What every physician needs to know about mechanical hemolysis:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie the abnormality:
- When do you need to get more aggressive tests?
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
“What if” scenarios.
- What other clinical manifestations may help me to diagnose mechanical hemolysis?
What other additional laboratory studies may be ordered?
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
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:
Worsening congestive heart failure
Worsening exercise tolerance, chest pain, or shortness of breath
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
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.
History of running or intense high impact physical activity
Kaposiform hemangioendotheliomas on exam
27 to 37 weeks pregnant
History of preeclampsia or eclampsia increases chances
Older than 34 years of maternal age
90% have malaise and right upper quadrant pain
Nausea and vomiting
Fever is not usually present
Oozing blood from GI, GU, or oral cavities
Thromboembolism in all size blood vessels
Obstetrical emergencies (placental abruption, amniotic fluid embolism)
Secondary microangiopathic hemolytic anemia
Ticlopidine or clopidogrel use
History of malignancy, especially metastatic
History of autoimmune disorders
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Complete blood count (CBC)
Kidney function testing
Liver function tests
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
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
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.
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
Decreased protease inhibitors (protein C, protein S, antithrombin)
Elevated PT, aPPT, and fibrin split products
Signs of sepsis on labs (elevated white blood cell count, end organ damage)
What conditions can underlie the abnormality:
Malfunctioning prosthetic valve
Anemia leading to increased cardiac output
Increased cardiac output from physical exertion
Microangiopathic hemolytic anemia
Escherichia coli 0157:H7 infection (Shiga toxin)
Secondary infections leading to DIC
Transplant related (graft-versus-host disease, tissue rejection)
Lupus and other vasculitidies
Cyclosporine (dose related)
Tacrolimus (dose related)
Cocaine (rare cases)
Kasabach-Merritt (giant hemangiomas)
Acute promyelocytic leukemia
Trousseau’s syndrome with solid tumor
Amniotic fluid embolism
Dead fetus syndrome
Acute hemolytic transfusion reactions
Bites from certain snakes
Fulminant hepatic failure
When do you need to get more aggressive tests?
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.
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.
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.
Blood cultures, other blood work geared towards underlying cause.
What imaging studies (if any) will be helpful?
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.
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.
CT of liver to evaluate for acute fatty liver of pregnancy or hepatic rupture.
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?
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
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.
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.
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?
Treating anemia, using beta-blockers, and valve repair help reduce complications, although post valve repair hemolysis can reoccur.
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.
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.
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?
Even with valve repair, recurrence can occur.
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.
Abnormalities improve 24 to 48 hours postpartum. Risk of recurrence with next pregnancy is possible.
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
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.
Plasma volume expansion
Mechanical destruction of RBCs from repetitive heel strikes
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
In atypical HUS it is due to a defect in complement H.
Activation of coagulation cascade leads to fibrin deposition in the vessels. Shear force increases from pregnancy.
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
- Darker urine while active, clear urine at rest.
- The medication history will help differentiate secondary causes of hemolysis.
- 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.
- History of recent illnesses, recent allergic reaction, recent blood transfusion.
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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