Hemolytic anemias due to physical injury to RBCs include:

• Microangiopathic hemolytic anemias (Fragmentation of RBCs when they pass through microvasculature containing thrombi. Schistocytes are seen in PS)
  • Thrombotic thrombocytopenic purpura
  • Hemolytic uremic syndrome/ Atypical hemolytic uremic syndrome
  • Preeclampsia/ Eclampsia with HELLP syndrome
  • Disseminated malignancy: Adenocarcinoma of GIT, breast or lung
  • Associated with malignancy
  • Vasculitis- Polyarteritis nodosa, Wagener's granulomatosis, acute glomerulonephritis, Rickettsia like infections
  • Systemic lupus erythematosus, scleroderma
  • Abnormalities of renal vasculature- Malignant hypertension, acute glomerulonephritis, scleroderma, allograft rejection
  • Disseminated intravascular coagulation
  • Malignant hypertension
  • Catastrophic APLA
  • Drugs- Cyclosporine, mitomycin, ticlopidine, clopidogrel, tacrolimus, cocaine
  • Systemic infections- Bacterial endocarditis, brucellosis, CMV, HIV, Adenovirus, herpes simplex virus, Ehrlichiosis, Rocky mountain spotted fever, E. Coli, Hepatitis, severe bacterial infections (meningococcus, pneumococcus), disseminated fungal infection
  • Total body irradiation
  • Snake bite
  • Pancreatitis
  • Organ transplantation and Allogeneic BMT
  • Drugs- Calcineurin inhibitors, Estrogen, mitomycin C, high dose chemotherapy, Ticlodipine, Quinine, quinidine, Ticlodipine, Simvastatin, INFα etc
• Physical injury at other sites (Schistocytes are seen in PS)
  • Atrioventricular malformations
  • Hemangioendotheliomas
  • Giant cavernous hemangiomas (KasabachMeritt syndrome)
  • Atrioventricular shunts
  • Transjugularintrahepaticportosystemic shunt
  • Cardiac abnormalities- Replaced valve, prosthesis, graft, regurgitant jets due to valvular abnormalities
  • March hemoglobinuria
• Physical injury to RBCs
  • Hypotonic lysis- Gain of large amounts of distilled water by IV infusion/ irrigation during surgery, near drowning, psychiatric polydipsia
  • Pore formation within RBC membrane by Bee/ Wasp sting, spider/scorpion bite
  • Cobra bite- Venom contains phospholipases which damage RBC membrane
  • Membrane damage by biotoxins- Bacillus cereus infection, sea cucumber/ sea anemone bites
  • Heat induced hemolytic anemia- Extensive burns, use of cell warmers, heat stroke (RBCs undergo budding and fragmentation at temperature of 120 degree F)
• Chemical injury to RBCs
  • Oxidizing agents- Hyperbaric oxygen, arsine gas, chlorates
  • Chemicals- Aniline, formaldehyde, hydroxylamine, lysol, mineral spirits, nitrobenzene
  • Metals- Lead, copper (Ingestion of copper sulphate, hemodialysis fluid contaminated by copper pipes, Wilson's disease)
  • Drugs- Ribavirin, phenazopyridine (urinary bladder analgesic)
• Anemia due to infections
  • Direct invasion of RBCs- Malaria, babesia, bartonella
  • Production of hemolysins- Cl. Perfingens
  • Septicemia/endocarditisby streptococci, staphylococci, salmonella and enterococci. Occurs due to direct toxic effect of bacterial product on RBCs.
  • Stimulation of immune response- Mycoplasma, HIV, CMV, EBV
  • Enhancing macrophage induced hemophagocytosis- Hemophilusinfluenzae
  • Microangiopathic hemolytic anemia- Shigella, camphylobacter, aspergillus
  • Induction of hypersplenism

HELLP syndrome

Introduction:

• HELLP stands for "Hemolysis, Elevated Liver enzyme, Low platelets"

Epidemiology:

• Occurs in 0.5% of all pregnancies
• Seen in 4-12% of pregnancies complicated by preeclampsia (Hypertension with proteinuria)
• Seen in 30-50% of pregnancies complicated by eclampsia(Hypertension with proteinuria- >300mg/24hrs and seizures)
• 2/3rd are diagnosed between 27-37 weeks of gestation
• Rest 1/3rd cases are diagnosed during post-partum period (up to 48 hrs after delivery)

Risk factors:

• European descent
• Multiparity
• Old maternal age 
• Chronic hypertension/ diabetes mellitus/ autoimmune disease

Pathogenesis:

Trophoblastic cells fail to properly penetrate spiral arteries of uterus

(?due to decreased placental expression of syncytin)

↓

Poorly perfused hypoxic placenta

↓

Release of soluble form of fms-like tyrosine kinase 1 (Soluble VEGF Receptor)

↓

Inhibition of effect of VEGF and angiogenesis

↓

Glomerular endothelial cell and placental endothelial cell dysfunction

↓

Increased vascular tone with hypertension

Proteinuria

Concurrent activation of coagulation system leading to platelet-fibrin deposition within capillaries- this leads to microangiopathic hemolytic anemia

↓

Multi-organ microvascular injury

Hepatic necrosis

Thrombocytopenia

Grading:Mississippi triple class system

Clinical Features:

• Malaise
• Right upper quadrant epigastric pain
• Nausea, vomiting
• Edema
• Headache
• Hypertension
• Seizures 

Complications:

• Rupture of liver
• Shock
• DIC
• Cerebrovascular accident
• Acute renal failure
• Eclampsia
• Pulmonary edema
• Retinal detachment
• Diabetes insipidus
• Perinatal death due to placental abruption or asphyxia

Investigations:

• Peripheral smear: Schistocytes, helmet cells, Burr cells, thrombocytopenia
• Reticulocyte count- Increased
• LDH- Increased (Usually >600U/dL) 
• S. Haptoglobin- Decreased
• Liver enzymes- Increased to more than 100 times. Return to normal 3-5 days after delivery
• PT, APTT- Normal
• D-dimer- Increased
• Liver USG- Large, irregular, well demarcated (geographical) areas of increased echogenicity 

Prognosis:

• Most patients stabilize within 24-48hrs following delivery 
• MODS/ IC bleed/DIC are associated with high risk of death
• Maternal mortality rate- 1-24%

Differential Diagnosis:

• TTP/HUS
• Sepsis
• DIC
• Connective tissue disease 
• APLA
• Acute fatty liver of pregnancy- Enzymes are elevated up to 5 times normal and PT/APTT are prolonged

Treatment:

• IV Magnesium sulphate- To control hypertension and decrease seizures
• Manage fluid and electrolytes
• Control of blood pressure
• Judicious transfusion of blood products
• Stimulation of fetal lung maturity by beclomethasone
• Delivery of fetus as early as possible 
  • >34 weeks deliver immediately
  • <34 weeks- Steroids to accelerate fetal lung maturation. Consider waiting if maternal and fetal status are reassuring.
• If HELLP, additional measures include
  • Inj. Dexamethasone- 10mg- IV- 12 hrly- Increases platelet count. Continue for at least 2days after delivery of recovery of counts
  • Plasma exchange in severe cases
  • Liver transplantation for hepatic necrosis 

Acute fatty liver of pregnancy

• It is rare, but a serious condition, seen in third trimester
• Seen usually in primiparas
• Clinical features
  • Nausea, vomiting
  • Right upper quadrant pain
  • Anorexia
  • Jaundice
  • Cholestatic liver function
  • Hypoglycemia- Seen in 50% of cases
• Characterized by
  • Elevated liver enzymes
  • Elevated conjugated bilirubin (Usually >5mg/dL)
  • Coagulopathy including thrombocytopenia
• Difficult to differentiate from HELLP
• Treatment-
  • Delivery of fetus
  • Supportive management

Disseminated Malignancy

Etiology:

• Usually mucinousadenocarcinomas of stomach, breast, and lungs
• Rarely due to other adenocarcinomas- Prostate, colon, gall bladder, pancreas, ovary
• Other malignancies- Hemangiopericytoma, hepatoma, melanoma, small cell carcinoma of lung, testicular cancer etc

Pathogenesis:

Circulating carcinoma mucins interact with leucocyte L Selectin and platelet P Selectin

↓

Excessive exposure to tissue factor on activated endothelial cells

↓

DIC with partial microvascular occlusion by platelet fibrin thrombi

↓

Microangiopathic hemolytic anemia

Investigations:

• Hemogram
  • Moderate to severe anemia
  • Schistocytes- 5-20% of RBCs
  • Burr cells, microspherocytes
  • Reticulocytosis
  • Nucleated RBCs
  • Leucoerythroblastic blood picture
  • Thrombocytopenia
  • Normal to high WBC count with immature myeloid precursors
• S. Unconjugatedbilirubin- Increased
• S. LDH- Increased
• S. Haptoglobin- Decreased
• DCT- Negative
• Bone marrow
  • Erythroid hyperplasia
  • 55% cases show presence of cancer cells
• Features of DIC may be found 

Prognosis:

• Life expectancy- 2-150days (Average- 21 days) 

Differential Diagnosis: Other causes of anemia in malignancies

• Anemia of chronic inflammation
• Blood loss
• Myelophthisis
• AIHA (in LPDs)
• Chemotherapy induced anemia

Treatment:

• Drugs which have been tried without success
  • Heparin
  • Glucocorticoids
  • Dipyridamole
  • Indomethacin
  • Aminocaproic acid
• Transfusion support
• Control of underlying malignancy 

Heart Valve hemolysis

Epidemiology:

• Incidence has drastically decreased due to use of newer generation prosthesis
• Now seen in less than 1% patients. But compensated hemolysis is seen in almost every patient. 
• Common causes for cardiac valve hemolysis include- calcific/ stenotic native valves, prosthetic valve dysfunction and perivalvular leak.
• Other causes of hemolysis include- ruptured chordate tendineae, aortic aneurysm, patch repair of cardiac defect, intraventricular assist devices and aortic balloon pumps.

Pathogenesis:

RBCs traverse the turbulent flow through or around the prosthetic valve

↓

Erythrocyte shearing and impaction against foreign substance/cardiac structures

↓

Fragmentation

Factors that increase the chances of hemolysis:

• Presence of central/ paravalvular regurgitation
• Placement of small valve prosthesis with resultant high transvalvular pressure gradients
• Regurgitation due to bioprosthetic valve failure
• Mechanical valves
• Double valve replacement 

Clinical Features:

• Anemia
• Icterus
• Dark urine after period of physical exercise
• Appearance of new murmur 

Grading:

Investigations:

•  Peripheral smear:
  • Moderate poikilocytosis, schistocytes are seen
  • Polychromasia
  • Normocytic normochromic anemia
• Features of intravascular hemolysis
• BM- Erythroid hyperplasia

Differential Diagnosis:

• Anemia of chronic disease due to endocarditis
• Anticoagulant induced GI bleed
• Nutritional deficiency 

Treatment:

• Iron and folate supplementation if deficient
• Surgical repair or replacement of malfunctioning prosthesis
• Other therapies tried
  • Beta-blockers to slow down the velocity of circulation
  • Erythropoietin to further stimulate erythropoiesis
  • Pentoxyphylline- 400mg- PO-TID- Increases deformability of RBCs
• Cholecystectomy for symptomatic cholelithiasis

Hemolysis due to cardiopulmonary bypass

• Post-perfusion syndrome: Characterized by intravascular hemolysis and leucopenia.
• Pathogenesis: Activation of complement pathway as the blood passes through the oxygenator. 
•  It presents with 
  • Fever
  • Acute respiratory distress
  • Acute kidney injury due to free hemoglobin in plasma
• Treatment: Supportive care till situation corrects itself.

March hemoglobinuria (Foot strike hemolysis)

• Presents with
  • Passage of dark colored urine after physical exertion in upright position
  • Nausea, abdominal cramps, aching in back/legs
  • Burning sensation in soles
• Pathogenesis: Red cell trauma within vessels of soles of feet during prolonged marching
• Severity of problem depends on 
  • Hardness of running surface
  • Distance of run
  • Heaviness of athletes stride
  • Protective adequacy of foot wear
• Prevention: Padded insoles

Kasabach Merritt phenomenon

• It is caused by enlarging Kaposiformhemangioendothelioma or tufted angioma (which is a locally aggressive tumor)
• It is characterized by
  • Thrombocytopenia
  • Microangiopathic hemolytic anemia
  • Consumptive coagulopathy
  • Hypofibrinogenemia
• Pathogenesis:
  • Endothelial cell abnormalities and vascular stasis leads to activation of platelets and clotting factors. This results in depletion of clotting factors and platelets. When RBCs traverse through tumor's abnormal, partial blocked channels, it leads to microangiopathic hemolytic anemia.
• Mortality- 30%
• Treatment- 
  • Surgical excision
  • For non-resectable tumors following may be tried- Glucocorticoids, interferon alpha, antifibrinolytic therapy, aspirin, LMWH, embolization, radiation, laser therapy, chemotherapy with vincristine/cyclophosphamide