Quick review of physiology
Thrombopoietin (TPO) is primarily produced in the liver, but also the kidneys and bone marrow. TPO acts to promote growth of megakaryocytes which shed platelets into circulation. TPO is constitutively secreted (meaning its rate of secretion is independent of any signalling). TPO receptors are found on both platelets and the megakaryocyte progenitors. As the number of platelets drop, there is more free TPO available to stimulate platelet production by binding to TPO receptors on the megakaryocytes. Conversely, the more platelets there are, the less TPO is available to stimulate platelet production by binding to those same TPO receptors on megakaryocytes.
TPO is constitutively secreted meaning that its rate of secreted is constant for the individual!
4 different causes for thrombocytopenia
Decreased platelet production
Decreased platelet production is due to the bone marrow failing which typically results in pancytopenia. Examples include aplastic anemia, myelofibrosis, myelodysplastic syndrome, leukemia and chemotherapy-induced bone marrow failure. Moderately low platelet production is also expected after periods of stress such as post-surgery.
Increased platelet destruction
Diseases that result in platelet destruction include ITP, DIC, TTP, HUS, HIT and HELLP (pregnancy). More details about each of these below.
Increased sequestration of platelets
Normally the spleen is responsible for sequestering platelets. However, when the spleen becomes congested as seen in portal hypertension and/or cirrhosis the spleen becomes engorged (splenomegaly) and is able to sequester even more platelets inside thus reducing the number of available platelets in the bloodstream available to form platelet plugs. The bone marrow does not respond by releasing more platelets into the blood because as mentioned earlier, platelet production is related to the amount of TPO that is available to bind to progenitor megakaryocytes. Since the platelets are only sequestered but not destroyed, much of the body’s TPO is still bound to the sequestered platelets instead of binding to the progenitor megakaryocytes and stimulating platelet production and shedding.
Factitious thrombocytopenia
Hemodilution
Hemodilution is seen in cases of trauma or surgery where the patient may have lost a significant amount of blood or fluids and is being resuscitated with products that do not contain platelets (RL, packed RBCs)
Pseudothrombocytopenia
EDTA is added to blood samples to prevent the blood from clotting. In some patients EDTA can cause platelets to agglutinate. The agglutinated platelets are counted as a single platelet leading to severe underestimation of platelet count, even though the patient may have completely normal platelet count in their own blood stream (where the patient does not have EDTA flowing)
Check with your lab to see if they use EDTA (samples collected with heparin or citrate do not lead to pseudothrombocytopenia)
Algorithm for thrombocytopenia
Look at the peripheral blood smear for
- Pseudothrombocytopenia by looking for platelet clumping
- Consistently large platelets suggesting a hereditary macrothrombocytopenia
- Schistocytes which may suggest a MAHA such as TTP, HUS, and DIC
- Blasts and other signs of leukemia that may cause thrombocytopenia
- Higher MPV indicates bone marrow working hard to replace lost platelets (similar to reticulocytosis in hemolytic anemia)
Additional basic laboratory investigations
- Lytes, liver enzymes, creatinine
- Coagulation screen (INR, aPTT, fibrinogen)
- LDH to screen for hemolytic anemia
- B12 level for nutritional deficiency cause of thrombocytopenia
Disease specific investigations and management
Isolated thrombocytopenia in an asymptomatic patient
Immune thrombocytopenic purpura (ITP)
ITP is the most common cause of isolated thrombocytopenia and is considered a diagnosis of exclusion since there is no specific or sensitive test to confirm the diagnosis of ITP. It is caused by antibodies directed at receptors on platelets which lead to the eventual removal of antibody bound platelet from the circulation via the spleen.
Laboratory studies that can be performed to help support the diagnosis of ITP in addition to CBC, basic metabolic panel, renal, LDH and peripheral blood smear include:
- HIV, HCV, H pylori testing to look for secondary infectious causes of ITP
- Bone marrow biopsy and aspirate should be performed in patients older than 60 years of age to rule out an initial presentation of myelodysplastic syndrome (MDS) or malignancy
- Ultrasound of abdomen to look for hepatosplenomegaly (which typically suggest a cause other than ITP such as sequestration from portal hypertension and cirrhosis)
ITP can be associated with various triggers
- Idiopathic
- Previous viral/bacterial infection (molecular mimicry)
- HIV, HCV
- Lupus
Management depends on the severity and age of the patient. Many patients are asymptomatic with moderately low platelet levels and therefore do not require any treatment, this is especially true in children. In children who are experiencing more episodes of potentially life-threatening bleeding such as gastrointestinal or intracranial bleeding, they may benefit from the administration of glucocorticoids and IVIG. Adults who have platelets less than 30, 000 (normal between 150, 000 and 400, 000), may also benefit from the administration of glucocorticoids with or without IVIG. If ITP is refractory to medical therapy, the definitive treatment for ITP is splenectomy. While splenectomy is the definitive option, it does make the patient vulnerable to infections from encapsulated organisms such as Streptococcus pneumoniae and Hemophillus influenza. Therefore, it is imperative for these patients to receive the corresponding vaccinations: Hib vaccine, pneumococcal vaccine (Prevnar-13), and the meningococcal vaccine. If splenectomy is contraindicated rituximab can also be provided.

How does IVIG work?
IVIG has multiple proposed mechanisms. One of the most accepted theories for its use in ITP and other autoimmune diseases is that the immunoglobulin blocks many of the Fc receptors on macrophages and other phagocytes thus preventing antibodies bound with platelets from binding to those receptors and being phagocytosed. IVIG in this way prevents the phagocytosis of antibody bound platelets.
Drug induced thrombocytopenic purpura (DITP)
DITP is ITP that is solely due to antibodies that bind to platelets but only when a specific drug (or food substance) is also in the blood as well. Diagnosis is fairly straightforward as stopping the offending drug typically results in a resolution of platelet count within 1-2 weeks.
Inpatient thrombocytopenia
Heparin induced thrombocytopenia (HIT)
There are 2 main types of HIT: type 1 HIT (pseudo-HIT) and type 2 HIT.
Type 1 HIT is a sort of pseudo-HIT because there is no antibody related mechanism. The thrombocytopenia that occurs in platelets is mild and is simply due to heparin in some patients causing platelets to aggregate (similar to how EDTA does), without any involvement of antibodies. The mild thrombocytopenia that results is clinically insignificant and patients can continue taking heparin while being observed for any deterioration.
Type 2 HIT is generally what people refer to when they mention HIT. It results in a much more severe form of thrombocytopenia and can be life threatening. When platelets are activated they release the cytokine platelet factor 4 (PF4). Heparin on its own does not stimulate an immune response, but when it binds to PF4 it forms the heparin/PF4 complex which is immunogenic. In certain individuals, they form antibodies which bind to this complex which can then bind to the Fc receptor on platelets, thus activating them and causing them to release even more PF4.
Clinical features of type 2 HIT
- Skin necrosis especially at the site of inection
- Limb gangrene
- Pre-test probability of HIT (4T score)
- Thrombocytopenia
- Time
- Onset within 5-14 days
- Earlier onset of HIT can occur in patients who have a prior history of exposure to heparin within the last 3 months
- Thrombosis
- Venous more often than arterial
- Other causes
Management involves immediate discontinuation of heparin (and switch to argatrobran)upon suspicion of HIT until a confirmatory ELISA test can be performed. In the meanwhile a nonheparin anticoagulant (but NOT warfarin until platelets are back into normal range) should be used.
Be especially vigilant for HIT for patients undergoing cardiac surgery!
DIC
Disseminated intravascular coagulation is a blood disorder that involves the inappropriate activation of the coagulation cascade characterized by both the formation of thrombi and the consumption of clotting factors and clotting factors. Therefore, in DIC patients are at risk for organ damage (e.g. renal and hepatic) due to inappropriate clotting and bleeding.
DIC is most commonly associated with severe septic shock, but it can also be seen in other situations that involve severe bodily stress: trauma, post-surgery, obstetric complication.
The International Society on Thrombosis and Hemostasis have come up with a scoring system to support the diagnosis of overt DIC which involve the four following criteria
- Platelet count
- Elevated fibrin degradation products (D-dimer levels)
- PT at upper limit of reference (INR, aPTT)
- Fibrinogen
Management of DIC is complex and is dependent on the patient’s specific clinical presentation.
- Blood loss = provide packed RBCs
- Prolonged aPTT or INR = provide FFP
- Low fibrinogen = provide cryoprecipitate/fibrinogen concentrate
- Fibrinogen
- Factor 8
- vWF
- Factor 13
- Low platelets + severe bleeding = transfuse platelets only with moderate to severe thrombocytopenia (there must be symptoms)
TTP
TTP is a disorder caused by a deficiency of ADAMTS13 which is the enzyme that cleaves vWF (glue in the endothelium that “catches” platelets). If the vWF are not cleaved they become very long and become too long at catch platelets which causes increased clotting. These microthrombi then causes red blood cells that pass by them to become damaged and fragmented.
The mnemonic for the pentad of clinical features of TTP is FAT RN:
- Fever
- Anemia
- Thrombocytopenia
- Renal impairment
- Neurological findings
You should find a normal coagulation profile (if abnormal think DIC) and schistocytes on the peripheral blood smear.
Management involves a procedure known as plasma exchange or PLEX where the antibodies that target ADAMTS13 are filtered out through exchanging the patient’s own plasma with donor fresh frozen plasma (containing presumably normal ADAMTS13). If you think it is TTP and cannot get PLEX then simply do a plasma infusion (but you are limited by how much plasma you can give due to the risk of volume overload.
Do not give platelets to a patient with TTP, you would just be adding fuel to the fire!
Rituximab can be used for long term therapy to prevent relapse.
HUS or aHUS
Two types of hemolytic uremia syndrome exist: typical and atypical.
Typical HUS is a microangiopathic hemolytic anemia that is clinically similar to TTP and usually presents in children who have recently experienced an episode of gastroenteritis and diarrhea. The pathogen that causes the episode of gastroenteritis is the O157:H7 subtype of enterohemorrhagic E. coli which releases the Shiga-like toxin. This toxin causes endothelial damage which leads to the formation of multiple thrombi. The thrombi then led to intrvascular hemolysis as blood cells pass by them leading to schistocytes being seen on the peripheral blood smear. Symptoms of HUS are similar to TTP except there is usually more renal injury, low platelets and anemia, and no neurological findings (unlike TTP).
Atypical HUS has a similar clinical presentation except that it occurs at any age, and does require a diarrheal illness prodrome.
Management of typical HUS is supportive with steroids but NO antibiotics which can worsen the illness.
Management of atypical HUS is similar to the management of TTP with the use of PLEX and in cases where there may be neurological involvement eculizumab can be used.
Triad of HUS is MAHA, renal injury and low platelets!
Pregnancy and thrombocytopenia
Gestational thrombocytopenia
Gestational thrombocytopenia is fairly common and is a physiologic response that occurs during the mid-second to third-trimester of pregnancy. Gestational thrombocytopenia is most likely the cause if
- Counts are not severely low and there are no bleeding symptoms (> 70)
- No past history of thrombocytopenia
- Resolves within 2 months post-partum
HELPP syndrome/Severe pre-eclampsia
HELPP syndrome is a complication of pregnancy stands for
- H = Hemolysis
- EL = elevated liver enzymes
- LP = low platelets
Suspect HELPP syndrome in patients with severe gestational hypertension (> 160/110), who also have right upper quadrant abdominal pain, proteinuria, elevated liver enzymes, low platelets and a positive hemolytic panel (increased LDH, increased bilirubin, low haptoglobin).
Management depends on the age of gestation. If age > 34 weeks or if the fetal status is deteriorating, induce labor and deliver the fetus. Management also involves IV fluids, blood transfusions if necessary and the use of IV anti-hypertensives (labetalol, hydralazine).