Kasabach-Merritt Phenomenon

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Article initiated by:
Fabliha A. Mukit, M.D.
All contributors:
Raima Siddiqui, Shiva Bohn, Paul O. Phelps, MD, FACS, S. Grace Prakalapakorn, MD, MPH, Fabliha A. Mukit, M.D., Michael T Yen, MD
Assigned editor:
Marguerite C. Weinert, MD, Paul O. Phelps, MD, FACS
Review:
Assigned status Up to Date
 by Paul O. Phelps, MD, FACS on September 1, 2024.


Disease Entity

Kasabach–Merritt Phenomenon (KMP) refers to the clinical constellation of thrombocytopenia, consumptive coagulopathy and purpura associated with Kaposiform haemangioedothelioma or tufted angioma, but not the more common infantile haemangioma.[1] The classic association of KMP is a vascular hemangioma resulting in thrombocytopenia that was first reported in a case by Kasabach and Merritt in 1940.[2]

Disease

Kasabach-Merritt Phenomenon is a clinically heterogeneous, life-threatening consumptive coagulopathy from a rapidly enlarging vascular tumor. The two vascular tumors that are exclusively associated with KMP are kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). KHEs and TAs lie on the same neoplastic spectrum and present similarly histologically. However, their clinical presentations differ in that KHEs are a locally aggressive tumor, while TAs are benign. [3]Most cases of KMP are reported in early infancy with a median age of onset of 5 weeks, but rare cases have been reported in the early neonatal period. [2] A vast majority of KMP vascular tumors are diagnosed at birth and the most common lesion sites are the face, head, neck, thoracic cavity, abdomen and retroperitoneum, and extremities. [4] KMP is a complication of these unique types of vascular tumors that cause platelet trapping, which leads to thrombosis and hemorrhage, along with the physical burden of the growing tumor to surrounding vital organs and structures. The risk of developing KMP increases with higher levels of infiltration and depth of the vascular tumor, which can cause a higher mortality rate.[3] [5] Patients with KHEs or TAs that are complicated by KMP will require a much more aggressive treatment approach. Current treatment of KMP is geared towards resolving the coagulopathy and reducing the tumor with corticosteroids and sirolimus. Once the coagulopathy has been stabilized, surgical removal of the vascular tumors may be possible. It is estimated that the mortality rate of KMP can be up to 50%. [6]

Historical Perspective

Kasabach-Merritt Phenomenon (originally named Kasabach-Merritt Syndrome) was first described by Haig Haigouni Kasabach and Katharine Krom Merritt in 1940 where they reported the first clinical association of a capillary hemangioma with intralesional platelet sequestration with resultant profound thrombocytopenia, microangiopathic hemolytic anemia, and disseminated intravascular coagulation (DIC) with hypofibrinogenemia with elevated split fibrin products (D-Dimers). [2]

Epidemiology

KMP typically occurs in infancy, with about 80% of KMP cases happening within the first year of life. This is due to the majority of KHE and TA cases occurring in early life and can result in KMP as a complication. [3][7] About 70% of patients with KHE and 10% of patients with TA can present with KMP. (10) KMP rarely occurs in adulthood, and both genders are equally affected. There is also no ethnic predisposition. [3]

Pathophysiology

The pathophysiology of KMP is unknown, however it is theorized that the complex vascular structure of KHEs and TAs play a role in the mechanism of KMP. Platelets become trapped within the convoluted tumor, resulting in platelet activation and fibrinogen consumption. [3] It is theorized that platelet entrapment may occur physically, or through repeated exposure to the tumor’s abnormal endothelium or sub-endothelium. The platelets then adhere and aggregate to these structures, starting the coagulation cascade. [8]

Positive immunohistochemistry for CD61, a platelet marker, and consumption of radiolabeled fibrinogen currently support this theory. [8][9][3][5] High flow rates of the arteriovenous shunts found in these vascular tumors act as another mechanism for the platelet activation needed for KMP to develop. Once the coagulation cascade has started in KMP, platelets and clotting factors continue to be consumed even though fibrinolysis starts to take place. This leads to bleeding within the tumor, which clinically presents as a rapidly growing KHE or TA. [8] The KMP cycle of platelet entrapment, consumption, and bleeding continues to occur until the tumor resolves or other forms of treatment are given. [8] Although rare, KMP can result in life threatening hemorrhage and cardiac failure, leading to death. [3]

Diagnosis

The diagnosis of KMP requires identifying a vascular tumor and the following laboratory evaluation: complete blood count, coagulation panel including PT and PTT. The laboratory evaluation should reveal thrombocytopenia, increased D-dimer, prolonged PT and PTT, and hypofibrinogenemia. [3] Hemolytic anemia can also occur from the convoluted vasculature of the tumor. [9] If the vascular tumor is a cutaneous lesion, a physical exam is sufficient for a diagnosis. However, visceral vascular tumors may require an MRI for diagnosis. [2]

Clinical Presentation

Cutaneous:

Cutaneous KHEs appear as firm, violaceous, and usually solitary lesions on the trunk and extremities. They tend to be poorly defined and can also be described as shiny, tender, and purpuric-like lesions.[8] Cutaneous TAs present similarly as violaceous macules or plaques, usually on the trunk.[5] In patients with KMP, the cutaneous KHE or TA will appear as a rapidly growing and painful lesion. [3]

Visceral:

Visceral KHEs are usually found within the retroperitoneum, in the form of a solitary lesion or multiple lesions affecting one or more organs. The visceral vascular tumors will also be rapidly growing in patients with KMP, however, if the tumors are within the retroperitoneum, it may be harder to identify clinically due to the expansive space for growth before clinical symptoms present. It should be noted that if rapidly growing lesions are present on the liver or the spleen in the infant, other tumor differential diagnoses should be considered to determine the cause. [3][8]

Ocular:

Although rare, TAs can present on either the top or bottom eyelid as a slowly progressive painless swelling over the course of a few months up to a few years. Redness and tenderness to eyelid palpation is another presentation of eyelid TAs that can be confused as an infectious etiology. The growing eyelid lesion can lead to blurry and double vision from poor ocular surface lubrication, ptosis, or ptosis induced astigmatism. [10][11]

Orbital TAs are also extremely rare and can present as a palpable mass with conjunctival hyperemia, chemosis, lid edema and blurry vision. There is additional potential to cause ocular pain, decreased vision, diplopia from restrictive extra-ocular movement. The most significant ocular comorbidity is orbital compartment syndrome which can lead to optic nerve compression and vision loss. [12]

KHEs of the eyelid have a similar presentation to eyelid TAs. Eyelid and conjunctival KHEs appear as a red protruding painless mass.[13] Orbital KHEs present as a mass that has varying clinical presentations depending on the size of the lesion. These tumors can cause proptosis, mechanical ptosis, or a lack of the afferent pupillary defect and eye movements.[14] Because of these presentations, diagnosis of TAs and KHEs are vital in early childhood in order to prevent future astigmatism, amblyopia, and strabismus.[15][16]

Diagnostic Imaging

Even though most vascular lesions are monitored with ultrasound, in the setting of KMP, it might be more beneficial to monitor the vascular lesion with a magnetic resonance imaging (MRI). An MRI of the vascular lesion would be able to delineate the location of the lesion, the extent of invasion and allow proper management. Additionally, if surgical management is indicated, the surgical plan would be aided by the details from the MRI to plan the approach.

MRI of KHEs produce diffuse enhancement of the lesion with poorly defined margins, typically spanning multiple layers. The MRI can also reveal hemosiderin deposits of KHEs. These hemosiderin deposits should have small feeding and draining vessels that can also be seen on the MRI. MRI of TAs typically show homogeneous enhancement with poorly defined margins, but do not span multiple layers.[8] [17]

Angiography is another form of diagnostic imaging that can be used to identify the vascular lesions associated with KMP. Although angiography is more invasive, it has the benefit of determining the size of the vascular lesion. In addition, angiography will show the number of feeder and collateral vessels, as well as the patency of these blood vessels prior to embolization. Thus, combining the characteristics of an angiography with an MRI, the magnetic resonance angiography (MRA), may be the most informative imaging for vascular lesions causing KMP. [8]

Histology

Although histology is not required to treat KMP, attempts of obtaining a biopsy should still be made in order to determine the subtype of the vascular tumor or if long term treatment is needed. Current management of severe cases of KMP is based on the findings of KMP, rather than the specific type of vascular tumor causing the phenomenon. [8][15]

Histologically, KHEs consist of spindle shaped endothelial cells arranged in irregular sheets and contain slit-like vascular channels. TAs appear as tufts of capillaries that present in a “cannonball” pattern or as different sized nodules. Although TAs and KHEs present differently, they have similar immunohistochemistry profiles. They both stain positive for the vascular markers CD31 and CD34, the lymphatic markers D2-40, LYVE1, and Prox-1, and negative for the marker for infantile hemangioma, GLUT-1. [5]

Physical Exam

Patients with KMP and a cutaneous KHE or TA will have rapidly growing painful macules or plaques that are purpuric, ecchymotic, or tense. The lesion can develop significant swelling. TAs are typically found exclusively on the trunk, while KHEs are usually found on the trunk, extremities, or retroperitoneum. These lesions can present as warm areas that are leathery or nodular to touch. KHEs and TAs can also present with hypertrichosis or hyperhidrosis upon examination. Patients with platelet counts less than 10,000 may show cutaneous petechiae. If the vascular tumor is within the retroperitoneum, a physical exam may not show a growing lesion, but abdominal distention may be present along with signs of organ dysfunction, or high-output heart failure. Occasionally, a palpable mass may be found. [9][3]

Ophthalmological relevance

KMP can become a complication when the hemangioma originates as a vascular malformation within the cavernous sinus, within the eye socket, or intracranially. This can present as a black rash on the patient’s eyelid or cause the eye to protrude outwards. KMP can also lead to amblyopia, strabismus, and astigmatism in the future. [18]

Differential Diagnosis

  • Angiosarcoma
  • Arteriovascular malformations
  • Consumption coagulopathy
  • Hemangioblastoma
  • Hepatic hemangiomas
  • Immune thrombocytopenic purpura
  • Infantile hemangioma
  • Teratoma
  • Neuroblastoma
  • Subcutaneous fat necrosis
  • Klippel-Trenaunay-Weber Syndrome
  • Sturge-Weber Syndrome

[3][19]

Management

Providing supportive care and treating the underlying vascular tumor is essential for the treatment of KMP. Current treatment of KMP focuses on stabilizing the patient’s coagulopathy and reducing the tumor.

Medical Management:

First Line Therapy:

Corticosteroids + Sirolimus

Although no standard of care has been established for the treatment of KMP in the United States, historically, corticosteroids were usually the first line treatment for KMP. [3][20]

Corticosteroids are used for the initial treatment due to its rapid response, cost effectiveness, and ease of management. However, they are rarely effective as a monotherapy. Their mechanism of action works by stopping the proliferation of the tumor’s endothelium and reducing inflammation. Once the coagulopathy of KMP has been remedied, prolonged exposure to steroids can cause adverse effects in children and neonates. Due to the side effect profile, steroids are gradually tapered down and a second immunomodulator agent such as Sirolimus, is used to prevent relapse. Sirolimus is then continued for a few months. [20][21]

Sirolimus has shown to be an effective treatment because of its antiangiogenic and proapoptotic characteristics. Sirolimus side effects include immunosuppression, elevated liver enzymes, hyperlipidemia, thrombocytosis, neutropenia, headache, mouth sores, and ineffective Bacillus Calmette-Guerin (BCG) vaccination. [21]

  • Dosage: oral prednisolone or IV methylprednisolone 2 mg/kg/day + sirolimus 0.8 mg/m2/day twice daily. [22][20]
Compression Therapy

Compression therapy is also considered a first line therapy or a first line adjunctive treatment, particularly if the vascular tumors are on the limbs, trunk, or scalp.[8] Either elastic compression or air pressure therapy are used to compress the affected region, causing ischemia and hypoxia and resulting in apoptosis of the vascular lesion cells. Compression therapy requires careful pressure control due to the possibility of inducing local congestion and ischemia.

  • 20–35 mmHg depending on the age of the patient[21]

Second Line Therapy:

Vincristine

Vincristine used to be a first line agent used alongside a corticosteroid, similarly to sirolimus. However, over the recent years, it has fallen to an adjunctive treatment or second line therapy. Vincristine requires a central venous catheter for treatment and can cause peripheral neuropathy, hence it has fallen out of favor.[20] The side effects of vincristine include peripheral neuropathy, constipation, abdominal pain, and elevation of liver enzymes, and possible tissue necrosis and secondary infection. [21]

  • Dosage: 0.05 mg/kg for infants <10 kg and 1 to 1.5 mg/m2 for infants >10 kg weekly[20] [22]

Third Line Therapy:

Antiplatelet Agents

Refractory KMP or recurrent KMP to corticosteroids and sirolimus can be treated with the antiplatelets aspirin or ticlopidine, plus vincristine. Since one of the main causes of KMP is platelet aggregation within the vascular tumors, antiplatelet treatments can act as an adjunctive treatment to prevent even more platelet aggregation and coagulopathy. (11) Currently, antifibrinolytics are not recommended for treatment within the United States, although a few successful cases of this treatment have been reported. (1, 11, 21) The anticoagulation agents heparin or low molecular weight heparin are also not recommended at this time because KMP is a specific type of coagulopathy that is different from the coagulopathies that use these agents as treatments. [20][21][22]

  • Dosage: aspirin 10 mg/kg/day, ticlopidine 10 mg/kg/day
Supportive Care

Patients with severe bleeding, DIC, or multiorgan failure should be given supportive care. Treatment of the thrombocytopenia with transfused platelets is not recommended, unless the patient is actively bleeding or undergoing a surgical procedure. This is to prevent the transfused platelets from worsening KMP, since the platelets would become trapped within the vascular tumors. The transfused platelets could also potentially cause the vascular tumors to grow due to the pro-angiogenic growth factors they carry. Cryoprecipitate or fresh frozen plasma can act as alternatives during cases of active bleeding or DIC. If patients with KMP are severely anemic or have symptomatic anemia, transfusion of packed red blood cells may be necessary. [3][20][22]

Vascular Embolization

Vascular embolization should be considered if the vascular tumor is large, has many feeder vessels, presents an inaccessible or high-risk surgical excision, recalcitrant to first- and second-line treatment, and/or with persistence of KMP coagulopathy. Embolization obstructs blood flow, inducing ischemia and necrosis of the tumor. This leads to tumor shrinkage and subsequent reduction platelet sequestration and consumption contributing to KMP. Embolism can also be effective at reducing the dose and frequency of glucocorticoid usage. Pingyangmycin (bleomycin), ethanol, iodine oil, and polyvinyl alcohol particles are used for embolism. Possible complications of vascular embolization include ulcers, blisters, necrosis of the tumor, myelosuppression, neurotoxicity, infarcts of nearby vital organs, and complications of the heart, brain, and lungs.[8][21]

Ablation

Radiofrequency ablation is an alternative treatment option for KMP and its associated vascular tumors. This treatment is best suited for deeper lesions, or when prior treatment options have failed. One of the limitations of this therapy it is a non-selective tissue treatment and can damage both tumors and surrounding tissue. Due to this, radiofrequency ablation is best performed in areas without important anatomical structures, such as nerves and blood vessels. [21]

Surgical Management

Surgery

The most definite treatment for the KHEs and TAs is surgery. However, once KMP develops, surgery is not the first line treatment due to the hemodynamic instability it can induce. Coagulopathy from KMP and the highly invasive nature of the vascular tumors tends to make surgery an unsafe choice. Once platelets have returned to normal and the tumor has shrunk through medical management, surgery can act as a viable treatment option. Single cutaneous vascular lesions can be cured with surgical excision. Multiple lesions on the spleen or liver are treated with a splenectomy or wedge resection/hepatectomy, respectively. [3][8][20][21]

Prognosis

The location of the vascular lesion can be correlated with the mortality rate. For skin tumors that undergo treatment, mortality rate is under 10%. However, retroperitoneal tumors have a mortality rate of 60% due to the large area available for tumor growth (and resultant consumption of platelets) prior to noticeable signs and symptoms.

The overall mortality rate for Kasabach-Merritt phenomenon is suspected to be between 12 to 50%, with the most common cause of death due to DIC related hemorrhage, followed by infiltration of organs, high-output cardiac failure, multi-organ failure, or sepsis. [23]

  1. ↑ O'Rafferty, Ciara, et al. "Recent advances in the pathobiology and management of Kasabach–Merritt phenomenon." British journal of haematology 171.1 (2015): 38-51.
  2. ↑ 2.0 2.1 2.2 2.3 Yadav, D., Maheshwari, A., Aneja, S., Seth, A., & Chandra, J. (2011). Neonatal Kasabach-Merritt phenomenon. Indian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology, 32(4), 238–241. https://doi.org/10.4103/0971-5851.95150
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Lewis, D., & Vaidya, R. (2022). Kasabach-Merritt Syndrome. StatPearls Publishing LLC. https://www.ncbi.nlm.nih.gov/books/NBK519053/
  4. ↑ Alaqeel, A. M., Alfurayh, N. A., Alhedyani, A. A., & Alajlan, S. M. (2016). Sirolimus for treatment of kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon. JAAD Case Reports, 2(6), 457–461. https://doi.org/10.1016/j.jdcr.2016.06.005
  5. ↑ 5.0 5.1 5.2 5.3 Mahajan, P., Margolin, J., & Iacobas, I. (2017). Kasabach-Merritt Phenomenon: Classic Presentation and Management Options. Clinical Medicine Insights: Blood Disorders, 10(1179545X17699849). https://doi.org/10.1177/1179545X17699849
  6. ↑ Maguiness, S., & Guenther, L. (2002). Kasabach-merritt syndrome. Journal of Cutaneous Medicine and Surgery, 6(4), 335–339. https://doi.org/10.1177/120347540200600405
  7. ↑ Arunachalam, P., VR Ravi Kumar, & Divya Swathi. (2012). Kasabach-Merritt syndrome with large cutaneous vascular tumors. Journal of Indian Association of Pediatric Surgeons, 17(1), 33–33. https://doi.org/10.4103/0971-9261.91086
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 Hall, G. W. (2001). Kasabach-merritt syndrome: pathogenesis and management. British Journal of Haematology, 112(4), 851–862. https://doi.org/10.1046/j.1365-2141.2001.02453.x
  9. ↑ 9.0 9.1 9.2 Kelly, M. (2010). Kasabach-Merritt Phenomenon. Pediatric Clinics of North America, 57(5), 1085–1089. https://doi.org/10.1016/j.pcl.2010.07.006
  10. ↑ Häußler, S. M., Uecker, F. C., Knopke, S., Roßner, F., Olze, H., & Böttcher, A. (2017). Tufted angiomas of the head and neck. HNO, 66(Suppl1), 1–6. https://doi.org/10.1007/s00106-017-0375-3
  11. ↑ Mittal, R., & Tripathy, D. (2013). Tufted angioma (Angioblastoma) of eyelid in adults-report of two cases. Diagnostic Pathology, 8(1). https://doi.org/10.1186/1746-1596-8-153
  12. ↑ Ozay, R., Çetinalp, N., Göçün, P., Doruk, E., & Duz, B. (2013). Resection of a huge tufted angioma of orbit and orbitocranial mesh reconstruction. Journal of Neurological Surgery. Part A, Central European Neurosurgery, 74 Suppl 1, e193-197. https://doi.org/10.1055/s-0033-1341415
  13. ↑ Cho, S. H., & Na, K. S. (2006). Haemangioendothelioma on the conjunctiva of the upper eyelid. Clinical and Experimental Ophthalmology, 34(8), 794–796. https://doi.org/10.1111/j.1442-9071.2006.01320.x
  14. ↑ Gelston, C. D., Said, S., & Durairaj, V. D. (2012). Orbital Kaposiform Hemangioendothelioma. Journal of Pediatric Ophthalmology & Strabismus, 49(6). https://doi.org/10.3928/01913913-20120508-04
  15. ↑ 15.0 15.1 PDQ Pediatric Treatment Editorial Board. (2002). Childhood Vascular Tumors Treatment (PDQ®): Health Professional Version. In PubMed. National Cancer Institute (US). https://www.ncbi.nlm.nih.gov/books/NBK343452/
  16. ↑ Torrado-Cobian, L. A., Griepentrog, G. J., Hodge, D. O., & Mohney, B. G. (2023). Prevalence and clinical features of orbital vascular anomalies in children. Orbit (Amsterdam, Netherlands), 1–5. https://doi.org/10.1080/01676830.2023.2166081
  17. ↑ Gong, X., Ying, H., Zhang, Z., Wang, L., Li, J., Ding, A., Zhou, L., Lin, X., & Xiong, P. (2019). Ultrasonography and magnetic resonance imaging features of kaposiform hemangioendothelioma and tufted angioma. The Journal of Dermatology, 46(10), 835–842. https://doi.org/10.1111/1346-8138.15025
  18. ↑ Wang, P., Wei, Z., Li, T., Zhao, N., & Chen, X. (2014). Clinical analysis of kasabach-merritt syndrome in 17 neonates. BMC Pediatrics, 14(1). https://doi.org/10.1186/1471-2431-14-146
  19. ↑ Osman, N. M. (2013). Kasabach – Merritt syndrome: A case report. Sudanese Journal of Paediatrics, 13(1), 49–52. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949964/
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 Mack, J. M., & Crary, S. E. (2022). How we approach coagulopathy with vascular anomalies. Pediatric Blood & Cancer, 69(Suppl 3), e29353. https://doi.org/10.1002/pbc.29353
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 Yao, W., Li, K., Qin, Z., Li, K., Zheng, J., Fan, X., Ma, L., Zhou, D., Liu, X., Li, W., Li, L., Ma, T., Wang Jin-hu, Ji, Y., Zhou, L., Huang, H., Gao, X., Huang, Z., Gu, S., & Yang, H. (2021). Standards of care for Kasabach−Merritt phenomenon in China. World Journal of Pediatrics, 17(2), 123–130. https://doi.org/10.1007/s12519-020-00379-9
  22. ↑ 22.0 22.1 22.2 22.3 Adams, D., & J Frieden, I. (2023, February 13). Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP) (M. Levy & R. Corona, Eds.). UpToDate; UpToDate, Inc.
  23. ↑ Maguiness, S., & Guenther, L. (2002). Kasabach-merritt syndrome. Journal of Cutaneous Medicine and Surgery, 6(4), 335–339. https://doi.org/10.1177/120347540200600405
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