Table of contents
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Introduction
- Sticky cells, made in bone marrow from megakaryocytes.
- TPO drives production of platelets (along with cytokines like IL-11)
- Normal lifespan 7-10 days (1/10th replace daily).
- Normal: 150,000-400,000
- Symptoms of Platelet Dysfunction:
- Mucocutaneous bleeding (primary hemostasis)
- Important Points:
- Do not transfuse platelets in HIT and TTP
- Avoid transfusing platelets in DIC (consider if bleeding)
Thrombocytopenia
- Defined as Platelet Count < 150,000
- Isolated thrombocytopenia is not due to bone marrow syndromes!
- Causes
- Underproduction:
- Vitamin B12, Folate deficiencies (often causes pancytopenia)
- Peripheral Destruction
- Splenic Sequestration
- Underproduction:
- Causes:
Causes of Thrombocytopenia
Underproduction
| Destruction:
Splenic Sequestration
|
- Often detected incidentally.
- Platelet Counts:
- 100,000-150,000 --> No increase in bleeding risk;
- 50,000-100,000 --> NOT significant bleeding risk
- <50,000 --> Mucocutaneous bleeding
- <10,000 --> Increased risk of spontaneous ICH (RARE! even with low plts).
Approach
- Establish Cause!
- Look at history of platelet counts, family hx, etc..
- Drugs, herbals, eating/drinking (i.e. tonic water has quinine), HIV, EBV etc..
- Physical Exam:
- Lymphadenopathy (lymphoproliferative/myeloproliferative)
- Hepatic
- Skin Exam (mucocutaneous bleeding? petechiae, ecchymosis?)
- Wet purpura are petechiae in oral mucosa = high risk of spontaneous intra-cranial hemorr.
- Labs:
- CBC, Diff
- (Anemia leukopenia --> bone marrow disease, leukocytosis --> acute/chronic leukemia)
- Peripheral Smear**
- Platelet Clumping? causes pseudothrombocytopenia.
- Sometimes clump in EDTA in purple-top tubes, laboratory artifact. Counter does not detect as many platelets).
- If suspect pseudo: Send blood in heparin or citrated tube, or blood film!!!
- Schistocytes: microangiopathic process?
- Platelet Clumping? causes pseudothrombocytopenia.
- Liver Chemistry, Creat, TSH, Electrolytes, B12, Folate, PT, aPTT, fibrinogen, D-Dimer
- Bone Marrow
- Bone Marrow biopsy is NOT routine, only indicated if:
- 1. Multiple cell lines affected
- 2. Myelodysplasia/leukemia consideration
- 3. If therapy for ITP is usuccessful
- Bone Marrow biopsy is NOT routine, only indicated if:
- CBC, Diff
Immune Thrombocytopenic Purpura
- Auto-antibodies against platelet surface --> platelet destruction
- ALSO Decreased platelet production (NEW studies), new drugs target production.
- Common, Children > Adults (often self-limited in children)
- Symptoms:
- Mild-to-Severe bleeding
- New onset thrombocytopenia, wet purpura, hemorrhagic symptoms.
- Diagnosis:
- Diagnosis of exclusion
- Supportive findings: otherwise normal CBC (or anemia from bleeding), absence of organ dysfunction, normal blood smear.
- Diagnosis of exclusion
- Labs:
- Normal CBC (or anemia from bleeding)
- No organ dysfunction
- Blood smear normal (can see larger platelets, just released from BM)
- Usually new platelets more effective = less bleeding than expected
- Hence: often patients asymptomatic
- ITP causes:
- Drug-Induced
- Autoimmune (Lupus, HIV, lymphoproliferative CLL, etc..)
- Treatment
- Not all patients require treatment (often plts 30-40, no bleeding, 15% risk of more severe ITP)
- Follow: CBC q2weeks or so
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Indications for treating ITP
1. Platelets < 30,000-40,000
2. Active Bleeding
- if plts < 30-40 or if bleeding.
- 1st Line: Corticosteroids is mainstay or therapy, but can taken time to take effect.
- Prednisone or Methylprednisolone (1-2mg/kg/day)
- Some suggest high-dose dexamethasone, for lower relapse rate. (not tested)
- Initial response: 75-80% of pts, relapses common
- Prednisone or Methylprednisolone (1-2mg/kg/day)
- If don't respond to steroids and continue to bleed:
- Can use adjunctive IVIG or (anti-D Ig, esp in pregnant) - especially if bleeding or plts < 10.
- More quick than steroids, often in actively bleeding (rare), or requiring surgery.
- IVIG quickly elevates platelet count while steroids are taking effect.
- Anti-D Immune globulin can be alternative if spleen intact and Rh-positive blood.
- Anti-D IgG attacks RBCs with Rh+ receptor, and its immune-mediated clearance saturates the Fc-gamma receptors in spleen, minimizing removal of ITP-antibody-coated platelets.
- More quick than steroids, often in actively bleeding (rare), or requiring surgery.
- Other Drugs: Rituximab, or Mycophenylate Mofetil
- Can use adjunctive IVIG or (anti-D Ig, esp in pregnant) - especially if bleeding or plts < 10.
- Splenectomy
- For refractory ITP.
- Effective in 75%, However rituximab replaced splenectomy in many places
- NEW: Etrombopag (PO), Romiplostim (IV) (Thrombopoietin receptor mimetic)
- Approved for refractory ITP (often need special prescribing privileges)
- Can increase platelet counts in patients with ITP
- Not all patients require treatment (often plts 30-40, no bleeding, 15% risk of more severe ITP)
Drug-Induced Thrombocytopenia
- Many drugs can do this, but mostly:
- Antibiotics (B-lactams, cephalosporins, sulfa, vancomycin)
- Quinine (off market)
- Still exists in tonic water
- GpIIBIIIA inhibitors
- Treatment:
- Discontinue offending blood, platelets should recover.
Heparin Induced Thrombocytopenia (HIT)
- 1-3% of patients treated with Unfractionated Heparin
- UFH has a 7-fold higher risk than LMWH.
- More likely post-CV or post-Ortho surgeries compared to medical pts.
- In Renal Failure: HIT is uncommon
- 5-10d after exposure to heparin, >50% decrease in platelet count.
- Some develop HIT rapidly in 1-2 days, but RARE. (esp if already received before).
- High risk of clotting - (24-fold increased risk)
- Pathophysiology:
- Platelet Factor 4 (in alpha-granules) binds heparin, develop antibodies to that complex.
- Fc portion of the antibody binds to platelets --> plt activation --> degranulate --> more PF 4 release --> etc.
- Antibodies bind glycosaminoglycans (heparin-like compounds) on endothelial cell surface, causing endothelial damage --> THROMBOSIS
- Presentation:
- Low platelets
- Arterial or Venous thrombotic events (despite thrombocytopenia)
- Diagnosis:
- Screen: Pre-Test Probability based on 4-T Score: (has very high NEGATIVE Predictive value)
- Prospectively validated tool
-
4-T Score of HIT (For Pre-Test probability)
2 points - T - Thrombocytopenia (>50% decline in plt number)
2 points - T - Timing (5-10 days after heparin administration)
2 points - T - Thrombosis (Confirmed new thrombosis)
2 points - T - Thrombocytopenia (Exclucing other causes)
Points Interpretation 0 - 3 Low Probability 4 - 5 Intermediate Probability 6 - 8 High Probabilit
- Diagnosis:
- Step 1:
- ELISA (EIA): Antibody test for Anti-PF4 (sensitive, but lacks sensitivity, lots of false-positives)
- Step 2: (High Sensitivity + High Specificity)
- Functional Assay: Heparin-induced platelet aggregation assay.
- (Radiolabeled C14 serotonin release assay).
- (incubate plts with C14 serotonin, then incubate with heparin concentrations, and check if C14 serotonin released into supernatant)
- Functional Assay: Heparin-induced platelet aggregation assay.
- Step 1:
- Caution: HIT possible <5days, thrombotic event can occur even after heparin d/c'ed.
- Can cause skin necrosis (similar to warfarin)
- Screen: Pre-Test Probability based on 4-T Score: (has very high NEGATIVE Predictive value)
- Treatment:
- STOP heparins (lines, heparin-impregnated catheters)
- Anticoagulate (24-fold increased risk)
- Options:
- Leparudin (from medicinal leech, CAUTION in renal impairment)
- Argatroban to treat hypercoagulable state (REQUIRED) - FDA approved
- Other: (Not FDA approved HIT treatments)
- Bivalirudin (Only for HIT + PCI in heart disease)
- Fondaparinux also has been used b/c easy single daily injection (evidence not as good, but still used in US+Europe for HIT).
- DO NOT USE WARFARIN IN ACUTE STATE => risk of limb gangrene based on one study. (use it later)
- DO NOT TRANSFUSE PLATELETS!!!
- Options:
Microangiopathic Hemolytic Anemia (MAHA)
- Abnormal activation of platelets and endothelial cells --> deposition of fibrin in peripheral vasculature.
- Leading to peripheral destruction of erythrocytes and decreased platelets.
- Clinical Features:
- Thrombocytopenia
- Schistocytes on blood smear
- Increased LDH
Disseminated Intravascular Coagulation (DIC)
- Begins with abnormal thrombin generation --> rapid consumption of clotting factors, platelets, accelerated fibrinolysis.
- Hemorrhage can result from low factors.
- Histopathology --> fibrino clot in microvasculature.
- Thrombotic microangiopathy can also occur (Schistocytes - only in 30%, not absolute)
- Conditions that cause DIC:
Obstetric complications Eclampsia Retained products Fetal demise Amniotic fluid embolus Placental abruption | Infection Gram-negative bacteria Gram-positive bacteria Rickettsial organisms Fungi Viruses (hemorrhagic fevers such as dengue, Ebola, in particular) | Tissue injury Crush injuries Severe burns Brain injury | Tumors Solid tumors Acute leukemias (especially acute promyelocytic leukemia) | Venoms Snake bites Brown recluse spider bites |
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Diagnostic Features:
- Low Platelets
- Prolonged: PTT, PT
- Low or decreasing Fibrinogen
- High D-Dimer
Schistocytes - only in 30%, only if angiopathy is present.
- Treatment:
- Treat underlying disorder
- Supportive Transfusions If Bleeding: Plasma, Cryoprecipitate (esp if fibrinogen low), platelets.
- Know that consumption of transfused products can make microvascular thrombosis worse
- Transfuse platelets only if bleeding
- Source: MKSAP 16/ACP
Thrombotic Thrombocytopenic Purpura (TTP)
- Grouped with HUS and atypical HUS because present and treated similarly (plasmapheresis)
- TTP: Thought to have an immune cause. (most have sporatic form).
- Pathophysiology:
- Protein called ADAMTS13 (protease that cleaves high-molecular weight multimers of vWF).
- vWF is a sticky protein that is usually in multimers (higher molecular weight multimers are stickier)
- ADAMTS13 breaks down the multimers to less sticky molecules.
- Acquired/Sporatic Form:
- Autoantibodies against ADAMTS13 --> causing more sticky vWF to accumulate --> deposition of fibrin.
- Fibrin causes fragmentation of RBCs --> Schistocytes
- Autoantibodies against ADAMTS13 --> causing more sticky vWF to accumulate --> deposition of fibrin.
- Congenital:
- Born with low or absent levels of ADAMTS13
- Protein called ADAMTS13 (protease that cleaves high-molecular weight multimers of vWF).
- Triggers:
- Drugs (Quinine, Ticlopidine, Mitomycin C, Cyclosporine, Gemcitabine)
- [Secondary to endothelial damage, doesn't cause antibodies]
- Pregnancy
- HIV/AIDs
- Transplant (solid organ or bone marrow)
- Drugs (Quinine, Ticlopidine, Mitomycin C, Cyclosporine, Gemcitabine)
- Symptoms: (pentad)
- 1. Fever
- 2. Mental Status Change (headache, confusion --> progress to seizures, coma)
- 3. Acute Renal Failure
- 4. Thrombocytopenia
- 5. MAHA (Schistocytes in blood film)
- Diagnosis:
- Suspect in patients with MAHA (Schistocytes, thrombocytopenia, high LDH).
- Lab Coagulation Tests (PT, PTT) are NORMAL!! (distinguishes it from DIC)
- **Peripheral Smear** --> Scistocytes, Nucleated RBCs, Low platelets
- ADAMTS13 Activity --> Used for prognosis only
- Treatment:
- LIFE THREATENING!
- 20% can die in first 24hrs. (almost always fatal if untreated)
- Plasma Exchange emergently if high suspicion - even before results (once daily, sometimes BID for 3-7d)
- Superior to simple plasma transfusion in RCT
- Plasma exchange decreases a 90% mortality to 10%
- Plasma Exchange gives intact ADAMTS13, and removing damaged one.
- FFP transfusion is inferior, but can do it if plasma exchange unavailable (better than nothing)
- keep going until platelet count is > 150,000 x2 days, and LDH normalizes.
- Superior to simple plasma transfusion in RCT
- DO NOT transfuse platelets, UNLESS bleeding
- Plts can cause sudden death (by causing more microvascular occlusion)
- Corticosteroids
- Almost always used, but no RCTs showing benefit.
- LIFE THREATENING!
Hemolytic Uremic Syndrome (HUS)
- Occurs in children, very rare
- Due to E.coli O157H7.
- Hallmark is Complement activation
- Characterized by more renal manifestations, and fewer neurologic sequelae
- Often preceeded by infectious diarrheal illness.
- Typical HUS (Infection-Related)
- Preceeded by infectious diarrhea (E.coli O157H7, or shingella species)
- Shinga toxin resembles antigens on renal endothelial cells, bind, and cause renal cell death.
- Atypical HUS (Congenital)
- Abnormality in complement proteins
- Treatment:
- Plasma exchange
- HUS does not respond to plasma exchange as well as TTP
Atypical HUS
- Genetic cause of HUS
- Inability to turn off C3 convertase leading to persistent complement activation
- Factor H usually inhibits C3. Factor H stopped by either antibody or genetically inactive.
TTP/HUS Mimics:
- Other causes of MAHA:
- Malignant HTN
- HELLP
- APLA
- Scleroderma renal crisis
Thrombocytopenias due to Underproduction
- Inadequate megakaryocyte in BM.
- Any BM failure syndrome:
- Aplastic Anemia, Myelodysplasia, Vit B12, Folate deficiency, Fanconi Anemia.
- Invasion of marrow by: leukemia, granulomatous disease
- Also: inonizing radiation, infection, drugs (esp EtOH)
- Platelet transfusions typically effective for preventing bleeding
Platelet Function Disorders
- Platelet count is OK but platelets aren't working.
- NOTE: NO routine recommendation to screen coagulation preoperatively.
- Guidelines: Screening for platelet dysfunction recommended ONLY for personal or family hx of mucocutaneous bleeding.
- Labs:
- "Bleeding Time Tests" - No longer performed (not reliable)
- PFA-100 (Platelet Factor Analyzer Assay - new "bleeding time"), screens for primary hemostasis
- Recommended for pts with personal or family hx of mucocutaneous or post-surgical bleeding.
- Whole citrated blood aspirated to an aperture in a cartrige. Membrane of aperture activates platelets, which clump and eventually block aperture, halting flow of blood.
- Closure time is recorded (prolonged in severe platelet dysfunction).
- Prolonged in vWF, or platelet dysfunction syndromes, but may be normal if mild.
- Platelet Aggregation Testing: (available only in certain centers)
- Suspend platelets, and measure light transmission.
- When aggregate --> increased light transmission
- Suspend platelets, and measure light transmission.
Acquired
- Uremia
- Dysfunctional platelets.
- DDAVP (Desmopression) is first line in a bleeding uremic patient.
- Dialysis eventually required to fix platelets.
- Conjugated estrogens can help with mucosal bleeding (if desmopressin/dialysis not effective)
- Myeloproliferative / Myelodysplastic syndrome
- Platelets may be disfunctional.
- Transfuse platelets if needed.
- Drugs / Herbs
- ASA irreversibly acetylates and inhibits COX in platelets, rendering them dysfunctional.
- NSAIDs causes platelet dysfunction, but is reversible.
- ADP-antagonist (clopidogrel) --> irreversible.
- Foods:
- Garlic
- Chinese black tree fungus
- Ginseng
- Patients with a predisposition (i.e. vWF disorder) can have more severe bleeding with these.
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