Thrombocytopenia

Steroid therapy

- can slow down the destruction of platelets and depress autoantibody production - Inhibits phagocytosis of antibody-coated platelets in the spleen and prolongs platelet survival. - Improves capillary resistance and thereby improves platelet economy. - Inhibits platelet antibody production

Clinical features of infants < 2yo with ITP

- higher male/female ratio - Less frequent occurrence of infection before ITP - Less frequent occurrence of chronic ITP - Poor response to treatment - More severe clinical course

Pseudothrombocytopenia

- platelet activation during blood collection - undercounting of megathrombocytes - in vitro agglutination of platelets due to EDTA - monoclonal antibodies that bind to platelet glycoprotein receptos such as abciximab, eptifibatide, tirofiban

Classification of TTP

1. Chronic Hereditary TTP 2. Sporadic TTP 3. Acute Acquired TTP 4. Secondary TTP

Criteria for Diagnosis of ITP

1. Clinical examination: purpura with an otherwise essentially normal physical examination, with no significant splenomegaly and no lymphadenopathy 2. Platelet count and blood smears:thrombocytopenia only, with no evidence of red cell or white blood cell abnormalities 3. Bone marrow: normal to increased number of megakaryocytes with normal myeloid and erythroid elements 4. Exclusion of secondary causes of thrombocytopenia, such as hypersplenism, microangiopathic hemolytic anemia, DIC, drug-induced thrombocytopenia, SLE, infections such as EBV, HIV, and parvovirus

Disorders of Platelet distribution or Pooling

1. Hypersplenism - Portal HTN, Gaucher disease, Cyanotic Congenital Heart Disease 2. Hypothermia

Causes of Thrombocytopenia

1. decreased bone marrow production 2. sequestration usually in enlarged spleen 3. increased platelet destruction

Expect response in steroid treatment

2-4 weeks (>20,000 platelets within a week) When there is no response to treatment after this alternative therapy should be given

The age with the greatest frequency of occurence

2-8 years old

ITP and H. pylori

50% of ITP patients have a concomitant H.pylori infection When you treat H. pylori, platelets will normalize H. pylori test: Urea breath test High response rate when you treat the underlying cause

Heparin Induced ELISA Test

97 % specificity and sensitivity with PF4/polyanion complex as the antigen. IgG-specific ELISAs increase specificity but may decrease sensitivity

Pathophysiology of HIT

- Platelet factor release - Platelet activation - Complexes with heparin - Production of IgG antibodies - Sequestration of platelets - Destruction of platelets in the spleen

Management for DIC

- Platelet transfusion in <10,000 or <50,000 if with bleeding or deranged protime of APTT - Cryoprecipitate if low fibrinogen

Clinical features

- Starts on 5-10 days of heparin therapy - Check CBC after 3-5 days - Usually they don't bleed - Thrombosis is the usual complication

Side effects of Steroid therapy

- Steroid toxicity (Moon facie) - Hyperglycemia - Risk for infection (some might be chronic hepatitis carriers or TB patients) - Adrenal insufficiency (especially when they are on steroids for 2 weeks nah, educate them not to stop steroids on their own

HIT

Check timing if heparin and anti-coagulation

Drugs responsible for suppression of megakaryocyte production

Chlorothiazides Estrogenic hormones Ethanol Tolbutamide

Liver cirrhosis

Low platelet count Abnormal PT and APTT

Platelet activation assay

Measures the ability of the patient's serum to activate platelets in the presence of heparin in a concentrationdependent manner. This test has lower sensitivity but higher specificity than the ELISA

DIC

can be acute or chronic. Treat the underlying cause

Drug induced Thrombocytopenia

check for list of medications and timing

Indications for Tx for ITP

start treatment when your platelet is below 30, but you transfuse when it's 10

Post-transfusion purpura

there is exposure to foreign platelet antigen It is commonly seen in multiparous women. There will be antibodies that will cause destruction of your own platelets Sudden onset of severe thrombocytopenia, usually less than 10,000cells/mm3 after 5-7 days

Manifestations of ITP

- Petechiae, Purpura, Mucocutaneous bleeding - Bleeding is usually rare, but still possible (intracerebral bleeding) - Wet purpura (blood blisters in the mouth) and retinal hemorrhages may herald life-threatening bleeding

Management for TTP-HUS

- Plasma exchange (same concept as dialysis) - Steroids (TTP still needs immunosuppression) - Don't transfuse platelet (it will just build up and clump

Drug-induced thrombocytopenia due to heparin differs from that seem with other drugs in 2 major ways

(1) The thrombocytopenia is not usually severe, with nadir counts rarely <20,000/μL. (2) Heparin-induced thrombocytopenia (HIT) is not associated with bleeding and, in fact, markedly increases the risk of thrombosis.

Splenectomy

- 2/3 of patient can go into complete remission but some can go into relapse even when splenectomized - Response occur in 5-10 days in splenectomy - Open method is more preferred than laparoscopic - Laparoscopic has lower rate of complications but there is a chance of the presence of accessory spleen Indication: o Relapse after steroid use

DIC

- Either be acute or chronic - Most common cause is infection - There is consumption of liver coagulation factors - Increase in fibrinogen degradation products - Will lead to significant bleeding, a vicious cycle - Chronic is common in cirrhotic patient

Prevention and Treatment for Post-transfusion purpura

- Give antibody suppresants such as IVIg - Avoid giving HbA1+ platelet - Give washed RBC to remove passenger platelets or contaminated platelets

Predisposing factors of ITP

A history of preceding viral infection is noted within the preceding 3 weeks in 50-80% of cases. Nonspecific upper respiratory infections are the most common cause in postinfectious cases. In about 20% of cases, a specific infection can be identified, such as rubella, measles, varicella, pertussis, mumps, infectious mononucleosis, cytomegalovirus, hepatitis A, B, C, parvovirus or bacterial infection. ITP may also be due to smallpox or live measles vaccination

Clinical Features of TTP

Anemia (mechanical destruction) Thrombocytopenia Stroke Microangiopathic hemolytic anemia DIC Purpura, Pallor, Jaundice Presence (usually) of hemoglobinuria and hemosiderinuria Increased unconjugated bilirubin Increased lactate dehydrogenase levels (sensitive index of response to therapy or development of relapse). Organ damage: o Fluctuating neurologic signs and symptoms o Progressive renal failure (occurs in 25% of chronic patients

Clinical Features of DIC

Bleeding Thrombosis Abnormal PT, APTT Low fibrinogen Low platelet count High d-dimer

ITP

Diagnosis of exclusion. Rule out other secondary causes

Evan's Syndrome

Direct Coombs (+) autoimmune hemolytic anemia with thrombocytopenia It is still immune mediated - 50% can be idiopathic but don't forget to check for secondary causes Secondary causes: o SLE o Malignancy o Infection Evans syndrome is the combination of autoimmune hemolytic anemia and thrombocytopenia and/or neutropenia. These patients have a poor response to steroids, IVIG, or splenectomy

Management for HIT

Don't give LMWH anymore Anticoagulant: fundaparinox, argatroban, bivalirudin Long term: > 1 week For thrombosis: - Coumadin for 3 months - Warfarin > 6 mos

Notes regarding platelet transfusion

Goal: platelets should be 50,000 and above At any level of platelet count but the patient is bleeding, you can transfuse platelets. For 50,000 platelet count, we can clear the patient for appendectomy, dental extraction. NSVD (but surgeons and OB nakulbaan, gusto nila mga 80,000) In the guidelines, maintain platelets at 10,000 to avoid spontaneous bleeding. (but 20k palang nakulbaan na ta) Goal is 100,000 and above is when the patient is for neuro surgeries and optha surgeries.

Viral causes of immune thrombocytopenia

HIV, CMV, EBV, varicella, rubella, rubeola, mumps, measels, pertussis, hepatitis, parvovirus B 19

Immune Thrombocytopenias

Idiopathic - ITP Secondary - Infection-induced - Drug-induced - Post-transfusion purpura - Autoimmune hemolytic anemia - SLE - Hyperthyroidism - Lymphoproliferative disorders Neonatal immune thrombocytopenia - Neonatal autoimmune thrombocytopenia - Neonatal alloimmune thrombocytopenia - Erythroblastosis fetalis

Pathophysiology of ITP

In ITP, there are autoantibodies against platelets. These platelet coated antibodies will be phagocytosed by your macrophages, extravascularly, in the spleen Compensatorily, there will be increase in platelet production. But if the production cannot keep up, it will present with thrombocytopenia. It can be mild, moderate or severe. If the bone marrow production cannot compensate with the platelet destruction in the peripheries because of autoantibodies, then it is severe thrombocytopenia

ITP and pregnancy

It is secondary to Gestational Thrombocytopenia In pregnancy, the platelet count should be more than 80,000/mm3 and above Start Tx at 2nd or 3rd trimester - Steroid: but can cause GDM - IVIg - Splenectomy: increase risk of preterm labor especially if done in 3rd trimester -

Pathophysiology of TTP-HUS

Normally the ultra-high-molecular-weight multimers of von Willebrand factor (VWF) produced by the endothelial cells are processed into smaller multimers by a plasma metalloproteinase called ADAMTS13 In TTP the activity of the protease is inhibited, and the ultra-high-molecular-weight multimers of VWF initiate platelet aggregation and thrombosis.

Non-immune thrombocytopenia

Platelet consumption - Microangiopathic hemolytic anemia - DIC - Virus associated hemophagocytic syndrome - Kasabach-Merritt syndrome - CHD Platelet destruction - Drugs (ristocetin, protamine sulfate, bleomycin) - Infections - Cardiac (prosthetic heart valves - Malignant hypertension

Management for ITP

Platelets < 20,000-30,000 no bleeding (Adult) - Steroids Platelets is 30,000-50,000 no bleeding - watch and regulate Platelets is 10,000-20,000 with significant bleeding - Start IVIg and Prednisone Chronic ITP ? 12 months and refractory to initial tx - Splenectomy If platelet is <50,000 with active bleeding - Steroids - IVIg - Rituximab

TTP HUS

Secondary to infection, drugs, malignancy or autoimmune Because of microvascular thrombosis you may have Acute kidney injury, increase creatinine, hematuria, proteinuria, fever In TTP, it should be Coomb's (-) and DIC screen (-), normal PT and APTT kid with recent illness --> renal failure + purpura / Low PLTs + hemolytic anemia (normal coags)

IVIG

Slow down platelet consumption - Accelerate autoantibody metabolism - Reduce autoantibody production Advantages: o Rapidly acting o No toxicity Disadvantages: o High cost o High relapse rate Indications: o Life threatening bleeding o Steroids are ineffective

Acute acquired TTP

This has been attributed to an autoantibody and is best termed autoimmune TTP because of the presence of ADAMT13 IgG inhibitors

Hemolytic uremia Syndrome

Triad: acute nephropathy, microangiopathic hemolytic anemia, thrombocytopenia; neutrophils damaging vascular endothelium; bloody diarrhea, oligouria/anuria, pulm congestion, left shift Escherichia coli O157:H7 is the most frequent, although not only, etiologic serotype. HUS not associated with diarrhea (termed DHUS) is more heterogeneous in presentation and course. Some children who develop DHUS have been found to have mutations in genes encoding factor H, a soluble complement regulator, and membrane cofactor protein that is mainly expressed in the kidney

Bacterial causes of immune thrombocytopenia

Tuberculosis Typhoid

TTP

a rare multisystem disease. It can be acute (acquired) or chronic (inherited). It may be secondary to an underlying disease platelet thrombi form in areas of endothelial injury to small vessels -> consumption of platelets

Idiopathic Thrombocytopenic Purpura

an acquired disorder in which there is immunemediated destruction of platelets and possibly inhibition of platelet release from the megakaryocyte Check secondary causes first before diagnosisng ITP - SLE, CLL, Evan's syndrome, AIHA, Autoimmune thyroid diseases, infection, vaccination, Transplantation

Alloimmunization

antibodies are produced each time you transfuse and the next time you transfuse, thse antibodies might attack your platelets

ITP in children (<10 yo)

has high remission rates within 6 months, usually after a viral infection

TTP-HUS

is a medical emergency. Consult a nephrologist and hematologist

Heparin-induced Thrombocytopenia

is defined by a fall in the platelet count to less than 150,000/mm3, or a decrease in the platelet count by 50% in patients with preexisting thrombocytopenia. It is due to an autoantibody directed against heparin in association with platelet factor 4. This antibody binds to and activates the Fc receptor on the platelet surface leading to platelet activation. HIT occurs 5 or more days after starting heparin, if the patient has not received heparin before. In patients with previous exposure, it can develop within 48 hours

ITP + Splenomegaly

it might not just be because of plain ITP, check also for cirrhosis, hypersplenism, low thrombopietin

Megakaryocyic thrombocytopenia

normal or increased megakaryocytes in the marrow

4 T's of HIT

o Thrombosis o Thrombocytopenia o Timing: within 3-7 days o <30 days ago of heparin exposure

Cirrhotic patients

patient will have deranged PT and APTT. Don't transfuse if without bleeding. Has deranged clotting factors 9, 10, 7, 2. Factor 8 is not affected because it's in the sinusoids

Drug Induced Thrombocytopenia

predictable decrease in platelet count occurs after treatment with many chemotherapeutic drugs due to bone marrow Platelet destruction due to exposure to the drug It can lead to megakaryocyte defect or decrease production Common in antibiotics (e.g. betalactams, rifampicin) The thrombocytopenia typically occurs after a period of initial exposure (median length 21 days), or upon reexposure, and usually resolves in 7-10 days after drug withdrawal

Chronic Hereditary TTP

unusually large multimers of von Willebrand factor (UL-vWF) bind to platelet GP Ib/IX and GP IIb/IIIa complexes efficiently and induce platelet aggregation. These UL-vWF multimers are synthesized by endothelial cells and processed into multimers of normal size through the action of a vWF-cleaving metalloproteinase, ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeat). In chronic relapsing TTP, mutations in the ADAMTS13 gene result in markedly decreased protease activity and the accumulation of very large size vWF multimers in the plasma that are responsible for the initiation and propagation of intravascular coagulopathy observed in TTP

ITP in adults

usually chronic and spontaneous remission is only 5%