PLATELET-MEDIATED BLEEDING DISORDERS

PLATELET-MEDIATED BLEEDING DISORDERS

Current Diagnosis

• Platelet-mediated bleeding disorders commonly present with bleeding from mucosal surfaces and/or skin. Bleeding caused by reduced platelet counts may present with petechiae or purpura, while abnormalities of function are more likely to present with bleeding after injury or menstruation.

• Evaluation of platelet function used to be measured by the bleeding time. However, it is now more commonly evaluated by the PFA-100 and/or platelet aggregation studies.

• Thrombocytopenia is most commonly caused by deficient production of platelets from the bone marrow, decreased platelet survival in the circulation, or sequestration of platelets by an enlarged spleen.

• Patients may bleed after trauma at platelet counts under 50,000/µL and develop petechiae or purpura at platelet counts under 20,000/

µL, but usually do not have severe bleeding unless platelet counts drop below 10,000/µL

• The most common causes of new thrombocytopenia in the hospitalized patient are drugs or infection, whereas the usual cause of new platelet function abnormalities are medications.

• Patients in the hospital and placed on heparin should have their platelet counts monitored, and a reduction of 50% should be evaluated for heparin-induced thrombocytopenia.

• Immune thrombocytopenic purpura (ITP) usually presents in outpatients as new-onset mucocutaneous bleeding associated with only a reduced platelet count or unexplained asymptomatic isolated thrombocytopenia.

• Drugs that inhibit platelet activation and aggregation, such as aspirin, clopidogrel (Plavix), and dipyridamole (Persantine) can lead to significant bleeding, especially after surgery or procedures. This effect may last for 7 to 10 days.

• Patients presenting with a lifetime history of easy bruising and or heavy menses should have careful evaluation of their bleeding history and family history of bleeding. If positive, studies to rule out von Willebrand disease or hereditary disorders of platelet granules such as storage pool disorder should be done.

Current Therapy

• Patients with severe thrombocytopenia (platelet counts < 10,000/µL) that is due to impaired production are at risk of severe bleeding and should be considered for platelet transfusions. The benefit of transfusing platelets when the platelet count reaches this level and the patient is not bleeding has been demonstrated as reducing bleeding in some patents in a recent study.

• Standard practice for platelet transfusions is to maintain platelet counts above 50,000/µL for patients with gastrointestinal bleeding and 75,000-100,000/µL for neurosurgical procedures.

• Patients with immune thrombocytopenia should not receive platelet transfusions unless they are having significant bleeding since response to platelet transfusion occurs in less than 10% of patients and is short lasting.

•   Patients with ITP who have no bleeding and platelet

counts > 30,000/µL can be followed without treatment since the risk of bleeding is low.

• In patients with ITP and thrombocytopenia less than 10,000/µL, initial treatment with high doses of corticosteroids in combination with IVIG (Gamunex) induces a rapid rise in platelets, usually within 24 hours.

• Current treatment for patients with ITP who fail prednisone treatment include splenectomy, rituximab (Rituxan),1 or thrombopoietin agonists (romiplostim [Nplate] or eltrombopag [Promacta]).

• Patients with chronic renal failure can develop severe bleeding diathesis which appears to be multifactorial including platelet dysfunction. Dialysis can reduce bleeding but not completely correct it. Other treatment which may help include desmopressin (DDAVP),1  tranexamic acid (Lysteda),1  and synthetic erythropoietin.1

• Patients with drug induced platelet dysfunction who may need to undergo surgery or who are bleeding may require platelet transfusions.

• Patients with inherited platelet disorders and mild bleeding can be treated with desmopressin (DDAVP) but if severe may require platelet transfusions.

1 Not FDA approved for this indication.

Platelets Role in Hemostasis

Platelets are small non-nucleated blood cells which are derived from bone marrow megakaryocytes. Their production is controlled by the hormone thrombopoietin produced in the liver and they survive in the circulation for 8 to 10 days. Upon blood vessel injury, they form a seal or plug at the site of injury to limit bleeding. This initial event, termed primary hemostasis, occurs after endothelial injury when the subendothelial surface is exposed to circulating blood. Platelets are drawn to the site via von Willebrand factor (vWF), which, in combination with other proteins including fibrillar collagen, fibronectin and laminin, leads to platelet adhesion. After platelets adhere to the vessel wall, they are activated, undergo a shape change and release products from their granules. These platelet granule products, including ADP and thromboxane A2, further potentiate this process. Fibrinogen then binds to platelets via GPIIb/IIIa on the platelet surface causing firm platelet aggregation. The platelet secretory release reaction and aggregation recruits other platelets forming a firm hemostatic plug. Platelets also support the coagulation phase by interacting with circulating clotting factors and providing a surface for generation of thrombin. Secondary hemostasis occurs and thrombin mediated fibrin mesh stabilizes the platelet plug.

Clinical Manifestations

The hallmark of platelet-mediated bleeding disorders is mucocutaneous bleeding such as nose bleeds, prolonged bleeding after tooth extractions, and heavy menstrual bleeding. When the platelet count drops below 30.000/µL one may also see petechiae or purpuric lesions, especially on lower extremities.

Quantitative Platelet Disorders (Thrombocytopenia)

Primary hemostasis depends on an adequate number of platelets to prevent bleeding. A significant reduction in platelets or thrombocytopenia is usually defined as < 100,000/µL. However, bleeding usually does not occur until the platelet count drops much lower. For example, spontaneous bleeding may only occur only when the platelet count is below 20,000/µL and severe life-threatening bleeding occurs only below 10,000/µL. Thrombocytopenia can develop due to inadequate platelet production from the bone marrow, reduced platelet survival in the circulation, or sequestration of platelets in the spleen. Differentiating the cause requires evaluation of the patients associated medical problems, physical findings, drug history, blood chemistry analysis, and possibly bone-marrow sampling.

Decreased platelet production is often the result of chemotherapeutic drugs for cancer, some antibiotics and antivirals (Table 1), or radiation therapy. These drugs may cause bone-marrow injury including damage to the megakaryocytes. Complete recovery may occur after stopping the offending agent. One common agent that can induce thrombocytopenia is alcohol. Thrombocytopenia associated with reduction in the white blood cell count and or red blood cell count should alert physicians to the possibility of a bone marrow disorder such as forms of leukemia or aplastic anemia. In cases where the cause is not evident, a bone marrow biopsy may be necessary to demonstrate whether there is a malignancy that may require urgent treatment.

Table 1

Drugs Commonly Implicated as Causes of Drug-Induced Thrombocytopenia

Category                                     Implicated in Several Reports
Heparin Unfractionated and LMWH
Cinchona alkaloids Quinidine, quinine
Platelet inhibitors Abciximab,  eptifibinate, tirofiban
Antirheumatic agents Gold salts
Antimicrobial agents Linezolid,  rifampin,  sulfonamides, vancomycin
Sedative  and anticonvulsants Valproic acid, phenytoin, carbamazepine
Histamine  receptor antagonists Cimetidine
Diuretic agents Chlorothiazide
Analgesic agents Acetaminophen,  naproxen, diclofenac
Chemotherapy agents Oxaliplatin, fludarabine, and others

Patients with reduced platelet production can often be observed without intervention depending on the severity of the thrombocytopenia, presence of bleeding, or the need to perform invasive procedures. Guidelines for transfusion of platelets to prevent bleeding (prophylactic transfusion) have changed in the last few years. With evidence that severe bleeding may not occur in most patients until the platelet count is below 10,000/µL, limited platelet resources, and potential for development of alloimmunization to platelets, transfusions are not usually given unless sustained platelet counts are below 10,000/µL. When platelets are transfused it is appropriate to measure the response with a platelet count 1 hour post- transfusion. The platelet count should rise 30,000 to 40,000/µL for the usual four-pack of platelet transfusion. Patients requiring frequent transfusions may require single-donor apheresis or HLA-matched platelets to obtain a good response.

Thrombocytopenia Resulting from Increased Platelet Destruction

Normally, platelets live in the circulation for 10 days, and the bone marrow replenishes them at the same rate that they are destroyed. Platelet survival may be altered by both nonimmune and immune processes. Severe infections will often lead to increased platelet destruction, and the platelet count returns to normal when the infection is adequately treated. Consumption of platelets also can occur in association with microangiopathic hemolytic anemia, as seen in disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP/HUS). It is important to review the blood smear to document fragmented red blood cells and evaluate coagulation parameters to help differentiate DIC from TTP/HUS and other causes of consumption. TTP/HUS may require specific and urgent treatment to prevent life-threatening complications. Platelet transfusions are not usually given for TTP as there are reports of patients deteriorating after transfusions.

Immune-mediated platelet destruction is seen in response to several common drugs, including the sulfonamides and vancomycin. The characteristic pattern of immune-mediated platelet destruction is a sharp drop in the platelet count 7 to 10 days after starting the drug.

The platelet count may drop to 5000/µL or less. Recognition is important because significant bleeding may occur and the platelet count will only improve after discontinuation of the drug.

Glycoprotein IIa/IIIb inhibitors, which are often used after cardiac stent placement, may cause a dramatic drop in the platelet count to as low as 1000/µL within hours of administration. This is important to recognize because this is one case where platelet transfusions may be necessary to prevent severe bleeding and it can be easily confused with other causes of low platelet counts.

Heparin-induced thrombocytopenia (HIT) is a unique drug reaction for several reasons. First, although thrombocytopenia is the initial sign of this entity, the major and feared complication is arterial and venous thromboses. It appears to affect 4% to 5% of patients exposed to unfractionated heparin and about 0.5% of patients exposed to low- molecular-weight heparin. Those at highest risk are female surgical patients who receive a minimum of 4 days of either type of heparin.

The classic pattern is exposure to heparin at any dose with development of antibodies to heparin at day 4 and a 50% reduction in platelet count by day 6. The antibodies responsible are to the heparin– platelet factor 4 complex (IgG-PF4). A suspicious clinical pattern and a high antibody titer measured by an ELISA assay are often diagnostic. Patients suspected of having HIT are at a high risk of thromboembolic disease within the first 24 hours of the drop in platelet count, and the heparin should be immediately stopped. However, despite the reduced platelet count, bleeding is unusual. Patients should be placed on an alternative anticoagulant, usually a direct thrombin inhibitor.

The platelet count takes about 2 weeks to return to normal, and warfarin (Coumadin) should not be started until the platelet count returns to normal to avoid warfarin-associated necrosis. By reducing protein C and protein S, warfarin creates a temporary hypercoagulable state and places the patient at risk for warfarin- associated necrosis during the time when patients are most susceptible to thrombosis from HIT.

Immune thrombocytopenic purpura (ITP), previously termed idiopathic thrombocytopenic purpura affects 1 to 3 people per 100,000, but is probably the most common cause of severe isolated thrombocytopenia seen in the outpatient setting. It affects all ages, although ITP in childhood has a unique natural history. Childhood ITP is often associated with viral illness, is commonly transient, and may not need treatment. In adults, 40% of patients may have protracted or recurrent episodes of ITP, and the majority of patients need treatment. It was demonstrated in the 1950s that ITP is caused by circulating antiplatelet antibodies, and, like many autoimmune diseases, it is more common in women. When ITP presents in association with other diseases such as systemic lupus erythematosus or chronic lymphatic leukemia, or in patients with HIV, management of the underlying disease is important. The clinical presentation of ITP depends on the degree of thrombocytopenia. Mild thrombocytopenia of 20,000 to 80,000/µL is often asymptomatic, whereas platelet counts under 20,000/µL may present with mucocutaneous bleeding and diffuse petechiae and purpura. Thrombocytopenia, an otherwise normal blood count and peripheral blood smear without evidence of splenomegaly in a patient with no other illness helps make a tentative diagnosis. A bone marrow biopsy is no longer considered necessary to confirm the diagnosis.

Treatment of ITP has changed over the last several years, and initial treatment after the diagnosis requires evaluation of the platelet count, whether it is increasing or decreasing, and the presence or absence of bleeding. Patients who have counts above 20,000/µL without bleeding and who are not in need of an invasive procedure can be observed without intervention. Patients with counts between 10,000 and 20,000/ µL may be started on oral prednisone at 1 mg/kg. Patients with severe thrombocytopenia less than 10,000/µL and those who are bleeding can receive high-dose dexamethasone (Decadron) at 40 mg daily for 4 days and IVIG (Gamunex). There is usually a response to treatment within 24 hours. Although usually not helpful or required, about 10% of patients will have a response to platelet transfusion, and this can be considered for patients presenting with low platelet counts and bleeding. Refractory or recurrent ITP is a common problem in these patients, and recommendations for treatment include splenectomy, rituximab (Rituxan),1 or thrombopoietin agonists. The choice of which to use depends on the patient and his or her clinical condition.

Thrombocytopenia Due to Hypersplenism

The platelet mass is distributed 70% in the circulation and 30% in the spleen. Enlargement of the spleen and/or alteration of blood flow in portal hypertension may increase platelet sequestration in the spleen and reduce the platelet count in the peripheral blood circulation.

Patients’ counts rarely drop below 20,000/µL. Thus, thrombocytopenia caused by hypersplenism does not usually need any intervention.

Patients with hepatitis C and cirrhosis may present with low platelet counts, and this may represent both hypersplenism and secondary immune thrombocytopenia. A trial of steroids may be used if these patients’ clinical situation requires therapy.

Qualitative Platelet Function Disorders

Acquired Qualitative Platelet Function Disorders

Acquired disorders of platelet function are commonly seen, because platelets are the target of medications used to prevent arterial and cardiac stent thrombosis. Spontaneous bleeding is not common, but bleeding resulting from trauma or surgery can be a significant clinical problem. Because many patients may be on multiple antiplatelet agents or anticoagulants at the same time, the risk of bleeding needs to be recognized. Acquired qualitative disorders of platelet function may be due to drugs, hematologic diseases, or medical illnesses.

Drugs are the most common cause of acquired platelet dysfunction with differing risks of bleeding due to different targets. Aspirin causes irreversible acetylation of cyclooxygenase I (COX-1) and inhibits generation of prostaglandin A2. Although it is considered a weak antiplatelet agent with up to 25 % resistance, aspirin increases the risk of bleeding in otherwise normal patients. Major bleeding was seen in up to 3.7% of patients and, when aspirin is used in combination with other antiplatelet agents or in patients with underlying bleeding disorders, the bleeding risk is higher. Clopidogrel (Plavix) is a thienopyridine prodrug, and the active metabolite irreversibly inhibits the surface receptor P2Y12  on platelets. In clinical trials the risk of major bleeding in patients taking clopidogrel was similar to what is described with aspirin. Clopidogrel may significantly increase bleeding after surgery. GPIIb/IIIa receptor antagonists used after cardiac stent placement inhibit platelet aggregation and can induce severe thrombocytopenia.

Malignancies of the bone marrow may produce abnormally functioning platelets or alter platelet function by affecting vWF. The myeloproliferative and myelodysplastic disorders may produce platelets with reduced numbers of granules and may have associated increased risk of gastrointestinal bleeding and bleeding after invasive procedures. Acquired von Willebrand disease an infrequent cause of abnormal bleeding, can be seen in patients with lymphoproliferative disease, multiple myeloma, and Waldenström macroglobulinemia.

Systemic illness can alter platelets and increase the bleeding risk.

Acute and chronic renal failure are common causes of platelet- function abnormalities. In uremia, hemorrhagic complications include upper gastrointestinal bleeding, pericardial bleeding, and intracranial bleeding. Bleeding in renal failure is thought to be multifactorial and includes impaired release of platelet granules, decreased prostaglandin formation, vWF dysfunction, and presence of severe anemia. Effective treatment includes improvement of the anemia with erythropoietin1 and/or desmopressin (DDAVP)1 or conjugated estrogens (Premarin).1

Hereditary Qualitative Platelet Function Disorders

Inherited abnormalities of platelet function are infrequent disorders that give rise to bleeding of varying severity. Inherited abnormalities of platelet function are often classified according to the type of genetic defect. Bernard-Soulier syndrome (BSS) is a severe bleeding disorder with autosomal recessive inheritance characterized by thrombocytopenia, decreased platelet adhesion, reduced platelet survival, and giant platelets on blood smear. Patients with BSS have defects in the GPIb-IX-V complex leading to reduced binding to vWF. Glanzmann thrombasthenia is an autosomal recessive disorder with defects of integrin αIIbβ3, a receptor on activated platelets that normally binds platelets during aggregation. Platelet aggregation to ADP and thrombin is abnormal. Patients with BSS and Glanzmann thrombasthenia who need treatment require platelet transfusions.

Hereditary disorders of platelet secretion are common reasons patients present to clinicians for evaluation of mucocutaneous bleeding. Defects in platelet dense granules (δ storage pool disease) are suspected in patients with bleeding and a negative workup for von Wilebrand disease. Diagnosis is made by platelet electron microscopy and or platelet aggregation studies. Granule deficiency associated with abnormalities of other lysosome-related organelles may lead to specific phenotypes such as Hermansky-Pudlak and Chediak Higashi disease. Gray platelet syndrome (GPS), or alpha granule deficiency, is an autosomal recessive disorder with mild bleeding. GPS patients may also be thrombocytopenic. Treatment for bleeding or in preparation for surgery includes desmopressin (DDAVP)1 or platelet transfusions.

References

1.     Aster R.H., Curtis B.R., McFarland J.G., Bougie D.W. Drug- induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost. 2009;7:911–918.

2.    Barbour T., Johnson S., Cohney S., Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012;27:2673–2685.

3.     Cuker A., Gimotty P.A., Crowther M.A., Warkentin T.E. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120:4160–4167.

4.    Estcourt L., Stanworth S., Doree C., et al. Prophylactic platelet transfusion in prevention of bleeding in patients with hematologic disorders and stem cell transplantation. Cochrane Database Syst Rev. 2012 May 16;5:doi:10.1002/14651858.CD004269.pub CD004269.

5.     Hedges S.J., Dehoney S.B., Hooper J.S., et al. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol. 2007;3:138–153.

6.      Jackson S. Arterial thrombosis: insidious, unpredictable, and deadly. Nat Med. 2011;17:1423–1436.

7.    Lakshamanan S., Cuker A. Contemporary management of immune thrombocytopenic purpura in adults. J Thromb Haemost. 2012;10:1988–1998.

8.    Nurden A., Nurden P. Advances in our understanding of the molecular basis of disorders of platelet function. J Thromb Haemost Suppl. 2011;1:76–91.

9.       Provan D., Stasi R., Newland A.C., et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168–186.

10.       Stanworth S.J., et al. Risk of bleeding and use of platelet transfusions in patients with hematologic malignancies: recurrent event analysis. Haematol. 2015;100(6):740–747.

11.     Tsantes A.E., Nikolopoulos G.K., Tsirigotis P., et al. Direct evidence for normalization of platelet function resulting from platelet count reduction in essential thrombocytosis. Blood Coagul. Fibrinolysis. 2011;22:457–462.

12.     Warkentin A.E., Donadni M.P., Spencer F.A., et al. Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systemic review and meta-analysis. J Thromb Haemost. 2012;10:512–520.

13.     Zucker M.L., Hagedorn C.H., Murphy C.A., et al. Mechanism of thrombocytopenia in chronic hepatitis C as evaluated by the immature platelet fraction. Int J Lab Hematol. 2012;34:525–532.

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

X