Microangiopathic Hemolytic Anemia

Question 1

What are the types of microangiopathic hemolytic anemia? What is the general presentation?

Answer 1

• As previously stated, microangiopathic hemolytic anemia anemia (MAHA) describes mechanical destruction of red blood cells as they circulate, resulting in hemolysis
• Patients will have signs of hemolytic anemia on laboratory evaluation, including:
  
  • low hemoglobin
  • elevated bilirubin
  • high lactate dehydrogenase (LDH)
  • low haptoglobin
• Many of the specific causes of MAHA- including TTP & DIC- are also associated with thrombocytopenia
  
  • Despite the low platelets that can accompany MAHA, part of the pathology is actually thrombosis and not necessarily bleeding
  • The thrombosis typically involves the microvasculature, which can result in widespread organ dysfunction, including renal impairment and stroke
• Bleeding can occur especially with DIC if it occurs rapidly and normal compensatory mechanisms are overwhelmed
  
  • This can set up a complicated picture of concomitant bleeding and thrombosis, and makes treatment extremely difficult

Question 2

What are the situations where MAHA can arise?

Answer 2

• Idiopathic, autoimmune TTP
• Hemolytic Uremic syndrome (HUS)
• Familial deficiency of ADAMTS13
• Medication related
  
  • Post-solid organ transplant with immunosuppressive agents such as calcineurin inhibitors
  • Chemotherapeutic agents: mitomycin, bleomycin, cisplatin, gemcitabine
  • Ticlopidine & clopidogrel (anti-platelet agents used primarily in cardiovascular disease)
  • Quinine
• Post-allogeneic stem cell transplant
• Pregnancy
• Disseminated intravascular coagulation (DIC; covered below)
• Vasculitis (as seen in conditions such as lupus)

Question 3

What is the mechanism of MAHA?

Answer 3

• Unfortunately, the mechanism for MAHA has only been worked out for few of these conditions, specifically:
  
  • idiopathic
  • autoimmune TTP
  • HUS
  • familial deficiency of ADAMTS13 protein
  • and DIC
• The lack of understanding of why MAHA complicates some patients post-stem cell transplant, or with some medications listed above, has greatly limited treatment options

Question 4

What is the etiology and pathophysiology of TTP?

Answer 4

• The term “TTP” is often used interchangeably with MAHA, but this is not accurate and can be misleading
• Idiopathic, autoimmune TTP is a rare, specific condition whereby an antibody develops against ADAMTS13, a metalloproteinase that cleaves von Willebrand’s protein
  
  • Without cleaving of von Willebrand’s factor, large multimers of the protein are exposed to the circulation, and allow for inappropriate platelet aggregation
  • Red blood cells passing through can be mechanically sheared by the platelet strands
  • The result is:
    
    • thrombocytopenia
    • microvascular occlusion
    • MAHA
• Pathophysiology
  
  • There is inappropriate platelet activation & aggregation in endothelium
  • Microangiopathic hemolytic anemia: occurs when red blood cells get sheared as they cross platelet strands (like a jelly donut getting pushed through piano strings)
  • Deficiency (familial form) and/or antibody (autoimmune form) to ADAMTS13
    
    • ADAMTS 13 is a metalloproteinase that cleaves von Willebrand’s factor (vWF)
    • Without ADAMTS13, there is no cleaving of vWF, which causes platelet activation & consumption
    • Platelets aggregate & form strands on vWF in the vasculature
    • Unclear what triggers process in most cases

Question 5

What are the clinical findings of TTP?

Answer 5

• Classic “pentad”: do not necessarily see all 5 of the pentad to make the diagnosis
  
  • You need at least thrombocytopenia and microangiopathic hemolytic anemia both present in order to qualify as having TTP
  • The other 3 presenting findings can be seen, but do not have to be seen, for the diagnosis to be made.
• The Pentad:
  
  • Thrombocytopenia, often severe
  • Microangiopathic hemolytic anemia
  • Renal insufficiency/failure
  • Mental status changes
  • Fever
• Clinical symptoms:
  
  • bruising
  • petechiae
  • mucosal bleeding
• Labs:
  
  • Low platelet count
  • Anemia
  • Elevated LDH
  • Low haptoglobin
  • Often: elevated creatinine
• Peripheral blood smear:
  
  • Low platelets
  • Red blood cell fragments (known as schistocytes)

Question 6

What is the treatment of TTP?

Answer 6

• Treatment (idiopathic/autoimmune)
  
  • Therapeutic plasma exchange (TPE)
    
    • Removes ADAMTS 13 antibody
    • Replenishes ADAMTS 13 protein
    • IgG mediated process: requires several TPE treatments, variable by patient
  • Corticosteroids: often given, unclear efficacy
  • Rituximab: limited data, but often given in patients who relapse
  • Other immunosuppression: given to patients who relapse despite above
• Treatment - Familial: since this due to a deficiency and is not immune-mediated, plasma exchange is not necessary
  
  • Infusion of fresh frozen plasma on a regular basis (often once monthly) replaces the missing ADAMTS protein

Question 7

What is the pathophysiology and presentation of hemolytic uremic syndrome (HUS)?

Answer 7

• HUS can be difficult to distinguish from TTP.
• The end result is essentially the same:
  
  • platelet activation and consumption
  • thrombocytopenia and hemolytic anemia
• A toxin that directly damages endothelial cells precipitates the process
  
  • The Shiga-toxin from E coli 0157:H7 that can lead to bloody diarrhea can lead to endothelial damage, resulting in platelet adhesion and subsequent trapping and destruction of red blood cells
• Renal dysfunction is very common in HUS
• Even though patients experience microangiopathic hemolytic anemia and thrombocytopenia, therapeutic plasma exchange is often not beneficial as the pathology is different

Question 8

What is the treatment of hemolytic uremic syndrome (HUS)?

Answer 8

• Largely supportive:
  
  • transfusions
  • electrolyte balance
  • dialysis
  • blood pressure control
• Antibiotics and antimotility agents do not prevent progression to HUS with enterohemorrhagic diarrhea (& may actually increase risk for HUS), and therefore NOT recommended
• TPE not beneficial
• Eculizumab may be helpful in severe cases with CNS involvement

Question 9

What are some general features of disseminated intravascular coagulation?

Answer 9

• DIC, also known as a “consumptive coagulopathy,” is a process that occurs in a number of different pathologic situations, including:
  
  • overwhelming infections
  • trauma
  • obstetric complications
• There is introduction of a procoagulant into the circulation that results in widespread, systemic activation of the coagulation cascade, in addition to platelet activation and aggregation
  
  • The result is fibrin-platelet deposition throughout the circulation resulting in microvascular occlusion & often organ dysfunction
• Patients have varying degrees of thrombocytopenia and coagulopathy from consuming the clotting proteins
  
  • If the process happens rapidly, whereby the liver and bone marrow are not able to keep up with production of coagulation proteins and platelets, respectively, patients can have severe bleeding in addition to microvascular occlusion
• The presence of both thrombosis and bleeding can make treatment of DIC extremely difficult
  
  • Targeting the underlying cause of the DIC process is key (eg, treating the infection)
• The fibrin-platelet strands in the microcirculation can result in red blood cell shearing as they circulate
  
  • However, it is important to note that MAHA does not always accompany DIC

Question 10

What is the etiology and pathophysiology of DIC?

Answer 10

• Widespread pathologic generation of thrombin, platelet activation, leading to consumption, microvascular occlusion & consumption of clotting proteins and platelets
  
  • Causes multiorgan dysfunction from microscopic thrombotic occlusion
    
    • Strokes
    • Kidney failure
    • Skin sloughing
    • Liver impairment, etc.
  • Consumption of clotting proteins and platelets as above
  • Proteolytic degradation of hemostatic elements
• Pathophysiology
  
  • Normal hemostatic regulation overwhelmed
  • Thrombin overproduction & fibrinolysis
    
    • Blood exposed to large amounts of TF → activation of extrinsic pathway
    • Large amount of thrombin→ consumption of coagulation proteins (“consumptive coagulopathy”)
    • Platelets bound & activated → aggregation with vascular occlusion, but also → thrombocytopenia
    • ↓ Antithrombin levels 2° binding to thrombin
    • When thrombin is overproduced in relation to the amount of plasmin present, it can → large vessel thrombosis
  • Plasmin is also generated
    
    • Fibrinolysis is therefore initiated
    • Together with consumption of clotting proteins & platelets, may cause bleeding

Question 11

What are some common causes of DIC?

Answer 11

• Associated conditions/Underlying causes
  
  • Infection (most common associated problem)
  • Trauma
  • Malignancy
  • Obstetrical complications
  • Burns
  • Vascular disorders

Question 12

What is the clinical presentation of DIC?

Answer 12

• Variable clinical expression - there is widespread thrombosis of microvasculature (so thrombotic problems), but with this, consumption of platelets/clotting proteins, increasing the risk for bleeding, as well.
  
  • Thrombosis and/or bleeding diathesis
  • The predominant clinical feature (clotting, bleeding) for each individual patient depends on complex balance thrombin production, consumption of clotting proteins, and initiation of thrombolysis
    
    • Fulminant DIC (ie, comes on suddenly) usually favors bleeding
    • Chronic DIC (ie, more indolent in presentation) usually favors thrombosis
  • Can see microangiopathic hemolytic anemia: breakdown of red blood cells as they pass through clots in microvasculature
• Clinical Features
  
  • Highly variable & often obscured by 1° disease
  • Widespread microthrombi → multiorgan system dysfunction
  • Bleeding, petechiae with severe thrombocytopenia and clotting factor consumption
  • Thrombosis of large vessels can also occur

Question 13

What are the lab findings of DIC?

Answer 13

• Evidence of coagulation protein consumption (prolonged PT/PTT/Thrombin Time (TT))
• Low fibrinogen
• Thrombocytopenia
• Elevated D-Dimer (by-product of cross-linked fibrin monomer degradation by plasmin)
• Evidence of microangiopathic hemolytic anemia on peripheral blood smear CAN be seen, but is not always seen

Question 14

What is the treatment of DIC?

Answer 14

• KEY: address & treat underlying disease
• Treatment of DIC itself largely supportive
• Blood products: Administer only if the patient is bleeding or at high risk for bleed
  
  • Platelets: administer prophylactically if <10K, or <50K and the patient is bleeding and/or requires a surgical procedure
  • Fresh Frozen Plasma (FFP): Administer if the patient is bleeding & there is a prolonged PT/PTT
  • Cryoprecipitate
    
    • Administer prophylactically if fibrinogen <50, or if it is <100 and there is bleeding/high bleeding risk
    • Cryoprecipitate is rich in vWF, FXIII, FVIII, fibrinogen
• Heparin/anticoagulation
  
  • Its use may increase bleeding risk in some patients
  • It can be used in DIC with thrombotic predomination (usually chronic)
    
    • So if a patient has DIC with a large clot (like a pulmonary embolism or DVT), then anticoagulation will often be used
• Activated protein C
  
  • PROWESS study (PROWESS is just the name of the study conducted) 2001: Showed there is a mortality benefit in patients with severe sepsis (mortality rates were 24.7 with activated protein C used, vs. 30.8% in those who did not receive it)
  • Major drawback of activated Protein C is increased bleeding risk
• Antifibrinolytics (such as ε-aminocaproic acid or aprotinin) are contraindicated in DIC due to thrombotic risks