. Review of peripheral
smear is diagnostic. 
Thrombocytopenia - Causes
Definition
A platelet count of less than the lower normal range for a particular lab (generally the normal platelet count for most laboratories is 130,000 to 400,000/mcL). For practical purposes, one should consider a platelet count of <100,000/mcL as a definition of thrombocytopenia.
Pathogenesis and Mechanism
Thrombocytopenia is caused by several mechanisms. The two most common ones are
decreased production in the bone marrow and increased destruction of platelets
(immune thrombocytopenia purpura, drug induced, etc) in the peripheral blood.
Thrombocytopenia due to dilution can occur in patients receiving multiple
transfusions or in pregnant women as a result of increased plasma volume.
Platelets are consumed in hypersplenism and disseminated intravascular
coagulation. Pseudo or spurious thrombocytopenia is a relatively common cause of
thrombocytopenia due to EDTA related platelet clumping
. Review of peripheral
smear is diagnostic.
Clumped platelets causing pseudothrombocytopenia.
Etiology
HIV and Thrombocytopenia:
About 40% of HIV patients have some degree of thrombocytopenia. In 10% of patients, low platelet count may be the initial manifestation. Primary HIV associated thrombocytopenia is the most common cause, due to increased destruction and ineffective production of platelets. Primary HIV associated thrombocytopenia may also be indistinguishable from immune thrombocytopenia purpura. Some HIV positive patients may have splenomegaly with subsequent platelet sequestration. The etiologies of thrombocytopenia in HIV are listed in Table 4.
Table 4. Etiology of thrombocytopenia in HIV patients.
Primary HIV associated thrombocytopenia
Hypersplenism
Opportunistic infections
Malignancy (Lymphoma, etc.)
Medications
TTP/HUS
Bone marrow problems (e.g. MDS)
TTP/HUS = Thrombotic thrombocytopenic purpura/Hemolytic Uremic Symptom
Sepsis and Thrombocytopenia:
Thrombocytopenia occurs in up to 20-35% of patients admitted to intensive care unit. Sepsis is responsible for half of these. There are several mechanisms involved: bone marrow suppression, EDTA related platelet clumping (pseudo thrombocytopenia), immune and non-immune disseminated intravascular coagulation destruction/consumption of platelets. There is an inverse relationship between the severity of sepsis and the platelet count. Thrombocytopenia is an independent risk factor for mortality in patients with sepsis.
Disseminated Intravascular Coagulation:
Disseminated intravascular coagulation results from injury to vascular endothelium, leading to exposure of tissue factor, which activates the extrinsic factor pathway in coagulation cascade. In this process, consumption of the coagulation factors and platelets leads to bleeding, hence the name consumptive coagulopathy. Several factors trigger disseminated intravascular coagulation, including sepsis, malignancy, extensive trauma/burns, intrauterine fetal death, etc. Prolonged prothrombin time and activated partial thromboplastin time, low fibrinogen, increased D-dimer, thrombocytopenia are all suggestive but not diagnostic. There is no specific treatment for disseminated intravascular coagulation other than addressing the underlying problem. Transfusion of blood products such as cryoprecipitate and platelets should be considered only if there is significant bleeding.
Thrombotic Thrombocytopenic Purpura:
This is a potentially life threatening entity which can be treated very effectively with total plasma exchange. Thrombotic thrombocytopenic purpura is thought to stem from deficiency of von Willibrand factor cleaving enzyme also known metaloprotease. It manifests as thrombocytopenia, microangiopathic hemolytic anemia (increased reticulocyte count, LDH, low haptoglobin and presence of fragmented red blood cells on blood smear), altered mental status, renal failure and fevers (the so called ‘pentad’). Unfortunately, there is no diagnostic test for thrombotic thrombocytopenic purpura. Presence of thrombocytopenia, microangiopathic hemolytic anemia with any of the aforementioned features is highly indicative of thrombotic thrombocytopenic purpura.
Immune Thrombocytopenic Purpura:
Immune thrombocytopenic purpura is usually idiopathic and occasionally may be secondary to an auto-immune process such as lupus, rheumatoid arthritis, or lymphoproliferative disorders (lymphomas or chronic lymphocytic leukemia). Infection with HIV, hepatitis B and C and helicobacter pylori may also be associated with immune thrombocytopenic purpura. Bleeding is rare despite severely low platelet count due to the presence of functional platelets. It is usually a diagnosis of exclusion. Presence of adequate or increased number of megakaryocytes in the bone marrow with no other explanation confirms immune thrombocytopenic purpura. The initial treatment is typically steroids. Intravenous immunoglobulin, rituximab, and splenectomy are other treatment modalities.
Hemolysis (Elevated Liver Enzymes and Low Platelets (HELLP) Syndrome):
HELLP is exclusive to pregnancy, and is an extreme form of pre-eclampsia. Although it typically occurs in third trimester, it can be seen in any time of pregnancy. Clinical manifestations include pain in the right upper quadrant, high blood pressure, thrombocytopenia, and elevated liver enzymes. Delivery is the treatment of choice.
Heparin Induced Thrombocytopenia:
This is a life threatening condition caused by exposure to either unfractionated or low molecular heparin. It is caused by the formation of antibodies against heparin and platelet factor 4 antibody complex. It occurs 5 days after the exposure to heparin, unless the patient has previously been exposed to heparin. Patients present with thrombocytopenia and venous or arterial thrombosis. Diagnosis is made by either serologic or functional assays. Heparin must be stopped if there is a clinical suspicion and a direct thrombin inhibitor (lepirudin, argatroban, etc.) must be started immediately even if there is no thrombosis.
A complete list of the various causes of thrombocytopenia is available in Table 1, 2, 3.
Table 1. Etiology of Thrombocytopenia
Infectious
Non-infectious
Sepsis with or without disseminated intravascular coagulation
Medications
Hepatitis B and C
Nutritional deficiencies (B12, folate or iron deficiency)
HIV infection
Bone marrow problems
TTP/HUS
HELLP syndrome
Disseminated intravascular coagulation
Alcohol
Hypersplenism
Post-transfusion purpura
Acute pure megakaryocytic aplasia
TTP/HUS = Thrombotic thrombocytopenic purpura/Hemolytic Uremic Symptom
HELLP – Hemolysis, elevated liver enzymes, low platelets
Table 2. Common medications causing thrombocytopenia
Antimicrobials
Others
Piperacillin-tazobactam
Heparin
Trimethaprim-sulfamethoxazole
H2 blockers (e.g. Ranitidine)
Vancomycin
Quinine
Rifampin
Valproic acid
Ganciclovir
Glycoprotein IIb/IIIa inhibitors
Linezolid
Chemotherapy (e.g. Gemcitabine)
Table 3. Congenital causes of thrombocytopenia
1. Von-Willibrand disease type 2B
2. Wiskot-Aldrich syndrome
3. Alport syndrome
4. Fanconi’s anemia
5. Bernard-Soulier syndrome
6. Thrombocytopenia with absent radius syndrome
