Malignancy and Microangiopathic Hemolytic Anemia

Recently there was a morning report during which we discussed anemia in a patient with cancer.

We discussed that when there is a decrease in one of the cell counts, the first step is to look at the rest of the cell counts and to determine if there is a decrease in more than one cell count. This is important as it determines the differential diagnosis.

Isolated decrease in red blood cells (hemoglobin)	Anemia
Isolated decrease in platelets	Thrombocytopenia
Isolated decrease in white blood cell count	Leukopenia
Decrease in hemoglobin and platelets	Anemia and thrombocytopenia – Need to think about microangiopathic hemolytic anemia
Decrease in red blood cells (hemoglobin), platelets and white blood cell count	Pancytopenia

In this case, the hemoglobin and platelets had decreased from previous values.

As such, we are dealing with anemia and thrombocytopenia. This is important diagnostic information. There are a variety of disorders associated with anemia and thrombocytopenia including:

-          - Aplastic anemia

-          - Hypersplenism

-          - Marrow involvement with malignancy

-          - Autoimmune red blood cell and platelet destruction

-          - Folate or vitamin B12 deficiency

-          - Microangiopathic hemolytic anemia

Microangiopathic hemolytic anemia

  Microangiopathic hemolytic anemia is important to think about and rule out as it is a serious condition. The first step to assess for microangiopathic hemolytic anemia is to get a blood smear (also called blood film).

What are we looking for? Fragments! (aka schistocytes)

If there are fragments, it is consistent with a microangiopathic hemolytic anemia. Fragments are broken apart red blood cells; the red blood cells are broken apart in the intravascular system when there is damage and clot formation in blood vessels that the red blood cells get trapped in and ripped apart. There could also be other indicators of hemolysis including: elevated LDH, elevated indirect bilirubin, and decreased haptoglobin. It is not an immune related cause of hemolysis so the DAT (direct antiglobulin test) should be negative.

Differential Diagnosis of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia

Disease	Pathophysiology	Causes	Clinical Presentation
Disseminated intravascular coagulation	Thrombi formation within blood vessels, mechanical damage to red blood cells, thrombocytopenia, consumption of clotting factors	Infection/sepsis Malignancy Trauma Obstetrical complications Intravascular hemolysis (i.e. transfusion reaction, malaria)	MAHA Thrombocytopenia Bleeding and thrombosis Organ dysfunction
Thrombotic thrombocytopenic purpura (TTP)	ADAMTS13 deficiency, causing large multimers of von Willebrand factor	Hereditary Acquired	MAHA Thrombocytopenia Mental status changes Renal failure Fever
Hemolytic uremic syndrome (HUS)	Shiga toxin-mediated thrombotic microangiopathy	Enteric infection with a Shiga toxin-secreting strain of Escherichia coli or Shigella dysenteriae	MAHA Thrombocytopenia Renal failure More common in children
Pregnancy related: HELLP syndrome, eclampsia	Unclear – may be related to preeclampsia and abnormal placental function	Obstetrical complication	Hemolysis Elevated liver enzymes Low platelets Proteinuria Hypertension RUQ pain, N+V Headache, visual changes
Hypertensive Emergency	Unclear – endothelial injury à fibrin strand formation à trapping and shearing of RBCs and plts	Severe hypertension	MAHA Thrombocytopenia Severe hypertension +/- renal dysfunction

Blood work in different causes of Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia

Disease	Hb	Platelets	Blood film	INR/PT	PTT	Other
Disseminated intravascular coagulation (DIC)	↓	↓	Schistocytes (often 0.5-1%)	Elevated	Elevated	High d-dimer Low fibrinogen
Thrombotic thrombocytopenic purpura (TTP)	↓	↓	Schistocytes	Normal	Normal	Normal d-dimer Normal fibrinogen +/- renal insufficiency Abnormally low ADAMTS13 activity
Hemolytic uremic syndrome (HUS)	↓	↓	Schistocytes	Normal	Normal	Normal d-dimer Normal fibrinogen AKI/Renal failure
HELLP syndrome	↓	↓	Schistocytes	Normal	Normal	Elevated liver enzymes

For further reading: George J and Nester C. Syndromes of Thrombotic Microangiopathy. NEJM. 2014;371(7):654-66.