22: Microangiopathic Hemolytic Anemia (MAHA)

• Extrinsic hemolytic anemia occurs when normal red blood cells (RBCs) are prematurely destroyed by conditions outside the RBCs.
• Extrinsic hemolytic anemia is divided into nonimmune and immune causes.
• Nonimmune causes usually involve physical or mechanical injury to RBCs.
• Immune hemolytic anemia is mediated by antibodies, complement, or both.
• ADAMTS13 is an enzyme that regulates the size of von Willebrand factor (VWF) by cleaving ultralong VWF multimers (ULVWF) into shorter segments.
• Eclampsia is a life-threatening pregnancy complication with sudden seizures when no other neurological causes exist.
• Preeclampsia is a pregnancy condition with high blood pressure (hypertension) and high levels of protein in the urine (proteinuria).

Microangiopathic Hemolytic Anemia (MAHA)

• Microangiopathic Hemolytic Anemia (MAHA) involves RBC fragmentation and thrombocytopenia from mechanical destruction in the vasculature.
• RBCs are fragmented in small blood vessels due to turbulence caused by microthrombi or damaged endothelium.
• Fragmentation creates schistocytes, which are irregularly shaped RBC fragments.
• Fragmented RBCs undergo intravascular hemolysis.
• The spleen clears rigid fragments through extravascular processes.

Clinical Laboratory Findings

• Decreased hemoglobin and hematocrit
• Increased reticulocyte count
• Elevated serum indirect (unconjugated) bilirubin
• Increased lactate dehydrogenase (LD) activity
• Low serum haptoglobin
• Elevated urine urobilinogen
• Presence of schistocytes (RBC fragments) on a peripheral blood smear
• Typically shows thrombocytopenia

MAHA associations

• MAHA is common in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC).
• Urgent intervention is needed to address the underlying cause of MAHA

Thrombotic Thrombocytopenic Purpura

• Thrombotic thrombocytopenic purpura (TTP): Characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and elevated serum LD activity.
• Pathophysiology: Severe deficiency of ADAMTS13 leads to accumulation of ultra-large von Willebrand factor (ULVWF) multimers, promoting platelet adhesion and microthrombi formation.
• Clinical Symptoms: Abrupt onset of MAHA and thrombocytopenia, potential neurologic dysfunction, fever, and renal failure.
• Laboratory Findings: Anemia, thrombocytopenia, schistocytes on blood smear, reticulocytosis, normal coagulation tests, increased LD and bilirubin, decreased haptoglobin, and varying levels of ADAMTS13 deficiency.

Hemolytic Uremic Syndrome

• Hemolytic uremic syndrome (HUS): Characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure due to glomerular microvasculature damage.

Pathophysiology

• Thrombocytopenia: Decreased platelet count due to consumption in microthrombi formation.
• Acute Renal Failure: Caused by damage to the glomerular microvasculature in the kidneys

HUS Types:

• Stx-HUS induced by Shiga toxin-producing bacteria (e.g., E. coli O157:H7) following gastroenteritis.
• Atypical HUS (aHUS): Caused by dysregulation of the complement pathway, not linked to diarrhea, and may have genetic or autoimmune origins.
• MAHA, thrombocytopenia, and acute renal failure.

Clinical Features

• Symptoms: Symptoms of MAHA, mild-to-moderate thrombocytopenia, acute renal failure signs (elevated creatinine, proteinuria, hematuria, urinary casts).

Laboratory Findings

• Hemolysis Evidence: Schistocytes, elevated LD and bilirubin, decreased haptoglobin.
• Thrombocytopenia: Platelet count mildly to moderately decreased.
• Renal Dysfunction: Elevated serum creatinine and abnormal urinalysis.
• ADAMTS13 Levels: Normal.

HELLP Syndrome

• HELLP Syndrome is a complication in pregnancy, comprising hemolysis, elevated liver enzymes, and low platelet count, typically in the third trimester.

Pathophysiology

• Endothelial dysfunction, platelet activation, and microvascular injury lead to hemolysis, liver damage, and thrombocytopenia.
• Symptoms: Symptoms of MAHA, right upper quadrant or epigastric pain, nausea, vomiting, headache, hypertension, and proteinuria.
• Laboratory Findings: Thrombocytopenia, anemia with schistocytes, elevated LD and bilirubin, elevated liver enzymes (AST, ALT), and normal coagulation tests.

Disseminated Intravascular Coagulation (DIC)

Pathophysiology

• Widespread activation of the hemostatic system leads to fibrin thrombi formation in the microvasculature and consumption of platelets and coagulation factors.
• Secondary activation of fibrinolysis contributes to bleeding.

Result

• Obstruction of the microvasculature causes organ ischemia.

Clinical Features

• Symptoms: Vary based on dominant process (thrombosis vs. bleeding), organ ischemia, petechiae, ecchymoses, gastrointestinal or mucosal bleeding.

Laboratory Findings

• Decreased platelet count.
• Schistocytes on a peripheral smear (in approximately 50% of cases).
• Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT).
• Decreased fibrinogen level.
• Elevated D-dimer

Key Diagnostic Differentiators

• DIC is distinguished from other microangiopathies like HELLP syndrome or TTP by certain factors
• Prolonged coagulation times (PT, aPTT).
• Decreased fibrinogen.
• Elevated D-dimer.
• TTP: Distinguished by severe ADAMTS13 deficiency and neurologic symptoms; normal coagulation tests.
• HUS: Primarily involves renal failure, with typical cases often following bloody diarrhea (e.g., Stx-HUS).
• HELLP Syndrome: Occurs exclusively in pregnancy, with unique elevated liver enzymes and normal coagulation studies.

Traumatic Cardiac Hemolytic Anemia

Pathophysiology

• Mechanical hemolysis due to turbulent blood flow through or around prosthetic cardiac valves or damaged cardiac valves.
• RBCs are mechanically fragmented, producing schistocytes.
• Severe hemolysis can occur with paravalvular leaks in prosthetic valves and chronic urinary hemoglobin loss may lead to iron deficiency anemia.

Laboratory Features

• Blood Smear: Presence of schistocytes.
• Hemolysis Markers: Elevated serum lactate dehydrogenase (LD) and indirect bilirubin, increased free plasma hemoglobin, and decreased serum haptoglobin.
• Reticulocyte Count: Elevated.
• Platelet Count: Typically within the reference interval.

Exercise-Induced Hemoglobinuria

Pathophysiology

• Caused by mechanical trauma from repetitive physical impact.
• RBC lysis occurs due to stress on the membrane, oxidative damage, or alterations in cytoskeletal proteins during strenuous exercise.

Laboratory Features

• Hemolysis Markers: Elevated free plasma hemoglobin, decreased serum haptoglobin, and presence of hemoglobinuria after exercise.
• Peripheral Blood Smear: Schistocytes are absent except in rare cases.
• Reticulocyte Count: Slightly increased.

Plasmodium Life Cycle

Mosquito to Human

• An infected Anopheles mosquito bites a human, injecting sporozoites into the bloodstream.

Liver Stage

• Sporozoites travel to the liver and invade liver cells, multiplying into merozoites.
• Liver cells burst, releasing merozoites into the blood.

Blood Stage

• Merozoites infect red blood cells (RBCs).
• Developing through stages: Ring form → Trophozoite → Schizont.
• Schizonts release new merozoites, continuing the infection cycle.

Human to Mosquito

• When another mosquito bites the infected human, it ingests gametocytes.
• Gametocytes develop into gametes in the mosquito, undergo sexual reproduction, and eventually form sporozoites again

Specific Plasmodium

• P. vivax & P. ovale can only invade reticulocytes
• P. malariae can only invade older RBCs
• P. vivax requires Duffy antigens for RBC invasion
• P. falciparum & P. knowlesi can invade cells of all ages

P. falciparum Infection

Anemia

• The adherence of Infected RBCs to endothelial cells in the microvasculature in places such as the liver or spleen.
• Direct destruction of infected RBCs during the parasite's life cycle.
• Inflammation can suppress erythropoiesis in the bone marrow, exacerbating the anemia
• Chronic hemolysis can lead to iron depletion, further contributing to anemia.

Neurologic Manifestations

• Infected RBCs obstructing blood flow occurs
• Binding leads to obstruction of blood flow, disrupting oxygen delivery to brain tissues.
• Inflammatory Response: Cytokine release from endothelial cells and immune cells contributes to local inflammation and endothelial dysfunction.
• Microvascular Obstruction: Leads to cerebral ischemia, edema, and neurologic symptoms such as seizures, confusion, and coma.

Hemolytic Anemia: Pathophysiology, Labs and Morphology

Babesiosis

• Hemolytic anemia caused by Babesia that occurs due to parasitemia, splenic RBC destruction and systemic response.

Clostridial Sepsis

• Caused by Clostridium perfringens, which produces toxins that hydrolyze RBC membrane phospholipids, leading to hemolysis.
• Causes hemolysis and severe anemia occur

Bartonellosis

• Caused by Bartonella bacilliformis, which adheres to RBCs, leading to destruction.
• Progresses in two stages: acute hemolysis and Verruga Peruana (chronic cutaneous lesions).

Drugs, Chemicals, and Venoms

• Drugs, chemicals, and venoms can either disrupt the RBC membrane, trigger complement-mediated lysis, or initiate DIC, leading to hemolysis.

Thermal Injury (Burns)

• Extensive burns cause direct thermal damage to RBC membranes, leading to hemolysis.
• Elevated hemolysis markers (e.g., LDH, bilirubin).
• Hemoglobinuria and darkened urine may be observed in severe cases.