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Microangiopathic Hemolytic Anemia

Microangiopathic hemolytic anemia is a group of disorders in which red blood cells get fragmented when passing through fibrin and platelet mesh of microthrombi intravascularly. It is seen in diseases of various origin. Clinical presentation includes fatigue, poor general condition, anemia, and thrombocytopenia. The diagnosis is made by peripheral blood smear examination and full blood workup, while treatment is directed at the underlying cause.


Presentation

Clinical presentation of MAHA partly depends on the underlying cause, but common features include fatigue and poor general condition because of anemia. Dark urine is often encountered as a result of hemoglobinuria. Numerous patients develop hemolytic uremic syndrome (HUS), which is characterized by diarrhea, abdominal pain, dehydration, and neurological complaints, and this presentation is more often encountered in children rather than in adults [12]. Fever is also a common finding in patients, while bone pain, respiratory complaints, and weight loss are encountered in cancer-associated MAHA [13], depending on the type of underlying malignancy. If the underlying cause is SLE, numerous symptoms that fall under the criteria for the diagnosis of this systemic autoimmune disease may be present, including hematuria, malar rash, light sensitivity, arthritis, oral ulcers, etc. Very high blood pressure may be noted in patients with malignant hypertension which is seen in renal diseases. Altered mental status and loss of consciousness may be seen in sepsis and severe systemic infections. As stated previously, various symptoms may be present, but in all patients with anemia, thrombocytopenia, and a poor general condition, a detailed diagnostic workup should be conducted, to identify the cause and start targeted treatment.

Exertional Dyspnea
  • A 36-year-old woman came to our hospital with lower back pain and progressive exertional dyspnea for 8 weeks. Hemolytic anemia, thrombocytopenia, and leukoerythroblastosis were found on admission.[ncbi.nlm.nih.gov]
Hemoptysis
  • A 70-year-old man with uremia was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
Anemia
  • We present the case of a patient with SCLS who developed microangiopathic hemolytic anemia (MAHA). We propose that this anemia is the result of ADAMTS-13 loss in the third-space fluid.[ncbi.nlm.nih.gov]
  • It has been reported that microangiopathic hemolytic anemia occasionally occurs in patients with severe diabetic microangiopathy.[ncbi.nlm.nih.gov]
  • A review of the literature regarding microangiopathic hemolytic anemia in cancer patients is discussed. In patients suffering from microangiopathic hemolytic anemia and thrombocytopenia, malignancy should be considered as a possible cause.[ncbi.nlm.nih.gov]
  • However, the hemolytic anemia recurred and was successfully treated with a course of fresh frozen plasma (FFP). Hemolytic anemia in women with eclampsia and the HELLP syndrome occurs secondary to microvascular endothelial damage.[ncbi.nlm.nih.gov]
  • […] with hemolytic anemia and porcine valve failure whose cases have been reported in the literature.[ncbi.nlm.nih.gov]
Pallor
  • Although pallor of the skin is a sign of anemia, it is not the most reliable sign; many other factors can affect complexion and skin color.[medical-dictionary.thefreedictionary.com]
  • On physical examination, mild pallor was noted and her vital signs were as follows: temperature, 98.0 F; heart rate, 90 beats per minute; respiratory rate, 16 breaths per minute; BP, 145/90 mmHg lying down and standing; and O 2 saturation, 98% on room[cjasn.asnjournals.org]
  • Signs Signs of anaemia: general pallor and pale conjunctivae. Tachycardia, tachypnoea and hypotension if severe. Mild jaundice may occur due to haemolysis. Splenomegaly: occurs with some causes - eg, hereditary spherocytosis.[patient.info]
  • Examination New onset of pallor and anemia Jaundice Gallstones Splenomegaly /- hepatomegaly INVESTIGATIONS Confirm haemolysis Increased absolute reticulocyte count LDH (elevation is more pronounced in intravascular hemolysis) Indirect Bilirubin (i.e.[lifeinthefastlane.com]
Atrial Septal Defect
  • We present a 7-year-old boy with atrial septal defect and pulmonary hypertension who developed microangiopathic hemolysis and thrombocytopenia.[ncbi.nlm.nih.gov]
Tachycardia
  • Severe anaemia, especially of sudden onset, may cause tachycardia, dyspnoea, angina and weakness. Gallstones may cause abdominal pain. Bilirubin stones can develop in patients with persistent haemolysis.[patient.info]
  • A resting tachycardia with a flow murmur may be present if the anemia is pronounced.[aafp.org]
Jaundice
  • A newborn infant with a large hepatic hemangioma developed congestive heart failure, consumption coagulopathy, microangiopathic hemolytic anemia, and obstructive jaundice.[ncbi.nlm.nih.gov]
  • Jaundice of the skin and sclera can occur as a result of hemolysis and the release of bilirubin into the blood stream, where it eventually finds its way into the skin and mucous membranes. (See also jaundice .)[medical-dictionary.thefreedictionary.com]
  • Obstructive jaundice may be superadded to hemolytic jaundice thereby creating diagnostic dilemma.[bioline.org.br]
  • Contrary to findings in compensated haemolytic jaundice there is, however, no increased intravascular haemolysis: the lifespan of intravascular erythrocyte is normal.[thieme-connect.com]
  • One third of the patients present with jaundice due to hemolytic anemia, liver metastasis or extrahepatic bile duct obstruction.[ispub.com]

Workup

In all patients with suspected MAHA, a complete blood count (CBC) should be performed, which will reveal anemia, thrombocytopenia, and a markedly increased red cell distribution width (RDW). RDW is a parameter that implies variations in size and shape of RBCs, and in the case of MAHA, many red blood cells are injured, leading to abnormal RDW results. With these findings, a peripheral blood smear examination should be performed, which will reveal the presence of schistocytes [14].

Additional laboratory tests should include bilirubin, haptoglobin, fibrinogen, lactate dehydrogenase, prothrombin time (PT), serum electrolytes, creatinine, blood urea nitrogen (BUN), urinalysis, and stool examination. Bilirubin is increased because of accelerated RBC degradation, and haptoglobin, which is an indicator of free hemoglobin in the circulation, will be increased. Fibrinogen, D-dimer, and increased PT are seen in states of increased coagulation, such as DIC, while kidney function parameters may be deranged as well. Urinalysis may include hemoglobinuria, while stool examination should include cultures for Enterobacteriaceae, especially in those that present with features of HUS. LDH is an indicator of cellular breakdown, and its values may rise together with liver transaminases. In all patients, direct Coombs' test should be performed to exclude autoimmune causes of anemia, and MAHA is distinguished from other forms of hemolytic anemia with a negative Coombs' test. Additionally, antiphospholipid antibodies should be measured in all patients, since a significant correlation between MAHA and these antibody subsets have been established [15].

If infections are presumed to be the cause of MAHA, blood cultures should be obtained, and in patients with altered mental state and consciousness, lumbar puncture is indicated as well. Imaging studies, such as plain X-rays, ultrasound, and CT/MRI are useful in establishing the potential focus of infection, but they are even more important in identifying malignant diseases.

Patient history is the most important part of the diagnostic workup, as it may reveal recent use of drugs that may induce MAHA [16].

Burr Cell
  • . • Damage evident in peripheral blood smears in the form of red cell fragments- schistocytes, “burr cells”, “helmet cells” and “triangle cells”. 6. HEMOLYTIC-UREMIC SYNDROME 7.[slideshare.net]
  • Review Topic QID: 101434 1 Bite cells and Heinz bodies 2 Sickle cells and target cells 3 Schistocytes and burr cells 4 Round macrocytes and target cells 5 Macrocytes and hypersegmented neutrophils M1 Select Answer to see Preferred Response PREFERRED RESPONSE[step1.medbullets.com]
Coombs Negative Hemolytic Anemia
  • The patients presented with an acute onset of Coombs negative hemolytic anemia and fragmentocytes in the peripheral blood smear which are typical for MAHA.[ncbi.nlm.nih.gov]
  • Cancer-related microangiopathic hemolytic anemia (CR-MAHA) is a paraneoplastic syndrome characterized by Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia.[ncbi.nlm.nih.gov]
Lactate Dehydrogenase Increased
  • Laboratory abnormalities Anemia Increased lactate dehydrogenase. Increased indirect bilirubin. Decreased haptoglobin. Increased urine urobilinogen. Increased reticulocyte count.[clinicaladvisor.com]
Haptoglobin Decreased
  • LAB FINDINGS • CBC – Anemia – Thrombocytopenia – Peripheral smear checking for schistocytes, burr cells, helmet cells, spherocytes and segmented red blood cells • LDH (elevated) • Haptoglobin (decreased) • Reticulocyte count (appropriate) 21. • PT/PTT[slideshare.net]
Hemoglobin Decreased
  • However, despite lowering her blood pressure to the near normal range and delivery of the nonviable fetus, her creatinine increased to 4 mg/dL, while her hemoglobin decreased to 6 g/dL and platelet count to 20 10 9 /L.[thrombosisjournal.biomedcentral.com]

Treatment

Treatment of MAHA should be directed at the underlying cause, along with appropriate symptomatic therapy.

Patients with diarrhea, dehydration, and suspected HUS, and those in whom the cause is undetermined, plasma exchange (PEX) therapy is indicated [17]. The PEX is to remove potentially harmful substances from the body and to reestablish normal coagulation. Since its introduction, PEX has substantially increased survival rates of patients with MAHA and other thrombotic events.

In the case of infection, appropriate antimicrobial therapy should be started immediately, depending on the causative pathogen. E. coli is one of the most common pathogens encountered and is known to cause HUS particularly in children. Treatment options include fluoroquinolones, cephalosporins, and trimethoprim-sulfamethoxazole, but resistant strains may require the use of carbapenems and colistin [18]. In the case of bacterial systemic infection, antimicrobial susceptibility testing is vital in achieving best results.

In patients diagnosed with SLE, appropriate therapy consisting of corticosteroids, non-steroidal anti-inflammatory (NSAID) drugs, cyclophosphamide, azathioprine, or other immunosuppressants is indicated. Malignant disease, when diagnosed, should be evaluated using TNM classification, and treated accordingly.

Prognosis

The prognosis of MAHA depends on the severity of the underlying illness. The diseases that cause this syndrome can be life-threatening, and numerous complications may arise, which signifies the importance of a prompt diagnosis and appropriate treatment. It was established that cancer patients who develop MAHA have a significantly poorer prognosis [11].

Etiology

MAHA can occur in diseases of various origins, including infectious, autoimmune, malignant, and iatrogenic. The principal causes include [3]:

Epidemiology

Because this syndrome occurs in a variety of diseases, and that it is commonly misdiagnosed as TTP, its exact incidence is unknown. However, MAHA is established as a paraneoplastic syndrome, and its presence should always lead to the suspicion of a malignant disease as a potential cause.

Sex distribution
Age distribution

Pathophysiology

MAHA occurs in the setting of diseases that induce coagulation pathways and lead to the formation of microthrombi in arterioles and the capillary system. Due to the microthrombi, the lumens of the blood vessels are narrowed providing a smaller area for passage of blood and blood products [10]. Consequently, red blood cells are damaged as they attempt to pass along the dense fibrin network and thrombi resulting in disruption of membrane integrity. Red blood cells can either lyse, and release hemoglobin into the circulation, or they can become fragmented, and in that case, are termed schistocytes, which are one of the main features of this disease. Schistocytes are cells which have some membrane integrity, did not lyse intravascularly and are not cleared inside the spleen, while the majority of injured RBCs are removed when passing through the spleen. Because of increased rate of RBC destruction, very high amounts of bilirubin is formed, resulting in hyperbilirubinemia.

In addition to RBC injury and the development of schistocytes, thrombocytopenia occurs as a result of extensive intravascular coagulation and depletion of coagulation factor, most commonly in the setting of DIC.

Prevention

Currently, strategies to prevent MAHA are unknown, but prompt diagnosis and treatment of the underlying cause may significantly improve outcomes in many patients.

Summary

Microangiopathic hemolytic anemia (MAHA) is a term that describes changes in blood vessels and erythrocyte morphology because of increased rate of coagulation and intravascular fibrin deposition. It was initially described in the 1950s [1] and was classified together with thrombotic thrombocytopenic purpura (TTP), because of their almost identical clinical and morphological features. However, MAHA was subsequently found to occur in numerous other diseases, primarily those that cause disseminated intravascular coagulation (DIC), including systemic infections, malignant hypertension, malignancies, pregnancy-related syndromes such as preeclampsia, systemic lupus erythematosus (SLE), and others. This differentiated it as a separate clinical entity from TTP. Certain drugs have also been established to cause this syndrome. The pathogenesis of MAHA starts with the formation of microthrombi and platelet and fibrin mesh in the vessels of smaller diameter, such as arterioles and capillaries. During the passage of erythrocytes through these partially obstructed blood vessels, severe damage to the erythrocyte wall occurs and results in cell lysis and fragmentation. The hallmark of MAHA is the development of schistocytes ( fragmented red blood cells), and hemoglobinemia because hemoglobin is released during RBC lysis. Other findings include bilirubinemia (because of RBC destruction in the spleen) and thrombocytopenia because the majority of patients develop MAHA secondary to DIC [2]. Epidemiological data regarding this disease is unknown, as this phenomenon develops in a plethora of diseases. Cancer-associated MAHA has been established in more than 150 patients and should be potentially interpreted as a paraneoplastic syndrome. The clinical presentation varies significantly between patients and depends on the underlying cause that led to MAHA, but fatigue, malaise, dark urine, neurological complaints such as visual disturbances are commonly encountered. Diagnostic workup should include a complete blood count, peripheral blood smear examination, biochemical blood tests, including bilirubin, liver transaminases, blood urea nitrogen (BUN), urinalysis and other kidney function parameters, and imaging techniques such as ultrasound and X-ray/CT/MRI. Treatment should be directed at the underlying cause, including treatment of infections, malignancies, autoimmune diseases, and cessation of drugs that may have triggered this disease.

Patient Information

Microangiopathic hemolytic anemia (MAHA) is a condition characterized by abnormal red blood cell shape and size, as well as their accelerated destruction. Red blood cells are damaged when they pass through a blood vessel that has a narrowed lumen due to the numerous thrombi partially occluding the vessel. This phenomenon is seen in diseases associated with abnormally high rates of coagulation, such as malignancies, various infections, autoimmune diseases, such as systemic lupus erythematosus, while it may also be seen after the use of certain drugs, and in patients who develop very high blood pressure suddenly. All these diseases induce the formation of thrombi, or blood clots, primarily in the smaller blood vessels, which impede normal blood flow, cause damage to red blood cells and lead to anemia. The main feature of MAHA is the presence of fragmented red blood cells called schistocytes, and their appearance on blood smear examination can be helpful in establishing the diagnosis. The clinical presentation of patients greatly varies, and primarily depends on the underlying cause. However, fatigue, malaise, and fever are present in virtually all patients, while dehydration, rash, altered mental state, diarrhea, vomiting, abdominal pain, dark urine and many other symptoms may also be present. The diagnosis is made after performing a thorough diagnostic panel, including complete blood count, which will reveal anemia and low platelet count (since they are all used up in the process of clot formation). Additionally, kidney function tests may be abnormal, bilirubin levels are high, and enzymes that show accelerated cellular degradation may be elevated, such as lactate dehydrogenase (LDH). Treatment is directed at the underlying cause. Antibiotics should be given in the case of infection, immunosuppressive therapy is indicated in the management of SLE and other autoimmune diseases, while appropriate therapy against malignant tumors is indicated. Plasma exchange therapy is used in the majority of patients as it eliminates harmful substances from the body, and attempts to restore the coagulation process back to normal. The prognosis depends on the cause, and the time of diagnosis, which is why an early diagnosis is vital in managing patients with MAHA.

References

Article

  1. Symmers WSC. Thrombotic Microangiopathic Haemolytic Anaemia. British Medical Journal. 1952;2(4790):897-903.
  2. Bull BS. Microangiopathic Hemolytic Anemia. California Medicine. 1972;116(5):49-50.
  3. George JN, Charania RS. Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia. Semin Thromb Hemost. 2013;39(2):153-60.
  4. Booth KK, Terrell DR, Vesely SK, George JN. Systemic infections mimicking thrombotic thrombocytopenic purpura. Am J Hematol 2011;86(9):743-751.
  5. Zhang B, Xing C, Yu X, et al. Renal Thrombotic Microangiopathies Induced by Severe Hypertension. Hypertens Res. 2008;31(3):479-83.
  6. Stroncek DF, Vercellotti GM, Hammerschmidt DE, et al. Characterization of multiple quinine-dependent antibodies in a patient with episodic hemolytic uremic syndrome and immune agranulocytosis. Blood. 1992;80(1):241-248.
  7. Said T, Al-Otaibi T, Al-Wahaib S , et al. Posttransplantation calcineurin inhibitor-induced hemolytic uremic syndrome: single-center experience. Transplant Proc. 2010;42(3):814-816.
  8. Eremina V, Jefferson JA, Kowalewska J , et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358(11):1129-1136.
  9. Humphreys BD, Sharman JP, Henderson JM , et al. Gemcitabine-associated thrombotic microangiopathy. Cancer. 2004;100(12):2664-2670.
  10. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012;91(4):195-205.
  11. Wilde JT, Robert KM, Greaves M, et al. Association between necropsy evidence of disseminated intravascular coagulation and coagulation variables before death in patients in intensive care units. J Clin Pathol. 1988;41(2):138-142.
  12. Chang HG, Tserenpuntsag B, Kacica M, et al. Hemolytic Uremic Syndrome Incidence in New York Emerg Infect Dis. 2004;10(5):928-931.
  13. Schrier SL. Extrinsic nonimmune hemolytic anemias. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, et al., eds. Hematology: basic principles and practice. 3d ed. Philadelphia: Churchill Livingstone. 2000;630–8.
  14. Dhaliwal G, Cornett PA, Tierney LM JR. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-606.
  15. G Espinosa, S Bucciarelli, R Cervera, et al. Thrombotic microangiopathic hemolytic anemia and antiphospholipid antibodies. Ann Rheum Dis. 2004;63:730-736.
  16. Mintzer DM, Billet SN, Chmielewski L. Drug-Induced Hematologic Syndromes. Advances in Hematology. 2009;1-11.
  17. Clark WF, Hildebrand A. Attending Rounds: Microangiopathic Hemolytic Anemia with Renal Insufficiency. Clinical Journal of the American Society of Nephrology : Clin J Am Soc Nephrol. 2012;7(2):342-347.
  18. DN Gilbert, Chambers HF, Eliopulos GM et al. The Sanford Guide to Antimicrobial Therapy 2015. 45th ed. Antimicrobial Therapy, Inc, Sperryville, VA; 2015.

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Last updated: 2018-06-21 17:51