Mechanical hemolysis

What every physician needs to know about mechanical hemolysis:

Mechanical hemolysis is due to excessive mechanical forces that damage red blood cells (RBCs).

  • Hallmark: fragmented red cells or schistocytes

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  • Schistocytes are not as flexible as normal RBCs and are cleared from the circulation by the mononuclear phagocyte system

  • Large amounts of lactate dehydrogenase (LDH) are released into the blood from end organ and skeletal muscle damage while haptoglobin is consumed (why LDH is high and haptoglobin is low in these cases)

With history, mechanical hemolysis usually falls into the following major categories:

  • Conditions of rapid turbulent blood flow in the heart or major arteries (examples include: valve-induced hemolysis, aortic coarctation, and arteriovenous fistulas)

  • Athletic activities involving impact (i.e. march hemoglobinuria)

  • Small blood vessel disorders (thrombotic thrombocytopenic purpura [TTP], Hemolytic uremic syndrome [HUS], HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets], disseminated intravascular coagulation [DIC], malignant hypertension), secondary microangiopathic processes

What features of the presentation will guide me toward possible causes and next treatment steps:

Bleeding from oral, gastrointestinal (GI), or genitourinary (GU) tracts is common in all mechanical hemolytic processes if there are accompanying coagulation defects, platelet reductions or dysfunction.

Pallor, dark urine, bruising, petechiae, and purpura can be present.

Features can be divided more specifically as follows:

Valve-induced hemolysis

  • Worsening congestive heart failure

  • Worsening exercise tolerance, chest pain, or shortness of breath

  • Pallor

  • Icterus

  • Dark urine (urine that is dark during periods of physical activity and lighter while at rest, is a sign)

  • New, more intense, or a change in a pre-existing murmur

TTP/HUS

  • Classic pentad is fever, hemolytic anemia, thrombocytopenia, renal disease and neurologic involvement (very few cases have the classic pentad)

  • Only thrombocytopenia and hemolytic anemia are needed to make the diagnosis

  • Can be of acute or insidious onset

  • Renal failure occurs in less than 10% of cases

  • Neurologic findings can be transient or persistent and include headache, visual changes, seizures, coma, motor deficits, or confusion

  • Abdominal pain, nausea, and vomiting are common

  • Hepatomegaly and splenomegaly can be seen

  • Diarrhea can present in those with infectious HUS

Atypical HUS presents with microangiopathic haemolytic anemia, thrombocytopenia, and anuric renal failure.

March hemoglobinuria

  • History of running or intense high impact physical activity

  • Mild anemia

Kasabach-Merritt

  • Young childhood

  • Kaposiform hemangioendotheliomas on exam

HELLP syndrome

  • 27 to 37 weeks pregnant

  • History of preeclampsia or eclampsia increases chances

  • European descent

  • Multiparity

  • Older than 34 years of maternal age

  • 90% have malaise and right upper quadrant pain

  • Nausea and vomiting

  • Fever is not usually present

DIC

  • Oozing blood from GI, GU, or oral cavities

  • Purpura

  • Shock

  • Thromboembolism in all size blood vessels

  • Hepatic failure

  • Jaundice

  • Hypoxia

  • Coma

  • Adrenal insufficiency

  • Obstetrical emergencies (placental abruption, amniotic fluid embolism)

Secondary microangiopathic hemolytic anemia

  • Ticlopidine or clopidogrel use

  • History of malignancy, especially metastatic

  • History of autoimmune disorders

  • Malignant hypertension

  • Cocaine-induced

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

General tests

  • Complete blood count (CBC)

  • Kidney function testing

  • Liver function tests

  • Electrolyte testing

  • LDH-elevated

  • Reticulocyte count – elevated

  • Serum haptoglobin level-low

  • Prothrombin time (PT)

  • Activated partial thromboplastin time (aPTT)

  • Fibrinogen (differentiates TTP and DIC)

  • Fibrin split products

Tests specific to each diagnosis

Valve-induced hemolysis

  • Echocardiogram should be done to evaluate prosthetic valves

  • Red cells are usually normochromic and normocytic

  • Severity is correlated with severity of hemolysis (higher LDH, lower haptoglobin)

  • Urine will be dark and will show hemosiderinuria

  • Absent hemoglobinuria

TTP/HUS

  • 50% of patients have thrombocytopenia with a platelet count less than 20,000/uL

  • Normal PT, aPTT, and fibrinogen levels

  • Troponin-T levels are usually elevated

Complement testing should be done in atypical HUS.

In diarrhea-associated HUS testing for pathogens with Shiga toxin should be done including E. coli and Shigella.

HELLP syndrome

  • Low haptoglobin levels which usually return to normal 24 to 30 hours post partum

  • Aspartic acid transaminase (AST) and alanine transaminase (ALT) can be over 100 times normal

  • Alkaline phosphatase and bilirubin levels are usually two to three times normal

  • Liver enzymes return to normal 3 to 5 days post partum

  • Hepatic ultrasonography may show “geographical” areas of increased echogenicity

DIC

  • Low platelets

  • Decreased protease inhibitors (protein C, protein S, antithrombin)

  • Elevated PT, aPPT, and fibrin split products

  • Low fibrinogen

  • Signs of sepsis on labs (elevated white blood cell count, end organ damage)

What conditions can underlie the abnormality:

Valve-induced hemolysis

  • Endocarditis

  • Malfunctioning prosthetic valve

  • Anemia leading to increased cardiac output

  • Increased cardiac output from physical exertion

  • Heart failure

Microangiopathic hemolytic anemia

  • TTP

  • Atypical HUS

  • Escherichia coli 0157:H7 infection (Shiga toxin)

  • Secondary infections leading to DIC

  • Transplant related (graft-versus-host disease, tissue rejection)

  • Malignancy

  • Preeclampsia, eclampsia

  • HELLP syndrome

  • Lupus and other vasculitidies

  • Antiphospholipid syndrome

  • Ticlopidine/clopidogrel

  • Quinine

  • Cyclosporine (dose related)

  • Tacrolimus (dose related)

  • Malignant hypertension

  • HIV

  • Snake venoms

  • Cocaine (rare cases)

  • Kasabach-Merritt (giant hemangiomas)

DIC

  • Sepsis

  • Trauma

  • Extensive surgery

  • Malignancy

  • Acute promyelocytic leukemia

  • Trousseau’s syndrome with solid tumor

  • Obstetrical complications

  • Amniotic fluid embolism

  • Placental rupture

  • Septic abortion

  • Dead fetus syndrome

  • Kasabach-Merritt syndrome

  • Acute hemolytic transfusion reactions

  • Bites from certain snakes

  • Heat stroke

  • Fulminant hepatic failure

  • Amphetamine overdose

  • Antiphospholipid syndrome

When do you need to get more aggressive tests?

Valve-induced hemolysis

Additional testing is not usually required but red cell labeling studies may show a shortened erythrocyte life span between 6 and 9 days. Marrow aspiration with show erythroid hyperplasia.

TTP/HUS

A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMSTS13) levels to detect acquired deficiency. Some forms of TTP do not lower ADAMSTS13 including autoimmune causes, quinine, and most malignancy associated TTP. If other conditions are suspected, then microbiologic and serologic testing for Shiga toxin-producing organisms, tests for antiphospholipid antibody syndrome, and autoimmune serologies may be needed.

HELLP syndrome

The patient should be admitted to the hospital and fetal monitoring should take place. Liver biopsy may be needed to differentiate a primary liver process if suspected.

DIC

Blood cultures, other blood work geared towards underlying cause.

What imaging studies (if any) will be helpful?

Valve-induced hemolysis

Echocardiogram of the heart and magnetic resonance imaging (MRI) of the kidneys can show decreased signal intensity in the renal cortex because of hemosiderin deposition.

TTP/HUS

Computed tomography (CT)/MRI of the brain to rule out another process in those with mental status changes. If secondary cause is the leading diagnosis, imaging geared towards that cause may be needed.

Renal imaging may need to be done in cases of HUS to differentiate from other renal pathology.

HELLP syndrome

CT of liver to evaluate for acute fatty liver of pregnancy or hepatic rupture.

DIC

Imaging studies to find underlying cause if unknown, or to look for bleeding in brain, lungs, or adrenal glands.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Valve-induced hemolysis

In severe hemolysis, emergent surgery for valve repair or percutaneous closure maybe necessary. Beta-blockade can help slow down the circulation in non-operative candidates

TTP/HUS

Emergent plasma exchange at one to one and a half times plasma volume daily is necessary to remove antibody inhibitors of the ADAMTS13 and replete the enzyme and should be started without delay in suspected cases. High dose glucocorticoids have also been shown to help and can be started immediately, for example, prednisone 1mg/kg/day. Rituximab can also be used in certain situations but is mainly used when plasma exchange and steroids do not work.

Typical HUS does not require specific treatment especially in the case of children. Supportive care with fluids is common.

In Atypical HUS, patients with complement H deficiency, eculizumab (a monoclonal protein against complement protein C5) has been shown to be effective for treatment and should be started as soon as a diagnosis is suspected to try to preserve renal function.

HELLP

Intravenous magnesium sulfate to prevent seizures and control hypertension should be started. Fetal monitoring should be done and in cases where fetal distress is present or if the gestational age is greater than 32 weeks, immediate delivery of the fetus will reverse HELLP syndrome within 72 hours of delivery.

DIC

Emergent correction of hypotension, acidosis, and hypoxia should be addressed first. After this, the underlying cause should be reversed to stop the DIC.

What other therapies are helpful for reducing complications?

Valve-induced hemolysis

Treating anemia, using beta-blockers, and valve repair help reduce complications, although post valve repair hemolysis can reoccur.

TTP

Once platelet count is greater than 50,000/uL, low dose aspirin should be started for thromboprophylaxis. Platelet transfusions are generally contraindicated! In refractory cases, immunosuppressive therapy such as Rituximab, Vincristine, cyclophosphamide, and even splenectomy can be used in refractory cases. Daily laboratory monitoring and continuous electrocardiographic monitoring decrease complications. Patients should also receive folic acid and vaccination for hepatitis B.

HELLP

Prompt delivery of the fetus will cure the disease. Prompt evaluation of fetal lung maturity and inducing fetal lung maturation with beclomethasone will speed up the delivery. Postpartum curettage helps lower mean arterial pressure and increases the platelet count. Transfusion therapy is indicated in those with severe deficits. Dexamethasone and plasma exchange can be used as adjunctive therapy if delivery is not possible.

DIC

In severe bleeding, plasma and platelet infusions are indicated to replenish factors and keep platelets above 20,000/uL. Activated protein C has been shown to show a slight mortality benefit in severe DIC. Heparin anticoagulation should be used with caution in those cases with thrombosis.

What should you tell the patient and the family about prognosis?

Valve-induced hemolysis

Even with valve repair, recurrence can occur.

TTP

Early treatment with plasma exchange results in a greater than 90% survival rate, without any complications. Patient may need prolonged corticosteroid therapy or plasma exchange. If these treatments do not work, then rituximab can be used to try to gain a response. Other medications such as danazol or cyclophosphamide can also be used.

Prognosis of typical and atypical HUS is good with high survival rates with supportive treatment or eculizumab. Kidney function can return to normal when eculizumab is started early. This is the key to try to preserve kidney function.

HELLP

Abnormalities improve 24 to 48 hours postpartum. Risk of recurrence with next pregnancy is possible.

DIC

Outcomes are good in those cases where the underlying cause can be treated. If the underlying cause is not found, the process usually is not reversed.

“What if” scenarios.

  • TTP can present in patients who are pregnant and look as though they have HELLP

  • Induction of delivery is crucial to resolve HELLP

If atypical HUS and TTP cannot be differentiated then plasma exchange should be promptly started.

  • Transfusions of platelets in TTP may make condition worse

  • Urgent use of second and third line treatments in refractory TTP helps prevent complications

  • Patients with DIC should first be stabilized, prior to workup or treatment of underlying causes.

  • The underlying disorder needs to be treated in patients with DIC

Pathophysiology

Valve-induced hemolysis

Shear is caused by a flowspeed difference (shear force). One side of a blood cell is exposed to a lower speed and the other side to a higher speed leading to fragmentation and hemolysis.

March hemoglobinuria

  • Plasma volume expansion

  • Mechanical destruction of RBCs from repetitive heel strikes

TTP

  • Deficiency of ADAMTS13 disintegrin and metalloprotease

  • Large multimers of von Willebrand factor accumulate and lead to platelet activation and clumping

  • Increased shear force leads to destruction of red blood cells

HUS

  • Shiga toxin

  • E.coli0517:H7

In atypical HUS it is due to a defect in complement H.

HELLP

Activation of coagulation cascade leads to fibrin deposition in the vessels. Shear force increases from pregnancy.

DIC

  • Endothelial and mononuclear cells release cytokines which in turn active tissue factor

  • Tissue factor actives coagulation on endothelial and mononuclear cells

  • Down regulation and inhibition of fibrinolysis by endothelial cells promotes intravascular fibrin deposition

  • Leading to consumption of platelets, fibrinogen, factors V and VIII, protein C, antithrombin, and components of the fibrinolytic system

What other clinical manifestations may help me to diagnose mechanical hemolysis?

History

  • Valve-inducted hemolysis

– Darker urine while active, clear urine at rest.

  • TTP

– The medication history will help differentiate secondary causes of hemolysis.

  • HUS

– Recent ingestion of undercooked meats especially hamburger. Recent ingestion of unclean produce such as spinach, unpasteurized apple juice, or swimming in pools or lakes that may have feces contamination will help with diagnosis.

  • DIC

– History of recent illnesses, recent allergic reaction, recent blood transfusion.

Examination

  • Hemangiomas

  • Petachiae or purpura

  • GI, GU, or oral bleeding

What other additional laboratory studies may be ordered?

Bone marrow biopsy may be helpful in unclear cases.

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