Thrombocytopenia

TTP - Thrombotic Thrombocytopenic Purpura

*A process, characterized by abnormal activation of platelets and endothelial cells, with von Willebrand factor (VWF) and fibrin deposition in the microvasculature, and peripheral destruction of platelets and red cells.*

ITP - Immune/Idiopathic Thrombocytopenic Purpura

*Diagnosis of exclusion. There is no diagnostic test* (Unlike AIHA) In children, usually provoked by viral illness. Spontaneously remits No specific therapy usually required. In adults, specific therapy required if platelet count is <20- 30 or if patient is bleeding. Platelets may be slightly bigger b/c they are newly formed

Platelet transfusions

*In ITP, transfused plts will not raise plt counts, so use only if severe bleeding* (ie bleeding causing a rapid Hgb drop or bleeding severe enough to cause end-organ damage) **In TTP--contra-indicated** *In DIC—give to treat bleeding* In *splenic sequestration*, transfused plts also home to spleen, so *reserve transfusions for severe bleeding.* In *hypo-production* - there tends to be a numerical trigger (10K) to transfuse.

TTP: Etiology

*Sporadic* (i.e. not familial or from secondary causes) cases are due to with an autoantibody against the protease which cleaves the ultra-large molecular weight multimers of von Willebrands factor. The protease is called *ADAMTS-13*, (A Disintegrin And Metalloprotease with Thrombospondin-like repeats). We can measure activity levels of ADAMTS-13, as well as the presence of an inhibitor to ADAMTS-13. *This antibody blocks the function of the protease, leading to accumulation of the ultra-large molecular weight vWF multimers.* *These ultra-large vWF multimers lead to abnormal platelet activation.*

DIC Treatment

1. TREAT THE UNDERLYING CAUSE!!! 2. Supplemental supportive treatment for patients who are bleeding or who are at risk for bleeding can include giving platelets, *fresh frozen plasma (FFP)* to replace clotting factors,* cryoprecipitate* to replace fibrinogen. Sometimes heparin at very low doses is used to try to prevent thrombin generation, but this is controversial.

What causes platelet Thrombocytopenia due to underproduction?

1. The hallmark of these disorders are is the presence of inadequate megakaryocyte numbers in the marrow. 2. Some causes include: a. *Marrow failure* - aplastic anemia, myelodysplasia, vitamin B12/folate deficiency, Fanconi's anemia b. *Marrow invasion* - leukemias, tumors, granulomatous diseases, fibrosis c. *Marrow injury* - drugs (especially remember alcohol, chemotherapy), radiation, infections d. Congenital - Wiskott-Aldrich Syndrome, Thrombocytopenia Absent Radius Syndrome (TAR), May-Hegglin (I'm not going to ask you about these)

DIC Diagnosis

2. Diagnosis relies on a. *Elevated PT* (prothrombin time), due to consumption of Factor VII, which has the shortest half life (4-5 hours). The aPTT may also be elevated if DIC is severe, as other clotting factors get consumed. b. *Fibrinogen levels should be low and progressively falling*, **If fibrin or PT is normal it is NOT DIC** c. *Elevated D-Dimers or FDPs* (fibrin degradation products), d. *Low platelets.* e. May also see low clotting factor levels. f. May be associated with microangiopathic hemolytic anemia (MAHA), which causes *schistocytes* on the peripheral blood smear, but MAHA does not need to be present (in fact—it's there only about 70% of the time).

ITP Second Line Therapy

2/3 of adult patients will relapse after steroid taper, or will fail to respond to steroids. In this case, we need second line treatment. This can include: *Rituximab*—off label use. Kills CD20 positive B cells *Splenectomy* (Don't forget to immunize against encapsulated organisms before spleen is out.) 2/3 of pts will respond to splenectomy and remain in remission for >10 years. There are two new agents which have been approved for use in refractory ITP. Romiplostim (NPlate) and eltrombopag (Promacta) are agents which stimulate the thrombopoietin receptor and thus stimulate platelet production.

HUS - Hemolytic Uremic Syndrome

Can overlap with TTP a. HUS has more renal manifestations, fewer neurologic sequelae b. HUS can be precipitated by *infectious diarrheal illness*, especially E. coli O157:H7 or Shigella. These bacteria elaborate a *Shiga toxin* which is similar to antigens on renal endothelial cells. The toxin binds and causes renal cell death c. This is much more of a pediatric disease d. HUS may respond less well to plasma exchange, but in an adult, we do not withhold PLEX because we suspect HUS. We might hold PLEX in a child.

Causes of massive splenomegaly

Chronic myelogenous leukemia (CML) Beta thalassemia major Infiltration— Sarcoidosis Gaucher's disease Myelofibrosis (either primary or secondary to PV or ET) Malaria Kala-azar (visceral leishmaniasis) Hairy Cell Leukemia

Common causes of splenomegaly

Cirrhosis (30%) Lymphoma (27%) Infection (AIDS, endocarditis) (23%) Congestion or inflammation (CHF) (8%) Primary splenic disease (splenic vein thrombosis) (4%) Other/unknown (5%)

DIC Etiologies

DIC may be initiated by a variety of causes, including sepsis, obstetrical disasters (amniotic fluid embolism, dead fetus, placental abruption), acute leukemias, severe burns, snake or insect venoms, shock.

DIC - Disseminated Intravascular Coagulation

Definition: *A process characterized by abnormal activation of coagulation, generation of thrombin, consumption of clotting factors, peripheral destruction of platelets, and activation of fibrinolysis.*

Atypical HUS

HUS *without* the diarrhea prodrome i. First hit is an inherited *defect in complement regulation, such that there is too much complement activation* 1. So this would be a deficiency in a complement inhibitor 2. Or over-expression of a complement activator ii. Next hit is is something that starts the process of complement activation such as an *infection or pregnancy* Clinical features/diagnosis: i. MAHA and thrombocytopenia ii. Renal dysfunction iii. Evidence of complement dysregulation (this one is the trickiest, since very few labs actually can do the assays for complement function and sequence the complement regulatory genes) c. Treatment i. PLEX ii. eculizumab (remember this one from treating PNH).

TTP Etiology cont'd

If not congenital or autoimmune, TTP can be induced by drugs, including ticlopidine, *quinine, cyclosporine, tacrolimus, gemcitabine.* Drug-induced TTP may not be related to problems with ADAMTS-13 Increased incidence with *pregnancy or AIDS*

TTP Prognosis

Incidence 1 in 50,000 *> 90% fatal without therapy* *80-90% survive with therapy* One third of patients will relapse within 10 yrs, most within one month of diagnosis. Accurate and prompt diagnosis and treatment is key to survival

First line ITP Therapy

Initial therapy relies on use of *corticosteroids* (e.g. prednisone, methylprednisolone). These can take 48-72 hrs to take effect. If platelet count is <10K or if patient is bleeding, need more rapid therapy--use *IVIg*

What causes platelet Thrombocytopenia due to Peripheral Destruction?

Non-immune mechanisms: e.g. DIC, TTP Immune Mechanisms: antibody-mediated platelet destruction can be provoked by drugs can be associated with HIV can be associated with other autoimmune disease can be idiopathic

Why do we start treating Atypical HUS with PLEX?

PLEX may not fully work, but we need to start this in case it turns out to be really TTP

Thrombocytosis

Primary - i.e. myeloproliferative syndromes Diseases include Essential Thrombocythemia, Polycythemia Vera, CML and myelofibrosis These platelets are both hyper- and hypo-functional May lead to thrombosis and/or bleeding Secondary - i.e. reactive Causes include inflammation, infection, bleeding, iron deficiency Treat the underlying cause. Usually does not lead to thrombosis

Heparin-Induced Thrombocytopenia

Seen in 1-3% of patients treated with heparin Usually, 7-10 d after heparin started, platelets fall by at least 30-50%- Caused by antibodies against the complex of heparin/PF4 *IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY.* Can lead, paradoxically, to *THROMBOSIS*, in some patients (the pathogenic antibodies lead to platelet activation).

What are symptoms of thrombocytopenia?

Symptoms of thrombocytopenia - "mucocutaneous bleeding" "AKA oozing and bruising" - i.e. epistaxis, gum bleeding, heavy menses, easy bruising, petechiae. a. NOT joint bleeds and muscle bleeds!! - these are more characteristic of hemophilia and other factor deficiencies. b. These symptoms are the symptoms of a defect in primary hemostasis

What is Thrombocytopenia and Thrombocytosis?

Thrombocytopenia: Too few platelets Thrombocytosis or Thrombcythemia: Too many platelets

Shiga toxin

Toxin produced by Shigella The toxin binds and causes renal cell death and cause infectious diarrhea that precedes HUS

TTP Treatment

Treatment relies on *PLASMA EXCHANGE (PLEX)* >> remove some of the autoantibodies and much of the ultra-high MW multimers of vWF. We are replacing fresh stores of the ADAMTS-13. Remove all inciting agents. We also use corticosteroids, but these are of limited benefit without PLEX. Secondary measures if no response to plasma exchange include splenectomy, vincristine. Rituximab has been used in cases of relapse. **AVOID PLATELET TRANSFUSIONS - THEY "FUEL THE FIRE"** >> Since abnormal platelet activation is one of the hallmarks of pathogenesis, transfusing fresh platelets can "fuel the fire" and lead to more microvascular occlusion.

**Thrombocytopenia: What are the three broad categories of causes?**

Underproduction Peripheral Destruction Splenic sequestration

Pseudothrombocytopenia

When evaluating a patient with thrombocytopenia, first, make sure the patient doesn't have pseudothrombocytopenia, AKA "platelet clumping" Certain pts make a substance that causes platelets to clump when blood is added to EDTA-anticoagulated test tubes - The Coulter counter fails to recognize the platelet clump as a mass of platelets because it's too large. *Plt count artifactually low* *Plt count is higher in vivo than what is reported.* No bleeding consequences No treatment needed

Pentad of TTP Diagnosis

a. Microangiopathic hemolytic anemia (MAHA) i. MUST have this feature ii. Characterized by elevated LDH (lLactate dehydrogenase), Schistocytes on the peripheral smear b. Thrombocytopenia - this feature MUST be present c. Fever - not always seen. d. Renal manifestations - hematuria, elevated creatinine, proteinuria. - not aways seen e. Neurologic manifestations - headache, confusion, sleepiness, coma, seizures, stroke - not always seen

At what level of platelets to you usually start to see symptoms?

around 50,000

Drugs which cause thrombocytopenia:

i. beta-lactam antibiotics, ii. Sulfa drugs, especially trimethoprim-sulfamethoxazole (Bactrim or Septra), iii. *HEPARIN* iv. quinine/quinidine v. GP IIb-IIIa inhibitors

Eculizumab for HUS

ii. Treat ultimately with eculizumab (remember this one from treating PNH). 1. This blocks C5, thus prevents terminal complement activation 2. Needs to be given at higher doses than for PNH—but still every 2 weeks—pretty much forever. At this dose, cost might be $700,000 or so per year

Should this person receive a platelet transfusion? 1. 55 y.o. man, plts 7, nl PT/aPTT, no schistos, no bleeding

no

Should this person receive a platelet transfusion? 5. 45 y.o. man plts 7, no bleeding, 2+ schistos

no - TTP (contra indicated)

Should this person receive a platelet transfusion? 2. 35 y.o. woman, plts 22, prolonged PT/aPTT, low fibrinogen, serious vaginal bleeding

yes

Should this person receive a platelet transfusion? 3. 45 y.o. man with leukemia, plts 7, no bleeding

yes

Should this person receive a platelet transfusion? 4. 45 y.o. man with splenomegaly, plts 23, 0 schistos, massive bleeding

yes