Thrombocytopenia

Etiology

Pseudothrombocytopenia

  • General Comments: in vitro artifact due to platelet agglutination via antibodies (usually, IgG, also IgM and IgA) when the calcium content is decreased by blood collection in purple top EDTA-containing blood collection tubes
    • If suspected, platelet count should be determined using a blue top sodium citrate-containing tube, a green top heparin-containing tube or via a peripheral smear of fingerstick blood
  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
  • IIb/IIIa Inhibitors (see IIb IIIa Inhibitors, [[IIb IIIa Inhibitors]]): platelet clumping due to EDTA in collection tube -> miscounting on automated detectors
    • Agents: platelet clumping has been reported with all 3 agents
      • Abciximab (ReoPro) (see Abciximab, [[Abciximab]])
      • Eptifibatide (Integrilin) (see Eptifibatide, [[Eptifibatide]])
      • Tirofiban (Aggrastat) (see Tirofiban, [[Tirofiban]])
    • EPIC Trial: incidence of pseudothrombocytopenia with abciximab was 1.1%, whereas the incidence of true acute thrombocytopenia was 2.7% with abciximab
    • Collect Blood in Citrate Tubes: may allow accurate counting in some, but not all cases of EDTA-associated clumping
    • Inspection of Smear: gold standard for accurate platelet count
  • Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
  • Platelet Cold Agglutinins

Impaired Platelet Production

  • Aplastic Anemia (see Aplastic Anemia, [[Aplastic Anemia]])
  • Bone Marrow Infiltration (due to Leukemia/Lymphoma/Myeloproliferative/Lymphoproliferative Disorders)
    • Acute Lymphocytic Leukemia (ALL)(see Acute Lymphocytic Leukemia, [[Acute Lymphocytic Leukemia]])
      • However, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Acute Myeloid Leukemia (AML) (see Acute Myeloid Leukemia, [[Acute Myeloid Leukemia]])
      • However, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Chronic Lymphocytic Leukemia (CLL) (see Chronic Lymphocytic Leukemia, [[Chronic Lymphocytic Leukemia]])
      • However, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Chronic Myeloid Leukemia (CML) (see Chronic Myeloid Leukemia, [[Chronic Myeloid Leukemia]])
      • However, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Lymphoma (see Lymphoma, [[Lymphoma]])
      • However, many patients with lymphoma have both marrow infiltration and splenic sequestration
  • Deficiency
    • Folate Deficiency (see Folate, [[Folate]])
    • Vitamin B12 Deficiency (see Vitamin B12, [[Vitamin B12]])
  • Chemotherapeutic Myelosuppressive Drugs: commonly cause impaired megakaryocyte proliferation and maturation
    • Severe Myelosuppression
      • Cytarabine (ARA-C, Cytosar-U) (see Cytarabine, [[Cytarabine]])
      • Daunorubicin (Daunomycin, Cerubidine) (see Daunorubicin, [[Daunorubicin]])
    • Moderate Myelosuppression
    • Mild Myelosuppression
  • Others Drugs/Toxins
  • Infection
  • Myelodysplastic Syndromes (see Myelodysplastic Syndrome, [[Myelodysplastic Syndrome]])
  • Other
    • Acquired Pure Megakaryocytic Thrombocytopenia
    • Congenital Amegakaryotic Hypoplasia: selective decrease in platelet production
    • Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
    • Radiation Therapy (see xxxx, [[xxxx]])
    • Thrombocytopenia with Absent Radii (TAR) Syndrome: selective decrease in platelet production

Splenic Platelet Sequestration/Hypersplenism (see Splenomegaly, [[Splenomegaly]])

  • Cirrhosis/End-Stage Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
    • Physiology: portal hypertension results in splenomegaly
  • Gaucher’s Disease (see Gaucher’s Disease, [[Gauchers Disease]])
    • Physiology: splenic infiltration with macrophages -> splenomegaly
  • Leukemia/Lymphoma/Myeloproliferative/Lymphoproliferative Disorders: splenic infiltration with tumor cells -> splenomegaly
    • Acute Lymphocytic Leukemia (ALL) (see Acute Lymphocytic Leukemia, [[Acute Lymphocytic Leukemia]]): however, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Acute Myeloid Leukemia (AML) (seeAcute Myeloid Leukemia, [[Acute Myeloid Leukemia]]): however, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Chronic Lymphocytic Leukemia (see Chronic Lymphocytic Leukemia, [[Chronic Lymphocytic Leukemia]]): however, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Chronic Myeloid Leukemia (CML) (see Chronic Myeloid Leukemia, [[Chronic Myeloid Leukemia]]): however, many patients with leukemia have both marrow infiltration and splenic sequestration
    • Lymphoma (see Lymphoma, [[Lymphoma]]): however, many patients with lymphoma have both marrow infiltration and splenic sequestration

Abnormal Platelet Distribution/Pooling

  • Hypothermia (see Hypothermia, [[Hypothermia]])
  • Massive Transfusion
    • Epidemiology: particularly in the trauma setting (see Trauma-General, [[Trauma-General]])
    • Physiology: due to dilution of platelets

Increased Platelet Destruction

Drug/Toxin (see also http://www.ouhsc.edu/platelets/index.html)

  • Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
  • Aminoglutethimide (Cytadren) (see Aminoglutethimide, [[Aminoglutethimide]])
  • Aminosalicylic Acid
  • Amiodarone (Cordarone) (see Amiodarone, [[Amiodarone]])
  • Amphotericin B (see Amphotericin, [[Amphotericin]])
  • Ampicillin (see Ampicillin, [[Ampicillin]])
  • Apronalide
  • Arsenical Drugs: used to treat syphilis
  • Aspirin (Acetylsalicylic Acid) (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]]): suspected etiology
  • Beans
  • Captopril (Capoten)) (see Captopril, [[Captopril]])
  • Carbamazepine (Tegretol) (see Carbamazepine, [[Carbamazepine]])
  • Chlorpropamide (Diabinese) (see Chlorpropamide, [[Chlorpropamide]]): suspected etiology
  • Chloroquine (see Chloroquine, [[Chloroquine]]): suspected etiology
  • Chlorothiazide (see Chlorothiazide, [[Chlorothiazide]]): suspected etiology
  • Cimetidine (Tagamet)(see Cimetidine, [[Cimetidine]])
  • Danazol ((Azol, Bonzol, Cyclomen, Danol, Nazol) (see Danazol, [[Danazol]])
  • Diatrizoate Meglumine (Hypaque Meglumine)
  • Diclofenac (Aclonac, Cataflam, Voltaren) (see Diclofenac, [[Diclofenac]])
  • Digitoxin/Digoxin (see Digoxin, [[Digoxin]])
  • Dipyridamole (Persantine) (see Dipyridamole, [[Dipyridamole]])
  • Ethambutol (see Ethambutol, [[Ethambutol]])
  • Famotidine (Pepcid) (see Famotidine, [[Famotidine]])
  • Fluconazole (Diflucan, Trican) (see Fluconazole, [[Fluconazole]])
  • Furosemide (Lasix) (see Furosemide, [[Furosemide]])
  • Gold (see Gold, [[Gold]]): suspected etiology
  • Glyburide (Diabeta, Micronase, Glynase) (see Glyburide, [[Glyburide]])
  • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
    • Heparin (Unfractionated) (see Heparin, [[Heparin]])
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
    • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]]): although this is actually a factor Xa inhibitor, there have been case reports of it causing HIT
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
  • Hydrochlorothiazide (HCTZ) (see Hydrochlorothiazide, [[Hydrochlorothiazide]]): suspected etiology -> usually mild (50-100k), but may persist for several months after discontinuation of drug
  • Ibuprofen (see Ibuprofen, [[Ibuprofen]])
  • IIb/IIIa Inhibitors (see IIb IIIa Inhibitors, [[IIb IIIa Inhibitors]]): abciximab, eptifibatide, tirofiban
    • Epidemiology: in the EPIC trial, the incidence of pseudothrombocytopenia with abciximab was 1.1%, whereas the incidence of true acute thrombocytopenia was 2.7% with abciximab
    • Physiology: believed to be due to preformed antibodies against neoepitopes exposed by alteration of the GP IIb/IIIa molecules
    • Clinical: can occur in a matter of hours
  • Imipenem (see Imipenem, [[Imipenem]])
  • Insecticides: suspected etiology
  • Iopanoic Acid
  • Levamisole (Ergamisol) (see Levamisole, [[Levamisole]])
  • Linezolid (Zyvox) (see Linezolid, [[Linezolid]])
  • Meclofenamate
  • Methicillin
  • Methyldopa (see Methyldopa, [[Methyldopa]])
  • Nalidixic Acid (see Nalidixic Acid, [[Nalidixic Acid]])
  • Naproxen (Naprosyn, Aleve) (see Naproxen, [[Naproxen]])
  • Novobiocin
  • Oxyphenbutazone
  • P-Aminosalicylate
  • Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
  • Piperacillin (see Piperacillin-Tazobactam, [[Piperacillin-Tazobactam]])
  • Procainamide (Pronestyl) (see Procainamide, [[Procainamide]])
  • Quinidine (see Quinidine, [[Quinidine]]): cinchona alkaloid
  • Quinine (see Quinine, [[Quinine]]): cinchona alkaloid
  • Rifampin (see Rifampin, [[Rifampin]])
  • Simvastatin (Zocor) (see Simvastatin, [[Simvastatin]])
  • Stibophen
  • Sulfonamides (see Sulfonamides, [[Sulfonamides]])
    • Sulfadiazine: suspected etiology
    • Sulfisoxazole: suspected etiology
    • Sulfamerazine: suspected etiology
    • Sulfamethazine: suspected etiology
    • Sulfamethoxypyridazine: suspected etiology
    • Sulfamethoxazole (see Sulfamethoxazole-Trimethoprim, [[Sulfamethoxazole-Trimethoprim]]): suspected etiology
    • Sulfatolamide: suspected etiology
    • Sulfathiazole
  • Tamoxifen (see Tamoxifen, [[Tamoxifen]])
  • Valproic Acid (see Valproic Acid, [[Valproic Acid]])
  • Vancomycin (see Vancomycin, [[Vancomycin]])

Immune Thrombocytopenic Purpura (ITP) (see Immune Thrombocytopenic Purpura, [[Immune Thrombocytopenic Purpura]])

Macroangiopathic Hemolytic Anemia

Microangiopathic Hemolytic Anemia (MAHA) + Thrombocytopenia (see Hemoytic Thrombocytopenic Syndromes)

Other

  • Post-Transfusion Purpura (see Post-Transfusion Purpura, [[Post-Transfusion Purpura]]): rare disorder with sudden-onset thrombocytopenia in patient who recently received transfusion of red cells, platelets, or plasma within 1 week prior to detection of thrombocytopenia
    • Antibodies against the human platelet antigen PlA1 are detected in most individuals with PTP
    • Patients with PTP almost universally are either multiparous women or persons who have received transfusions previously
    • Severe thrombocytopenia and bleeding is typical. Initial treatment consists of administration of IVIG (1 g/kg/d for 2 days) which should be administered as soon as the diagnosis is suspected
    • Platelets are not indicated unless severe bleeding is present, but if they are to be administered, HLA-matched platelets are preferred
    • A second course or IVIG, plasma exchange, corticosteroids, or splenectomy may be used in case of refractoriness
    • PlA1-negative or washed blood products are preferred for subsequent transfusions
  • Pregnancy (see Pregnancy, [[Pregnancy]]): Gestational thrombocytopenia results from progressive expansion of the blood volume that typically occurs during pregnancy, leading to hemodilution
    • Cytopenias result, although production of blood cells is normal or increased
    • Platelet counts < 100,000/mcL, however, are observed in < 10% of pregnant women in the third trimester; decreases to < 70,000/mcL should prompt consideration of pregnancy-related ITP (see above) as well as preeclampsia or a pregnancy-related thrombotic microangiopathy

Unknown/Other Mechanism

  • Bumetanide (Bumex): rare reports of thrombocytopenia
  • Sepsis (see Sepsis, [[Sepsis]])
    • Physiology: multiple mechanisms have been implicated
      • Consumptive Coagulopathy: related to sepsis-induced platelet activation with/without frank disseminated intravascular coagulation (DIC)
      • Hemodilution: associated with intravenous fluid resuscitation
      • Increased Circulating Histones (JAMA, 2016) [MEDLINE]
      • Platelet Sequestration

Physiology

Normal Platelet Physiology

  • Normal Platelet Life Span: usually 7-10 days
  • Role of Spleen in Platelet Trafficking
    • Splenic Sequestration: approximately 33% of the total platelet mass is normally sequestered in the spleen
    • Splenectomy: will increase the platelet count by 33%
    • Splenomegaly: will increase the number of sequestered platelets

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Thrombocytopenia

Peripheral Blood Smear (see xxxx, [[xxxx]])

  • Check fro Platelet Clumping

Clinical Locations of Hemorrhage

  • Central Nervous System Hemorrhage: central nervous system hemorrhage is the major cause of bleeding-related deaths in patients with severe congenital factor deficiencies
  • Epistaxis (see Epistaxis, [[Epistaxis]])
  • Excessive Menstrual Bleeding
    • Menorrhagia (see Menorrhagia, [[Menorrhagia]]): loss of >80 mL of blood per cycle (or >4 super pads or tampons per day) or menses lasting >7 days
  • Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]]): gastrointestinal hemorrhage in presence of a bleeding disorder is usually associated with underlying gastrointestinal tract pathology
    • Von Willebrand Disease (Especially Types 2 and 3): has been associated with angiodysplasia of the bowel and gastrointestinal hemorrhage
  • Hemarthrosis (see Hemarthrosis, [[Hemarthrosis]])
    • Moderate-Severe Factor II/Prothrombin Deficiency (see Prothrombin Deficiency, [[Prothrombin Deficiency]])
    • Moderate-Severe Factor V Deficiency (see Factor V Deficiency, [[Factor V Deficiency]])
    • Moderate-Severe Factor VII Deficiency (see Factor VII Deficiency, [[Factor VII Deficiency]])
    • Moderate-Severe Congenital Factor VIII Deficiency (Hemophilia A) (see Hemophilia A, [[Hemophilia A]])
    • Moderate-Severe Factor IX Deficiency (Hemophilia B) (see Hemophilia B, [[Hemophilia B]])
    • Moderate-Severe Factor X Deficiency (see Factor X Deficiency, [[Factor X Deficiency]])
    • Moderate-Severe Fibrinogen Deficiency (see Afibrinogenemia, [[Afibrinogenemia]])
    • Von Willebrand Disease (see Von Willebrand Disease, [[Von Willebrand Disease]]): with factor VIII levels <5%
  • Hematuria (see Hematuria, [[Hematuria]]): hematuria in presence of a bleeding disorder is usually associated with underlying urinary tract pathology
  • Hemoperitoneum (see Hemoperitoneum, [[Hemoperitoneum]]): has been reported in association with rupture of ovarian cysts in association with a bleeding disorder
  • Mucosal/Gingival Bleeding
    • Platelet Adhesion Defect: may have increased bleeding after dental cleanings or gum manipulation
  • Muscle Hematoma
    • Anti-Factor VIII Antibody (see Anti-Factor VIII Antibody, [[Anti-Factor VIII Antibody]]): common
    • Moderate-Severe Factor II/Prothrombin Deficiency (see Prothrombin Deficiency, [[Prothrombin Deficiency]])
    • Moderate-Severe Factor V Deficiency (see Factor V Deficiency, [[Factor V Deficiency]])
    • Moderate-Severe Factor VII Deficiency (see Factor VII Deficiency, [[Factor VII Deficiency]])
    • Moderate-Severe Congenital Factor VIII Deficiency (Hemophilia A) (see Hemophilia A, [[Hemophilia A]])
    • Moderate-Severe Factor IX Deficiency (Hemophilia B) (see Hemophilia B, [[Hemophilia B]])
    • Moderate-Severe Factor X Deficiency (see Factor X Deficiency, [[Factor X Deficiency]])
    • Moderate-Severe Fibrinogen Deficiency (see Afibrinogenemia, [[Afibrinogenemia]])
  • Post-Partum Hemorrhage
    • Common in women with underlying bleeding disorders
    • In women with type 1 Von Willebrand Disease and symptomatic hemophilia carriers in whom levels of Von Willebrand factor and factor VIII usually normalize during pregnancy, the onset of post-partum hemorrhage may be delayed
    • Women with a history of postpartum hemorrhage have a high risk of recurrence with subsequent pregnancies
  • Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage, [[Retroperitoneal Hemorrhage]])
  • Surgical Bleeding
    • Post-Colonoscopic Polypectomy (see Colonoscopy, [[Colonoscopy]]): delayed bleeding may occur
    • Post-Tonsillectomy (see Tonsillectomy, [[Tonsillectomy]]): Bleeding may occur early after surgery or after approximately 7 days postoperatively (with loss of the eschar at the surgical site)

Clinical Patterns of Bleeding

COAGULOPATHY1

Clinical Manifestations

Hemorrhagic Manifestations

  • xxx

  • The incidence of bleeding increases as platelet counts decrease below 10,000/!L. In two recent studies, the use of smaller doses of platelet concentrates resulted in a greater number of transfusions being required. The incidence of significant bleeding was greater with lower dose transfusion in one study, and not different in the other study. Current studies are addressing the issue of prophylactic versus therapeutic transfusions in patients with platelet counts less than 10,000/μL. Alloimmunization is decreased by the use of leukocyte-reduced platelets. Post- transfusion increments in platelet count decrease as the number of units transfused increases because of the development of alloimmunization. ABO incompatibility decreases the increment in platelet count post transfusion.

Treatment

Platelet Transfusion (see Platelet Transfusion, [[Platelet Transfusion]])

  • xxx

References

  • Dose of prophylactic platelet transfusions and the prevention of hemorrhage. N Engl J Med 2010; 362:600-613.
  • A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 2009; 113:1564-1573.
  • Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program 2007:172- 178
  • Pseudothrombocytopenia after abciximab (Reopro) treatment. Circulation 1999; 100:1460
  • Thrombocytopenia complicating treatment with intravenous IIb/IIIa receptor inhibitors: a pooled analysis. Am Heart J 2000; 140:206-211
  • Histone-Associated Thrombocytopenia in Patients Who Are Critically Ill. JAMA. 2016;315(8):817-819. doi:10.1001/jama.2016.0136 [MEDLINE]