Lecture 13_ Platelet Disorders

It suggests a structural lesion.

A family history of bleeding or bleeding since childhood indicates hereditary coagulopathies.

It indicates a primary hemostasis disorder.

Hematoma or hemarthrosis is associated with secondary hemostasis disorders.

Mucosal bleeding or bruising is nonspecific and often indicates primary hemostasis.

Petechiae are red or purple spots caused by minor hemorrhage, indicating issues with primary hemostasis.

A hematoma is clotted blood within tissues or articular spaces, indicating problems with secondary hemostasis.

Petechial and purpuric hemorrhages are commonly associated with meningitis and endocarditis.

Cutaneous petechiae and purpura can occur as a drug reaction without causing thrombocytopenia.

Scurvy and Ehlers-Danlos syndrome are associated with microvascular bleeding due to collagen defects.

Symptoms include purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis.

Hereditary hemorrhagic telangiectasia is associated with a TGF-ẞ mutation.

Perivascular amyloidosis weakens vessel walls, commonly seen in light-chain amyloidosis.

Thrombocytopenia is defined as a platelet count below the lower limit of normal, resulting from either reduced production or increased destruction.

The grades of thrombocytopenia are mild (100-150 x 10³/mm³), moderate (50-99 x 10³/mm³), and severe (<50 x 10³/mm³).

Surgical bleeding is typically observed when the platelet count is below 50 x 10³/mm³.

Thrombocytopenia is usually not recognized clinically until the platelet count is below 100 x 10³/mm³.

Usually self-limited, rarely develops into chronic ITP

Chronic immune thrombocytopenia commonly affects adults aged 20-40 years.

Chronic immune thrombocytopenia is more common in women.

Clonal expansion of CD8+ cytotoxic lymphocytes may play a role independent of autoantibodies.

HIV-associated thrombocytopenia is the most common cause.

Thrombocytopenia may occur at any time during HIV infection.

Platelet aggregation and activation occur, leading to the formation of a haemostatic plug.

Defects of primary hemostasis and defects of secondary hemostasis.

Thrombocytopenia and elevated creatinine levels indicate a potential diagnosis of HUS.

It may be due to direct effects of HIV on hematopoietic stem cells or immune processes.

Thrombocytopenia is more common with progressive immunosuppression.

Splenomegaly may present in patients with HIV-associated thrombocytopenia.

An HIV test should be considered if thrombocytopenia is unexplained.

In TTP, PT (INR) is normal or slightly increased, unlike DIC which is increased.

Fibrinogen levels in TTP are normal.

Therapies for TTP include plasma exchange and vincristine.

Common clinical presentations include easy bruising, bleeding such as menorrhagia, purpura, and petechial rash.

Treatment is supportive and may include DDAVP or a similar approach to Glanzmann's Disease.

TTP is associated with schistocytes in red blood cells.

Platelet activation leads to the formation of a platelet plug, crucial for stopping bleeding.

The key function of platelets is quickly forming mechanical plugs in response to vascular injury.

Platelets adhere to the site of vascular injury.

ITP is not sick, while TTP and DIC are both sick.

The initial cell type is the Hemocytoblast.

The final product is Platelets.

The Megakaryocyte releases fragments to form platelets.

The stages are Hemocytoblast, Megakaryoblast, Promegakaryocyte, Megakaryocyte, and Platelets.

The key components are no platelet activation, abnormal platelet function, and vessel abnormality.

The main issue is abnormal coagulation factors.

Tissue factor is released from damaged blood vessels.

Fibrin forms a blood clot, which is essential for hemostasis.

The correlation between platelet count and bleeding risk varies according to the clinical condition and may be unpredictable.

Spontaneous bleeding is associated with a platelet count below 10 x 10³/mm³.

Common causes include immune thrombocytopenia (ITP) and gestational thrombocytopenia during pregnancy, while less common causes are occult liver disease, myelodysplastic syndrome, congenital thrombocytopenia, and HIV infection.

Causes include drug-induced thrombocytopenia and immune thrombocytopenia (ITP).

Common causes include heparin-induced thrombocytopenia, immune thrombocytopenic purpura, drug-induced thrombocytopenia, liver disease, sepsis with DIC, cancer with DIC, and pregnancy-related conditions.

Less common causes include thrombotic thrombocytopenic purpura, drug-induced thrombotic microangiopathy, hemolytic uremic syndrome, lymphoma, acute leukemia, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, and nutrient deficiencies.

ITP is one of the most common autoimmune disorders affecting platelet levels.

The two types are acute and chronic immune thrombocytopenia.

ITP is more common in boys during childhood and in women if middle-aged.

Primary ITP has no other causes, while secondary ITP is due to medications or systemic disorders.

ITP may involve autoreactive T cells and autoantibodies targeting platelet GP IIb/IIIa complex or Ib/IX.

It is usually self-limiting and lasts for weeks.

It is almost exclusively found in children.

It is usually preceded by a viral infection or vaccination.

Usually, treatment is not needed.

The causes for autoantibody production are unclear, likely due to exposure to cryptantigens or pseudoantigens.

They induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily in the spleen.

Usually sudden onset

Mild bleeding or petechiae unless platelet count is less than 20 x 10³/mm³

Secondary thrombocytopenia

Clinical diagnosis in well-appearing patients with mucocutaneous bleeding and laboratory confirmation of isolated thrombocytopenia

Observation regardless of platelet count

IVIg, Rhlg, corticosteroids, etc.

Autoantibodies against platelet GPIIb/IIIa or GPIb/IX are associated with chronic immune thrombocytopenia.

Reduced platelet lifespan is due to antibody-mediated destruction and impaired platelet production from megakaryocyte damage.

Chronic immune thrombocytopenia is diagnosed by exclusion in patients with isolated thrombocytopenia.

Common features include insidious onset, bleeding in skin or mucosa such as petechiae and purpura, potential for severe hemorrhage, variability in thrombocytopenia severity, and possible splenomegaly.

First-line: corticosteroids. For acute or severe bleeding: IVIg and platelet transfusion. Second-line/chronic options: splenectomy, rituximab or other immunosuppressants, and thrombopoietin receptor agonists (eltrombopag, romiplostim).

It should be considered for hospitalized patients.

Drugs can cause impairment of platelets either directly or immune mediated.

No, it is not dose related.

Heparin is one of the most reported agents, particularly causing HIT.

The primary method for diagnosis is taking a medication history.

The treatment involves withdrawing the offending agent.

A complication of heparin therapy characterized by a decrease in platelet count, primarily associated with unfractionated heparin.

Type I: nonimmune, transient, mild thrombocytopenia within 1–2 days after heparin exposure and not usually associated with thrombosis. Type II: immune-mediated (anti‑PF4/heparin antibodies), occurs 4–10 days after exposure, causes platelet activation and carries high risk of thrombosis.

Unfractionated heparin (UFH) is associated with a higher risk than low molecular weight heparin (LMWH).

Type II is life- and limb-threatening due to thrombotic complications and is the most clinically significant form of HIT.

Type I typically presents within the first 2 days after exposure to heparin.

In general medical practice, HIT refers to Type II heparin-induced thrombocytopenia.

It is caused by antibodies that bind to complexes of heparin and platelet factor 4 (PF4), activating platelets and promoting a prothrombotic state.

Thromboembolism usually presents with venous thrombosis, such as deep venous thrombosis and pulmonary embolism, and may also include arterial thrombosis like myocardial infarction.

Diagnosis is based on clinical findings, characteristics of thrombocytopenia, and laboratory studies of HIT antibodies.

The treatment involves discontinuing all heparin products and administering anticoagulations.

The prognosis includes severe consequences such as limb loss, stroke, or death occurring in 6-10% of cases.

The treatment focuses on preventing major bleeding and treating any signs of bleeding other than petechiae.

Antiretroviral therapies and IVIg are among the treatments available.

Rare disorder with widespread platelet-rich microthrombi in small vessels causing microangiopathic hemolytic anemia and thrombocytopenia; can be hereditary (severe ADAMTS13 deficiency) or acquired (autoantibodies); median onset 40–52 years; classically presents with pentad of MAHA, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease.

TTP usually occurs in adults with a median age of 40 to 52 years.

The pentad includes microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease.

TTP needs to be differentiated from hemolytic-uremic syndrome based on its specific clinical features and presentation.

Factors include deficiency of ADAMTS13, infections like E. coli O157:H7, certain medications, and pregnancy-related autoantibodies.

ADAMTS13 cleaves ultra-large von Willebrand Factor (vWF) multimers to prevent excessive platelet activation and thrombus formation.

A severe deficiency of ADAMTS13 results in uncleaved ultra-large vWF multimers, causing free-flowing vWF-platelet thrombus formation.

Clinical features include acute or subacute onset, neurologic dysfunction, hemolytic anemia, thrombocytopenia, fever, and dark urine from hemoglobinuria.

RBC fragmentation consistent with a microangiopathic hemolytic process is observed in TTP.

Megakaryocytic hyperplasia is found in the bone marrow to produce more platelets in TTP.

The pathological features include prominent hyaline thrombi within the glomerulus and small arterioles, appearing as pink, amorphous masses occluding vessel lumens.

Laboratory findings in TTP typically include normal or slightly elevated white blood cell count, moderately depressed hemoglobin (8-9 g/dL), platelet count ranging from 20-50 x 10³/mm³, moderate-to-severe schistocytosis, normal PT, aPTT, D-dimer, normal or high fibrinogen, and ADAMTS13 activity testing.

TTP is characterized by an endothelial defect.

The primary treatment for TTP is plasma exchange, which removes antibodies and VWF multimers while repleting ADAMTS13.

Plasma exchange reduces mortality from 90% to 15% in TTP patients.

Plasma exchange should be initiated in such cases.

Cryopoor plasma or corticosteroids are used for refractory TTP.

Platelet transfusion is contraindicated in TTP because it can exacerbate the condition.

It is characterized by progressive renal failure, microangiopathic hemolytic anemia, and thrombocytopenia.

Hemolytic-uremic syndrome is the most common cause of acute kidney injury in children.

It is more common in summer.

Commonly associated infections include those from S dysenteriae, E coli (O157:H7), and Salmonella typhi.

Toxin-caused endothelium injury is the primary event.

Atypical HUS presents similarly to typical HUS but is unassociated with Shiga-like toxin and commonly lacks prodromal diarrhea.

Atypical HUS accounts for 5-10% of all hemolytic-uremic syndrome cases.

Atypical HUS usually has a poor prognosis, often progressing to end-stage renal disease or irreversible brain damage.

Atypical HUS may be associated with defects in complement factor H, membrane cofactor protein (CD46), or factor I.

Up to 25% of patients with atypical HUS may die during the acute phase.

The pathogenesis of HUS is initiated by EHEC Stx1 and Stx2 variants leading to Stx retrograde trafficking and subsequent ER stress and inflammation.

Damage to endothelial cells is the primary event for HUS.

aHUS is characterized by decreased CFH, increased CFB, decreased CFI, and increased C3, leading to aberrant complement activation.

ADAMTS13 deficiency, mostly due to auto-antibody, leads to the persistence of UL-VWF and formation of platelet thrombi rich in VWF multimers in TTP.

Common clinical features include gastroenteritis with fever and bloody diarrhea, irritability, lethargy, seizures, acute renal failure, hypertension, edema, renal failure, hemolytic anemia, and defected ADAMTS-13 activity.

DIC is characterized by prolonged PT, aPTT, elevated fibrin degradation products, and D-dimer, indicating a more serious illness.

TTP is associated with mutations of the ADAMTS13 gene or the presence of acquired anti-ADAMTS13 antibodies.

Systemic vasculitis typically presents with other systemic symptoms like arthralgias and rash, and lacks a prodromal diarrheal illness.

Supportive care including red cell transfusion, platelet transfusion for significant bleeding, fluid and electrolyte management, and dialysis.

Plasma exchange is indicated for atypical HUS.

Peak incidence at 40 years

TTP is more common in females, while HUS has an equal gender distribution.

Yes, HUS is linked to E. coli 0157:H7.

Re-occurrence is common in TTP and rare in HUS.

Renal failure is uncommon in TTP but common in HUS.

Thrombocytopenia is severe in TTP and moderate to severe in HUS.

TTP involves multiple organs, while HUS is limited to the kidney.

Neurologic involvement is common in TTP and uncommon in HUS.

The initial step is to assess platelet count and creatinine levels.

A PLASMIC score of ≥5 indicates the need to collect ADAMTS13 and initiate emergent TPE.

The recommended treatment is to continue daily TPE and immunosuppressive drugs until platelet count and LDH normalize.

The treatment approach for aHUS is to discontinue TPE and begin treatment with eculizumab while monitoring renal function for improvement.

The key symptoms include anemia, schistocytes, increased bilirubin, decreased haptoglobin, and increased LDH.

It predicts the likelihood of ADAMTS13 levels being less than 10%.

A platelet count of less than 30 × 10⁹/L is a criterion.

An MCV of less than 90 fL is a criterion.

A creatinine level of less than 2.0 mg/dL is included.

An INR of less than 1.5 is a criterion.

Evidence includes a reticulocyte count greater than 2.5%, indirect bilirubin greater than 2.0 mg/dL, or undetectable haptoglobin.

It is one of the criteria used to assess the risk of low ADAMTS13 levels.

Having such a history disqualifies the patient from a lower risk category in the scoring system.

Diarrhea, particularly in children, is a key symptom that prompts testing for STEC/EHEC in suspected HUS cases.

If STEC/EHEC testing is positive, typical HUS management includes supportive measures such as aggressive fluid support and dialysis.

If STEC/EHEC testing is negative, it is important to consider alternative diagnoses for the symptoms presented.

Factitious reasons include clotted specimens, wrong patient, and pseudothrombocytopenia due to EDTA-dependent platelet agglutinins.

Consider drug use, infections, vaccinations, nutritional status, family history, and transfusion history in an allosensitized patient.

It helps identify evidence of bleeding, as CNS bleeding is a common cause of death in these patients.

Lymphadenopathy, hepatosplenomegaly, and other masses should be examined to suggest a disseminated disorder.

It is important to check for occult blood, which can indicate bleeding complications.

The skin should be examined in detail for signs of bleeding or petechiae.

Usually, no treatment is required for reactive thrombocytosis to correct platelet count.

Myeloproliferative diseases are a neoplastic cause of thrombocytosis.

Glanzmann's Disease is a rare condition caused by deficiencies of the fibrinogen receptor αIIbβ3, leading to platelet type bleeding.

Patients with Glanzmann's Disease experience platelet type bleeding from mucosa and skin.

Management includes avoiding medications that affect platelet function and treating anemia, with platelet transfusion for bleeding patients.

Recombinant Factor VIIa may be considered for bleeding patients with Glanzmann's Disease.

Bernard-Soulier Syndrome is characterized by thrombocytopenia, giant platelets, and qualitative platelet defects leading to a bleeding tendency.

It is caused by the absence or decreased expression of the GPIb/IX/V complex on platelets, which is a receptor for von Willebrand factor.

Bernard-Soulier Syndrome is inherited in an autosomal recessive manner.