Thrombocytopenia

Isolated thrombocytopenia is a deficiency of platelets in the blood and one of the most common disorders encountered in the inpatient setting. A thorough history and examination is required to identify and treat the underlying cause. Management may initially be guided by the severity of symptoms, which can range from mild bruising to significant bleeding.

In this section, we provide a table to summarize common etiologies of thrombocytopenia and an algorithm to guide workup, followed by a discussion of the following thrombocytopenic conditions:

• Immune thrombocytopenia purpura (ITP)

• Heparin-induced thrombocytopenia (HIT)

• Disseminated intravascular coagulation (DIC)

• Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)

(Republished with permission of American Society of Hematology, from How to Approach Thrombocytopenia. Hematology Am Soc Hematol Educ Program 2012.)

Immune Thrombocytopenia Purpura (ITP)

Diagnosis

ITP is a diagnosis of exclusion and defined as a platelet count <100,000 per mm³ in the absence of other causes.

• Primary ITP is an acquired autoimmune disorder classified by the time elapsed since diagnosis:

  • new diagnosis (<3 months)

  • persistent (3-12 months)

  • chronic (>12 months)

• Causes of secondary ITP are summarized in the following table:

  

  (Source: Immune Thrombocytopenia. N Engl J Med 2019.)

• Drug-induced ITP (DITP): A frequently updated list of drugs that can cause DITP can be found here.

Treatment

The American Society of Hematology (ASH) guidelines recommend treatment of ITP in patients with severe bleeding or low platelet counts (<30,000 per mm³). Treatment for episodes of severe bleeding can range from platelet transfusions to other supportive measures (e.g., tranexamic acid).

The numerous options for the treatment of ITP are summarized in the following table:

Heparin-Induced Thrombocytopenia (HIT)

HIT is an acquired immune-mediated drug reaction wherein the patient develops an antibody to the complex of heparin and platelet factor 4 (PF4). Although thrombocytopenia is a key feature, antibody binding to the heparin-PF4 complex leads to platelet activation and significant risk of thrombosis, both arterial and venous (about 50% of patients with HIT develop thrombosis).

HIT most often occurs 5 to 14 days after initiating heparin therapy. However, HIT can develop infrequently either earlier (after a recent previous exposure to heparin) or much later after heparin exposure.

Diagnosis

• The 4T Scoring System is used to evaluate the pretest probability of HIT.

  

  (Source: NEJM Knowledge+. Massachusetts Medical Society. Last reviewed, August 2020.)

• The PF4 antibody test is the most sensitive test available, but false positives are common due to the low threshold used for a positive test to maximize sensitivity.

• Optical density (OD): Always ask the lab for the OD in order to assess the likelihood of true HIT.

  • Many labs use an OD cutoff of 0.4 for a positive test, but most patients with an OD of 0.4 do not have HIT.

  • An OD >1.5 is almost always a true positive.

  • If the OD is equivocal but there is a high clinical suspicion for HIT, the serotonin-release assay (SRA) can be ordered (only after consultation with a hematologist); although SRA is usually the most specific test, it is less sensitive than the PF4 test for HIT.

The following flowchart describes the recommended approach to diagnosis and management of HIT:

(Source: Heparin-Induced Thrombocytopenia. N Engl J Med 2015.)

Management

If HIT is suspected based on the 4T score and high clinical suspicion:

• All heparin should be stopped (including flushes for intravascular lines [e.g., intravenous or central venous catheters] that often contain heparin to prevent line clots) and a workup should be performed (as described in the algorithm above).

• If a patient is on warfarin at the time of diagnosis, hold warfarin and administer vitamin K to reverse (warfarin may increase risk of thrombosis in HIT via depletion of protein C).

• The most common alternative agents for anticoagulation therapy in patients diagnosed with HIT are the direct thrombin inhibitors argatroban and bivalirudin; subcutaneous fondaparinux (which has no heparin cross-reactivity) can also be used. Direct oral anticoagulants (DOACs) are increasingly being used as off-label options in clinically stable individuals.

  • Argatroban or fondaparinux are preferred for urgent surgery and nonurgent cardiac surgery.

  • Avoid argatroban with liver dysfunction.

  • Avoid bivalirudin and fondaparinux in patients with renal dysfunction.

  • DOACs should not be used in patients who require IV anticoagulation, have life or limb threatening thrombosis, or have hepatic dysfunction (Child-Pugh Class B and C).

• Guidelines on DOAC use and dosing recommendations for HIT and HITT are available from the American Society of Hematology.

Risk for thrombosis: Patients with HIT are at high risk for thrombosis. Therefore, upper- and lower-extremity ultrasounds are reasonable to rule out occult thrombosis, which will affect treatment duration.

• Clots can occur in odd locations in patients with HIT, including distal veins (a common presentation is a cold, blue toe after cardiac surgery) or the adrenal veins (leading to adrenal hemorrhage). Consider HIT in a patient with adrenal hemorrhage, thrombocytopenia, and recent heparin exposure.

• Risk of clotting can persist for >30 days in patients with HIT. Therefore, anticoagulation therapy, usually with warfarin, should be started once the patient is stabilized and platelets have risen to ≥150,000 per mm³. DOACs could also be considered in this setting.

  • Continue non-warfarin anticoagulation therapy until platelets are >150,000 per mm³and bridge to warfarin.

  • Duration of treatment is approximately one month if no thrombosis is present and 3 months if thrombosis is present.

  • Heparinoid medications should be avoided in these patients indefinitely.

Disseminated Intravascular Coagulation (DIC)

DIC is a broadly defined diagnosis that includes many different pathophysiological mechanisms. All cases of DIC are characterized by a consumptive coagulopathy driven by thrombotic microangiopathy. DIC causes the fibrinolytic system to be overactivated, usually secondary to abnormal thrombin generation. Clinical presentation is variable and reflects consequences of small-vessel thrombosis that may present as dyspnea, chest pain, stroke, or individual organ failure combined with coagulation defects.

Diagnosis

No single test for DIC exists. The diagnosis must always be considered in patients with the following conditions:

• Severe infectious diseases

• Malignancy

• Trauma

• Obstetrical complications

• Vascular malformations

• Severe immunologic reactions

• Heat stroke

• Post-cardiopulmonary resuscitation

The common laboratory profile in DIC is:

• elevated international normalized ratio (INR) and D-dimer levels (D-dimer levels increase with age and must be interpreted with caution)

• low platelets and fibrinogen

The following table describes a diagnostic scoring system developed by the International Society on Thrombosis and Hemostasis (ISTH) to help identify DIC. The ISTH DIC score can help determine if current laboratory changes are compatible with overt DIC

(Source: Bleeding and Coagulopathies in Critical Care. N Engl J Med 2014.)

Management

• Primary management of DIC involves treating the underlying illness. Supportive care is directed at coagulation abnormalities.

• Platelet transfusion may be indicated along with administration of cryoprecipitate as a source of fibrinogen. If international normalized ratio (INR), partial thromboplastin time (PTT), or both >2.5 ULN remain abnormal after administration of cryoprecipitate and the patient is still bleeding, fresh frozen plasma can be administered.

• Always administer vitamin K when using products that include coagulation factors, such as cryoprecipitate or fresh frozen plasma. Hypocalcemia may result from transfusion of multiple blood products and calcium replacement therapy may be needed.

• When DIC presents predominantly as excessive coagulation activation (thrombotic DIC), administration of low-dose unfractionated heparin can be considered, although evidence of its efficacy is sparse.

• No conclusive evidence supports repletion of specific anticoagulant proteins or clotting factors.

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS)

TTP and HUS are consumptive thrombocytopenias associated with microangiopathic hemolysis and a spectrum of clinical findings. Both TTP and HUS are rare diagnoses, but must be ruled out in all patients with thrombocytopenia. The presence of fragmented RBCs (schistocytes) on the peripheral-blood smear should raise the suspicion of these conditions.

(Source: Thrombotic Thrombocytopenic Purpura. N Engl J Med 2019.)

The following algorithm summarizes the evaluation of patients presenting with microangiopathic hemolytic anemia and thrombocytopenia:

(Source: Syndromes of Thrombotic Microangiopathy. N Engl J Med 2014.)

Treatment

TTP is a clinical emergency. Mortality is as high as 90% without treatment but can be reduced to 10%-20% with proper treatment. Treatment includes the following:

• daily therapeutic plasma exchange (TPE) until resolution of symptoms, recovery of platelet count, and cessation of hemolysis

• steroids if the patient is presumed autoimmune (most cases)

• rituximab in patients experiencing relapse or continue to have refractoriness to steroids and TPE

• caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, can also be considered

• recombinant ADAMTS13 is currently being studied for treatment of acquired TTP and is used in congenital TTP

• if TPE is not available, FFP should be given to temporize; platelets should not be administered