Thrombotic Thrombocytopenic Purpura

Hematology

Clinicals - History

Fact Explanation
Introduction Thrombotic Thrombocytopenic Purpura is a haematological disorder. It is characterized by thrombus formation in small blood vessels of the body. As thrombus consume platelets in the blood it causes reduction in platelet count (thrombocytopenia). So there ia a bleeding tendency associated with this disease. Introduction
Thrombotic Thrombocytopenic Purpura is a haematological disorder. It is characterized by thrombus formation in small blood vessels of the body. As thrombus consume platelets in the blood it causes reduction in platelet count (thrombocytopenia). So there ia a bleeding tendency associated with this disease.
History of suggestive of increased bleeding tendency Patient will present with multiple bruises on the skin/mucous membranes, groups of pinpoint-sized dots on the skin and bleeding from mucus membranes like gum bleeding, nasal bleeding, per rectal bleeding, menorrhagia and haematuria. Bleeding under the skin/ mucous membranes will leads to these purpura and petechiae. History of suggestive of increased bleeding tendency
Patient will present with multiple bruises on the skin/mucous membranes, groups of pinpoint-sized dots on the skin and bleeding from mucus membranes like gum bleeding, nasal bleeding, per rectal bleeding, menorrhagia and haematuria. Bleeding under the skin/ mucous membranes will leads to these purpura and petechiae.
Easy fatigue, shortness of breath, tiredness This condition is associated with microangiopathic hemolytic anemia which is a caused by red blood cell destruction with mechanical injury while passing throught thrombus formed blood vessls . This causes fragmentation of red blood cells and hemolysis giving features of anaemia. Easy fatigue, shortness of breath, tiredness
This condition is associated with microangiopathic hemolytic anemia which is a caused by red blood cell destruction with mechanical injury while passing throught thrombus formed blood vessls . This causes fragmentation of red blood cells and hemolysis giving features of anaemia.
Yellowish discoloration of eyes This is due to the excessive destruction of red blood cells causing jaundice. Yellowish discoloration of eyes
This is due to the excessive destruction of red blood cells causing jaundice.
dark red urine from hemoglobinuria With microangiopathic hemolytic anemia, red blood cells are become fragments and destroyed,. Whith this excessive haemolysis free plasma haemoglobin level is increased and they filtere via kidneys causing hemoglobinuria. dark red urine from hemoglobinuria
With microangiopathic hemolytic anemia, red blood cells are become fragments and destroyed,. Whith this excessive haemolysis free plasma haemoglobin level is increased and they filtere via kidneys causing hemoglobinuria.
low/ none urine out put, red colored urine and/ or frothy urine Oliguria/anuria , haematuria and protein urea are presentations in renal involvement. Focal/segmental microthrombi formation is the common reason in here for renal failure. low/ none urine out put, red colored urine and/ or frothy urine
Oliguria/anuria , haematuria and protein urea are presentations in renal involvement. Focal/segmental microthrombi formation is the common reason in here for renal failure.
Neurologic manifestations Neurologic manifestations such as alteration in mental statuslike confusion and drowsiness, seizures, muscle paralysis, paresthesias, visual problems and headache. With extensive microthrombil formation in various parts of the brain will leads to these neurological manifestations. Brain ischemia causing transient ischemic attacks and strokes are common in this patients. Neurologic manifestations
Neurologic manifestations such as alteration in mental statuslike confusion and drowsiness, seizures, muscle paralysis, paresthesias, visual problems and headache. With extensive microthrombil formation in various parts of the brain will leads to these neurological manifestations. Brain ischemia causing transient ischemic attacks and strokes are common in this patients.
History of episodic exacerbations Fever, infections, diarrheal conditions, trauma, surgery or pregnancy like stressful situations are common precipitating factors.According to available data In this condition fever occurs in approximately half of the patients. Some drugs like cyclosporin A, cisplatin and quinine are identified to be associated with Thrombotic Thrombocytopenic Purpura. History of episodic exacerbations
Fever, infections, diarrheal conditions, trauma, surgery or pregnancy like stressful situations are common precipitating factors.According to available data In this condition fever occurs in approximately half of the patients. Some drugs like cyclosporin A, cisplatin and quinine are identified to be associated with Thrombotic Thrombocytopenic Purpura.
sudden onset abdominal pain, nausea and vomiting As this is a mutisystem disease this can affect bowel causing bowel ischemia with thrombi formation leading to these symptoms. sudden onset abdominal pain, nausea and vomiting
As this is a mutisystem disease this can affect bowel causing bowel ischemia with thrombi formation leading to these symptoms.
History of chest pain, palpitation, shortness of breath The presence of systemic microvascular ischemia in these patients can affect cardiac function causing problems with conduction defects and can ultimately leads to cardiac failure History of chest pain, palpitation, shortness of breath
The presence of systemic microvascular ischemia in these patients can affect cardiac function causing problems with conduction defects and can ultimately leads to cardiac failure
Family history of similer llness, strokes in neonatal period, sudden deaths. In hereditary form there will be a positive family history in between genetically related people. Family history of similer llness, strokes in neonatal period, sudden deaths.
In hereditary form there will be a positive family history in between genetically related people.

Clinicals - Examination

Fact Explanation
Signs of increase bleeding tendency There will be multiple purpura/ ecchymotic patches and groups of petechiaeand evidence of gum/ nasal bleeding of bleeding from other mucus membranes.Thrombotic Thrombocytopenic Purpura is one of haematological disorder characterized with clotting in small vessels of the body causing reduction in platelet count (thrombocytopenia) causing these signs. Signs of increase bleeding tendency
There will be multiple purpura/ ecchymotic patches and groups of petechiaeand evidence of gum/ nasal bleeding of bleeding from other mucus membranes.Thrombotic Thrombocytopenic Purpura is one of haematological disorder characterized with clotting in small vessels of the body causing reduction in platelet count (thrombocytopenia) causing these signs.
Pallor This condition is associated with microangiopathic hemolytic anemia causing red blood cell destruction giving signs of anaemia. Due to the mechanical injury with high shear stress created by microvascular thrombosis is believed to cause fragmentation of red blood cells and hemolysis. Pallor
This condition is associated with microangiopathic hemolytic anemia causing red blood cell destruction giving signs of anaemia. Due to the mechanical injury with high shear stress created by microvascular thrombosis is believed to cause fragmentation of red blood cells and hemolysis.
Jaundice This is due to the excessive destruction of red blood cells causing jaundice. Jaundice
This is due to the excessive destruction of red blood cells causing jaundice.
Fever fever is seem to be occurs in approximately half of the patients. Fever
fever is seem to be occurs in approximately half of the patients.
Examination of urine Examination of urine will reveals dark red urine from hemoglobinuria/ haematurea. With microangiopathic hemolytic anemia in which red blood cells are destroyed, free plasma haemoglobin level is increased.This excess hemoglobin filtere by the kidneys and excrete it into the urine, giving urine a dark red color.
Haematuria will be present in renal involvement of this condition. Focal and segmental distribution of microthrombi most commonly leads to renal failure.
Examination of urine
Examination of urine will reveals dark red urine from hemoglobinuria/ haematurea. With microangiopathic hemolytic anemia in which red blood cells are destroyed, free plasma haemoglobin level is increased.This excess hemoglobin filtere by the kidneys and excrete it into the urine, giving urine a dark red color.
Haematuria will be present in renal involvement of this condition. Focal and segmental distribution of microthrombi most commonly leads to renal failure.
Neurologic examination Neurologic examination reveals alteration in mental status( confusion/ drowsiness), development of seizures, hemiplegia, paresthesias, visual disturbance and aphasia. With focal and segmental distribution of microthrombi, these neurological manifestations can be seen. Trensient ischemic attacks and strokes are common in theses patients. Neurologic examination
Neurologic examination reveals alteration in mental status( confusion/ drowsiness), development of seizures, hemiplegia, paresthesias, visual disturbance and aphasia. With focal and segmental distribution of microthrombi, these neurological manifestations can be seen. Trensient ischemic attacks and strokes are common in theses patients.
Splenomegaly Splenomegaly may present but organomegaly is not typical. Splenomegaly
Splenomegaly may present but organomegaly is not typical.
Cardiovascular examination Cardiovascular examination reveals dyspnoic patient, irregular pulse and features of cardiac failure like ankle oedema, gallop rhythm. The presence of systemic microvascular ischemia in these patients can affect cardiac fuction causing conduction defects and these leads finally to cardiac failure Cardiovascular examination
Cardiovascular examination reveals dyspnoic patient, irregular pulse and features of cardiac failure like ankle oedema, gallop rhythm. The presence of systemic microvascular ischemia in these patients can affect cardiac fuction causing conduction defects and these leads finally to cardiac failure

Investigations - Diagnosis

Fact Explanation
Full blood count Thrombotic Thrombocytopenic Purpura associated with thrombocytopenia and low haemoglobin levels. If there is any ongoing infection there will be increase in WBC count as well. Full blood count
Thrombotic Thrombocytopenic Purpura associated with thrombocytopenia and low haemoglobin levels. If there is any ongoing infection there will be increase in WBC count as well.
Peripheral blood film examination A peripheral blood smear examination will reveals thrombocytopenia and red cell fragmentation(schistocytes) as prominent
features.
Peripheral blood film examination
A peripheral blood smear examination will reveals thrombocytopenia and red cell fragmentation(schistocytes) as prominent
features.
ADAMTS13 activity assay A patient with Thrombotic Thrombocytopenic Purpura due to autoimmune inhibitors of ADAMTS13 typically has very low( less than 10%) ADAMYS13 activity level in their plasma. ADAMTS13 activity assay
A patient with Thrombotic Thrombocytopenic Purpura due to autoimmune inhibitors of ADAMTS13 typically has very low( less than 10%) ADAMYS13 activity level in their plasma.
ADAMTS13-inhibiting antibodies titer Several studies have shown that the presence of inhibitors of ADAMTS13 in most patients are presenting with acute TTP. Inhibitors of ADAMTS13 will persist with fluctuating titers for months to years during periods of clinical remission. With the excessive increase of ADAMTS13 inhibitor titers ADAMTS13 activity will suppress below the threshold level causing relapse of TTP. ADAMTS13-inhibiting antibodies titer
Several studies have shown that the presence of inhibitors of ADAMTS13 in most patients are presenting with acute TTP. Inhibitors of ADAMTS13 will persist with fluctuating titers for months to years during periods of clinical remission. With the excessive increase of ADAMTS13 inhibitor titers ADAMTS13 activity will suppress below the threshold level causing relapse of TTP.
DNA sequence analysis for mutation of the ADAMTS13 gene Inhibitory antibodies of ADAMTS13 causes a profound deficiency of the protease. according to available data there is more than forty different mutations of the ADAMTS13 gene including mis-senses, non-senses, frame-shifting deletions or insertions, and intronic splicing mutations which are distributed throughout the various domains of ADAMTS13. The majority of these mutations affect the sequence of metalloprotease-spacer domains that are critical for expression of proteolytic activity. DNA sequence analysis for mutation of the ADAMTS13 gene
Inhibitory antibodies of ADAMTS13 causes a profound deficiency of the protease. according to available data there is more than forty different mutations of the ADAMTS13 gene including mis-senses, non-senses, frame-shifting deletions or insertions, and intronic splicing mutations which are distributed throughout the various domains of ADAMTS13. The majority of these mutations affect the sequence of metalloprotease-spacer domains that are critical for expression of proteolytic activity.
Analysis of the VWF multimers In early stage of remission there is an increase in the platelet count which is often coincides with the appearance of ultra large VWF multimers. Because at this stage ADAMTS13 activity remains very low but that is sufficient to ameliorate the binding between VWF and platelet. Ultra large VWF multimers can be seen among patients in remission with persistently low ADAMTS13 activity levels. Analysis of the VWF multimers
In early stage of remission there is an increase in the platelet count which is often coincides with the appearance of ultra large VWF multimers. Because at this stage ADAMTS13 activity remains very low but that is sufficient to ameliorate the binding between VWF and platelet. Ultra large VWF multimers can be seen among patients in remission with persistently low ADAMTS13 activity levels.
PT/INR, APTT As there is no clotting factor defect these tests are normal and helps in differentiating this bleeding tendency with other clotting disorders. PT/INR, APTT
As there is no clotting factor defect these tests are normal and helps in differentiating this bleeding tendency with other clotting disorders.
D Dimer In disseminated intravascular coagulation there is elevated levels of D Dimer. This is useful in excluding the differential diagnosis. D Dimer
In disseminated intravascular coagulation there is elevated levels of D Dimer. This is useful in excluding the differential diagnosis.
Computed tomography (CT) scanning and magnetic resonance imaging (MRI) CT scanning or MRI useful in the history or physical findings suggest towards serious internal bleeding or other neurological manifestations to exclude brain ischemia. Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
CT scanning or MRI useful in the history or physical findings suggest towards serious internal bleeding or other neurological manifestations to exclude brain ischemia.
Renal function tests like serum creatinine, blood urea and Urine full report In Thrombotic Thrombocytopenic Purpura renal involvement is common leading to renal failure. In a case of renal involvement there may be proteinuria with hyaline and granular cases in the urine, elevated serum creatinine levels and blood urea levels. So these tests will useful in screening the renal failure in Thrombotic Thrombocytopenic Purpura and to exclude HUS. Renal function tests like serum creatinine, blood urea and Urine full report
In Thrombotic Thrombocytopenic Purpura renal involvement is common leading to renal failure. In a case of renal involvement there may be proteinuria with hyaline and granular cases in the urine, elevated serum creatinine levels and blood urea levels. So these tests will useful in screening the renal failure in Thrombotic Thrombocytopenic Purpura and to exclude HUS.

Investigations - Management

Fact Explanation
Full Blood Count This is useful in followup as well to see the level of thrombocytopenia and low haemoglobin level. Full Blood Count
This is useful in followup as well to see the level of thrombocytopenia and low haemoglobin level.
Reticulocyte count This also useful in follow up. Reticulocyte count
This also useful in follow up.
haptoglobin level Due to haemolysis this is useful in routine assessment of patient with newly diagnosed Thrombotic Thrombocytopenic Purpura. haptoglobin level
Due to haemolysis this is useful in routine assessment of patient with newly diagnosed Thrombotic Thrombocytopenic Purpura.
Serum LDH level Serum LDH level is usually high in these patients during an acute exacerbation due to tissue necrosis with systemic micro thrombi and haemolysis. Serum LDH level
Serum LDH level is usually high in these patients during an acute exacerbation due to tissue necrosis with systemic micro thrombi and haemolysis.
Clotting profile with prothrombin time and activated partial thromboplastin time This is useful in excluding any associated clotting factor deficiency. Clotting profile with prothrombin time and activated partial thromboplastin time
This is useful in excluding any associated clotting factor deficiency.
echocardiogram, electrocardiogram These tests are useful in assessing the cardiac function. echocardiogram, electrocardiogram
These tests are useful in assessing the cardiac function.
Full Blood Count Assess the degree of thrombocytopenia and anaemia will helpful in deciding the patients present condition. Full Blood Count
Assess the degree of thrombocytopenia and anaemia will helpful in deciding the patients present condition.
Computed tomography (CT) scanning and magnetic resonance imaging (MRI) CT scanning or MRI useful in the history or physical findings suggest of serious internal bleeding. Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
CT scanning or MRI useful in the history or physical findings suggest of serious internal bleeding.
Serum troponin level The presence of systemic microvascular ischemia in these patients can affect cardiac fuction causing conduction defects and congestive cardiac failure. In these patient serum troponin level is very important to assess the cardiac status. Serum troponin level
The presence of systemic microvascular ischemia in these patients can affect cardiac fuction causing conduction defects and congestive cardiac failure. In these patient serum troponin level is very important to assess the cardiac status.
Blood grouping and cross matching This is useful in management if the transfusion is needed. Blood grouping and cross matching
This is useful in management if the transfusion is needed.
Renal function tests like serum creatinine, blood urea and Urine full report In Thrombotic Thrombocytopenic Purpura renal involvement is common, focal and segmental distribution of microthrombi most commonly leads to renal failure. In a case of renal involvement there may be proteinuria with hyaline and granular cases in the urine, elevated serum creatinine levels and blood urea levels. So these tests will useful in screening the renal failure. Renal function tests like serum creatinine, blood urea and Urine full report
In Thrombotic Thrombocytopenic Purpura renal involvement is common, focal and segmental distribution of microthrombi most commonly leads to renal failure. In a case of renal involvement there may be proteinuria with hyaline and granular cases in the urine, elevated serum creatinine levels and blood urea levels. So these tests will useful in screening the renal failure.
HIV serology, hepatitis B and C serology, cytomegalovirus serology these infections can precipitate the condition and also due to the treatments these patients are at high risk for getting blood born infections. So during the management screening for these infections are very useful. HIV serology, hepatitis B and C serology, cytomegalovirus serology
these infections can precipitate the condition and also due to the treatments these patients are at high risk for getting blood born infections. So during the management screening for these infections are very useful.

Management - Supportive

Fact Explanation
Health education Thrombotic Thrombocytopenic Purpura is one of life-threatening haematological disorder causing thrombotic microangiopathy which causes significant morbidity and mortality unless promptly recognized and treated. This is a multi systemic condition and patient should be aware about the condition, symptoms, treatment options complications and prognosis. Health education
Thrombotic Thrombocytopenic Purpura is one of life-threatening haematological disorder causing thrombotic microangiopathy which causes significant morbidity and mortality unless promptly recognized and treated. This is a multi systemic condition and patient should be aware about the condition, symptoms, treatment options complications and prognosis.
Antiplatelet agents Low-dose aspirin is given to patients with Thrombotic Thrombocytopenic Purpura (platelet count need to be more than 50 × 109/L). This is given as a supportive care. It is known to improve early survival. Antiplatelet agents
Low-dose aspirin is given to patients with Thrombotic Thrombocytopenic Purpura (platelet count need to be more than 50 × 109/L). This is given as a supportive care. It is known to improve early survival.
Antithrombotic therapy As these patients are at high risk of deep venous thrombosis pharmacological DVT prophylaxis with low molecular weight heparin) and nonpharmacological DVT prophylaxis like with graded compression stockings need to be considered. Antithrombotic therapy
As these patients are at high risk of deep venous thrombosis pharmacological DVT prophylaxis with low molecular weight heparin) and nonpharmacological DVT prophylaxis like with graded compression stockings need to be considered.
Central venous access Central venous lines need to be inserted in to patient with severe thrombocytopenia. This is useful in plasma exchange and it is highly advisable in patients with neurological symptoms or signs of neurological instability. Central venous catheters should be inserted regardless of platelet count. Central venous access
Central venous lines need to be inserted in to patient with severe thrombocytopenia. This is useful in plasma exchange and it is highly advisable in patients with neurological symptoms or signs of neurological instability. Central venous catheters should be inserted regardless of platelet count.
Hepatitis B prophylaxis Patients with previous hepatitis B infection are at risk reactivation following rituximab therapy as it causes B-cell depletion . As prophylaxis antiviral agents need to be considered. Hepatitis B prophylaxis
Patients with previous hepatitis B infection are at risk reactivation following rituximab therapy as it causes B-cell depletion . As prophylaxis antiviral agents need to be considered.
Folic acid Folic acid need to be given to all patients due to the hemolytic state. Folic acid
Folic acid need to be given to all patients due to the hemolytic state.
During pregnancy patient should be treated with methylprednisolone and plasma exchange in a similar way to non pregnant patients This can occur during pregnancy due to the changes in immune regulation or as a precipitation of an episode of symptomatic patient with congenital thrombotic thrombocytopenic purpura. In pregnancy methylprednisolone and plasma exchange can be used in a similar way to nonpregnant patients. But rituximab is not adviced during pregnancy due to risks to the developing fetus.The delivery of the baby does not necessarily in the resolution of the episode. During pregnancy patient should be treated with methylprednisolone and plasma exchange in a similar way to non pregnant patients
This can occur during pregnancy due to the changes in immune regulation or as a precipitation of an episode of symptomatic patient with congenital thrombotic thrombocytopenic purpura. In pregnancy methylprednisolone and plasma exchange can be used in a similar way to nonpregnant patients. But rituximab is not adviced during pregnancy due to risks to the developing fetus.The delivery of the baby does not necessarily in the resolution of the episode.
Retroviral therapy, plasma exchange and corticosteroids for HIV-associated patients HIV infection is an important cause of this disease. Adequate virological suppression is important.Combined with highly active antiretroviral therapy, plasma exchange and corticosteroid alone (without rituximab) is usually enought to achieve a remission from the acute episode. Retroviral therapy, plasma exchange and corticosteroids for HIV-associated patients
HIV infection is an important cause of this disease. Adequate virological suppression is important.Combined with highly active antiretroviral therapy, plasma exchange and corticosteroid alone (without rituximab) is usually enought to achieve a remission from the acute episode.

Management - Specific

Fact Explanation
Plasma exchange Plasma exchange is the most important acute intervention in Thrombotic Thrombocytopenic Purpura management and this is indicated in all patients with suspected disease. in here both removal of autoantibody by the exchange process (in acquired TTP) as well as supplementation of ADAMTS13 activity in the exchanged plasma. Plasma exchange
Plasma exchange is the most important acute intervention in Thrombotic Thrombocytopenic Purpura management and this is indicated in all patients with suspected disease. in here both removal of autoantibody by the exchange process (in acquired TTP) as well as supplementation of ADAMTS13 activity in the exchanged plasma.
Rituximab This anti-CD20 antibody rituximab is a safe and effective treatment for newly diagnosed Thrombotic Thrombocytopenic Purpura. It is use in acute illness and to prevent relapses. Rituximab
This anti-CD20 antibody rituximab is a safe and effective treatment for newly diagnosed Thrombotic Thrombocytopenic Purpura. It is use in acute illness and to prevent relapses.
Corticosteroids Steroids(eg; methylprednisolone) causes rapid immunosuppression and they used initially. Steroids are given intravenously daily for 3 days. The first dose usually administered immediately after the first plasma exchange. Corticosteroids
Steroids(eg; methylprednisolone) causes rapid immunosuppression and they used initially. Steroids are given intravenously daily for 3 days. The first dose usually administered immediately after the first plasma exchange.
Other immunosuppressive medication Second-line immunosuppression like mycophenolate mofetil, cyclosporine, and vincristine can be used in rituximab intolerance . Other immunosuppressive medication
Second-line immunosuppression like mycophenolate mofetil, cyclosporine, and vincristine can be used in rituximab intolerance .
Splenectomy Role of splenectomy in the current management of Thrombotic Thrombocytopenic Purpura is limited as there is little evidence regarding its efficacy and safety. This is done for relapsing disease. Splenectomy
Role of splenectomy in the current management of Thrombotic Thrombocytopenic Purpura is limited as there is little evidence regarding its efficacy and safety. This is done for relapsing disease.
Recombinant ADAMTS13 Recombinant form of ADAMTS13 helps to achieve higher ADAMTS13 activity. Recombinant ADAMTS13
Recombinant form of ADAMTS13 helps to achieve higher ADAMTS13 activity.
Anti-vWF nanobody This is a bivalent nanobody which is a therapeutic protein derived from the heavy chain variable region of heavy chain. It bind to the N-terminus of the vWF A1 domain and subsequently block its interaction with platelets. Anti-vWF nanobody
This is a bivalent nanobody which is a therapeutic protein derived from the heavy chain variable region of heavy chain. It bind to the N-terminus of the vWF A1 domain and subsequently block its interaction with platelets.
N-acetyl cysteine It is having multiple effects including reduction of vWF multimer size and inhibition of platelet aggregation. N-acetyl cysteine
It is having multiple effects including reduction of vWF multimer size and inhibition of platelet aggregation.
Novel immunosuppressive agents Other B-cell targeted immunotherapy like Bruton tyrosine kinase inhibitors also known to effective in treatments. Novel immunosuppressive agents
Other B-cell targeted immunotherapy like Bruton tyrosine kinase inhibitors also known to effective in treatments.

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