Autoimmune hemolytic anemia differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Overview

A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The diagnosis of autoimmune hemolytic anemia can sometimes be made by first ruling out these other causes. It is important to distinguish amongst these conditions since the prognosis and treatment of each condition is different.

Differentiating Autoimmune hemolytic anemia from other Diseases

Differential diagnosis of "Bleeding disorders":

Category	Sub-category	Diseases		History	Clinical manifestation					Laboratory testing					Comments
					Petechia|Petechiae	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Platelet count	Bleeding time (BT)	Prothrombin time (PT)	Activated partial thromboplastin time (aPTT)	Thrombin time (TT)
Platelet disorders	Thrombocytopenia	Infection-Induced thrombocytopenia		History of prior infection	+	+	+	+	+	↓	↑	N	N	N	-
		Medications-Induced thrombocytopenia		History of medications such as: Furosemide Nonsteroidal anti-inflammatory drugs (NSAIDs) Penicillin Quinidine Quinine Ranitidine Sulfonamides Linezolid	+	+	+	+	+	↓	↑	N	N	N	Most important par of treatment is discontinuing of the medication.
		Heparin-Induced thrombocytopenia		Thrombosis Unexplained thrombocytopenia up to 3 weeks after the end of heparin therapy	+	+	+	+	+	↓	↑	N	N	↑	For more information click here: Heparin-induced thrombocytopenia.
		Immune Thrombocytopenic Purpura (ITP)		History of prior infection or no history	+	+	+	+	+	↓	↑	N	N	N	-
		Inherited Thrombocytopenia		Family history	+	+	+	+	+	↓	↑	N	N	N	-
		Thrombotic Thrombocytopenic Purpura (TTP)		History of: Cancer Bone marrow transplantation Pregnancy Medication Platelet aggregation inhibitors (ticlopidine and clopidogrel) Immunosuppressants (cyclosporine, mitomycin, tacrolimus/FK506, interferon-α) HIV-1 infection	+	+	+	+	+	↓	↑	N	N	N	-
		Hemolytic Uremic Syndrome		History of: Infections Malignancy, cancer chemotherapy and ionizing radiation Calcineurin inhibitors and transplantation Pregnancy, HELLP syndrome and oral contraceptive pill Systemic lupus erythematosis and antiphospholipid antibody syndrome Glomerulopathy Familial, not included in part 1	+	+	+	+	+	↓	↑	N	N	N	-
	Thromobcytosis	Iron deficiency anemia Inflammatory diseases Splenectomy Essential thrombocytosis		Digital pain Gangrene Erythromelalgia Headache Paresthesias Transient ischemic attacks	−	−	−	+/-	+/-	↑	Ν/↑	ɴ	ɴ	N	-
	Qualitative Disorders of Platelet Function	Inherited Disorders of Platelet Function	Glanzmann’s thrombasthenia	Positive family history	+	+	+	-	Rare	N/↓	↑	ɴ	ɴ	N	AR inheritance Absence of the platelet Gp IIb/IIIa receptor/ Diminished for GP 2B-3A on flow cytometry
			Bernard-Soulier syndrome	Positive family history	+	+	+	-	-	N/↓	↑	N	N	N	AR inheritance Absence of the platelet Gp Ib-IX-V receptor On PBS: giant platelets Ristocetin - no aggregation
			Platelet storage pool disorder (SPD): Hermansky-Pudlak syndrome Chediak-Higashi syndrome Gray platelet syndrome	Positive family history Hairy-cell leukemia Cardiovascular bypass	+	+	+	-	-	N/↓	↑	N	N	N	AD inheritance Abnormalities of platelet granule formation
		Acquired Disorders of Platelet Function	Uremia Cardiopulmonary bypass Hematologic disorders such as: myeloproliferative and myelodysplastic syndromes	+	+	+	+/-	+/-	N/↓	↑	N	N	N	-
		Von Willebrand Disease		Easy bruising Epistaxis Oral cavity bleeding Bleeding after dental extraction/surgery Menorrhagia Postpartum hemorrhage	+	+	+	+/-	+/-	↑	Ν	↑	↑	N	See the table below for the details about types.
Vessel wall disorders	Metabolic and Inflammatory Disorders		Acute febrile illnesses Mixed cryoglobulinemia Monoclonal gammopathies Certain pathogens, such as the rickettsiae causing Rocky Mountain spotted fever Vitamin C deficiency Cushing’s syndrome Chronic glucocorticoid therapy Aging Vasculitis such as Henoch-Schönlein,	History of the underlying disease.	+	+	+/-	-	-	N	↑/N	N	N	N	-
	Inherited Disorders of the Vessel Wall		Marfan’s syndrome Ehlers-Danlos syndrome Pseudoxanthoma elasticum Hereditary hemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu disease)	Positive family history	+	+	+/-	-	-	N	↑/N	N	N	N	-
Coagulation factor disorders	Fibrinogen deficiency		Different types of the fibrinogen disorders: Congenital afibrinogenemia Congenital hypofibrinogenemia Fibrinogen storage disease Congenital dysfibrinogenemia Hereditary fibrinogen Aα-Chain amyloidosis Acquired dysfibrinogenemia Congenital hypodysfibrinogenemiaCryofibrinogenemia Acquired hypofibrinogenemia	Epistaxis Easy bruising Menorrhagia Muscle bleeds Hemarthrosis Bleeding from the umbilical cord stump after birth Bleeding after dental surgery or tooth extraction Abnormal bleeding during or after injury, surgery, or childbirth Gastrointestinal hemorrhage Cerebral hemorrhage Thrombosis	_	+	+	+/-	+	N	↑	↑	↑	↑	Impaired fibrin cross linking or clot dissolution. The severity of bleeding in patients with fibrinogen disorders can be mild or severe, with higher bleeding risk in those with afibrinogenemia or lower levels of functional fibrinogen. The age of onset is also variable, with earlier onset in those with more severe deficiency.
	Prothrombin deficiency			Easy bruising Epistaxis Soft-tissue hemorrhage Excessive postoperative bleeding Menorrhagia Muscle hematomas Hemarthrosis Intracranial bleeding	+	+	+	+	+	N	N	↑	↑	↑	-
	Factor V deficiency			Excessive bruising with minor injuries Epistaxis Hemarthrosis Menorrhagia Intracerebral hemorrhages Pulmonary hemorrhage	_	+	+	+	+	N	↑	↑	↑	N	The severity of bleeding is only partly related to the degree of factor V deficiency. Some patients with undetectable plasma levels of factor V experience only relatively mild bleeding.
	Factor VII deficiency			Easy bruising Mucosal bleeding Postoperative bleeding Menorrhagia Soft tissue hematomas Thrombosis			+	+	+	N		↑	N	N	Thrombosis occurs in inherited factor VII deficiency most cases are associated with the administration of factor VII replacement therapy
	Factor X deficiency			Prolonged bleeding following circumcision Easy bruising Hematuria Menorrhagia Abortion Postpartum hemorrhage Epistaxis Pseudotumors Intracranial bleeding Hemarthroses	+	+	+	+	+	N	N	↑	↑	N	-
	Factor XII deficiency			Majority,asymptomatic Recurrent miscarriages Painful leg ulcers	_	_	_	_	_	N	N	N	↑	N
	High molecular weight kininogen (HMWK) deficiency			Possibility of positive family history of bleeding	_	_	_	_	_	N	N	N	↑	N
	Prekallikrein deficiency			Possibility of positive family history of bleeding	_	_	_	_	_	N	N	N	↑	N
	Factor XIII deficiency		Types: Sub unit A mutation disease (more common) Sub unit B mutation disease	Possibility of positive family history of bleeding	-/+	-/+	-/+	-/+	-/+	N	N/	N/↑	N	N	Impaired fibrin cross linking or clot dissolution The severity of factor XIII deficiency bleeds can be different in different patients
	Hemophilia	Type A deficiency		Eeasy bruising Inadequate clotting in trauma or mild injury Spontaneous hemorrhage Hemarthrosis Epistaxis Gingival bleeding	_	_	+	+	+	N	N	N	↑	N	-
		Type B deficiency		Neonatal bleeding Trauma-related soft-tissue hemorrhage Hemarthrosis Hematomas	_	_	+	+	+	N	N	N	↑	N	-
		Type C deficiency		Family history Bleeding after surgery or injury	_	_	+	Rare	Rare	N	N	N	↑	N	-
Rare diseases	Disseminated Intravascular Coagulation		Trauma Burn Crush injury Sepsis Malignancy Obstetric complication: abruption, amniotic fluid embolism Hemolytic anemia	+	+	_	+	+	↓	↑	↑	↑	N	-
	Vitamin K Deficiency		Bleeding after trauma Epistaxis Hematoma Gastrointestinal bleeding Menorrhagia Hematuria Gum bleeding Oozing from venipuncture sites Easy bruisability	+	+	+	+	+	N	↑	↑	Normal or mildly prolonged	N	-

Different types of Von-Willebrand diseases can be differentiated from each other based on the following table:

Type of VWD		Type of factor deficiency	Prevalence	Inheritance pattern	Clinical manifestations	VWF activity	RIPA	Factor VIII
Type 1		Quantitative/ partial	60-70%	AD	Bleeding severity mild to severe	↓	↓	↓
Type 2	2A	Qualitative	10%	AD/AR	Moderate to severe bleeding	↓	↓	N or ↓
	2B	Qualitative	5%	AD	Thrombocytopenia Moderate to severe bleeding	↓	↑	N or↓
	2M	Qualitative	<1%	AD/AR	Moderate to severe bleeding	↓	↓	N or ↓
	2N	Qualitative	<1%	AR	Clinically similar to hemophilia A with joint, soft tissue, urinary bleeding	N	N	↓
Type 3		Complete deficiency	1-2%	AR	Clinically similar to hemophilia A with joint and soft tissue bleeding Severe mucosal bleeding	Absent	↓	Low, 1-10%

For more information on Von Willebrand disease click here

Characteristic	Causes	Pathophysiology	Laboratory abnormalities	Physical examination	Therapy	Other associations
Autoimmune hemolytic anemia	Abnormal immune activation Failure of self vs. non-self recognition Infections Chronic lymphocytic leukemia Non-Hodgkin's lymphoma Rheumatologic disease	Polyclonal antibody production that binds to and targets red blood cells for destruction intravascurly or extravascularly	Positive Coombs' test for IgG Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Pallor Jaundice Shortness of breath Tachypnea	Removal of offending agent Corticosteroids Cyclophosphamide Cyclosporine A Azathioprine Rituximab Splenectomy	Hemolysis can occur at warm or cold temperatures
Microangiopathic hemolytic anemia	Thrombotic thrombocytopenia purpura Hemolytic uremic syndrome Disseminated intravascular coagulation	Formation of small vessel microthombi	Schistocytes on peripheral blood smear Low hemoglobin Thrombocytopenia Elevated creatinine	Bleeding Thrombosis Pyrexia Altered mental status Neurologic deficits Impaired urine output	Treatment of the underlying cause Plasmapheresis if thrombotic thrombocytopenia purpura is the underlying cause	Can be life-threatening pending the underlying cause TTP required immediate treatment
Paroxysmal cold hemoglobinuria	Production of Donath-Landsteiner antibody, triggered by viral or bacterial infection	Biphasic hemolysin (IgG) that binds red blood cells and low temperatures and triggers complement-mediated intravascular hemolysis at warm temperatures	Positive Donath-Landsteiner antibody Microscopic hematuria Negative Coombs' test for IgG or C3d Negative cold agglutinin titer Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Hematuria in the presence of cold weather Jaundice	Removal of offending agent Steroids Alternative immunosuppression	Associated with syphilis Maternal IgG can cross the placenta and affect the fetus
Paroxysmal nocturnal hemoglobinuria	Genetic defect in anchoring proteins for complement factors on red blood cells	Hemolysis due to loss of complement inhibition on the red blood cell surface, which in turn is due to defect in CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) or other glycophosphatidylinositol-anchored proteins on the red blood cell membrane	Absence of CD55 and CD59 by flow cytometry	Splenomegaly Abdominal tenderness Pallor	Eculizumab Immunosuppressive therapy	Associated with myelodysplastic syndrome Associated with mesenteric and portal venous thrombosis Risk for progression to acute myeloid leukemia
Hereditary spherocytosis	Mutation in ankyrin Mutation in alpha- or beta-spectrin Mutation in band 3 Mutation in protein 4.2	Diminished membrane integrity Increased red blood cell fragility Splenic destruction of deformed red blood cells	Positive eosin-5-maleimide binding to red blood cells Positive osmotic fragility testing Spherocytes on peripheral blood smear	Pallor Jaundice Splenomegaly	Removal of offending medication High-dose vitamin B6 (up to 200mg daily) Avoidance of splenectomy Symptomatic transfusion support with iron chelation as needed	Can be autosomal dominant or recessive
Pernicious anemia	Autoimmune gastritis Production of anti-intrinsic factor antibodies Production of anti-parietal cell antibodies	Impaired vitamin B12 absorption due to absence of intrinsic factor	Low vitamin B12 level Presence of anti-intrinsic factor antibodies Presence of anti-parietal cell antibodies	Gastrointestinal discomfort Weakness Tingling Paresthesias	Lifelong vitamin B12 therapy (1000mcg daily)	Associated with diabetes, thyroid disease, vitiligo and other autoimmune conditions
Chronic lymphocytic leukemia	Mutations in hematopoietic stem cells and B lymphocytes	Clonal proliferation of malignant B lymphocytes	Elevated absolute lymphocyte count Anemia (Rai stage III) and thrombocytopenia (Rai stage IV)	Lymph node enlargement Splenomegaly in Rai stage II Hepatomegaly in Rai stage II Pallor Bleeding	Chemotherapy with rituximab Ibrutinib Venetoclax	Secondary autoimmune hemolytic anemia occurs in 10-25% of patients with CLL Treatment with corticosteroids or anti-leukemic therapy will correct the underlying anemia

References

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