma exchange has been either tapered gradually or abruptly discontinued. However, consideration must be given to the increased risk of thrombosis or infection with prolonged duration of the central venous catheter.
Recurrent or relapsed disease must be treated initially with emergent plasma exchange.
.Response to therapy depends on the prognosis of the underlying etiology of DIC.
With adequate management, the coagulopathy associated with DIC is reversible.
Complications of the HELLP syndrome include hepatic hematoma or infarction.
Following delivery of the fetus, resolution of MAHA, thrombocytopenia and liver injury is expected within 48 hours.
Patients should be monitored with laboratory tests for at least 2 days postpartum.
Patients should be discharged from the hospital after demonstrating adequate blood pressure control on an oral regimen.
Adequate blood pressure control can reverse the acute kidney injury.
Heart valve hemolysis
Ongoing hemolysis can lead to iron deficiency.
Supplementation with oral iron and oral folate preparations is recommended.
Red blood cells become destroyed by poorly functioning valve prostheses due to shear stress, large pressure gradients and physical contact with defective valve leaflets. Surgical evaluation for valve repair/replacement is recommended.
If the initial management choice has failed to result in clinical and laboratory improvement, then misdiagnosis should be strongly considered.
Serial laboratory evaluation of hemoglobin and hematocrit, platelet count, LDH and presence of schistocytes on the peripheral smear is required to assess MAHA disease activity.
Follow-up of TTP-HUS
Patients require laboratory monitoring of their hemoglobin, platelet count, LDH and peripheral smear to evaluate for persistent disease and for relapse (recurrent disease after 30 days).
LDH is a sensitive but nonspecific surrogate marker for ongoing hemolysis.
The overall relapse rate of idiopathic TTP is 18%, and can recur up to 10 years after initial presentation.
Patients with isolated, typical HUS are expected to make a full neurologic and renal recovery.
Serial measurement of ADAMTS13 activity may be predictive for increased risk of relapse.
Despite a broad differential diagnosis for MAHA, the underlying pathophysiology is identical. Due to mechanical obstruction of the lumen of small blood vessels, red blood cells physically break apart and sustain irreversible membrane damage. The nature of the physical obstruction varies with the underlying cause (see below), but endothelial injury is the common precipitating factor. The final common pathway is activation of inflammation and coagulation. The organ-specific thrombotic microangiopathy causes local tissue ischemia and hemorrhage, which leads to organ dysfunction.
The laboratory abnormalities are all a direct result of red blood cell fragmentation. Red blood cell destruction causes the release of LDH and hemoglobin into the circulation. Hemoglobin is converted into indirect bilirubin by the liver, causing jaundice and elevated indirect bilirubin. Free hemoglobin is scavenged by haptoglobin, which leads to decreased circulating levels of (unbound) haptoglobin. As a compensatory mechanism for the anemia, reticulocytes are released into the circulation from the bone marrow.
Under normal circumstances, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs 13) cleaves von Willebrand factor (VWF) into shorter segments. Agonists such as Shiga toxin, inflammatory cytokines, or estrogens stimulate endothelial cells to secrete ultra large VWF multimers that anchor to the endothelial cell surface and are able to accumulate intravascularly due to a deficiency of ADAMTS13 activity in familial or acquired autoantibody-mediated TTP.
The end result is rapid platelet binding to the highly adherent, long VWF multimers, and subsequent platelet aggregation, leading to the accumulation of microvascular platelet thrombi. Familial TTP results from homozygous or compound heterozygous mutations in the ADAMTS13 gene, leading to defects in ADAMTS13 production or secretion, and severely deficient to absent ADAMTS13 activity. Acquired causes include immune dysregulation occurring with certain medications, pregnancy and HIV, leading to the production of polyclonal inhibitory autoantibodies against ADAMTS13.
The causative organism in typical HUS is enterohemorrhagic E. coli (predominantly serotype 0157:H7) or Shigella species in more than 90% of developed countries. Enterohemorrhagic E. coli is a noninvasive pathogen. Following ingestion of contaminated food products (fruit, vegetables, meat, milk products) or water, bacteria will colonize in the terminal ileum and follicle-associated epithelium of Peyer's patches. Bacteria adhere to gut mucosa and secrete virulence factors (such as Shiga toxin, lipopolysaccharide) .
Shiga toxin binds to its receptor (Gb3) which is present on glomerular epithelium, as well as the brain and pancreas. This toxin exerts cytotoxic effects, endothelial activation and upregulation of cell surface adhesion molecules. Secretion of ultra large VWF is also induced by Shiga toxin, and perpetuated by the presence of inflammatory cytokines. Shiga toxins and IL-6 may additionally interfere with VWF cleavage by ADAMTS13.
Platelets bind to injured endothelium, and thrombocytopenia results from the platelet consumption in multiple microthrombi. Red blood cell fragmentation may be caused by mechanical shearing in thrombosed microvasculature or by oxidative injury. Shiga toxin and other virulence factors migrate across the damaged intestinal epithelium and gain access to the circulation, where they may bind to circulating blood cells, induce tissue factor expression and thrombin generation, and propagate thrombus formation.
In the kidneys, there is cellular apoptosis in the renal cortex, with injury seen in both tubular and glomerular epithelial cells.
Instead of a single infectious etiology, atypical HUS is most frequently the result of inherited disorders of complement regulation. Mutations have been described in complement regulator genes (membrane cofactor protein, factor H, and factor I) in addition to gain-of-function mutations (C3, factor B). Abnormalities in the regulation of C3, factor H, factor I, factor B, and CD46 have been identified, and anti-Factor H antibodies have also been hypothesized to play a role. Again, renal tubular epithelial cells are affected and since these are the most sensitive to injury, patients present with acute kidney injury.
Exposure of sub-endothelial tissue factor (as in surgery, trauma or tissue injury due to chemotherapy) incites the unrestrained activation of the coagulation cascade.
Tissue factor is also overexpressed on tumor cells (in malignancy) and macrophages (in infections and sepsis).
In addition to coagulation activation, there is also inhibition of endogenous anticoagulants (antithrombin III, protein C, tissue factor pathway inhibitor) and inhibition of fibrinolysis.
The net result is widespread, microvascular thrombosis, which leads to multiorgan system failure.
Bleeding can occur due to consumption of platelets and clotting factors.
Mechanism is not clearly defined, but there are several hypotheses: One of the most important of which is that endothelial injury results from the hypertension associated with pre-eclampsia.
Placental release of procoagulant particles can cause coagulation activation.
Elevated arterial pressures in the afferent vasculature of the kidney causes direct endothelial damage to renal blood vessels.
Cancer is often grouped with DIC and the presentation varies with the underlying tumor type.
In acute promyelocytic leukemia, annexin expressed on leukemia blasts upregulates plasmin and causes hyperfibrinolysis with a bleeding phenotype.
Solid tumors express tissue factor and cancer procoagulant, causing DIC with a thrombotic phenotype.
Immune complexes (antigen-antibody) can deposit in blood vessels, causing local obstruction.
Autoantibodies form against ADAMTS13, presenting as TTP.
Antiphospholipid syndrome causes intravascular thrombosis.
Idiopathic TTP and familial TTP are associated with ADAMTS13 deficiency.
Acquired (secondary) causes of TTP are associated with antibody against ADAMTS13 leading to reduced protease activity.
Secondary causes include: malignancy, pregnancy, HIV infection, rheumatologic diseases, hematopoietic stem cell transplant, solid organ transplant and medications.
Overall, incidence is increased for women and African-Americans.
Medications associated with TTP, atypical HUS and DIC
|Medications associated with TTP, atypical HUS and DIC|
Malignancies associated with TTP and DIC
|Malignancies associated with TTP and DIC|
|Acute myeloid leukemia - promyelocytic and monocytic subtypes|
|Mucinous adenocarcinoma of the stomach|
|Adenocarcinoma of the lung|
Typical HUS (D+ HUS)
95% of HUS is the "typical" (diarrhea-associated) form.
E. Coli 0157:H7 is the causative organism in 80% of cases and is found in undercooked meat, unpasteurized fruit and unsanitary water.
Shiga-toxin induces endothelial damage and may be exacerbated by antibiotic administration for the E. coli infection.
Person-to-person transmission is common.
Children are much more commonly affected than adults.
Peak exposure time is June-September.
One third of cases present with fever and neurologic symptoms (irritability, seizures or coma).
Atypical HUS (D- HUS)
Diarrhea is not a presenting feature.
Streptococcus pneumoniae is the causative organism in 40% of cases.
Complement dysregulation induces endothelial damage.
Adults are more commonly affected than children.
DIC does not exist in isolation; it is always secondary to an underlying cause.
Causes include: sepsis, trauma, surgery, malignancy or obstetrical catastrophes.
DIC is a complication of 7% of solid tumor malignancies and 20% of acute leukemias.
HELLP syndrome complicates 0.5-0.9% of all pregnancies and 10-20% of pregnancies with severe preeclampsia.
In approximately 20% of patients, HELLP syndrome develops in isolation, without any prior signs or symptoms of preeclampsia.
This syndrome develops late into the third trimester, most commonly between 28 and 36 weeks of gestation.
HELLP syndrome can present after delivery of the fetus in 30% of cases.
MAHA is a complication of malignant hypertension in approximately 25% of cases.
The mortality rate of untreated TTP is 90%. With plasma exchange, the mortality rate is 59% in non-idiopathic TTP and 15% in idiopathic TTP. Overall, 30-day mortality is estimated to be 16% with plasma exchange. Overall, five- year survival is 55% and is better for patients with idiopathic disease.
Typical HUS carries a mortality rate of 5%. Younger children have a better prognosis than adolescents and adults.
Poor prognostic factors include CNS involvement or other extra-renal disease
Atypical HUS carries a mortality rate of 15-25%. Younger children with typical HUS tend to make a full recovery, while adults and all patients with atypical HUS have a poorer prognosis. At one year, 25% of all patients have chronic renal failure (CrCl < 40 mL/min).
HELLP during pregnancy
The recurrence rate of HELLP for subsequent pregnancies is 5%
Patients are at an increased risk of pre-eclampsia in future pregnancies, especially with a history of essential hypertension
Renal function will improve in 50-80% of cases with adequate blood pressure control.
The 10-year overall survival is approximately 50%.
Patients with one presentation of malignant hypertension develop an increased risk of future neurologic, cardiologic and renal complications.
MAHA in malignant hypertension predicts a higher likelihood of the need for acute hemodialysis.
Special considerations for nursing and allied health professionals.
What's the evidence?
Description of the Problem
Ideguchi, H, Ishikawa, A, Futata, Y, Yamada, Y, Ono, Y. "A comprehensive scheme for the systematic investigation of hemolytic anemia". Ann Clin Lab Sci. vol. 24. 1994. pp. 412-21.(This paper provides a systematic and practical method to approach the differential diagnosis of hemolysis.)
Veyradier, A, Meyer, D. "Thrombotic thrombocytopenic purpura and its diagnosis". Journal of Thrombosis and Haemostasis. vol. 3. 2005. pp. 2420-7.(This paper includes a comprehensive discussion of the mechanisms of TTP, which is useful for background reading.)
Zipfel, PF, Heinen, S, Skerka, C. "Thromboticmicroangiopathies: new insights and new challenges". Curr Opin Nephrol Hypertens. vol. 19. 2010. pp. 372-8.(This paper discusses the most current updates and novel developments in the diagnosis and treatment of TTP/HUS when faced with a potential clinical presentation.)
Moake, J. "Thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies". Best Pract Res Clin Haematol. vol. 22. 2009. pp. 567-76.(This paper summarizes several underlying causes of microangiopathic hemolytic anemia and is useful in forming a differential diagnosis.)
Burns, ER, Lou, Y, Pathak, A. "Morphologic diagnosis of thrombotic thrombocytopenic purpura". Am J Hematol. vol. 75. 2004. pp. 18-21.(This study describes the use of absolute number of schistocytes in the diagnosis of MAHA.)
George, JN. "Evaluation and management of patients with thrombotic thrombocytopenic purpura". J Intensive Care Med. vol. 22. 2007. pp. 82-91.(This is an excellent discussion of the differential diagnosis of MAHA for the clinical intensivist, with a focus on appropriate initial management.)
Mayer, SA, Aledort, LM. "Thrombotic microangiopathy: differential diagnosis, pathophysiology, and therapeutic strategies". Mt Siani J Med. vol. 72. 2005. pp. 166-75.(This is an excellent overview of the multiple etiologies of microangiopathic hemolytic anemia that can assist in the initial workup.)
George, JN. "Clinical practice: Thrombotic thrombocytopenic purpura". NEJM. vol. 354. 2006. pp. 1927-35.(This paper provides step-by-step, practical guidelines for the management of TTP in the context of a clinical case.)
Sarode, R. "Atypical presentations of thrombotic thrombocytopenic purpura: A review". Journal of Clinical Apheresis. vol. 24. 2009. pp. 47-52.(This paper discusses clinical presentations of TTP that require heightened clinical acumen to make the diagnosis. Patients with acute coronary syndrome, acute stroke, visual changes or pancreatitis who do not respond to conventional therapy should raise the suspicion of TTP.
Rock, GA, Shumak, KH, Buskard, NA, Blanchette, Vs, Kelton, JG. "Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura". NEJM. vol. 325. 1991. pp. 393-7.(This landmark paper established the superiority of plasma exchange over simple plasma infusion in the treatment of TTP.)
Ziegler, ZR, Shadduck, Rk, Gryn, JF, Rintels, PB, George, JN. "Cryoprecipitate poor plasma does not improve early response in primary adult thrombocytopenic purpura (TTP)". J Clin Apheresis. vol. 16. 2001. pp. 19-22.(This paper showed that fresh frozen plasma was adequate to use for exchange therapy and that cryoprecipitate poor plasma was unnecessary.)
Walsh, TS, Wyncoll, DLA, Stanworth, SJ. "Managing anaemia in critically ill adults". BMJ. vol. 341. 2010. pp. 547-51.(This paper discusses the risks associated with red blood cell transfusion.)
Hayward, CP, Sutton, DM, Carter, WH, Campbell, ED, Scott, JG. "Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome". Arch Intern Med. vol. 154. 1994. pp. 982-7.(This paper discussed the need to improve outcomes and proposed additional novel therapies for the treatment of TTP-HUS.)
Levi, M, Toh, CH, Thachil, J, Watson, HG. "Guidelines for the diagnosis and management of disseminated intravascular coagulation". British Journal of Haematology. vol. 145. 2009. pp. 24-33.(This is an outstanding, evidence-based series of guidelines for clinicians treating DIC.)
Barbui, T, Falanga, A. "Disseminated intravascular coagulation in acute leukemia". Semin Throm Haemost. vol. 27. 2001. pp. 593-604.(This paper discusses the emergent management of DIC as the presenting sign of acute leukemia.)
Gordon, LI, Kwann, HC. "Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the cancer patient". Semin Thromb Hemost. vol. 25. 1999. pp. 217-21.(This paper discusses the presentation and management of TTP/HUS for patients with various tumor types.)
Mecozzi, G, Milano, AD, De Carlo, M, Sorrentino, F, Pratali, S. "Intravascular hemolysis in patients with new-generation prosthetic heart valves: a prospective study". J Thorac Cardiovasc Sug. vol. 123. 2002. pp. 550-6.(This prospective study describes acute and chronic presentations of hemolysis in patients with heart valves.)
Benz, K, Amann, K. "Thrombotic microangiopathy: new insights". Curr Opin Nephrol Hypertens. vol. 19. 2010. pp. 242.(This paper differentiates between ADAMTS13 deficiency as the mechanism of TTP pathogenesis and complement dysregulation as the inciting event in HUS.)
Levi, M, Meijers, JC. "DIC: Which laboratory tests are most useful?". Blood Rev. 2010.(This recent paper, based on expert opinion, provides a practical approach for diagnosing DIC based on readily available laboratory tests.)
Levi, M, ten Cate, H. "Disseminated intravascular coagulation". NEJM. vol. 341. 1999. pp. 586-92.(This is an excellent review of the pathophysiology, diagnosis, and treatment options in DIC.)
Martin, JN, Magann, EF, Blake, PG. "Analysis of 454 pregnancies with severe preeclampsia/eclampsia HELLP syndrome using the 3-class system of classification". Am J Obstet Gynecol. vol. 68. 1993. pp. 386-91.(This paper discusses diagnosis of pregnancy-related MAHA.)
Shibagaki, Y, Fujita, T. "Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP): can we differentiate one from the other?". Hypertens Res. vol. 28. 2005. pp. 89-95.(Two cases are presented, in which the presence of thrombocytopenia and an activity assay for ADAMTS13 were shown to be useful in distinguishing between the diagnoses of malignant hypertension and HUS/TTP. These cases present real-life, practical examples of determining the cause of microangiopathic hemolytic anemia.)
Al-Shahi, R, Mason, JC, Rao, R, Hurd, C, Thompson, EM. "Systemic lupus erythematosus, microangiopathic hemolytic anemia, and anti CD-36 antibodies". British Journal of Rheumatology. vol. 36. 1997. pp. 794-8.(This paper discusses the differential diagnosis of MAHA in lupus through presentation of a case report and offers several hypotheses for the underlying pathophysiology.)
Elliott, MA, Letendre, L, Gastineau, DA, Winters, JL, Pruthi, RK. "Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration". Eur J Haematol. vol. 85. 2010. pp. 43-50.(This paper reports that occult cancers can present with MAHA and thrombocytopenia, and patients treated with plasma exchange, as for TTP, will have worse outcomes.)
Francis, KK, Kalyanam, N, Terrell, DR, Vesely, SK, George, JN. "Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases". Oncologist. vol. 12. 2007. pp. 11-9.(This paper discusses the need to consider a diagnosis of disseminated cancer in patients with presumed TTP that fail to respond appropriately to plasma exchange therapy.)
Dang, CV. "Runner’s anemia". JAMA. vol. 286. 2001. pp. 714-6.(This paper describes long-distance running as a potential cause of MAHA in an otherwise healthy individual.)
Barros, MM, Blajchman, MA, Bordin, JO. "Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and the treatment". Transfus Med Rev. vol. 24. 2010. pp. 195-210.(This paper discusses the pathogenesis and treatment for autoimmune hemolytic anemia, which can assist clinicians in distinguishing AIHA from MAHA.)
Michael, M, Elliott, EJ, Craig, JC, Ridley, G, Hodson, EM. "Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials". Am J Kidney Disease. vol. 53. 2009. pp. 259-72.(This comprehensive analysis of multiple RCTs provides evidence in support of plasma exchange as definitive therapy for TTP and supportive care as definitive therapy for HUS.)
Patel, A, Patel, H, Patel, A. "Thrombotic thrombocytopenic purpura: the masquerader". South Med J. vol. 102. 2009. pp. 504-9.(This paper underscores the importance of making the correct diagnosis when faced with a patient with MAHA in order to institute timely and effective therapy.)
Bitzan, M. "Treatment options for HUS secondary to Escherichia coli 0157:H7". Kidney Int Suppl. vol. 112. 2009. pp. S62-S66.(This paper provides treatment recommendations for critical care physicians caring for patients with HUS and acute kidney injury.)
Bitzan, M, Schaefer, F, Reymond, D. "Treatment of typical (enteropathic) hemolytic uremic syndrome". Semin Thromb Hemost. vol. 36. 2010. pp. 594-610.(This review includes novel therapeutic approaches, including monoclonal antibodies directed at Shiga toxin.)
Sadler, JE. "Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura". Blood. vol. 112. 2008. pp. 11-8.(This review of treatment options for relapsed and refractory TTP suggests that rituximab may provide benefit as first-line therapy along with plasmapheresis and that this combination warrants further investigation.)
Bernard, GR, Vincent, JL, Laterre, PF, LaRosa, SP, Dhainaut, J-F. "Efficacy and safety of recombinant human activated protein C for severe sepsis". NEJM. vol. 344. 2001. pp. 699-709.(This is the landmark Phase III, randomized, controlled, international trial that led to the FDA approval of activated protein C for severe sepsis complicated by DIC.)
Haram, K, Svendsen, E, Abildgaard, U. "The HELLP syndrome: clinical issues and management. A Review". BMC Pregnancy Childbirth. vol. 9. 2009. pp. 8.(This review provides practical guidance for management of patients with the HELLP syndrome, including recommendations for steroid dosing, hemodynamic goals and surveillance of the mother and fetus.)
Woudstra, DM, Chandra, S, Hofmeyr, GJ, Dowswell, T. "Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy". Cochrane Database Syst Review. vol. 9. 2010. pp. CD008148.(This Cochrane Review presents a comprehensive analysis of 11 trials of women with HELLP and concludes that there is insufficient evidence to recommend the routine use of steroids as a therapeutic maneuver in HELLP syndrome.)
Shavit, L, Reinus, C, Slotki, I. "Severe renal failure and microangiopathic hemolysis induced by malignant hypertension - case series and review of literature". Clin Nephrol. vol. 73. 2010. pp. 147-52.(This case series of three patients describes the importance of blood pressure control and reports on varied prognosis despite similar pathologic diagnoses of MAHA.)
Disease monitoring, follow-up and disposition
Kobayashi, T, Wada, H, Kamikura, Y, Matsumoto, T, Mori, Y. "Decreased ADAMTS13 activity in plasma from patients with thrombotic thrombocytopenic purpura". Thromb Res. vol. 119. 2007. pp. 447-52.(This study found that low levels of ADAMTS-13 activity could be helpful in the diagnosis of TTP.)
Kobayashi, T, Wada, H, Nishioka, N, Yamamoto, M, Matsumoto, T. "ADAMTS13 related markers and von Willebrand factor in plasma from patients with thrombotic microangiopathy (TMA)". Thromb Res. vol. 121. 2008. pp. 849-54.(This study further investigated research laboratory tests that may be useful in the diagnosis and management of TTP.)
Michael, M, Elliott, EJ, Ridley, GF, Hodson, EM, Craig, JC. "Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura". Cochrane Database Syst Rev. vol. 1. 2009. pp. CD003595.(This Cochrane Review concluded that plasma exchange was the most effective therapy for TTP and dialysis and supportive measures were most effective for typical HUS.)
Pene, F, Vigneau, C, Auburtin, M, Moreau, D, Zahar, JR. "Outcome of severe adult thrombotic microangiopathies in the intensive care unit". Intensive Care Med. vol. 31. 2005. pp. 71-8.(This study correlated neurologic impairment with poor outcome and underscores the importance of emergent plasmapheresis as first-line therapy.)
Sibai, BM. "Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count". Obstet Gynecol. vol. 103. 2004. pp. 981-91.(This paper summarizes controversies in the literature and provides expert recommendations for management of HELLP syndrome.)
Vaughn, CJ, Delanty, N. "Hypertensive emergencies". Lancet. vol. 356. 2000. pp. 411-7.(This paper provides a discussion of the natural history of MAHA in hypertensive emergency.)
Levandovsky, M, Harvey, D, Lara, P, Wun, T. "Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. (TTP-HUS): a 24-year clinical experience with 178 patients". J Hematol Oncol. vol. 1. 2008. pp. 23.(This study provides long-term follow-up data on TTP-HUS patients.)
Martin, DL, MacDonald, KL, White, KE, Soler, JT, Osterholm, MT. "The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota". NEJM. vol. 323. 1990. pp. 1161-7.(This paper describes the expected clinical course of patients with HUS.)
Wyllie, BF, Garg, AX, Macnab, J, Rock, GA, Clark, WF. "Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome: a new index predicting response to plasma exchange". Br J Haematol. vol. 132. 2006. pp. 204-9.(This retrospective analysis developed a new predictive model in TTP comprised of age (>40 years), anemia (Hb <9 g/dL) and fever. It differed from the historical model, the Rose Index, in its exclusion of sex, thrombocytopenia, renal function and neurologic function in the model.)
Jin, M, Casper, TC, Cataland, SR, Kennedy, MS, Lin, S, Li, YJ. "Relationship between ADAMTS13 activity in clinical remission and the risk of TTP relapse". Br J Haematol. vol. 141. 2008. pp. 651-8.(This paper presents evidence for the use of ADAMTS13 testing in the prognosis of TTP.)
Benz, K, Amann, K. "Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS)/thrombocytic thrombocytopenic purpura (TTP)". Thromb Haemost. vol. 101. 1002. pp. 265-70.(This paper discusses the features of TTP/HUS that can be detected with pathologic techniques from light microscopy to electron microscopy.)
Coppo, P, Veyradier, A. "Thrombotic microangiopathies: towards a pathophysiology-based classification". Cardiovasc Hematol Disord Drug Targets. vol. 9. 2009. pp. 36-50.(This review summarizes recent understanding of the molecular pathogenesis of TTP and HUS.)
Moake, J. "Thrombotic microangiopathies: multimers, metalloprotease, and beyond". Clin Transl Sci. vol. 5. 2009. pp. 366-73.(This review summarizes the recent literature that has clarified our understanding of the mechanisms of TTP, HUS and HELLP.)
Zheng, XL, Sadler, JE. "Pathogenesis of thrombotic microangiopathies". Annu Rev Pathol. vol. 3. 2008. pp. 249-77.(This paper discusses the role of ADAMTS13 in TTP and complement dysfunction in diarrhea-negative-HUS.)
Furlan, M, Robles, R, Galbusera, M, Remuzzi, G, Kyrle, PA. "von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome". NEJM. vol. 339. 1998. pp. 1578-84.(This was an early paper that discovered unusually large multimers of von Willebrand factor in TTP and generated hypotheses for further research in this area.)
Moake, JL. "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Semin Hematol. vol. 41. 2004. pp. 4-14.(The role of an absent or mutated ADAMTS-13 metalloprotease is elucidated as it applies to the pathogenesis of microvascular thrombosis.)
Tsai, HM, Lian, EC. "Antibodies to von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome". NEJM. vol. 339. 1998. pp. 1585-94.(This paper identifies ADAMTS13 antibodies in the pathophysiology of acquired TTP/HUS.)
Tarr, PI. "Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis". Kidney Int Suppl. vol. 112. 2009. pp. S29-S32.(This paper effectively and clearly correlates the underlying pathogenesis with clinical features of HUS.)
Karpman, D, Sartz, L, Johnson, S. "Pathophysiology of typical hemolytic uremic syndrome". Semin Thromb Hemost. vol. 36. 2010 Sep. pp. 575-85.(This paper discusses the pathogenesis of HUS at the level of endothelial cell-toxin interactions.)
Levi, M. "Disseminated intravascular coagulation". Crit Care Med. vol. 35. 2007. pp. 2191-5.(This review provides well-organized descriptions and figures to aid in understanding of the pathophysiology of DIC.)
Moake, JL. "Thrombotic Microangiopathies". NEJM. vol. 347. 2002. pp. 589-600.(This paper presents an excellent overview of the differential diagnosis of MAHA.)
George, JN. "The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (Experience of The Oklahoma TTP-HUS Registry, 1989-2007)". Kidney Int Suppl. vol. 112. 2009. pp. S8-S10.(This paper classifies TTP and HUS into distinct etiologic categories, based on clinical features at presentation.)
George, JN. "The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome". Curr Opin Hematol. vol. 10. 2003. pp. 339-44.(This retrospective case series identifies the late third trimester and early post-partum time periods as conferring the highest risk of developing TTP-HUS during pregnancy.)
Hunt, BJ, Tueger, S, Pattison, J, Cavenagh, J, D’Cruz, DP. "Microangiopathic haemolytic anaemia secondary to lupus nephritis: an important differential diagnosis of thrombotic thrombocytopenic purpura". Lupus. vol. 16. 2007. pp. 358-62.(This paper suggests that MAHA associated with lupus more closely resembles the pathologic findings in HUS than those of TTP.)
Noris, M, Remuzzi, G. "Thrombotic microangiopathy after kidney transplantation". Am J Transplant. vol. 10. 2010. pp. 1517-23.(This paper discusses the epidemiology, pathogenesis and prognosis of MAHA after renal transplants, among various indications for transplant.)
Noris, M, Remuzzi, G. "Hemolytic uremic syndrome". J Am Soc Nephrol. vol. 16. 2005. pp. 1035-50.(This is a comprehensive review of epidemiology, pathophysiology, diagnosis and management of HUS.)
Pennington, H. "Escherichia coli 0157". Lancet. vol. 376. 2010. pp. 1428-35.(This is a comprehensive review of the epidemiology of HUS due to E. Coli 0157.)
Safdar, N, Said, A, Gangnon, RE, Maki, DG. "Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli 0157:H7 enteritis: ameta-analysis". JAMA. vol. 288. 2002. pp. 996-1001.(This paper discusses the risks of antibiotic administration as first-line therapy for HUS and argues against their use.)
Levi, M. "Disseminated intravascular coagulation in cancer patients". Best Practice & Research Clinical Hematology. vol. 22. 2009. pp. 129-36.(This paper provides an excellent overview of the mechanisms of DIC in both solid tumors and hematologic malignancies.)
Kirkpatrick, CA. "The HELLP syndrome". Acta Clin Belg. vol. 65. 2010. pp. 91-7.(This review discusses new developments in the epidemiology, pathogenesis and treatment of the HELLP syndrome in the past 10 years.)
Zheng, XL, Kaufman, RM, Goodnough, LT, Sadler, JE. "Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura". Blood. vol. 103. 2004. pp. 4043-9.(This study found that mortality is higher in idiopathic TTP compared with TTP from an identifiable cause, and that measures of ADAMTS13 inhibitor titers may be helpful in estimating prognosis.)
George, JN. "The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: evaluation, management, and long-term outcomes experience of the Oklahoma TTP-HUS Registry, 1989-2007". Kidney Int Suppl. vol. 112. 2009. pp. S52-S54.(This cohort study describes the expected clinical course of patients, categorized by various causes of TTP and HUS.)
Forzley, BR, Clark, WF. "TTP/HUS and prognosis: the syndrome and the disease(s)". Kidney Int Suppl. vol. 112. 2009. pp. S59-S61.(This recent update on prognosis in TTP/HUS stratifies patients into mortality risk-groups based on the underlying cause of TTP and initial response to therapy.)
Vesely, SK, George, JN, Lammle, B, Studt, JD, Alberio, L. "ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients". Blood. vol. 102. 2003. pp. 60-8.(This study measured ADAMTS13 activity in TTP-HUS patients prior to initiation of plasma exchange and found that the absolute levels did not correlate with eventual clinical outcome.)
Burrus, TM, Wijdicks, EF, Rabinstein, AA. "Brain lesions are most often reversible in acute thrombotic thrombocytopenic purpura". Neurology. vol. 73. 2009. pp. 66-70.(This retrospective analysis found that complete neurologic recovery is possible in TTP patients who present with devastating neurologic symptoms.)
Garg, AX, Suri, RS, Barrowman, N, Rehman, F, Matsell, D. "Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression". JAMA. vol. 290. 2003. pp. 1360-70.(This meta analysis provides a comprehensive evaluation of renal outcomes in patients with typical HUS.)
Scheiring, J, Andreoli, SP, Zimmerhackl, LB. "Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS)". Pediatr Nephrol. vol. 23. 2008. pp. 1749-60.(This discussion of children describes the expected disease course and prognosis of HUS.)
Zhang, B, Xing, C, Yu, X, Sun, B, Zhao, X. "Renal thrombotic microangiopathies induced by severe hypertension". Hypertens Res. vol. 3. 2008. pp. 479-83.(This study of 21 patients found that renal outcomes were poorer for patients with TTP-HUS than for patients with malignant hypertension.)
Habli, M, Eftekhari, N, Weibracht, E, Bombrys, A, Khabbaz, M. "Long-term maternal and subsequent pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome". Am J Obstet Gynecol. vol. 201. 2009. pp. 385.e1-5.(This study reviewed patients with a history of HELLP syndrome and tabulated morbidity after 5 years. Interestingly, there was an increased risk of development of depression and anxiety in patients with a history of HELLP.)
van den Born, BJ, Honnebier, UP, Koopmans, RP, van Montfrans, GA. "Microangiopathic hemolysis and renal failure in malignant hypertension". Hypertension. vol. 45. 2005. pp. 246-51.(This retrospective analysis concluded that the presence of MAHA in malignant hypertension is predictive and prognostic for renal failure.)
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